(Studies in Systems, Decision and Control, 366) Ahmad Taher Azar, Aboul Ella Hassanien - Modeling, Control and Drug Development For COVI

Studies in Systems, Decision and Control 366
Ahmad Taher Azar

Aboul Ella Hassanien Editors
Modeling, Control and

Drug Development
for COVID-19 Outbreak
Prevention
Studies in Systems, Decision and Control
Volume 366
Series Editor
Janusz Kacprzyk, Systems Research Institute, Polish Academy of Sciences,
Warsaw, Poland
The series “Studies in Systems, Decision and Control” (SSDC) covers both new
developments and advances, as well as the state of the art, in the various areas of
broadly perceived systems, decision making and control–quickly, up to date and
with a high quality. The intent is to cover the theory, applications, and perspectives
on the state of the art and future developments relevant to systems, decision
making, control, complex processes and related areas, as embedded in the fields of
engineering, computer science, physics, economics, social and life sciences, as well
as the paradigms and methodologies behind them. The series contains monographs,
textbooks, lecture notes and edited volumes in systems, decision making and
control spanning the areas of Cyber-Physical Systems, Autonomous Systems,
Sensor Networks, Control Systems, Energy Systems, Automotive Systems,
Biological Systems, Vehicular Networking and Connected Vehicles, Aerospace
Systems, Automation, Manufacturing, Smart Grids, Nonlinear Systems, Power
Systems, Robotics, Social Systems, Economic Systems and other. Of particular
value to both the contributors and the readership are the short publication timeframe
and the world-wide distribution and exposure which enable both a wide and rapid
dissemination of research output.
Indexed by SCOPUS, DBLP, WTI Frankfurt eG, zbMATH, SCImago.
All books published in the series are submitted for consideration in Web of Science.
More information about this series at http://www.springer.com/series/13304

Ahmad Taher Azar · Aboul Ella Hassanien
Editors
Modeling, Control and Drug

Development for COVID-19
Outbreak Prevention
Editors
Ahmad Taher Azar Aboul Ella Hassanien
Faculty of Computers and Artificial Faculty of Computers and Artificial
Intelligence Intelligence
Benha University Cairo University
Benha, Egypt Giza, Egypt
College of Computer and Information Scientific Research Group in Egypt (SRGE)
Sciences Giza, Egypt
Prince Sultan University
Riyadh, Saudi Arabia
ISSN 2198-4182 ISSN 2198-4190 (electronic)

Studies in Systems, Decision and Control
ISBN 978-3-030-72833-5 ISBN 978-3-030-72834-2 (eBook)
https://doi.org/10.1007/978-3-030-72834-2
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2022
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse
of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or
the editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface
The novel coronavirus (COVID-19), which has circulated around the world since
December 2019, has sickened hundreds of thousands of people, shut down major
cities, caused unparalleled global travel bans and driven the global dissemination
of disinformation and hysteria. Numerous mathematical and statistical models are
being developed to forecast the future of coronavirus disease 2019 (COVID-19)
epidemics worldwide. Such forecasts have far-reaching effects for how rapidly and
vigorously policymakers are working to curb the epidemic. However, the main and
most efficient application of epidemiological models is to measure the relative impact
of different measures on the reduction of disease burden rather than to make precise
predictive forecasts on the magnitude or length of disease burdens. For forecasts,
“models are not crystal balls,” as Ferguson pointed out in a recent review of the role
of modeling. Nevertheless, users of epidemiological models, including policymakers,
the population and the government, frequently rely on abstract infection forecasts
and mortality projections. These indicators of possible disease burden are important
for policymakers who view future results in the context of their healthcare resources.
The primary emphasis of this book will be on the kinds of measures that may
aim to minimize the numbers of COVID-19, since the strategies performed would,
of course, decide the actual empirical truth. Model predictions are used to estimate
potential demand for health care, including how many intensive care beds will be
required, when and where air problems are most likely to occur and the amount
of healthcare staff expected to respond effectively. Short-term projections may be
crucial to aid planning, but it is usually unnecessary to focus on long-term predictions
for such purposes. In addition, estimation model forecasts are used to determine
local, state and national policies. When is the large number of cases expected? If
social isolation is successful and the number of new cases needing hospitalization
is constant or diminishing, when is it time to start returning to work or school? Will
the big meetings be free again? In these reasons, projections are expected to only
have insight into the magnitude of what is ahead and cannot forecast the precise
course of the disease weeks or months in advance. The book will also concentrate
on computational simulations that may help speed up the development of drugs to
counter the novel coronavirus responsible for COVID-19.
v
vi Preface
Both novice and expert readers should find this book a useful reference in the
field of mathematical modeling, system dynamics modeling, statistical analysis and
drug development.
The book is primarily meant for researchers from academia and industry, working
on research areas such as engineering, control engineering, biomedical engineering,
medical informatics, computer science, decision support systems and data analytics.
The book can also be used at the graduate or advanced undergraduate level and many
others.
As the editors, we hope that the chapters in this well-structured book will stimulate
further research in modeling, control and drug development for COVID-19 outbreak
prevention and utilize them in real-world applications.
We hope sincerely that this book, covering so many different topics, will be very
useful for all readers.
We want to thank all the reviewers for their diligence in reviewing the chapters.
Special thanks go to Springer, especially the book editorial team.
Prof. Ahmad Taher Azar

Faculty of Computers and Artificial Intelligence
Benha University
Benha, Egypt
ahmad.azar@fci.bu.edu.eg
ahmad_t_azar@ieee.org
College of Computer and Information Sciences
Prince Sultan University
Riyadh, Saudi Arabia
aazar@psu.edu.sa
Prof. Aboul Ella Hassanien
Faculty of Computers and Artificial Intelligence
Cairo University
Giza, Egypt
Scientific Research Group in Egypt (SRGE)
Giza, Egypt
aboitcairo@gmail.com
https://www.egyptscience.net
Contents
Some Computational and Theoretical Results of COVID-19

via Mathematical Model Involving Caputo-Fabrizo Derivative . . . . . . . . 1
Eiman, Kamal Shah, Muhammad Sarwar, and Hussam Alrabaiah
Time Series Modelling and Prediction of the Coronavirus
Outbreaks (COVID-19) in the World . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Mohsen Maleki
AI and Robotics in the Fight Against COVID-19 Pandemic . . . . . . . . . . . 57
Alaa Khamis, Jun Meng, Jin Wang, Ahmad Taher Azar,
Edson Prestes, Howard Li, Ibrahim A. Hameed, and Tamas Haidegger
A Model-Based Analysis to Predict and Control the Dynamics
of COVID-19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Manotosh Mandal, Soovoojeet Jana, Sayani Adak, Anupam Khatua,
and Tapan Kumar Kar
Long Tails of Mean-Field COVID-19 Epidemic Curves:
Implications of a Hidden Metapopulational Dynamics . . . . . . . . . . . . . . . 119
Eugene B. Postnikov
Prediction of Confirmed, Recovered and Casualties’ Cases
of COVID-19 in India by Autoregressive Integrated Moving
Average (ARIMA) Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Sarbjit Singh, Kulwinder Singh Parmar, Jatinder Kumar,
and Jatinder Kaur
Dynamical Modeling and COVID-19 Pandemic . . . . . . . . . . . . . . . . . . . . . 183
Muhammad Shahzad, Faisal Sultan, Mehboob Ali, and Soma Mustafa
SARS-CoV-2: Potential Drug Targets and Its Virtual Screening . . . . . . . 203
Raghvendra Dubey and Kushagra Dubey
vii
viii Contents
COVID-19 Modeling Under Uncertainty: Statistical Data

Analysis for Unveiling True Spreading Dynamics and Guiding
Correct Epidemiological Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Anamaria Sanchez-Daza, David Medina-Ortiz,
Alvaro Olivera-Nappa, and Sebastian Contreras
Application of Mathematical Modelling Approach in COVID-19
Transmission and Interventions Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Joseph Bamidele Awotunde, Roseline Oluwaseun Ogundokun,
Abidemi Emmanuel Adeniyi, Kazeem Moses Abiodun,
and Gbemisola Janet Ajamu
Robust Statistical Modeling of COVID-19 Prevalence in African
Epicentres’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Adewale F. Lukman, Aladeitan Benedicta,
Joseph Bamidele Awotunde, Charle E. Okon, Olajumoke Oludoun,
Abiodun Oluwakemi, Opeyemi E. Ayinde, Olusegun O. Alabi,
and Abidemi Emmanuel Adeniyi
Modeling Covid-19 Cases in West African Countries:
A Comparative Analysis of Quartic Curve Estimation Models
and Estimators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Kayode Ayinde, Hamidu Abimbola Bello, Rauf Ibrahim Rauf,
Omokova Mary Attah, Ugochinyere Ihuoma Nwosu,
Oluwatoyin Kikelomo Bodunwa, Oluwadare Olatunde Ojo,
Roseline Oluwaseun Ogundokun, Taiwo Stephen Fayose,
Rasaki Yinka Akinbo, Adebowale Olusola Adejumo,
Oluwatosin Akinsola, Abayomi Ayodele Akomolafe,
Timothy Olabisi Olatayo, Olabimpe Bodunde Aladeniyi,
Emmanuel Idowu Olamide, and Samuel Olayemi Olanrewaju
Investigation of COVID-19 Using an Artificial Intelligence
Based Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Sayani Adak, Soovoojeet Jana, and T. K. Kar
Optimal Control Design of Impulsive SQEIAR Epidemic
Models with Application to COVID-19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Zohreh Abbasi, Mohsen Shafieirad, Amir Hossein Amiri Mehra,
Iman Zamani, and Asier Ibeas
Siddha Medicine and Computer Modeling: A Treasure
for SARS-CoV-2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
M. S. Shree Devi, P. Sathiyarajeswaran, D. Thirumal Kumar,
S. Udhaya Kumar, R. Siva, George Priya Doss, and K. Kanakavalli
Contents ix
Modeling SARS-CoV-2: Mitigation Interventions and Increased

Mobility Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Mario Santana-Cibrian, Manuel A. Acuña-Zegarra,
Marco Tulio Angulo, Andreu Comas-García,
Esteban A. Hernández-Vargas, and Jorge X. Velasco-Hernandez
Assessing the Impact of Public Compliance on the Use
of Non-pharmaceutical Intervention with Cost-Effectiveness
Analysis on the Transmission Dynamics of COVID-19: Insight
from Mathematical Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Michael O. Adeniyi, Segun I. Oke, Matthew I. Ekum,
Temitope Benson, and Matthew O. Adewole
A Comparative Study of Amino Acid Encoding Methods
for Predicting Drug-Target Interactions in COVID-19 Disease . . . . . . . . 619
Talha Burak Alakus and Ibrahim Turkoglu
COVID-19 Drug Repositioning: Present Status and Prospects . . . . . . . . 645
Chandana Mohanty, Chiluka Vinod, Sarbari Acharya,
and Nikita Mahapatra
Understanding COVID-19 in Brazil: Socioeconomic Impacts,
Statistical Analysis and Future Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Yaohao Peng, Alex Rodrigues do Nascimento,
Igor Ferreira do Nascimento, João Gabriel de Moraes Souza,
Tatsuya Nagata, Pedro Henrique Melo Albuquerque,
Herbert Kimura, and Mateus Hiro Nagata
COVID-19: Automated Detection and Monitoring of Patients
Worldwide Using Machine Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Gaurav Gupta, Ahmad Waleed Salehi, Brijbhushan Sharma,
Nagesh Kumar, Sonia, and Pankaj Vaidya
A Mathematical Model and Strategy to Guide the Reopening
of BRICS Economies During the COVID-19 Pandemic . . . . . . . . . . . . . . . 763
Habib Noorbhai and Ridhwaan Suliman
Epidemic Prediction and Analysis of COVID-19: A Mathematical
Modelling Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
Khondoker Nazmoon Nabi
Ensemble Learning Models Coupled with Urban Mobility
Information Applied to Predict COVID-19 Incidence Cases . . . . . . . . . . . 821
Matheus Henrique Dal Molin Ribeiro, Ramon Gomes da Silva,
José Henrique Kleinübing Larcher, Viviana Cocco Mariani,
and Leandro dos Santos Coelho
x Contents
The Multi-group Susceptible Infected Recovered Model

with Stage Progression: A Epidemiological Modelling
of Forecasting COVID Cases in the Philippines . . . . . . . . . . . . . . . . . . . . . . 859
Ricardo L. Dizon
Telehealth and Pharmacological Strategies of COVID-19
Prevention: Current and Future Developments . . . . . . . . . . . . . . . . . . . . . . 897
Gopi Battineni, Giulio Nittari, Graziano Pallotta,
Getu Gamo Sagaro, Nalini Chintalapudi, and Francesco Amenta
Forecasting on Global Dynamics for Coronavirus (COVID-19)
Outbreak Using Time Series Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
Soumyadeep Debnath, Subrata Modak, and Dhrubasish Sarkar
Some Fractional Mathematical Models of the COVID-19
Outbreak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957
H. Mohammadi and Sh. Rezapour
Nowcasting of COVID-19 Confirmed Cases: Foundations,
Trends, and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
Tanujit Chakraborty, Indrajit Ghosh, Tirna Mahajan, and Tejasvi Arora
Covid-19 Pandemic and Coronaviruses from Discovery
to Treatment: A Tale of Two Decades of 21st Century . . . . . . . . . . . . . . . . 1065
Muhammad Akhlaq, Zaheer-Ud-Din Babar, Mahvish Ajaz,
Muzammil Ahmad Khan, Erkan Kilinc, Muhammad Adeel,
Muhammad Badar, Asif Nawaz, and Aamir Jalil
Does Pandemics Effects Human Future? Decisive Role
of COVID-19 in Human Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
Muhammad Akhlaq, Aamir Jalil, Abid Hussain, Aisha Siddiqua,
and Muhammad Imran
Some Computational and Theoretical
Results of COVID-19 via Mathematical
Model Involving Caputo-Fabrizo
Derivative
Eiman, Kamal Shah, Muhammad Sarwar, and Hussam Alrabaiah
Abstract In recent time a threatful outbreak known as Corona Virus-19 Infec-

tious Disease (COVID-19) is spreading with very fast speed throughout the globe.
Nearly 1.293106 million people have been died and more than 52.775271 million are
infected due to the mentioned infection. Up to date no vaccine or cure has introduced.
Some precautionary measures have been taken by every country of the world to con-
trol the disease. Many countries have implemented strict lock downed in their locality
so that immigration of people of here and there is reduced. It has been observed that
immigration of people and their freely moment from one place to other place has
greatly transmitted the disease. As the mentioned disease is very rapidly spreading
from person to person. Currently various mathematical models have been developed
to understand the transmission dynamics of the aforesaid disease. In this regard very
rarely the immigration term has considered. Since fractional calculus has been found
useful for the comprehensive description of many real world phenomenon and pro-
cess. In this regard, the said area has given much attention in last few decades. Since
fractional derivative gas been defined by numbers of ways. Two types of operators
involving singular and nonsingular kernels are increasing used in recent times. Due
to the global and nonsingular nature of Caputo-Fabrizo type fractional order deriva-
tive is used in this chapter. Here we consider a simple two compartments model
inspired from famous Prey-Predator system is considered under the Caputo-Fabrizo
type fractional order derivative. First of all a qualitative analysis addressing exis-
tence of at least one solution and its uniqueness is investigated using Banach and
Krassnoselskii’s type fixed point theorem. Since stability theory is important aspects
of qualitative theory. Therefore the concerned aspects is also investigated. Further
on using Laplace transform coupled with Adomian decomposition method is used to
developed series type solutions to the proposed model. The concerned techniques is
Eiman · K. Shah (B) · M. Sarwar

Department of Mathematics, University of Malakand,
Chakdara, Khyber Pakhtunkhawa, Pakistan
H. Alrabaiah
Al Ain University, Al Ain, UAE
e-mail: hussam.alrabaiah@aau.ac.ae
Mathematics Department, Tafila Technical University, Tafila, Jordan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1
A. T. Azar and A. E. Hassanien (eds.), Modeling, Control and Drug Development
for COVID-19 Outbreak Prevention, Studies in Systems, Decision
and Control 366, https://doi.org/10.1007/978-3-030-72834-2_1
2 Eiman et al.
a powerful tool to study nonlinear problems for semi-analytical solution. Some real
values for the concerned parameters and compartments are used in our results to dis-
cuss the model through graphs by using Matlab. The graphical presentations are given
to investigate the transmission of the disease under various values of immigration
parameters.
Keywords Covid-19 mathematical model · Non singular derivative · Fixed point

theory · Semi-analytical solutions
1 Introduction
Currently, a threatful disease which is spreading all over the globe with fastest speed
known as Coronavirus-19 disease (COVID-19) has significantly changed the life
styles of people in the whole globe. More than fifty million people have been infected.
Also, more than one millions have been died due to this disease. Initially this disease
was originated from a sea food market in Wuhan city of China in the end of 2019.
During February and March 2020, the disease was spread in the whole city and nearly
0.84 million people were infected and more than five thousands died. After taking
strict measure by the Chinese government the infection was controlled up to the end
of April 2020, for detail see [1]. Due to traveling of people the infection was then
transmitted to most of the countries world wide. The researchers have investigated
that infection is also transmitting from person to person. In this regards various
measure for protection of maximum people have taken all over the world. Because
WHO has announced it a pandemic [2–4]. Since scientists and researchers are trying
to investigate cure or vaccine for the aforesaid outbreak so that in future such like
pandemic may be controlled.
During March and April, Italy, Iran, Spain were the most infected countries in the
world from COVID-19. Recently USA, UK, Russia, Brazil, India, etc. are the top most
infected countries in the world. In current situation the infection is spreading with
very rapid rate in all over the world. Various countries of the world during the month
of March, April and May 2020 implemented serious lock downed. Some countries
of the wold announced curfew in their countries like Saudi Arabia, UAE, Qater, etc.,
but still the infection is spreading with high rate in their countries. The researchers,
scientists and medical specialists are working day and night to prepare vaccine for the
said infection. But upto date no hope. The economical situation of many countries in
the wold has been challenged. Large numbers of companies, organizations have been
stopped their productions. As a result millions of people have been deprived from
their jobs. Therefore in last few months poverty and unemployment ratio has greatly
increased in various countries of the world. Besides from these the health systems of
most powerful countries of the world like USA, Europe has been challenged due to
COVID-19. In short the world is facing a threatful situation as faced in past during
world war. Actually from the history of human being on this earth we observe that
such like outbreaks had been occurred in which millions of people lost their lives.
Some Computational and Theoretical Results of COVID-19 via … 3
During the outbreak in 1920 called Spanish flue nearly ten million people had been
died world wide. Such like outbreak when again appeared during 1970 then that time
it had been killed 50 million people in Europe, North and South America. During
2003 and then 2008 SARS and MARS were also two serious infectious disease in
which nearly thousand people were died [5].
The present COVID-19 is an infectious disease caused by severe acute respiratory
syndrome Coronavirus 2 (SARS-CoV-2). Here we remark that fever, cough, fatigue,
shortness of breath, and loss of smell and taste are the common symptoms of the
disease. But the most dangerous thing is that that in some people the symptoms are not
appearing clearly. Such people are the silent spreader of the disease in society. Since
the infection transmitted from person to person and the silent spreaders transmitted
it easily. Therefore many countries have advised their public to keep social distance
and avoid gathering and other social activities where many people are crowding.
The duration from exposure to onset of symptoms is typically around five days,
but may range from two to fourteen days [6]. Basically the virus spread between
people during close contact and most often via small droplets released by coughing
sneezing, and talking with an infected one. Various methods are adopting in world
to cure the infected people. Also some precautionary measures are taking by the
people worldwide include frequent hand washing, maintaining social distance from
others (especially from those with symptoms), quarantine (especially for those with
symptoms), covering coughs and avoiding to touch their face without washing hands,
for detail see [7, 8]. Further it is believed that human contracted this virus from wild
animals like Bats and pangolin [2, 9].
Throughout the world researchers are trying to make policy procedure so that the
infection may be minimized further and prevent it from spreading. Since biological
phenomenon may be also investigated for future prediction, control and to understand
the dynamics by using mathematical model. Bernoulli was the first mathematician
who gave idea of mathematical model during eighteenth hundred century. The first
mathematical model which represents relationships between susceptible(uninfected),
infected and recovered people was given in 1927 by Kermack and McKendrick, see
[10]. After that significant improvement were done in the area of mathematical mod-
eling. Various mathematical models for infectious disease have been studied. Now
the area devoted to mathematical modeling is a warm area of research, see [11–14].
The mathematical models can help in future predictions, planing and to form control
strategies to eliminate or stop disease from further spreading in society. Keeping in
mind the importance of infectious disease, researchers have also formed some mathe-
matical models which are addressing the current COVID-19. Hence researchers have
extensively worked on this area and many models were created or updated, we refer
few as [4, 15, 16]. But mostly these models were investigated under integer order
derivatives in which few are [17, 18]. Since integer order derivative is local operator
and does not permit greater degree of freedom. Therefore many researchers prefer to
model real world problems by using arbitrary order derivative. Because in last few
decades significant interest has been showed in fractional calculus by researchers
of different disciplines of science and engineering. The concerned area has many
applications in modeling various real world problems. Since fractional derivative is
4 Eiman et al.
usually a definite integral includes classical derivative as a special case. Also it geo-
metrically produce the whole spectrum or accumulation of a function. The aforesaid
derivative has been defined by numbers of ways. In other words, various mathe-
maticians have given different definitions of fractional order derivative [19]. Among
these definitions the most notable definitions were those given by Riemann-Liouville
and Caputo. The said definitions have been increasingly used in applications in last
many decades, for detail see [20–22]. Infact fractional order differential equations (
FODEs) have many applications in modeling of real world problems including bio-
logical, physical and chemical phenomenons. The mentioned operator differential
order has the ability to describe many feature of hereditary and memory materials
more explicitly than classical order. Therefore significantly FODEs have used in last
few decades in modeling side [23–25].
Dealing FODEs for their exact or numerical solutions in last two decades many
techniques, methods and theories were established. These include qualitative theory
of existence of solution by fixed point theory, analytical solutions by perturbation
and decomposition techniques and spectral analysis, (for detail see [26–29]). As we
know that the mentioned techniques were increasingly adopted for ordinary FODEs.
The ordinary FODEs are involving Caputo or Riemann definitions include singular
kernel which is local in nature. Therefore some authors have defined the fractional
derivative by replacing singular kernel by nonsingular kernel. In this regards, in
2016 the definitions of fractional derivative involving nonsingular kernel was first
define by Caputo and Fabrizio, see [30]. This definition has got much attention in last
two years. Since the aforesaid derivative was found suitable in description of some
mathematical models. Also their integral for a function was the mean of the function
itself and its Riemann-Liouville integral. The problems involving the Caputo-Fabrizo
derivative of fractional order (CFFD) were treated by using homotopy method, Ado-
mian decomposition method very rarely. But to the best of our knowledge, there is no
detail study about decompositions techniques coupled with integral transform like
Laplace transform yet introduced for FODEs under CFFD.
Here, we state that the concerned model given in (1) deals the relationship of prey
and predator in an ecological system as
ḣ(t) = a1 (t)h(t) − b1 (t)h(t)i(t),
i̇(t) = a2 (t)h(t)i(t) − b2 (t)i(t), (1)
h(0) = h0 , i(0) = i0 ,
where h0 ≥ 0, i0 ≥ 0. The coefficients are linear continues and bounded functions.

The model (1) has been investigated by using homotopy perturbation method for
ordinary Caputo derivative in [33]. In the previous time in many localities, unex-
pected large quotas in animal and fish catches had been reported occasionally. This
phenomenon gave birth to well known prey-predator relationship. Therefore in 1920,
Lotka and Volterra introduced the above well known model. So far the concerned
model has been studied for various purposes and from various directions, for detail
we refer [34–36].
To understand the dynamics of COVID-19, it was necessary to develop a math-
ematical model to estimate the transmissibility and dynamic of the transmission of
the virus. In this regards various models were constructed or updated. Also several
researches focusing on mathematical modeling of COVID-19. Since a great cause of
transmission of the disease is due to immigration which has very rarely considered in
mathematical of COVID-19 up to date. Since the immigration is an important param-
eter which has great impact on the transmission of the aforesaid infection. Therefore
motivated from the model (1), the author [37] has constructed the following system
for the transmission of COVID-19 in the presence of immigration
ḣ(t) = ah(t) − bh(t)i(t) + ei(t),
i̇(t) = bh(t)i(t) + ci(t) − di(t) − ei(t),
h(0) = h0 , i(0) = i0 ,
where the nonlinear functions f , g : J × R2 → R are continuous. Now as we know

that ordinary calculus has less degree of freedom and in most situation a real world
phenomena is not explained in comprehensive way. On the other hand fractional
calculus has more degree of freedom and posses the capability to describe various
process and phenomenon in more realistic and comprehensive ways. Further the
involving of nonsingular kernel in some fractional order differential operators are
further have the ability to describe the aforesaid process in more easy and under-
standable way. Also FODEs involving such operators are easy to handle by using the
usual analytical or numerical techniques. Therefore motivated from the model (2) ,
the following modified COVID-19 model is formed as
CF
Dtα h(t) = ah(t) − bh(t)i(t) + ei(t),
CF
Dtα i(t) = bh(t)i(t) + ci(t) − di(t) − ei(t), (2)
h(0) = h0 , i(0) = i0 ,
where α ∈ (0, 1] and CF Dt denoted Caputo-Fabrizo derivative. The parameters

involve in the model (2) are described as in Table 1.
Therefore in this paper, existence theory of solution and semi-analytical results to
the considered model for t ∈ J = [0, τ ], are investigated, where 0 ≤ t ≤ τ < ∞.
First qualitative results corresponding to the model are studied. The required
results are devoted to existence and uniqueness of the solution. Existence results
about solution are obtained via using fixed point theory due to Krassnoselskii and
Banach. Also some approximate analytical results are established via Laplace trans-
6 Eiman et al.
Table 1 Description of the parameters of the model (2)

Parameters The physical interpretation
h(t) Susceptible population
i(t) Infected population
a Immigration rate of healthy individuals
b The infection rate and define as b = 1− protection rate
c Immigration rate of infected individuals
d The collective death rate of both natural and corona
e The cure rate
form and Adomian decomposition method. The concerned approximate results are
demonstrated by graphs using Matlab.
The chapter is organized as: In Part 1, introduction about the problem is given.
In Part 2, some fundamental results are provided. In Part 3, existence results to the
considered model are developed. Part 4 presents some results about stability results.
In Part 5 is devoted to general procedure for approximate solution. In Part 6 is devoted
to results and discussion. Last Part 7 is devoted to brief conclusion and some future
prediction.
2 Preliminaries
Definition 1 [38, 39] Let h ∈ H1 (0, τ ), τ > 0, α ∈ (0, 1), then the CFFD is recalled
as

CF α M (α) t t−ξ
Dt (h(t)) = h (t) exp − α d ξ,
1−α 0 1−α
M (α) is known as normalization function and statistics M (1) = M (0) = 1. More-

over if h does not fall in H1 (0, τ ), then the derivative is defined as
t
M (α) t−ξ
CF
Dtα (h(t)) = (h(t) − h(ξ )) exp − α d ξ.
1−α 1−α
0
Definition 2 [38] Integral in Caputo-Fabrizo form of h is given as

(1 − α) α t
CF
Itα [h(t)] = h(t) + h(ξ )d ξ, α ∈ (0, 1].
M (α) M (α) 0
Lemma 1 Let y ∈ L[0, τ ], then the solution of FODE given for α ∈ (0, 1]
CF
Dtα h(t) = y(t), t ∈ [0, τ ],
h(0) = h0
is given by

(1 − α) α t
h(t) = h0 + y(t) + y(ξ )d ξ.
M (α) M (α) 0
Definition 3 [38] The Laplace transform of CF Dtα h(t) with M (α) = 1 is given as
sL [h(t)] − h(0)
L [CF Dtα h(t)] = , s ≥ 0, α ∈ (0, 1].
s + α(1 − s)
Note: Corresponding to existence theory, let J = [0, τ ] and 0 ≤ t ≤ τ < ∞, we

define space as Z = C([0, τ ] × R, R) equipped with norm as W = supt∈J
|W (t)|.
Theorem 1 [40] “Let B be a convex subset of Z and we have two operators F, G
with
1. F(W ) + G(W ) ∈ B for every W ∈ B;
2. F is contraction;
3. G is continuous and compact.
Then the operator equation F(W ) + G(W ) = W has at least one solution.”
Theorem 2 Inview of condition h > 0, i > 0 at all t = 0, the solutions h ≥ 0, i ≥ 0
of model (2) are non-negative for all t > 0.
Proof From the initial conditions we have from model (2)
CF
Dtα h(t)|(h=0, i=0) ≥ 0,
(3)
CF
Dtα i(t)|(h=0, i=0) ≥ 0.
Hence inview of the continuity of solutions it follows that h ≥ 0, i ≥ 0 for all t ≥ 0.
3 Existence and Uniqueness Results of Fractional Order

System (2)
Here in this part some results about existence and uniqueness are given about the
solution of the proposed model 2. We consider the considered model (2) as
⎧ CF α
⎨ Dt h(t) =
⎪ f (t, h(t), i(t)),
CF α
Dt i(t) = g(t, h(t), i(t)),
⎪
⎩
h(0) = h0 , i(0) = i0 ,
8 Eiman et al.
where the nonlinear functions f , g : J × R2 → R are continuous. Upon using inte-

gral operator CF Itα on both sides of (4) and putting initial conditions, one has
⎧
⎪ (1−α)
t
⎪
⎨h(t) = h0 + M (α)
f (t, h(t), i(t)) + α
M (α)(α)
(t − ξ )α−1 f (ξ, h(ξ ), i(ξ ))d ξ,
0
t (4)
⎪
⎪ (1−α) α
⎩i(t) = i0 + M (α)
g(t, h(t), i(t)) + M (α)(α)
(t − ξ )α−1 g(ξ, h(ξ ), i(ξ ))d ξ.
0
Which further may be written as

(1 − α) α t
W (t) = W0 + F (t, W (t)) + F (ξ, W (ξ ))d ξ, (5)
M (α) M (α) 0
where

h(t) h0 f (t, h(t), i(t))

W (t) = , W0 = , F (t, W (t)) = (6)
i(t), i0 , g(t, h(t), i(t)).
Now to derive our results we define the following assumption as:

(A1) There exists constants LF > 0 such that for each W , W¯ ∈ Z such that
|F (t, W (t)) − F (t, W¯ (t))| ≤ LF [|W − W¯ |],
(A2) There exists constants CF , CF > 0 and MF > 0 such that
|F (t, W (t))| ≤ CF |W | + MF .
Using (5) and (6), the operators are defined as:
(1 − α)
F(W ) = W0 (t) + F (t, W (t)) ,
M (α)
t
α
G(W ) = F (ξ, W (ξ ))d ξ. (7)
M (α)
0
Theorem 3 Under the continuity of F together with assumption (A1, A2), integral
equation (5) has at least one solution if MLF(α) < 1.
Proof Let B = {W ∈ Z : W ≤ ρ, ρ > 0} be closed and convex subset of Z ,

we need to prove that F : B → B is contraction. Let W , W¯ ∈ B, we have

(1 − α)
FW − FW¯ = sup F (t, W (t)) − (F (t, W¯ (t))
t∈J M (α)
(1 − α)
≤ LF sup |W (t) − W¯ (t)|
M (α) t∈J
LF
≤ W − W¯ .
M (α)
Hence F is contraction.
For G to be compact and continuous, let any W ∈ B, we have
t
α

G(W ) = sup F (ξ, W (ξ ))d ξ
M (α)
t∈J
0
τ
≤ [CF ρ + MF ]. (8)
M (α)
From (8) one concludes that G is bounded. Also F is continuous so is G. In same

line one can prove that G is equi-continues by taking t1 < t2 ∈ J . By using Arzelá-
Ascoli theorem, the operator G is completely continues operator and also uniformly
bounded proved already. Hence G is relatively compact. By Krassnoselskii’s fixed
point theorem the problem (5) has at leat one solution. Consequently the considered
system 2 has at least one solution.
Theorem 4 Under assumption (A1), the consider system has unique solution if
(1+τ )LF
M (α)
< 1.
Proof Let define T:Z → Z by

(1 − α) α t
T(W ) = W0 + F (t, W (t)) + F (ξ, W (ξ ))d ξ.
M (α) M (α) 0
Let W , W¯ ∈ Z, we have

(1 − α)
¯ (t))
T(W ) − T(W¯ ) ≤ sup F (t, W (t)) − F (t, W
t∈J M (α)
t
α
+ sup |F (ξ, W (ξ )) − F (ξ, W¯ (ξ ))|d ξ
M (α) t∈J 0
(1 + τ )LF
≤ W − W¯ . (9)
M (α)
Hence T is contraction and the concerned problem (5) has unique solution and so
the considered model (2) has unique solution.
10 Eiman et al.
4 Stability Results
Here we recall some definition of Ulam stability

Definition 4 The integral equation (5) is Ulam- Hyers stable with ε > 0 if for
inequality
t

W (t) − W0 + F (t, W (t)) (1 − α) + α F (ξ, W (ξ ))d ξ ≤ ε, t ∈ J
M (α) M (α)
0
we have at most one solution W¯ and constant CF such that
|W (t) − W¯ (t)| ≤ CF ε, ∀ t ∈ J .
Also the integral equation (5) is generalized Ulam- Hyers stable if we have nonde-
creasing mapping : (0, 1) → R+ such that
|W (t) − W¯ (t)| ≤ CF (ε), ∀ x ∈ J
with (0) = 0.
The given remark is needed.
Remark 1 If we have function φ(t) depends on W ∈ Z which vanishes at zero.
1. |φ(t)| ≤ ε, ∀ t ∈ J ;
2. CF Dαt W (t) = F (t, W (t)) + φ(t), ∀ t ∈ J .
Remark 2 Considered the perturbed problem

CF
Dαt W (t) = F (t, W (t)) + φ(t), ∀ t ∈ J ,
W (0) = W0
whose solution is provided by

t
(1 − α) α
W (t) = W0 + F (t, W (t)) + F (ξ, W (ξ ))d ξ
M (α) M (α) 0
t
(1 − α) α
+φ + φ(ξ ))d ξ, ∀ t ∈ J . (10)
M (α) M (α) 0
Hence from (11) using Remark 1 as

t

W (t) − W0 + F (t, W (t)) (1 − α) + α F (ξ, W (ξ ))d ξ
M (α) M (α) 0
t
(1 − α) α
= φ + φ(ξ ))d ξ
M (α) M (α) 0
(1 − α)ε αετ
≤ +
M (α) M (α)
≤
τ,α ε, ∀ t ∈ J , (11)
(1+τ )
where
τ,α = M (α)
.
Theorem 5 Inview of hypothesis (A1) and using Remarks 1 and 2, the solution of
the integral equation (5) is Ulam-Hyers and generalized Ulam-Hyers stable if
(1 + τ )LF
ϒ= < 1.
M (α)
Consequently the approximate results of the model (2) under our investigation are
Ulam-Hyers and generalized Ulam-Hyers stable.
Proof Consider W , W¯ ∈ Z be any solution and at most one solution respectively
of the problem (5), then we have
t
(1 − α) α
W − W¯ = max W (t) − W0 + F (t, W¯ (t)) + F (ξ, W¯ (ξ ))d ξ
t∈J M (α) M (α) 0
t
(1 − α) α
≤ max W (t) − W0 + F (t, W (t)) + F (ξ, W (ξ ))d ξ
t∈J M (α) M (α) 0
t
(1 − α) α
+ max F (t, W (t)) + F (ξ, W (ξ ))d ξ
t∈J M (α) M (α) 0
t
(1 − α) α
− F (t, W¯ (t)) + F (ξ, W¯ (ξ ))d ξ
M (α) M (α) 0
≤
τ,α ε + ϒW − W¯ . (12)
From (12), we have after simplification as

τ,α
W − W¯ ≤ ε. (13)
1−ϒ
Hence the integral equation (5) is Ulam-Hyers stable. Further if we let (ε) = ε,
then (13) implies that

τ, α
W − W¯ ≤ (ε), (14)
1−ϒ
clearly in (14) (0) = 0. Hence the integral equation (5) is generalized Ulam-Hyers
stable. Consequently the model (2) is Ulam and generalized Ulam-Hyers stable.
12 Eiman et al.
5 Semi-analytical Results
Here we investigate the semi-analytical results. Applying Laplace transformation on

both sides of (2) as

L [CF Dαt h(t)] = L ah(t) − bh(t)i(t) + ei(t)

L [CF Dαt h(t)] = L bh(t)i(t) + (c − d − e)i(t) . (15)
Using initial condition, (1) yields

h0 (s + α(1 − s))
L [h(t)] = + L ah(t) − bh(t)i(t) + ei(t)
s s

i0 (s + α(1 − s))
L [i(t)] = + L bh(t)i(t) + (c − d − e)i(t) . (16)
s s
Now let us assume the required solution in the form of infinite series as
∞
∞

h(t) = hn (t), i(t) = in (t) (17)
n=0 n=0
and expressing nonlinear terms in terms of Adomian polynomials as

1 dn
n

An (h, i) = N λ k
h (t)i (t) . (18)
n! d λ n k k
k=0 λ=0
Here we compute few Adomian polynomials as
n = 0: A0 (h, i) = h0 i0 ,
n = 1: A1 (h, i) = h1 i0 + h0 i1 ,
n = 2: A2 (h, i) = h2 i0 + h1 i1 + i2 h0 ,
n = 3: A3 (h, i) = h3 i0 + h2 i1 + h1 i2 + h0 i3
and so on. Using (17) and (18) in (19), we have

∞ ∞ ∞ ∞
h0 (s + α(1 − s))
L hn (t) = + L a hn (t) − b An (h, i) + e in (t)
s s
n=0 n=0 n=0 n=0
∞ ∞ ∞

i0 (s + α(1 − s))
L in (t) = + L b An (h, i) + (c − d − e) in (t) . (19)
s s
n=0 n=0 n=0
Comparing terms on both sides of (19), we have
h0 i0
L [h0 (t)] = , L [i0 (t)] = ,
s s
s + α(1 − s)
L [h1 (t)] = L ah0 (t) − bA0 (t) + ei0 (t)
s

s + α(1 − s)
L [i1 (t)] = L bA0 (t) + (c − d − e)i0 (t) ,
s

s + α(1 − s)
L [h2 (t)] = L ah1 (t) − bA1 (t) + ei1 (t)
s

s + α(1 − s)
L [i2 (t)] = L bA1 (t) + (c − d − e)i1 (t)
s
..
.
s + α(1 − s)
L [hn+1 (t)] = L ahn (t) − bAn (t) + ein (t)
s

s + α(1 − s)
L [in+1 (t)] = L bAn (t) + (c − d − e)in (t) , n ≥ 0. (20)
s
Now utilizing inverse Laplace transform in (20), we get few terms of series solution
as
h0 (t) = h0 , i0 (t) = i0

−1 s + α(1 − s)
h1 (t) = L L ah0 (t) − bA0 (t) + ei0 (t)
s

−1 s + α(1 − s)
i1 (t) = L L bA0 (t) + (c − d − e)i0 (t)
s

−1 s + α(1 − s)
h2 (t) = L L ah1 (t) − bA1 (t) + ei1 (t)
s

−1 s + α(1 − s)
i2 (t) = L L bA1 (t) + (c − d − e)i1 (t)
s
..
.
s + α(1 − s)
hn+1 (t) = L −1 L ahn (t) − bAn (t) + ein (t)
s

s + α(1 − s)
in+1 (t) = L −1 L bAn (t) + (c − d − e)in (t) , n ≥ 0. (21)
s
Evaluating inverse Laplace transform and using D1 = ah0 − bh0 i0 + ei0 , D2 =

bh0 i0 + (c − d − e)i0 , we have from (22), we have
14 Eiman et al.
h0 (t) = h0 , i0 (t) = i0
h1 (t) = D1 [1 + α(t − 1)], i1 (t) = D2 [1 + α(t − 1)]
2
2 t
h2 (t) = [(aD1 + eD2 ) − b(i0 D1 + h0 D2 )] 1 + α − 2t + 1 + 2α(t − 1)
2!
2
2 t
i2 (t) = [b(i0 D1 + h0 D2 ) + (c − d − e)D2 ] 1 + α − 2t + 1 + 2α(t − 1)
2!
(22)
and so on. In this way the other terms may be computed. Using these values we get
approximate solution from (22) in the form of infinite series as
h(t) = h0 + h1 (t) + h2 (t) + · · · , i(t) = i0 + i1 (t) + i2 (t) + · · · . (23)
Remark 3 Convergence of the proposed method as proved in [10, 42] here is pre-
sented for the considered method.
Theorem 6 If Z be the Banach spaces and T : Z → Z is nonlinear opera-

tor which obeys contraction property with all W , W¯ ∈ Z , T(W ) − T(W¯ ) ≤
L W − W¯ 0 < L < 1. Thank to Banach theorem T has a unique fixed point W ,
with T(W ) = W , where W = (h, i). The series given in (23) may be expressed as

n−1
Wn = T(Wn−1 , Wn−1 = Wl , n = 1, 2, 3, · · · .
l=0
Further W0 = W0 ∈ Bρ (W ), with Bρ (W ) = {W¯ ∈ Z : W¯ − W < ρ}. We have

1. Wn ∈ Bρ (W );
2. limn→∞ Wn = W0 .
Proof Here we prove first assertion of Theorem 6 by using mathematical induction

procedure as:
W − W0 = T(W ) − T(W0 ) (24)

≤ L W − W0 .
Let the result is true for n = m − 1, then one has
W − W0 ≤ L m−1 W − W0 . (25)
Now generalize the results for n = m by using (24) and (25), we have
Wm − W0 = TWm−1 − T(W )

≤ L Wm−1 − W
≤ L .L m−1 W0 − W
= L m W0 − W
≤ L mρ
which implies that Wn − W0 ≤ L n ρ. (26)
From (26), we have Wn ∈ Bρ (W ). Further since
Wn − W0 ≤ L n ρ → 0 as n → ∞.
So we have
lim Wn = W0 .
n→∞
6 Results and Discussion
Let split the density of the whole population into two parts in percent of a locality.
Here we take the case of Pakistan. let healthy population in percentage be h(0) =
0.9945455% and infected be i(0) = 0.0054545%. Here it is to be noted that h(0) +
i(0) = 1%. That currently on June 11, 2020 in Pakistan in the whole population of
220 million there are 0.12 million confirmed cases. Initially in Pakistan the infection
was recorded when some infected people returned from Iran entered the country at
the end of February, 2020. After that government took initially strict measures and
those people were isolated but some of them already have gone to their villages due
to which the infection started to transmit. Also one cause is of medical team who
were curing those infected people in differen quarantined of the country. During
the end of March and April government implemented strict lock downed and even
shops and markets, education institutions were closed. The transmission rate was in
control. Unfortunately in May 2020 some relaxation was given markets shops were
permitted to re-open. Also the people start avoiding to follow the protocol necessary
for COVID-19. The situation is now becoming very worst. The current transmission
of the disease in the country and its different locality is shown in Figs. 1, 2, 3, 4 and
5 taken from [43].
From Figs. 1, 2, 3, 4 and 5, one can see that the infection has been transmitted
nearly in all area of the country. More than 0.128 million people have been infected
and more than thirty thousand people have been recovered. But the transmission rate
is exponential which is very dangerous for the country and our health system can not
bear it. Therefore of some emergency serious step like strict curfew, lock downed and
16 Eiman et al.
Fig. 1 Transmission of COVID-19 from 25 February 2020 to 10 June 2020
Fig. 2 Exponential growth of COVID-19 from 25 February 2020 to 10 June 2020
Fig. 3 Trends of spreading of COVID-19 from 25 February 2020 to 10 June 2020

Fig. 4 Transmission of COVID-19 in different areas of the country from 25 February 2020 to 10
June 2020
Fig. 5 Transmission of COVID-19 in different adminstration of the country from 25 February 2020
to 10 June 2020
minimizing the immigration of people within the country are implemented. Some
better consequence may be meet in this regards.
Keeping the above data here we use Matlab to present the solution for first ten
terms through graphs for different cases.
6.1 Case I
Here some numerical values to the parameters are assigned as in Table 2 We plot
the approximate solution (23) for first ten terms for the thirty weekends in Fig. 6 as
From Fig. 6, we see that for greater values of a, c, the population of healthy class is
rapidly decreasing and the consequently the population of infected class is increases.
Hence at this rate in coming thirty weekends the infection will grow in Pakistan
with very fast speed as the immigration has been allowed by the government. Also
the decay is fastest at small fractional order while the growth in infection is high
18 Eiman et al.

Parameters Numerical value of the parameter
h(0) 0.9945455%
i(0) 0.0054545%
a 0.0005 assumed
b 0.0005 assumed
c 0.0005 assumed
d 0.0005 assumed
e 0.0003 assumed
1 1.2
0.75 0.75
0.9
0.85 0.85
1
0.8 0.95 0.95
1.0 1.0
0.7
0.8
Infected class
Healthy class
0.6
0.5 0.6
0.4
0.4
0.3
0.2
0.2
0.1
0 0
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Time Time
Fig. 6 Dynamical behavior of approximate results of the considered model for different fractional
orders using the given values of the parameters of Case-I
at lowest fractional order. As the fractional order α → 1, the concerned solution of

fractional order will coincides with integer order solution.
6.2 Case II
Here we slightly decrease the values of immigration parameters as in Table 3

We plot the approximate solution (23) for first ten terms for the thirty weekends in
Fig. 7 as From Fig. 7, one can see that by decreasing the immigration parameters a, c
values the growth of the infection becomes slow and hence heathy population decline
will also be slow as compared to Case-I. The corresponding decline and growth are
different at different fractional order. On small fractional order the process is rapid
as compared to greater order.

h(0) 0.9945455%
i(0) 0.0054545%
a 0.00001 assumed
b 0.05 assumed
c 0.00001 assumed
d 0.0005 assumed
e 0.0003 assumed
1 1
0.9 0.75 0.9 0.75

0.8 0.85 0.8 0.85
0.95 0.95
0.7 0.7
1.0 1.0
Infected class
Healthy class
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Time Time
orders using the given values of the parameters in Case-II
6.3 Case III
Here we slightly decrease the values of immigration parameters as in Table 4

We plot the approximate solution (23) for first ten terms for the thirty weekends
in Fig. 8 as
Increasing the protection/cure rate e, and minimizing the immigration rate a of
healthy people and infected people c, we see that the the concerned infection rate
may be decreased to stable position and healthy population may be increased. Here
we remark that the concerned values of parameters have assumed and the density of
the population is taken real about Pakistan.
20 Eiman et al.

h(0) 0.9945455%
i(0) 0.0054545%
a 0.0000001 assumed
b 0.05 assumed
c 0.0000001 assumed
d 0.0005 assumed
e 0.50 assumed
1 0.7
0.9 0.75
0.75
0.85 0.6
0.8 0.85
0.95
0.5
0.95
0.7 1.0
Healthy class
Infected class
1.0
0.6 0.4
0.5
0.3
0.4
0.2
0.3
0.1
0.2
0.1 0
0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90
Time Time
orders using the given values of the parameters in Case-III
6.4 Case IV
Here we take larger value for cure rate and other value of immigration parameters
as in Table 5 We plot the approximate solution (23) for first ten terms for the thirty
weekends in Fig. 9 as
Increasing the protection/cure rate e, and keeping the proper social distance among
the people density of healthy people increase and that of infected class is reducing.
Here we remark that the concerned values of parameters have assumed and the density
of the population is taken real about Pakistan.
Remark 4 Keeping the above information in mind we give some future prediction if
immigration of people of both healthy and infected are allowed completely. Also by
reducing the protection measure, we give a comparison between real and approximate
data for infected and death people for coming thirty weekends. In coming thirty
weekends in Pakistan the growth of infected class is shown in Fig. 10.

h(0) 0.9945455%
i(0) 0.0054545%
a 0.00002 assumed
b 0.05 assumed
c 0.005 assumed
d 0.005 assumed
e 0.99 assumed
× 10-3
1 5
4.5 0.75
0.999 0.85
4
0.95
0.75 Infected class 3.5 1.0
Healthy class
0.998 0.85
0.85 3
0.997 1.0 2.5
2
0.996
1.5
1
0.995
0.5
0.994 0
0 5 10 15 20 25 30 0 5 10 15 20 25 30
Time Time
orders using the given values of the parameters in Case-IV
Further as a results more chances of increase in fatality. Therefore expected death

cases for approximate and real data for next thirty weekends is shown in Fig. 11.
7 Conclusion
A dynamical system addressing the relationship healthy and infected classes of the
current COVID-19 has been investigated under nonsingular kernel type derivative.
We have first proved the existence of the given model by using fixed point theory.
Then we have established some results about Ulam-Hyers stability for the consid-
ered model. By utilizing an iterative method of Laplace transform and Adomian
decomposition method, we have established series type solution for the model under
consideration. We have taken some real initial values for the compartments of the
models h and i and for parameters we assumed different values. We have plotted
the approximate solutions for fist few terms corresponding to different fractional
order for the thirty weekends. This is model has not been tested on any experimental
22 Eiman et al.
× 104
15
Approximate data
Real data
10
Infected class
0 5 10 15 20 25 30
Time
Fig. 10 Comparison between real and approximated infected for next thirty weekends in Pakistan
5000
4500
Approximate data
Expected death cases
4000 Real data

3500
3000
2500
2000
1500
1000
500
0 5 10 15 20 25 30
Time
Fig. 11 Comparison between real and approximated death cases for next thirty weekends in Pak-
istan
data yet. The model is just an indication to observe what will happen if we do not
control the immigration of individuals in the community. Further we have adopted
fractional order derivative due to the fact that such differential operators are global in
nature and describe the hereditary and characteristic properties of various process in
more comprehensive ways as compared to integer order derivative. Further various
parameters like immigration rates of infected and healthy people, cure and birth rate
also have significant impact on the transmission dynamics of COVID-19. A Greater
protection rate may also help in reducing the infection. Also keeping social distance
and avoid gathering may also help in reducing the transmission of infection. In other
words if people do not follow up the guide lines corresponding to COVID-19, in
coming days the infection may transmitted with very rapid speed in the community.
In future more death cases may occurred and the situation will become very worst.
In future the proposed model may be further extended by involving natural death
rates and recovered class to formulate three compartments model. The new obtain
model will be investigated via different kinds of fractional order derivatives. More
general and comprehensive analysis will be developed.
Competing Interest
We have no competing interest of interest regarding this research work.
Acknowledgment
All authors have read and approved the final version. All authors are thankful to the
reviewers for their careful reading.
Authors contribution
All authors have equal contribution.
Availability of data
This is not applicable in our work.
Funding
This is not applicable in our work.
References
1. Li, Q., et al.: Early transmission dynamics in Wuhan, China, of novel coronavirus-infected
pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020)
2. Zhou, P., et al.: A pneumonia outbreak associated with a new coronavirus of probable bat
origin. Nature 579(7798), 270–273 (2020)
3. World Health Organization: Coronavirus disease 2019 (COVID-19) Situation Report-62 (2020)
4. Lu, H., Stratton, C.W., Tang, Y.W.: Outbreak of Pneumonia of Unknown Etiology in Wuhan
China: the mystery and the miracle. J. Med. Virol. 92(4), 401–402 (2020)
5. World Health Organization: Severe acute respiratory syndrome (SARS). Weekly Epidemio-
logical Record= Relevé épidémiologique hebdomadaire 78(13), 89 (2003)
6. Xiao, H., et al.: Social capital and sleep quality in individuals who self-isolated for 14 days
during the coronavirus disease (COVID-19) outbreak in January 2020 in China. Med. Sci.
Monitor Int. Med. J. xp. Clin. Res. 26(2020), e923921–1 (2019)
7. Forida, P., et al.: The symptoms, contagious process, prevention and post treatment of covid-19.
Eur. J. Physiotherapy Rehab. Stud. 2020, 11p (2020)
8. World Health Organization: Advice on the use of masks in the context of COVID-19: interim
guidance, 5 June 2020. No. WHO/2019-nCov/IPC_Masks/2020.4. World Health Organization
(2020)
9. Poon, L.L.M., et al.: Identification of a novel coronavirus in bats. J. Virol. 79(4), 2001–2009
(2005)
10. Kermack, W.O., McKendrick, A.G.: A contribution to the mathematical theory of epidemics.
Proc. R. Soc. London 115, 700 (1927)
11. Brauer, F.: The Kermack-McKendrick epidemic model revisited. Math. Biosci. 198(2), 119–
131 (2005)
24 Eiman et al.
12. Brauer, F., Castillo-Chavez, C.: Mathematical Models in Population Biology and Epidemiology.
Springer, New York (2001)
13. Hethcote, H.W.: The mathematics of infectious diseases. SIAM Rev. 42(4), 599–653 (2000)
14. Hethcote, H.W., Van Ark, J.W.: Modeling HIV Transmission and AIDS in the United States.
Lecture Notes in Biomathematics, vol. 95. Springer, Berlin, Heidelberg, New York (1992)
15. Lin, Q., et al.: A conceptual model for the coronavirus disease, (COVID-19) outbreak in Wuhan,
China with individual reaction and governmental action. Int. J. Infect. Dis. 93(2020), 211–216
(2019)
16. Yousaf, M., et al.: Statistical analysis of forecasting COVID-19 for Upcoming Month in Pak-
istan. Chaos, Solitons Fractals 138, 109926 (2020)
17. Shah, K., et al.: Qualitative analysis of a mathematical model in the time of COVID-19. BioMed.
Res. Int. 2020, 11 (2020)
18. Abdo, M.S., et al.: On a comprehensive model of the novel coronavirus (COVID-19) under
Mittag-Leffler derivative. Chaos, Solitons Fractals 138, 109926 (2020)
19. Naghipour, A., Manafian, J.: Application of the Laplace Adomian decomposition method and
implicit methods for solving Burger, s equations. TWMS J. Pure Appl. Math 6(1), 68–77 (2015)
20. Thieme, H.R.: Convergence results and a Poincaré-Bendixson trichotomy for asymptotically
autonomous differential equations. J. Math. Biol. 30(7), 755–763 (1992)
21. Biazar, J.: Solution of the epidemic model by Adomian decomposition method. Appl. Math.
Comput. 173(2), 1101–1106 (2006)
22. Podlubny, I.: Fractional Differential Equations, Mathematics in Science and Engineering. Aca-
demic, New York (1999)
23. Kilbas, A.A., Srivastava, H., Trujillo, J.: Theory and Application of Fractional Differential
Equations, North Holland Mathematics Studies, vol. 204. Elseveir, Amsterdam (2006)
24. El-Saka, H.A.A.: The fractional-order SIS epidemic model with variable population size. J.
Egyptian. Math. Soci. 22, 50–54 (2014)
25. Toledo-Hernandez, Rasiel, Rico-Ramirez, Vicente, Iglesias-Silva, Gustavo A., Diwekar,
Urmila M.: A fractional calculus approach to the dynamic optimization of biological reac-
tive systems. Part I: Fractional models for biological reactions. Chem. Eng. Sci. 117, 217–228
(2014)
26. Wang, Z., Yang, D., Ma, T., Sun, N.: Stability analysis for nonlinear fractional-order systems
based on comparison principle. Nonlinear Dyn. 75(1–2), 387–402 (2014)
27. Haq, F., Shah, K., Rahman, G.: Muhammad Shahzad, Numerical solution of fractional order
smoking model via Laplace Adomian decomposition method. Alexandria Eng. J. 57(2), 1061–
1069 (2018)
28. Ali, A., Shah, K., Khan, R.A.: Numerical treatment for traveling wave solutions of fractional
Whitham-Broer-Kaup equations. Alexandria Eng. J. 57(3), 1991–1998 (2018)
29. Kiymaz, O.: An Algorithm for solving initial value problems using Laplace Adomian Decom-
position Method. Appl. Math. Sci. 3(30), 1453–1459 (2009)
30. Caputo, M., Fabrizio, M.: A new definition of fractional derivative without singular kernel.
Progr. Fract. Differ. Appl. 1(2), 1–13 (2015)
31. Abdeljawad, T., Baleanu, D.: On fractional derivatives with exponential kernel and their discrete
versions. Rep. Math. Phys. 80(1), 11–27 (2017)
32. Abdeljawad, T.: Fractional operators with exponential kernels and a Lyapunov type inequality.
Adv. Differ. Equ. 2017(1), 313 (2017)
33. Yiha, M.D., Koya, P.R., Tibebu, T.: Analysis of prey-predator system with prey population
experiencing critical depensation growth function. Am. J. Appl. Math. 3(6), 327–334 (2015)
34. Abrams, P.A.: The evolution of predator-prey interactions: theory and evidence. Annu. Rev.
Ecol. Syst. 31, 79–105 (2000)
35. Berryman, A.: The origins and evolution of predator-prey theory. Ecology 73, 1530–1535
(1992)
36. Tahara, T., et al.: Asymptotic stability of a modified Lotka-Volterra model with small immi-
grations. Sci. Rep. 8(1), 7029 (2018)
37. Nag, S.: A mathematical model in the time of Covid-19, a preprint 13 March 2020
38. Singh, J., et al.: Analysis of an El Nino-Southern Oscillation model with a new fractional
derivative. Chaos, Solitons Fractals 99, 109–115 (2017)
39. Tarasov, V.E.: Caputo-Fabrizio operator in terms of integer derivatives: memory or distributed
lag. Comput. Appl. Math. 38(3), 113 (2019)
40. Burton, T.A.: Krasnoselskii N-tupled fixed point theorem with applications to fractional non-
linear dynamical system. Adv. Math. Phys. 2019. 9 pp (2019). (Article ID 6763842)
41. Shah, K., Jarad, F., Abdeljawad, T.: On a nonlinear fractional order model of dengue fever
disease under Caputo-Fabrizio derivative. Alexandria Eng. J. 59(4), 2305–2313 (2020)
42. Haq, F., Shah, K., Rahman, G., Shahzad, M.: Numerical solution of fractional order smoking
model via Laplace Adomian decomposition method. Alexandria Eng. J. 57(2), 1061–1069
(2018)
43. Official website (http://covid.gov.pk), NIH (https://www.nih.org.pk/novel-coranavirus-2019-
ncov/), 11 June 2020
Time Series Modelling and Prediction
of the Coronavirus Outbreaks
(COVID-19) in the World
Mohsen Maleki
Abstract Coronaviruses are a huge family of viruses that affect neurological,

gastrointestinal, hepatic and respiratory systems. The numbers of confirmed cases
are increased daily in different countries, especially in Unites State America, Spain,
Italy, Germany, China, Iran, South Korea and others. The spread of the COVID-19
has many dangers and needs strict special plans and policies. Therefore, to consider
the plans and policies, the predicting and forecasting the future confirmed cases
are critical. The time series models are useful to model data that are gathered and
indexed by time. Classical time series is based on the assumption that the error terms
are symmetric. But there exist many situations in the real world that assumption of
symmetric distribution of the error terms is not satisfactory. In our methodology,
we consider the time series models based on the two-piece scale mixtures of normal
(TP–SMN) distributions. The mentioned class of distributions is a rich class of distri-
butions family that covers the robust symmetric/asymmetric light/heavy tailed distri-
butions. The proposed time series models works well than ordinary Gaussian and
symmetry models (especially for COVID-19 datasets), and were fitted initially to the
historical COVID-19 datasets. Then, the time series that has the best fit to each of
the dataset is selected. Finally, the selected models are used to predict the number of
confirmed cases and death rate of COVID-19 in the world.
Keywords Coronaviruses · COVID-19 · Forecasting · Autoregressive model ·

Autoregressive-moving average model · Maximum likelihood estimates · Two
pieces scale mixtures of normal distributions
1 Introduction
Coronaviruses are a huge family of viruses that affect neurological, gastrointestinal,

hepatic and respiratory systems. This family can be grown among humans, bats, mice,
M. Maleki (B)
Department of Statistics, Faculty of Mathematics and Statistics, University of Isfahan,
81746-73441, Isfahan, Iran
e-mail: m.maleki.stat@gmail.com

28 M. Maleki
livestock, birds, and others [8]. Some types of coronavirus, called SARS coronavirus
(SARS-CoV) and MERS coronavirus (MERS-CoV), with details of their distribu-
tions have studied by Cauchemez et al. [7]. Late in year 2019, the World Health
Organization (WHO) reported many cases in China with respiratory diseases. A new
type of coronavirus, named COVID-19 (it may be also named 2019-nCoV), was
spread in Wuhan. The scientists believe that the COVID-19 acts in human similar to
that are in bats. However, to know the main source of the COVID-19, more scientific
studies are needed. Based on the reports, the COVID-19 has been observed in others
cities in China and also in about other 198 countries (up to 06 February 2020). The
Centers for Disease Control and Prevention (CDC) verified that the COVID-19 is
distributed from human to human. Based on the CDC’s reports, the COVID-19 is
spread by touching surfaces, close contact, air, or objects that contain viral particles.
The COVID-19 is a dangerous virus, because the incubation period of the COVID-19
is at least 14 days [9], and it can spread to others in the incubation period.
The number of confirmed cases has rapidly increased daily in different countries.
The spread of the COVID-19 has many dangers and needs strict special plans and
policies. Therefore, to consider the plans and policies, the prediction and forecasting
the future confirmed cases are critical. The number of the unreported COVID-19
cases in China has been mathematically estimated by [36]. Based on the information
of some Japanese passengers in Wuhan, [30] estimated the rate of the infection for
COVID-19 in Wuhan. The results indicated a rate of 9.5% for infection and a rate from
0.3 to 0.6%, for death. Since the size of the considered population is very small, there
is doubt in about accuracy of estimated rates. Based on a mathematical model, [33]
concluded that the transmission risk of COVID-19 is averagely about 6.47 persons
and predicted the time that the peak of COVID-19 will be reached. Al-qaness et al.
[1] proposed an optimization method, named FPASSA-ANFIS, to model the number
of confirmed cases of COVID-19 and to predict its future values using previous
recorded dataset in China. They introduced a technique that was a combination
of salp swarm algorithm, flower pollination algorithm, and adaptive neuro-fuzzy
inference system. Generally, the salp swarm algorithm was applied to develop flower
pollination algorithm to prevent its disadvantages such as returning trapped at the
local optimum. The theory of FPASSA-ANFIS model is based on the improvement in
the ability and accuracy of adaptive neuro-fuzzy inference system by considering the
parameters of adaptive neuro-fuzzy inference system using salp swarm and flower
pollination algorithms. The ability and applicability of FPASSA-ANFIS technique
were studied using the real dataset including the outbreak of the COVID-19 given
by World Health Organization. Moreover, FPASSA-ANFIS technique was applied
to forecast the confirmed cases in future days.
The modeling, estimating and forecasting the characteristics of the epidemio-
logical problems were considered in some previous researches. For example, the
forecasting of the cases and transmission risk of West Nile virus (WNV) [11], the
forecasting of the infection of hepatitis A virus [34], the forecasting of the seasonal
outbreaks of influenza [32], the forecasting of the outbreaks of Ebola [31], predicting
the outbreaks of the MERS [29].
Time Series Modelling and Prediction of the Coronavirus … 29
Time series models are useful to models data that gathered and indexed by time.
Time series analysis has been used effectively to model, estimate, forecast and predict
real practical problems, see Zarrin et al. [35], Maleki et al. [23–26] and references
therein. Classical time series is based on the assumption that the error terms are
symmetric. But there exist many situations in the real world that assumption of
symmetrically distribution of the error terms is not satisfactory (see e.g., Maleki and
Arellano-Valle [17], Maleki and Nematollahi [21], Ghasami et al. [12, 13], Maleki
et al. [23, 24]), so in our methodology we consider the time series models based
on the two–piece distributions, especially two–piece scale mixture normal (TP–
SMN) distributions which had introduced by Arellano-Valle et al. [3] and Maleki
and Mahmoudi [20].
The scale mixtures of normal (SMN) family are flexible symmetric distributions
which contains the light/heavy tailed members: The Normal (N), Student-t (T ), Slash
(SL) and Contaminated Normal (CN) distributions as its well-known members [2].
This family can be used as a robust inference of time series models. Moreover, using
a time series model which also deals with atypical data in asymmetrical variables
is desirable in applications as well. Therefore, the asymmetrical family of distribu-
tions which also covers robust inferences is essential to the studies on the statistical
models such as the AR model. One way to construct the skewed version of the SMN
family was first used by Branco and Dey [5] in order to have the robust inference
on asymmetrical data. They extended the SMN class to scale mixtures of skew–
normal (SMSN) family of distributions. This family has been widely considered in
many applications due to its strong flexibility for atypical data such as: time series
data [14, 17, 23, 24]. Another way to construct the skewed version of the SMN
family is using the methodology of two-piece distributions which was investigated
by Arellano-Valle et al. [3], Maleki and Mahmoudi [21, 22], Hoseinzadeh et al. [15,
16], Contreras-Reyes et al. [10], Maleki et al. [18, 19] and Barkhordar et al. [4]. This
way, the SMN class is extended to the two-piece scale mixtures of normal (TP-SMN)
class which cover simultaneously the robust and asymmetrical aims with members
that are called the two-piece Normal (TP–N), two-piece Student–t (TP–T ), two-piece
Slash (TP–SL) and two–piece Contaminated Normal (TP–CN) distributions. Addi-
tionally, their corresponding symmetric SMN members are in the proposed model as
well.
The asymmetric autoregressive process (with the assumption of non-Gaussian
white noise) has been recently considered in many applications especially medicine,
virology and biology in which time series models and their skewed structures can
be more useful compared to the models where the underlying distribution may have
outliers or/and skewed behavior. In fact, in order to overcome such a problem, some
researchers have applied non-normal time series models. Some of these models that
have been recently considered are summarized in the literature section. The ESN
distribution was introduced by Arellano-Valle et al. [3], and later it was studied by
Maleki and Nematollahi [21] considered the AR model based on the finite mixtures
of the scale mixtures related to normal family of distributions. Ghasami et al. [12]
introduced the AR process with generalized hyperbolic innovations and obtained
Maximum Likelihood (ML) estimates of the parameters.
30 M. Maleki
The proposed time series (Autoregressive and Autoregressive–Moving Average)

models include the symmetric Gaussian and symmetric/asymmetric lightly/heavy–
tailed non–Gaussian autoregressive models, and were fitted initially to the historical
COVID-19 datasets. Then, the time series that has the best fit to each of the dataset
is selected. Finally, the selected models are used to predict the number of confirmed
cases and death rate of COVID-19 in the world. The main contribution points of the
current chapter are as follows, first: an improved time series model is introduced
applying TP–SMN distributions, and second, the new efficient predictive model is
applied to predict and estimate the confirmed cases and death rate of COVID-19 in
the world, using past and current datasets.
2 TP-SMN Family of Distributions
In this section, some needed properties of the TP–SMN family of distributions for
the proposed AR model are examined.
A general location-scale two-piece family of distributions [3], (Eq. 8) has the
following density:

2 y−μ
g(y|μ, σ, γ ) = f I(−∞, μ] (y)
σ a(γ ) + b(γ ) σ b(γ )

y−μ
+f I(μ,+∞) (y) , (1)
σ a(γ )
where f (·) is an (standardized) symmetric (around zero) density with its support
on R, μ ∈ R is a location parameter, σ > 0 is a scale parameter, and a(γ ) > 0
and b(γ ) > 0 are differentiable functions of skewness parameter γ . Considering
the standardized SMN-densities as f (·), a(γ ) = 1 − γ and b(γ ) = γ , the proposed
TP–SMN family of distributions is concluded [20].
The celebrated well-known SMN family introduced by Andrews and Mallows
[2] and is considered as the basis of the robust asymmetry TP–SMN family, has the
following probability density function (pdf) and stochastic representation.
Let X ∼ S M N (μ, σ, ν), then
∞

f S M N (x|μ, σ, ν) = φ x|μ, u −1 σ 2 d H ( u|ν), x ∈ R, (2)

0
and
X = μ + σ U −1/2 W, (3)

where φ ·|μ, σ 2 represents the density of N μ, σ 2 distribution, H (·|ν) is the

cumulative distribution function (cdf) of the scale mixing random variable U which
can be indexed by a scalar or vector of parameters ν, and W is a standard normal
random variable that is independent of U .
The TP–SMN is a rich family of distributions that covers the asymmetric light-
tailed TP–N, and asymmetric heavy-tailed TP–T, TP–SL and TP–CN distributions
and their corresponding symmetric members. Following a general two-piece from
Arellano-Valle et al. [3], based on the SMN distributions, in terms of density, for
y ∈ R, this family is represented as

2(1 − γ ) f S M N (y|μ, σ (1 − γ ) , ν), y ≤ μ,
g(y|μ, σ, γ , ν) = (4)
2γ f S M N (y|μ, σ γ , ν), y > μ,
where 0 < γ < 1 is the slant parameter, f S M N (·|μ, σ, ν) is given by (2), and it is
denoted by Y ∼ TP-SMN (μ, σ, ν, γ ).
Lemma 1 Let Y ∼ TP–SMN (μ, σ, γ , ν), then Y has also another stochastic
representation given by
Y = S1 Y − + S2 Y + ,
where Y _ ∼ S M N (μ, σ1 , ν)I A (y) and Y + ∼ S M N (μ, σ2 , ν)I Ac (y), for which
σ1 = σ (1 − γ ), σ2 = σ γ , A = (−∞, μ)and S M N (·)I A (·)denotes the truncated
SMN–distribution on the interval A, and S = (S1 , S2 ) such that S1 + S2 = 1has
following probability mass function (pmf):
s1 s2
σ1 σ2
P(S = s) = ; s1 , s2 = 0, 1, s1 + s2 = 1.
σ1 + σ2 σ1 + σ2
Lemma 2 Let Y ∼ TP–SMN (μ, σ, γ , ν),

(a) E(Y ) = μ −b;
(b) Var(Y ) = σ 2 c2 k2 (ν) − b2 c12 .
√
where = σ (1
− 2γ ), b = 2/π k1 (ν), cr = γ r +1 + (−1)r (1 − γ )r +1 and
kr (ν) = E U −r/2 , for which U is the scale mixing variable in of SMN random
variable (see Arellano-Valle et al. [3], Maleki and Mahmoudi [20] and Moravveji
et al. [28], for more statistical properties of the TP–SMN family).
Note that finite values of parameters imply the finiteness of the mean and vari-
ance. Different TP–SMN member distributions in (4) are obtained by some several
distributions for scale mixing random variable U in (3), as in Table 1. Also, note that
when γ = 0.5, the asymmetry TP–SMN family becomes the well-known symmetry
SMN family.
In fact, the two-piece distributions can be represented as the two–component
mixture with separated supports, i.e., left and right half basic distributions, especially
32 M. Maleki
Table 1 Some members of the TP–SMN distributions

Dist f S M N (·), y ∈ R Pdf or pmf of U kr = E U − r/2

Two-piece φ y; μ, σ 2 U = 1 w.p.1 –
normal
(TP-N)
ν
ν ν
r/2 ( ν−r
2 )

2, 2
Two-piece t ν+1 Gamma
ν+1
, ν >r
2 d −
(TP-T) √
( ν2 ) π νσ
1+ ν
2
; ν=ν 2 ( ν2 )
1
u ν−1 φ y; μ, u −1 σ 2 du; ν = Beta(ν, 1), ν > 0 2ν−r , ν>

2ν r
Two-piece ν 2
0
slash ν
(TP-SL)

ν
+1− ν
Two-piece νφ y; μ, τ −1 σ 2 + ν I(u t =τ ) + γ r/2
contaminated
(1 − ν)φ y; μ, σ 2 ; ν = (ν, τ ) (1 − ν)I(u t =1) ;

normal
(TP-CN) 0 < ν < 1, 0 < τ ≤ 1
when Y ∼ TP–SMN (μ, σ, ν, γ ) with pdf given in (4), two–component mixture left
and right half SMN distributions with special component probabilities as follows:
σ1
g(y|μ, σ1 , σ2 , ν) = 2 f S M N (y|μ, σ1 , ν)I(−∞,μ] (y)
σ1 + σ2
σ2
+2 f S M N (y|μ, σ2 , ν)I(μ,+∞) (y). (5)
σ1 + σ2
Note in (5) that, the scale parameter σ and skewness parameter γ in (4) are
recovered in the form of σ = σ1 + σ2 and γ = σ2 /(σ1 + σ2 ).
By using auxiliary (latent) variables Z j ; j = 1, 2, in terms of the components
of the mixture (5), the TP–SMN random variable can have the following stochastic
representation

Y |Z 1 = 1 ∼ S M N (μ, σ1 , ν)I A (yi ),
(6)
Y |Z 2 = 1 ∼ S M N (μ, σ2 , ν)I Ac (yi ),
where A = (−∞, μ) and S M N (·)I A (·) denotes the truncated SMN-distribution

on the interval A, and Z = (Z 1 , Z 2 ) has a multinomial distribution with the
following probability mass function (pmf):
z 1 z 2
σ1 σ2
P(Z = z) = ; z 1 , z 2 = 0, 1, (7)
σ1 + σ2 σ1 + σ2
and is denoted by Z ∼ M(1, σ1 /(σ1 + σ2 ), σ2 /(σ1 + σ2 )). Note

that each component
is a Bernoulli

(component-label) random variables
Z j ∼ Binomial 1, σ j /(σ1 + σ2 ) ; j = 1, 2, and also Z 1 + Z 2 = 1.
Maleki and Mahmoudi [20] obtained the ML estimates of the TP–SMN parame-
ters. The ML estimates are robust if the norm of influence function (IF) is bounded.
Ghasami et al. [13] had shown the robustness of the TP–SMN family.
3 The Robust Class of TP–SMN Autoregressive Model
In this section, the TP–SMN Autoregressive (TP–SMN–AR) model is introduced by

Ghasami et al. [13], and the ML estimates of this model are obtained.
3.1 TP–SMN–AR(p) Model
The TP–SMN Autoregressive model with order p, denoted by TP–SMN–AR ( p)

model with intercept is defined by

p
Xt = μ + ϕ j X t− j + εt , t = 0, ±1, ±2, . . . , (8)
j=1

where ϕ = ϕ1 , . . . , ϕ p is an unknown vector of autoregressive coefficients
and {εt } is a sequence of i.i.d. noises distributed as follows,
iid.
εt ∼ T P-S M N (0, σ, ν, γ ), t = 0, ±1, ±2, . . . . (9)
Hereafter, this process is called the TP–SMN–AR ( p) model with vector of

parameters = (ϕ, μ, σ1 , σ2 , ν) .
Considering the AR model (8), to have a simpler representation, the model can be

rewritten as X t = μ + ϕ X t−1 + εt , where X t−1 = X t−1 , . . . , X t− p with sample

vector X = X − p+1 , . . . , X 0 , X 1 , . . . , X n .
Therefore, the conditional likelihood function of the proposed TP–SMN–AR ( p)
model, conditionally on initial non stochastic sample X − p+1 , . . . , X 0 and using the
mixture representation form of the TP–SMN pdf given in (5) is

n

( |x) = log g X t |X t−1 = x t−1 xt |ϕ x t−1 + μ, σ1 , σ2 , ν . (10)

t=1
Due to the complexity of the SMN–densities in the pdf (5), finding the ML esti-
mates of the model parameters from (10) are tractable. However, using the new
suitable hierarchically form of the TP–SMN family besides the model, an EM–type
algorithm is applied to estimate the model parameters as it follows.
Let D = (X, U) be the complete data where, as defined before, X is the observed
data and U = (U1 , . . . , Un ) and Z t = (Z t1 , Z t2 ) ; t = 1, . . . , n are the missing
(latent) data. From Eqs. (4)–(7) and the stochastic representation of SMN family in
(3), it is noticed that the TP–SMN–AR model via (8) can be written in a hierarchically
form and represented as
34 M. Maleki
X t |X t−1 = x t−1 , Ut = u t ,
ind.
Z ti = 1 ∼ N ϕ x t−1 + μ, u −1 t σi
2
ITt (xt )2−i ITtc (xt )i−1 ,

ind. iid. σ1 σ2
Ut |Z ti = 1 ∼ H (ut |v)Z t ∼ M 1, , , (11)
σ1 + σ2 σ1 + σ2

for t = 1, . . . , n and i = 1, 2, where Tt = −∞, ϕ x t−1 + μ and N (·)IT (·)

denotes the truncated normal distribution on the interval T .
The above hierarchical representation of the TP–SMN–AR model will be used to
obtain the ML estimates via ECME algorithm. The ECME algorithm is a generaliza-
tion of the ECM-algorithm introduced by Meng and Rubin [27], which is an extension
of the EM–algorithm. It can be obtained by replacing some CM-steps which maxi-
mize the constrained expected complete-data log–likelihood function using the steps
that maximize the correspondingly constrained actual likelihood function.
3.2 ML Estimates of the TP–SMN–AR(p) Model Parameters
In the TP-SMN-AR(p) with vector of parameters = (ϕ, μ, σ1 , σ2 , ν) , considering

the hierarchical representation (11), the conditional augmented likelihood function
of the proposed model is

n
2

L() = φ X t |ϕ x t−1 + μ, u −1
t σi h( u t |ν)
2
t=1 i=1

Z ti
p( z t |σ1 , σ2 )ITt (xt )2−i ITtc (xt )i−1 ,

where Tt = −∞, ϕ x t−1 + μ , t = 1, . . . , n. After ignoring constants and

using auxiliary (latent) variables, the completed log-likelihood function is in the
form:
2
1
n 2
X t − ϕ X t−1 − μ
() = −n log(σ1 + σ2 ) − Z ti Ut
2 t=1 i=1 σi

n
2
+ Z ti log h(Ut |ν), (12)
t=1 i=1

where = (β, μ, σ1 , σ2 , ν) . Defining the quantities ẑ ti = E Z ti |, X and

ŵti = E Ut Z ti |, X , and using known properties of conditional expectation

ŵti = κ̂ti ẑ ti , is obtained where κ̂ti = E Ut |
O, yt Z ti = 1 , t = 1, . . . , n, i = 1, 2,
and

2 σ̂1 /σ̂1 + σ̂2 f S M N xt |ϕ̂ x t−1 + μ̂, σ̂1 , ν̂ I−∞,x β̂ (yi )
i
ẑ t1 =

g xt |ϕ̂ x t−1 + μ̂, σ̂1 , σ̂2 , ν̂
= I−∞,ϕ̂ x (x
t ),
t−1 +μ̂
where g(·|·) is the TP–SMN pdf defined in (5), and ẑ t2 = 1 − ẑ t1 . The first
conditional expectation for the TP–SMN–AR members, are given by:
(i) TP–N–AR model: κ̂ti = 1,
ν̂+1
(ii) TP–T –AR model: κ̂ti = ν̂+dti
,
2ν̂+1 P1 (ν̂+3/2,dti /2)
(iii) TP–SL–AR model: κ̂ti = dti P1 (ν̂+1/2,dti /2)
,
κ̂ti = τ̂ ν̂e−τ̂ dti /2 + (1−ν̂ )e−dti /2 .
2 −τ̂ dti /2 −dti /2
τ̂ ν̂e + 1−ν̂ e
(iv) TP–CN–AR model:
( )

2
where dti = xt −ϕ̂ σ̂xi t−1 −μ̂ , and Px (a, b) denotes the distribution function of the
Gamma (a, b) distribution evaluated at x.
Now, the E–Step on the (k + 1)th iteration of the ECME algorithm
requires the
(k)

(k)

calculation of Q–function, i.e., in the form of Q | = E θ ()| , X .

So,
E–Step:
2
1 (k) X t − ϕ X t−1 − μ
n 2
(k)
Q | = −n log(σ1 + σ2 ) − ŵti
2 t=1 i=1 σi

n
2 (k)

+ E Z ti log h(Ut |ν)| , X ,

i=1 j=1
(k)

where ŵti(k) = E Ut Z ti | , X = κ̂ti(k) ẑ ti(k) .
CM–steps:
CM–step 1 of the ECME algorithm:
n −1
(k+1)

n

ϕ̂ = α̂t(k) X t−1 X
t−1 α̂t(k) X t − μ̂(k) X t−1 , (13)
t=1 t=1
2
where α̂t(k) = i=1 ŵti(k) σi2(k) .
n
(k+1)
t=1 α̂t(k) X t − ϕ̂ X t−1
μ̂(k+1) = n (k)
. (14)
t=1 α̂t
36 M. Maleki
CM–steps 3–4 of the ECME algorithm:

Update σ̂i(k+1) ; i = 1, 2, by solving the following stressed cubic equations
σi3 + pσi + q = 0; i = 1, 2, (15)
2
(k+1)
where p = − n1 nt=1 ŵti(k) X t − ϕ̂ X t−1 − μ̂(k+1) , for which q =
pσ2 I(i=1) + pσ1 I(i=2) . Note that p, q < 0, so this cubic equation has unique just root
in the (0, +∞) interval.
CML–step of the ECME algorithm:

(k+1)
ν (k+1) = argmaxν ϕ̂ , μ̂(k+1) , σ̂1(k+1) , σ̂2(k+1) , ν X , (16)
where ( ·|X) is the log–likelihood function given in (10).

ECME
The algorithm
(k)iterates
until a sufficient convergence rule is satisfied, e.g.
(k+1)

if X X − 1 ≤ ε under the determined tolerance ε, which
is usually is employed ε = 10−2 , but the choice of tolerance may vary in different
applications.
3.3 Modeling the Confirmed and Cured Cases

of the COVID-19 in the World
The coronavirus (COVID-19) is affecting many countries and territories around the
world and two international conveyances. The daily data related the COVID-19 in
the world, are reporting by the China National Health Commission (NHC) and World
Health Organization (WHO). In this part we fit the TP–SMN–AR time series model
to the total confirmed COVID-19 cases from 22-Jan-2020 to 30-Apr-2020 and also
to the total cured COVID-19 cases from 02-Feb-2020 to 30-Apr-2020, in the world.
Time series plots of the total confirmed and cured cases are plotted in Figs. 1
and 2 respectively. The proposed time series plots are not stationary because they
are increasing and have trends. After some suitable transformations described in the
[6], the stationary data which are ready to modeling are obtained. Also based some
model well-known selection criteria the best TP–SMN–AR models (the autoregres-
sive models based on the two-piece t distributions) were fitted to the stationary series
of the confirmed and cured cases given by
• The confirmed COVID-19 cases; T P−S M N −A R(7) model:
X t = −0.9399X t−1 − 1.0438X t−2 − 1.1067X t−3 − 0.9825X t−4

− 0.9364X t−5 − 0.8105X t−6 − 0.3623X t−7 + Z t ,
where
Total Cured Cases Total Confirmed Cases
2020
0e+00 2e+05 4e+05 6e+05 8e+05 1e+06 0 500000 1500000 2500000
of 2020
2020-02-02 2020-01-22
2020-02-04 2020-01-24
2020-02-06 2020-01-26
2020-01-28
2020-02-08
2020-01-30
2020-02-10
2020-02-01
2020-02-12
2020-02-03
2020-02-14
2020-02-05
2020-02-16 2020-02-07
2020-02-18 2020-02-09
2020-02-20 2020-02-11
2020-02-13
2020-02-22
2020-02-15
2020-02-24
2020-02-17
2020-02-26
2020-02-19
2020-02-28
2020-02-21
2020-03-01 2020-02-23
2020-03-03 2020-02-25
2020-03-05 2020-02-27
2020-03-07 2020-02-29
2020-03-09 2020-03-02
2020-03-04
2020-03-11
2020-03-06
2020-03-13
2020-03-08
2020-03-15
2020-03-10
2020-03-17
2020-03-12
Time
Time
2020-03-19 2020-03-14
2020-03-21 2020-03-16
2020-03-23 2020-03-18
2020-03-20
2020-03-25
2020-03-22
2020-03-27
Time Series Modelling and Prediction of the Coronavirus …
2020-03-24
2020-03-29
2020-03-26
2020-03-31
2020-03-28
2020-04-02 2020-03-30
2020-04-04 2020-04-01
2020-04-06 2020-04-03
2020-04-08 2020-04-05
2020-04-10 2020-04-07
2020-04-09
2020-04-12
2020-04-11
2020-04-14
2020-04-13
2020-04-16
2020-04-15
2020-04-18
2020-04-17
2020-04-20 2020-04-19
Total cured COVID-19 cases in the world from 02-Feb up to 30-Apr of 2020
2020-04-22 2020-04-21
Total confirmed COVID-19 cases in the world from 22-Jan up to 30-Apr of 2020
2020-04-24 2020-04-23
2020-04-25
2020-04-26
2020-04-27
2020-04-28
2020-04-29
2020-04-30
Fig. 1 Time series plot of the total confirmed COVID-19 cases in the world from 22-Jan to 30-Apr
37
Fig. 2 Time series plot of the total cured COVID-19 cases in the world from 02-Feb to 30-Apr of
38 M. Maleki
Z t ∼ T P−T (μ = −103.3424, σ = 4084.3481, γ = 0.4559, ν = 2.1000).
• The cured COVID-19 cases; T P−S M N −A R(2) model:
X t = −0.5865X t−1 − 0.2020X t−2 + Z t ,
where
Z t ∼ T P−T (μ = −0.0048, σ = 0.0250, γ = 0.4756, ν = 3.1146).
The histograms of the estimated errors (residuals) based on the estimated heavy-
tailed TP–SMN densities are superimposed on them in Fig. 3 shows the suitable
performance of the estimated models to the stationary series of total confirmed and
cured COVID-19 cases datasets. Also the auto–correlation function (ACF) plots of
the residuals presented in Fig. 4 shows the suitability of the fitted models.
To further demonstrate the good fit of the model, we eliminated the last 10 data
of the confirmed and cured cases (2020-Apr-21 to 2020-Apr-30), then fitted the TP–
SMN–AR models on them and forecast these data. Table 2 contains the predictions
and 98% confidence intervals for them. Also Figs. 5, 6 and 7, show the forecasted
values which superimposed the plots of the real values of the confirmed and cured
COVID-19 cases in the world.
To evaluate the accuracy of the suggested data prediction of the datasets, the mean
relative percentage error (MAPE) index is then used to, which for the confirmed
COVID-19 cases is 0.22% and for the cured COVID-19 cases is 1.6% which these
low values show the suitability of the proposed models for predicting.
Fig. 3 Histograms of the residuals of the fitted models on the confirmed COVID-19 cases (a), and
the cured COVID-19 cases (b) datasets in the world, with their superimposed estimated densities
(a) (b)
1.0
1.0
0.8
0.8
0.6
0.6
ACF
ACF
0.4
0.4
0.2
0.2
0.0
0.0
-0.2
-0.2
0 5 10 15 0 5 10 15
Lag Lag
Fig. 4 ACF of the residuals of the fitted models on the confirmed COVID-19 cases (a), and the
cured COVID-19 cases (b)
Table 2 The real values of the total confirmed and cured COVID-19 cases in the world data from
2020-Apr-21 to 2020-Apr-30 with predictions and 98% confidence interval
COVID-19 data Date Real value Prediction Lower C.I Upper
Confirmed cases 2020-Apr-21 2,556,720 2,556,806 2,545,942 2,568,200
2020-Apr-22 2,637,439 2,637,409 2,626,722 2,648,536
2020-Apr-23 2,722,857 2,721,410 2,710,914 2,732,294
2020-Apr-24 2,828,682 2,808,860 2,798,439 2,819,720
2020-Apr-25 2,919,404 2,937,529 2,925,690 2,948,566
2020-Apr-26 2,993,292 3,004,212 2,992,353 3,015,772
2020-Apr-27 3,059,944 3,064,943 3,052,694 3,077,488
2020-Apr-28 3,136,505 3,129,841 3,117,773 3,143,146
2020-Apr-29 3,218,183 3,218,199 3,204,951 3,231,956
2020-Apr-30 3,304,220 3,302,211 3,289,979 3,315,769
Cured cases 2020-Apr-21 691,650 670,555 638,016 707,815
2020-Apr-22 718,761 722,622 689,342 761,654
2020-Apr-23 746,924 753,685 716,873 795,415
2020-Apr-24 815,145 775,550 737,065 858,978
2020-Apr-25 854,466 864,671 818,679 914,842
2020-Apr-26 877,411 904,511 854,466 957,290
2020-Apr-27 921,320 914,058 865,114 968,022
2020-Apr-28 953,309 954,201 903,560 1,010,487
2020-Apr-29 1,000,033 985,264 932,903 1,043,419
2020-Apr-30 1,039,028 1,038,689 984,279 1,099,247
40
Total Cured Cases of COVID-19 in the World Total Cured Cases of COVID-19 in the World
0e+00 2e+05 4e+05 6e+05 8e+05 1e+06 0 500000 1500000 2500000
2020-02-02 2020-01-22
2020-02-04 2020-01-24
2020-02-06 2020-01-26
2020-01-28
2020-02-08
to 30-Apr of 2020
to 30-Apr of 2020
2020-01-30
2020-02-10
2020-02-01
2020-02-12
2020-02-03
2020-02-14 2020-02-05
2020-02-16 2020-02-07
Real Data
Real Data
2020-02-18 2020-02-09
2020-02-20 2020-02-11
2020-02-22 2020-02-13
Predicted Data
Predicted Data
2020-02-15
2020-02-24
2020-02-17
2020-02-26
2020-02-19
2020-02-28
2020-02-21
2020-03-01 2020-02-23
2020-03-03 2020-02-25
2020-03-05 2020-02-27
2020-03-07 2020-02-29
2020-03-09 2020-03-02
2020-03-04
2020-03-11
2020-03-06
2020-03-13
2020-03-08
2020-03-15
2020-03-10
2020-03-17 2020-03-12
Time
Time
2020-03-19 2020-03-14
2020-03-21 2020-03-16
2020-03-23 2020-03-18
2020-03-25 2020-03-20
2020-03-22
2020-03-27
2020-03-24
2020-03-29
2020-03-26
2020-03-31
2020-03-28
2020-04-02 2020-03-30
2020-04-04 2020-04-01
2020-04-06 2020-04-03
2020-04-08 2020-04-05
2020-04-10 2020-04-07
2020-04-09
2020-04-12
2020-04-11
2020-04-14
2020-04-13
2020-04-16
2020-04-15
2020-04-18 2020-04-17
Predicted and real values from from 21-April to 30-April 2020 in the world
Predicted and real values from from 21-April to 30-April 2020 in the world
2020-04-20 2020-04-19
2020-04-22 2020-04-21
2020-04-24 2020-04-23
2020-04-26 2020-04-25
2020-04-27
2020-04-28
2020-04-29
2020-04-30
Fig. 6 Time series plot of the cured COVID-19 cases data and predicted data from 2020-Apr-21
Fig. 5 Time series plot of the confirmed COVID-19 cases data and predicted data from 2020-Apr-21
able than ordinary fitted autoregressive time series models. In fact some statistical
gressive time series models which the proposed fitted models are more reason-
Finally note that the proposed TP–SMN–AR models involves the ordinary autore-
M. Maleki
(a) (b)
1200000
Total Confirmed Cases of COVID-19 in the World
Real Data Real Data
Total Cured Cases of COVID-19 in the World

3200000
Predicted Data Predicted Data

C.I. 98% C.I. 98%
1000000
2800000
800000
600000
2400000
Apr-21
Apr-22
Apr-23
Apr-24
Apr-25
Apr-26
Apr-27
Apr-28
Apr-29
Apr-30
Apr-21
Apr-22
Apr-23
Apr-24
Apr-25
Apr-26
Apr-27
Apr-28
Apr-29
Apr-30
Fig. 7 Time series plots of the real values and predicted confirmed COVID-19 cases (a) and cured
COVID-19 cases (b) datasets from 2020-Apr-21 up to 2020-Apr-30 with 98% confidence intervals
criteria such as Akaike information criteria, Bayesian information criteria, Box–

Pierce and Ljung–Box tests on the residuals, demonstrate us that the proposed fitted
TP–SMN–AR models are more reasonable than other well-known counterparts.
4 The Robust Class of TP–SMN Autoregressive–Moving

Average Model
In this section, the TP–SMN Autoregressive–Moving Average (TP–SMN–ARMA)

model is a generalization of the proposed autoregressive process in the previous part
and introduced by Maleki et al. [24]. The autoregressive moving-average (ARMA)
model is one of the most useful and capable time series models used in the modeling
and prediction of real data. The ARMA model provides a parsimonious descrip-
tion of a (weakly) stationary stochastic process in terms of two polynomials, first
the autoregressive (AR) and second for the moving average (MA) defined as follows.
Definition 1 A stationary time series model {X t } is the ARMA process with p autore-
gressive terms and q moving-average terms denoted by {X t } ∼ A R M A( p, q),
contains the A R( p) and M A(q) models, defines as:
X t − α1 X t−1 − · · · − α p X t− p = Z t + η1 Z t−1 + · · · + ηq Z t−1 ;

t = 0, ±1, ±2, . . . , {Z t } ∼ W N 0, σ 2 (17)

42 M. Maleki
where the error terms {Z t } are generally assumed to be uncorrelated and identically
distributed random variables (WN) sampled from a distribution with zero mean and
variance σ 2 .
4.1 TP–SMN–ARMA(p,q) Model
The TP–SMN–ARMA model with orders p and q, denoted by TP–SMN–ARMA

( p, q) model with intercept is defined as follows.
The A R M A( p, q) model (17) with i.i.d. noise TP–SMN innovations is consid-
ered, for which {Z t } is independent sequence of i.i.d. noises TP–SMN random
variables in the form of
{Z t } ∼ T P−S M N (b, σ, ν, γ ), t = 0, ±1, ±2, . . . , (18)

for which α = α1 , . . . , α p and η = η1 , . . . , ηq are AR and MA coef-
ficients of the TP–SMN–ARMA model, respectively. Hereafter, we will refer to
this model as {X t } ∼ T P−S M N −A R M A( p, q) with the model parameter
= (α, η, μ, σ1 , σ2 , ν) (based on the TP–SMN representation from Lemma 1).
Remark 1 Let {X t } ∼ T P−S M N −A R M A( p, q). The process {X t } has a one-

∞
sided M A(∞) process in the form of X t = ∞ j=0 ψ j Z t− j , which, if j=0 ψ j < ∞,
it converges in the mean, also this process is strictly stationary with the following
mean and covariance functions
1 + η1 + · · · + ηq
μ X (t) = E(X t ) = μz ; γ X (h)
1 − α1 − · · · − α p
= Cov(X t , X t+h ) = σz2 ξ (h), (19)
∞
where μz = E(Z t ), σz2 = Var(Z t ) (given by Lemma 2), ξ (h) = j=0 ψ j+|h| ψ j .
Also γ X (h) tends to zero as h tends to infinity.
4.2 ML Estimates of the TP–SMN–ARMA(p,q) Model

Parameters
Considering sample X = (X 1 , . . . , X n ) and sub-samples in the form Xt−1 =

X t−1 , . . . , X t− p and also z t−1 = Z t−1 , . . . , Z t−q for conditionally on initial

values X 0 = X 0 , . . . , X − p+1 and Z 0 = Z 0 , . . . , Z −q+1 , and using Marko-
vian property of the A R M A( p, q) model, the conditional likelihood function condi-
tionally on initial values is L() = f X (X|X 0 , Z 0 , ) = nt=1 g(Z t |X 0 , Z 0 , ). So
the log–likelihood function is given by

n
n

() = t () = log g X t − α Xt−1 − η z t−1 , (20)

t=1 t=1
where g(·) is the TP–SMN pdf given in (4).

Complexity of the SMN–densities in the pdf (4), leads to tractability of finding
the Maximum–Likelihood (ML) estimates of the model parameters from (20). But,
using the Lemma 1, concludes a suitable hierarchically form of the TP–SMN family
besides the proposed ARMA model, to employ an EM–type algorithm for estimating
the model parameters.
Considering the Lemma 1, and stochastic representation of SMN family, let
D = (X, U, S) be the complete data where X is the observed data and U =
(U1 , . . . , Un ) and S = (St1 , St2 ) ; t = 1, . . . , n are the missing (latent) data. It
is noticed that the TP–SMN–ARMA model via (17) and (18) can be written in the
following hierarchically form
X t |Xt−1 , z t−1 , Ut = u t , Sti

= 1 ∼ N α Xt−1 + η z t−1 + μ, u −1
t σi
2
I At (xt )2−i I Act (xt )i−1 ,
Ut |Sti = 1 ∼ H ( u t |ν),
St ∼ Multinomial(1, σ1 /(σ1 + σ2 ), σ2 /(σ1 + σ2 )), (21)

for t = 1, . . . , n and i = 1, 2, where At = −∞, α Xt−1 + η z t−1 + μ and

N (·)I A (·) denotes the truncated normal distribution on the interval A.
The hierarchical representation of the TP–SMN–ARMA model in (17) will
be used to obtain the ML estimates via ECME algorithm. The ECME algo-
rithm is a generalization of the EM–algorithm. So considering the proposed the
T P−S M N −A R M A( p, q) and (17), ignoring constants, the conditional log–likeli-
hood function is
2
1
n 2
X t − α Xt−1 − η z t−1 − μ
c () = −n log(σ1 + σ2 ) − Sti Ut
2 t=1 i=1 σi

n
2
+ Sti log h(Ut |ν), (22)
t=1 i=1
where = (ϕ, θ , μ, σ1 , σ2 , ν) .

Remark 2 The conditional expectations ŝt1 = E Sti |
O, X =

I−∞,α̂ X +η̂ z +μ̂ (xt ) and ŝt2 = 1 − ŝt1 , ŵti = E Ut Sti | O, X = κ̂ti ŝti

t−1 t−1
for κ̂ti = E Ut |O, X, Sti = 1 , t = 1, . . . , n, i = 1, 2 for the TP–SMN–ARMA

members are as follows:
44 M. Maleki
(i) TP–N–ARMA model: κ̂ti = 1,

ν̂+1
(ii) TP–T –ARMA model: κ̂ti = ν̂+dti
,
2ν̂+1 P1 (ν̂+3/2,dti /2)
(iii) TP–SL–ARMA model: κ̂ti = dti P1 (ν̂+1/2,dti /2)
,
τ̂ 2 ν̂e−τ̂ dti /2 +(1−ν̂ )e−dti /2
(iv) TP–CN–ARMA model: κ̂ti = τ̂ ν̂e−τ̂ dti /2 + 1−ν̂ e−dti /2 .
( )
2

where dti = xt − α̂ Xt−1 − η̂ z t−1 − μ̂ /σ̂i2 , and Px (a, b) denotes the
cumulative distribution function of the Gamma (a, b) distribution evaluated at x.
E–Step:
2

1 (k) X t − α Xt−1 − η z t−1 − μ
n 2
O(k) = −n log(σ1 + σ2 ) −
Q | ŵti
2 t=1 i=1 σi

n
2

+ O(k) , X ,
E Sti log h(Ut |ν)|
i=1 j=1
where ŵti(k) = κ̂ti(k) ŝti(k) has obtained by Remark 2.
CM–steps:
n −1

n
(k+1) (k)
α̂ = ζ̂t(k) Xt−1 X
t−1 ζ̂t(k) X t − η̂ z t−1 − μ̂(k) Xt−1 , (23)
t=1 t=1
2
where ζ̂t(k) = i=1 ŵti(k) σi2(k) .
n −1

n
(k+1) (k+1)
η̂ = ζ̂t(k) z t−1 z
t−1 ζ̂t(k) X t − α̂ Xt−1 − μ̂(k) z t−1 . (24)
t=1 t=1

n
(k) (k+1) (k+1)
t=1 ζ̂t X t − α̂ Xt−1 − η̂ z t−1
μ̂(k+1) = n (k)
. (25)
t=1 ζ̂t

solving the stressed cubic equations σi3 + pσi + q = 0; i =
1, 2, concluding the updates σ̂i(k+1) ; i = 1, 2, where p =
2
(k) (k+1) (k+1)
n
− n1 t=1 ŵti X t − α̂ Xt−1 − η̂ z t−1 − μ̂(k+1) , for which q =
pσ2 I(i=1) + pσ1 I(i=2) . Note that p < 0 and q < 0, so this cubic equation
has unique just root in the (0, +∞) interval.
CML–step of the ECME algorithm is:

(k+1) (k+1)
ν (k+1) = argmaxν α̂ , η̂ , μ̂(k+1) , σ̂1(k+1) , σ̂2(k+1) , ν , (26)
where (·) is the log–likelihood function given in (20).

Finally note, the(k+1)
proposed
algorithm
iterates until a sufficient convergence rule is
(k)
satisfied, i.e., − 1 ≤ ε under the determined tolerance ε.
4.3 Modeling the Confirmed Cases and Death Rate

of Coronavirus
The daily data related the COVID-19 in the world, are reporting by the China National
Health Commission (NHC) and World Health Organization (WHO). In this part we
fit the maintained time series models to the total confirmed cases in the world include
and exclude China from 22-Jan-2020 up to 08-Apr-2020.
Time series plots of the total and daily cases in the world from 22-Jan up to 08-Apr
of 2020 which are confirmed is given in Fig. 8. Stationary differenced time series
data with order 3 (i.e. ∇ 3 X t = X t − 3X t−1 + 3X t−2 + X t−3 ) is considered. Using the
Dickey–Fuller test leads to p–value = 0.01 with alternative hypothesis: stationary.
Total confirmed COVID-19 cases in the world

1500000
Total Coronavirus Cases
1000000
500000
0
Feb-19
Feb-23
Jan-22
Jan-24
Jan-28
Jan-30
Feb-01
Jan-26
Feb-03
Feb-05
Feb-07
Feb-09
Feb-11
Feb-13
Feb-15
Feb-17
Feb-21
Feb-25
Feb-27
Feb-29
Mar-02
Mar-04
Mar-06
Mar-08
Mar-10
Mar-12
Mar-14
Mar-16
Mar-18
Mar-20
Mar-22
Mar-24
Mar-26
Mar-28
Mar-30
Apr-01
Apr-03
Apr-05
Apr-07
Time
Fig. 8 Time series plot of the total confirmed cases of COVID-19 in the world from 22-Jan up to
08-Apr of 2020
46 M. Maleki
Partial Auto Correlation Function (PACF) of differenced data

0.2
0.1
0.0
Partial ACF
-0.1
-0.2
-0.3
-0.4
-0.5
5 10 15
Lag
Fig. 9 PACF of the stationary transformed total COVID-19 data in the world
Obviously number of cases (total and daily) in any days depend the number on
them in the previous day(s), so the ARMA model can be suitable model for the
COVID-19 cases data.
Some model selection criteria are Akaike information criteria AIC = 2k−2 ;

and Bayesian information criteria BIC = k log n − 2 , where is the

maximized log-likelihood function (7) and k is the number of estimated parameters.
The proposed criteria have used to choose the best TP–SMN–ARMA model with
the best fitted orders. These criteria and partial auto-covariance function (PACF) in
Fig. 9, demonstrate the following TP−T−ARMA (7, 0) is the best model
X t + 0.8994X t−1 + 0.9817X t−2 + 0.9336X t−3 + 0.7858X t−4

+ 0.6506X t−5 + 0.4597X t−6 + 0.2662X t−7 = Z t ,
where
{Z t } ∼ T P − T (μ = 8.847374, σ = 2766.178, γ = 0.5362869, ν = 2.100046).
The histogram of the estimated errors (residuals) based on the estimated TP–T
density (near symmetry but heavy-tailed) is superimposed on it shows the suitable
performance of the estimated model to COVID-19 data (Fig. 10). To further demon-
strate the good fit of the model, we eliminated the last 10 data (2020-Mar-30 up
to 2020-Apr-08), then fitted the TP–SMN–ARMA model and forecast these data.
Figures 11, 12 and Table 3, show the forecasted real values of the COVID-19 in the
world data are close. Table 3 contains the predictions and 98% confidence intervals
for them.
Fig. 10 Histogram of the residuals of the fitted time series model on COVID-19 data in the world
with superimposed estimated TP–T density
Predicted and real values from 30-March up to 08-April 2020
Real Data
1400000
Predicted Data
Total Coronavirus Cases in the World
C.I. 98%
1200000
1000000
800000
Apr-01
Apr-02
Apr-03
Apr-04
Apr-05
Apr-06
Apr-07
Apr-08
Mar-30
Mar-31
Fig. 11 Time series plot of real values and predicted COVID-19 data from 2020-Mar-30 up to
2020-Apr-08 with 98% confidence interval bounds
48 M. Maleki
1500000 Predicted and real values from from 30-March up to 08-April 2020 in the world
Predicted Data
Total Coronavirus Cases in the World
Real Data
1000000
500000
0
Apr-01
Apr-03
Apr-05
Apr-07
Jan-22
Jan-24
Jan-26
Jan-28
Jan-30
Feb-01
Feb-03
Feb-05
Feb-07
Feb-09
Feb-11
Feb-13
Feb-15
Feb-17
Feb-19
Feb-21
Mar-02
Mar-04
Mar-06
Mar-24
Mar-26
Mar-28
Feb-23
Feb-25
Feb-27
Feb-29
Mar-08
Mar-10
Mar-12
Mar-14
Mar-16
Mar-18
Mar-20
Mar-22
Mar-30
Time
Fig. 12 Time series plot of COVID-19 data and predicted data from 2020-Mar-30 up to 08-Apr of
2020
Table 3 The real values of the COVID-19 in the world data from 2020-Mar-30 up to 2020-Apr-08
with predictions and 98% confidence interval
Date Real value Prediction Lower Upper
2020-Mar-30 785,828 783,114 776,624 789,937
2020-Mar-31 859,620 852,651 845,272 859,197
2020-Apr-01 936,637 937,797 930,885 944,428
2020-Apr-02 1,016,734 1,016,045 1,008,173 1,022,633
2020-Apr-03 1,118,414 1,101,645 1,093,850 1,108,143
2020-Apr-04 1,203,235 1,223,923 1,215,528 1,230,375
2020-Apr-05 1,274,653 1,286,735 1,277,745 1,295,487
2020-Apr-06 1,348,564 1,348,163 1,338,874 1,357,682
2020-Apr-07 1,430,981 1,426,889 1,417,614 1,435,226
2020-Apr-08 1,518,023 1,520,874 1,511,512 1,529,308
The mean relative percentage error (MAPE) index given by

1 X i − X i

n
M AP E = ,
n i=1 X i

where X n+1 = E(X n+1 |X n , . . . , X 1 ), is then used to evaluate the accuracy of

the suggested data prediction, which for the proposed predictions is 0.60% which
ACF of residulas
1.0
0.8
0.6
ACF
0.4
0.2
0.0
-0.2
0 5 10 15
Lag
Fig. 13 ACF of the residuals of fitted time series model to total COVID-19 in the world data
shows the suitability of the proposed model for predicting. Note that, this criterion
for the modeling via the ordinary Gaussian–ARMA model (also, the simplest TP–
SMN–ARMA member) is 0.89%. Also the AIC and BIC criteria for the best fitted
TP–SMN–ARMA are 1290.49 and 1298.02, and for the best fitted Gaussian–ARMA
model are 1524.14 and 1544.12, respectively.
Finally the p-value = 0.972 from the Box–Pierce and p-value = 0.931 from the
Ljung–Box tests indicate the independency of residuals. Also the auto–correlation
function (ACF) plot of the residuals presented in Fig. 13 shows the suitability of the
TP–T–ARMA(7,0) model to the total confirmed cased of the COVID-19 dataset.
Now, we consider and model the death rate of COVID-19 in the world from 02-
Feb-2020 up to 08-Apr-2020, which this daily data also has reported by the China
National Health Commission (NHC) and World Health Organization (WHO).
Time series plots of the death rate of coronavirus in the world from 02-Feb-2020
up to 08-Apr-2020, is given in Fig. 14. Stationary differenced with order 3 (i.e.
∇ 3 X t = X t − 3X t−1 + 3X t−2 + X t−3 ) is considered. Using the Dickey–Fuller test
leads to p–value = 0.01 which demonstrate the stationarity of differenced data.
Using the model selection criteria and methodology in the previous data,
demonstrate that best TP–SMN–ARMA model with the best fitted orders isTP–
T–ARMA(7,1), the PACF in Fig. 15 also approximately satisfy it. Therefore the
following TP–SMN–ARMA is the best model
X t + 1.3760X t−1 + 1.4183X t−2 + 1.1401X t−3 + 0.9269X t−4

+ 0.6482X t−5 + 0.3181X t−6 + 0.1752X t−7 = Z t − .0628Z t−1 ,
where
50 M. Maleki
40 Death rate of COVID-19 in the world

Death Rate of Coronavirus
30
20
10
0
Feb-02
Feb-04
Feb-06
Feb-08
Feb-10
Feb-12
Feb-14
Feb-16
Feb-18
Feb-20
Feb-22
Feb-24
Feb-26
Feb-28
Mar-01
Mar-03
Mar-05
Mar-07
Mar-09
Mar-11
Mar-13
Mar-15
Mar-17
Mar-19
Mar-21
Mar-23
Mar-25
Mar-27
Mar-29
Mar-31
Apr-02
Apr-04
Apr-06
Apr-08
Time
Fig. 14 Time series plot of the death rate of COVID-19 in the world from 2020-Mar-30 up to
08-Apr of 2020
Partial Auto Correlation Function (PACF) of differenced data

0.2
0.0
Partial ACF
-0.2
-0.4
5 10 15
Lag
Fig. 15 PACF of the stationary transformed death rate of COVID-19 data in the world
{Z t } ∼ T P − T (μ = 0.056836, σ = 0.2664454, γ = 0.297544, ν = 2.826561).
The histogram of the estimated errors (residuals) based on the estimated TP–
T density (heavy-tailed and asymmetry) is superimposed on it shows the suitable
RESIDUAL OF TP-T-ARMA MODEL

3.0
2.5
2.0
Density
1.5
1.0
0.5
0.0
-0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4
residual
Fig. 16 Histogram of the residuals of the fitted time series model on the death rate of COVID-19
in the world data with superimposed estimated TP–T density
performance of the estimated model to death rate of COVID-19 in the world (Fig. 16).
Same as previous data, we eliminated the last 10 data (2020-Mar-30 up to 2020-Apr-
08, then fitted the TP–SMN–ARMA model and forecast these data.
Figures 17, 18 and Table 4, show the forecasted real values of the death rate of
COVID-19 in the world data are close. Table 4 contains the predictions and also 98%
confidence intervals for them.
The MAPE for the second proposed predictions is 1.30% demonstrating the
suitability of the proposed model for prediction. Note that, this criterion for the
modeling via the ordinary Gaussian–ARMA model (also, the simplest TP–SMN–
ARMA member) is 1.70%. Also the AIC and BIC criteria for the best fitted TP–
SMN–ARMA are −4.42 and 18.05, and for the best fitted Gaussian–ARMA model are
76.68 and 95.07, respectively.
Finally, the p-value = 0.974 from the Box–Pierce and p-value = 0.873 from the
Ljung–Box tests indicate the independence of residuals. Also, the ACF plot of the
residuals presented in Fig. 19 demonstrates the suitability of the TP–T–ARMA(7,1)
model to the death rate of COVID-19 in the world dataset.
52 M. Maleki
Predicted and real values from 30-March up to 08-April 2020
Real Data
24
Predicted Data
C.I. 98%
Death rate of COVID-19 in the world
22
20
18
16
Mar-30
Mar-31
Apr-01
Apr-02
Apr-03
Apr-04
Apr-05
Apr-06
Apr-07
Apr-08
Fig. 17 Time series plot of real values and predicted death rate of COVID-19 in the world data
from 2020-Mar-30 up to 2020-Apr-28 with 98% confidence interval
Predicted and real values from from 30-March up to 08-April 2020 in the world
Predicted Data
Death rate of COVID-19 in the world
Real Data
Time
Fig. 18 Time series plot of death rate of COVID-19 in the world data and predicted data from
2020-Mar-30 up to 2020-Mar-08
Table 4 The real values of the death rate of COVID-19 in the world data from 2020-Mar-30 up to
2020-Apr-08 with predictions and 98% confidence interval
Date Real value Prediction Lower Upper
2020-Mar-30 18.59 19.00 18.55 19.39
2020-Mar-31 19.19 18.75 18.29 19.17
2020-Apr-01 19.55 19.45 18.98 19.89
2020-Apr-02 20.03 19.87 19.41 20.31
2020-Apr-03 20.48 20.32 19.86 20.76
2020-Apr-04 20.79 20.97 20.51 21.41
2020-Apr-05 20.86 21.16 20.70 21.60
2020-Apr-06 21.13 20.86 20.41 21.31
2020-Apr-07 21.35 21.12 20.68 21.59
2020-Apr-08 21.12 21.51 21.09 22.00
ACF of residulas
1.0
0.8
0.6
ACF
0.4
0.2
0.0
-0.2
0 5 10 15
Lag
Fig. 19 ACF of the residuals of the fitted time series model to the death rate of COVID-19 in the
world data
5 Conclusion
Coronaviruses are a huge family of viruses that affect neurological, gastrointestinal,

hepatic, and respiratory systems. The numbers of confirmed cases are increased daily
in different countries, especially in China, Iran, South Korea, Italy and others. The
spread of the COVID-19 has many dangers and needs strict special plans and policies.
Therefore, to consider the plans and policies, the predicting and forecasting the future
confirmed cases are critical. The time series models are useful to model data that
54 M. Maleki
gathered and indexed by time. Classical time series is based on the assumption that
the error terms are symmetric. But there exist many situations in the real world that
the assumption of symmetric distribution of the error terms is not satisfactory. In our
methodology, we considered the time series models based on the two-piece scale
mixture normal (TP–SMN) distributions. The proposed time series models were
fitted initially to the historical COVID-19 datasets. Then, the time series that had the
best fit to a dataset was selected. Finally, the selected models were used to predict
the number of confirmed COVID-19 cases. The results indicate that the proposed
method performs well in forecasting the future confirmed COVID-19 cases. Also
all of criteria demonstrate that the proposed models are more reasonable that the
ordinary Gaussian time series model (, which also is the simplest members of our
proposed model).
References
1. Al-qaness, M.A.A., Ewees, A.A., Fan, H., Abd El Aziz, M.: Optimization method for
forecasting confirmed cases of COVID-19 in China. J. Clin. Med. 9, 674 (2020)
2. Andrews, D.R., Mallows, C.L.: Scale mixture of normal distribution. J. Roy. Stat. Soc. B 36,
99–102 (1974)
3. Arellano-Valle, R.B., Gómez, H., Quintana, F.A.: Statistical inference for a general class of
asymmetric distributions. J. Stat. Plann. Infer. 128, 427–443 (2005)
4. Barkhordar, Z., Maleki, M., Khodadadi, Z., Wraith, D., Negahdari, F.: A Bayesian approach on
the two-piece scale mixtures of normal homoscedastic nonlinear regression models. J. Appl.
Stat. (2020). https://doi.org/10.1080/02664763.2020.1854203
5. Branco, M.D., Dey, D.K.: A general class of multivariate skew-elliptical distributions. J.
Multivar. Anal. 79, 99–113 (2001)
6. Brockwell, P.J., Davis, R.A.: Time Series and Forecasting. Springer, New York (1996)
7. Cauchemez, S., Van Kerkhove, M., Riley, S., Donnelly, C., Fraser, C., Ferguson, N.: Transmis-
sion scenarios for Middle East respiratory syndrome coronavirus (MERS-CoV) and how to tell
them apart. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull 18, 20503 (2013)
8. Chen, Y., Liu, Q., Guo, D.: Emerging coronaviruses: genome structure, replication, and
pathogenesis. J. Med. Virol. (2020). https://doi.org/10.1002/jmv.25681
9. Cheng, Z.J., Shan, J.: 2019 Novel coronavirus: where we are and what we know. Infection
(2020). https://doi.org/10.1007/s15010-020-01401-y
10. Contreras-Reyes, J.E., Maleki, M., Cortés, D.D.: Skew-reflected-Gompertz information quanti-
fiers with application to sea surface temperature records. Mathematics 7(5), 403 (2019). https://
doi.org/10.3390/math7050403
11. DeFelice, N.B., Little, E., Campbell, S.R., Shaman, J.: Ensemble forecast of human West Nile
virus cases and mosquito infection rates. Nat. Commun. 8, 1–6 (2017)
12. Ghasami, S., Khodadadi, Z., Maleki, M.: Autoregressive processes with generalized hyperbolic
innovations. Commun. Stat. Comput. Simul. 49(12), 3080–3092 (2019). https://doi.org/10.
1080/03610918.2018.1535066
13. Ghasami, S., Maleki, M., Khodadadi, Z.: Leptokurtic and platykurtic class of robust symmet-
rical and asymmetrical time series models. J. Comput. Appl. Math. 112806 (2020). https://doi.
org/10.1016/j.cam.2020.112806
14. Hajrajabi, A., Maleki, M.: Nonlinear semiparametric autoregressive model with finite mixtures
of scale mixtures of skew normal innovations. J. Appl. Stat. 46(11), 2010–2029 (2019)
15. Hoseinzadeh, A., Maleki, M., Khodadadi, Z.: Heteroscedastic nonlinear regression models
using asymmetric and heavy tailed two-piece distributions. AStA Adv. Stat. Anal. (2020).
https://doi.org/10.1007/s10182-020-00384-3
16. Hoseinzadeh, A., Maleki, M., Khodadadi, Z., Contreras-Reyes, J.E.: The skew-reflected-
Gompertz distribution for analyzing symmetric and asymmetric data. J. Comput. Appl. Math.
349, 132–141 (2019)
17. Maleki, M., Arellano-Valle, R.B.: Maximum a-posteriori estimation of autoregressive processes
based on finite mixtures of scale-mixtures of skew-normal distributions. J. Stat. Comput. Simul.
87, 1061–1083 (2017)
18. Maleki, M., Barkhordar, Z., Khodadadi, Z., Wraith, D.: A robust class of homoscedastic
nonlinear regression models. J. Stat. Comput. Simul. 89(14), 2765–2781 (2019a)
19. Maleki, M. Contreras-Reyes, J.E., Mahmoudi, M.R.: Robust mixture modeling based on two-
piece scale mixtures of normal family. Axioms 8(2), 38 (2019b)
20. Maleki, M., Mahmoudi, M.R.: Two-piece location-scale distributions based on scale mixtures
of normal family. Commun. Stat. Theory Methods 46(24), 12356–12369 (2017)
21. Maleki, M., Nematollahi, A.R.: Autoregressive models with mixture of scale mixtures of
Gaussian innovations. Iran. J. Sci. Technol., Trans. A: Sci. 41, 1099–1107 (2017a)
22. Maleki, M., Nematollahi, A.R.: Bayesian approach to epsilon-skew-normal family. Commun.
Stat. Theory Methods 46(15), 7546–7561 (2017b)
23. Maleki, M., Mahmoudi, M.R., Heydari, M.H., Pho, K.H.: Modeling and forecasting the spread
and death rate of coronavirus (COVID-19) in the world using time series models. Chaos,
Solitons & Fractals, 110151 (2020a). https://doi.org/10.1016/j.chaos.2020.110151
24. Maleki, M., Mahmoudi, M.R., Wraith, D., Pho, K.H.: Time series modelling to forecast the
confirmed and recovered cases of COVID-19. Travel Med. Infect. Dis. 101742 (2020b). https://
doi.org/10.1016/j.tmaid.2020.101742
25. Maleki, M., Hajrajabi, A., Arellano-Valle, R.B.: Symmetrical and asymmetrical mixture
autoregressive processes. Bra. J. Probab. Stat. 34(2), 273–290 (2020c)
26. Maleki, M., Wraith, D., Mahmoudi, M.R., Contreras-Reyes, J.E.: Asymmetric heavy-tailed
vector auto-regressive processes with application to financial data. J. Stat. Comput. Simul.
90(2), 324–340 (2020d)
27. Meng, X., Rubin, D.B.: Maximum likelihood estimation via the ECM algorithm: a general
framework. Biometrika 80, 267–278 (1993)
28. Moravveji, M., Khodadadi, Z., Maleki, M.: A Bayesian Analysis of two-piece distributions
based on the scale mixtures of normal family. Iran. J. Sci. Technol., Trans. A: Sci. 43(3),
991–1001 (2019)
29. Nah, K., Otsuki, S., Chowell, G., Nishiura, H.: Predicting the international spread of Middle
East respiratory syndrome (MERS). BMC Infect. Dis. 16, 356 (2016)
30. Nishiura, H., Kobayashi, T., Yang, Y., Hayashi, K., Miyama, T., Kinoshita, R., Linton, N.M.,
Jung, S.m., Yuan, B., Suzuki, A., et al.: The rate of underascertainment of novel coronavirus
(2019-nCoV) infection: estimation using Japanese passengers data on evacuation flights. J.
Clin. Med. 9, 419 (2020)
31. Shaman, J., Yang, W., Kandula, S.: Inference and forecast of the current West African Ebola
outbreak in Guinea, Sierra Leone and Liberia. PLoS Curr. (2014). https://doi.org/10.1371/cur
rents.outbreaks.3408774290b1a0f2dd7cae877c8b8ff6
32. Shaman, J., Karspeck, A.: Forecasting seasonal outbreaks of influenza. Proc. Natl. Acad. Sci.
USA 2012, 109, 20425–20430. J. Clin. Med. 9, 674 (2020)
33. Tang, B., Wang, X., Li, Q., Bragazzi, N.L., Tang, S., Xiao, Y., Wu, J.: Estimation of the
transmission risk of the 2019-nCoV and its implication for public health interventions. J. Clin.
Med. 9, 462 (2020)
34. Ture, M., Kurt, I.: Comparison of four different time series methods to forecast hepatitis a virus
infection. Expert Syst. Appl. 31, 41–46 (2006)
35. Zarrin, P., Maleki, M., Khodadadi, Z., Arellano-Valle, R.B.: Time series process based on the
unrestricted skew normal process. J. Stat. Comput. Simul. 89(1), 38–51 (2018)
36. Zhao, S., Musa, S.S., Lin, Q., Ran, J., Yang, G., Wang, W., Lou, Y., Yang, L., Gao, D., He, D.,
et al.: Estimating the unreported number of novel coronavirus (2019-nCoV) cases in China in
the first half of January 2020: A Data-driven modelling analysis of the early outbreak. J. Clin.
Med. 9, 388 (2020)
AI and Robotics in the Fight Against
COVID-19 Pandemic
Alaa Khamis, Jun Meng, Jin Wang, Ahmad Taher Azar, Edson Prestes,
Howard Li, Ibrahim A. Hameed, and Tamas Haidegger
A. Khamis (B)
General Motors Canada, 500 Wentworth St W, Oshawa, ON L1J 6J2, Canada
e-mail: alaa.khamis@gm.com
J. Meng
College of Electrical Engineering, Zhejiang University, YuQuan Campus, No.38 ZheDa Road,
Hangzhou 310027, Zhejiang, China
e-mail: junmeng@zju.edu.cn
J. Wang
Robotics Institute, Zhejiang University, YuQuan Campus, No.38 ZheDa Road, Hangzhou 310027,
China
e-mail: dwjcom@zju.edu.cn
A. T. Azar
Faculty of Computers and Artificial Intelligence, Benha University, Benha 13518, Egypt
e-mails: ahmad.azar@fci.bu.edu.eg; ahmad_t_azar@ieee.org
College of Computer and Information Sciences, Prince Sultan University, Riyadh 11586, Saudi
Arabia
e-mails: aazar@psu.edu.sa
E. Prestes
Informatics Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
e-mail: edson.prestes@ieee.org
H. Li
Department of Electrical and Computer Engineering, University of New Brunswick, Saint John,
Canada
e-mail: howard@unb.ca
I. A. Hameed
Department of ICT and Natural Sciences, Norwegian University of Science and Technology
(NTNU), Larsgårdsvegen 2, 6009 Ålesund, Norway
e-mail: ibib@ntnu.no
T. Haidegger
EKIK, Obuda Univeristy, Becsi ut 96b, 1034 Budapest, Hungary
e-mail: haidegger@irob.uni-obuda.hu
Austrian Center for Medical Innovation and Technology (ACMIT), Viktor-Kalpan-str.2, 2700
Wiener Neustadt, Austria

58 A. Khamis et al.
Abstract The outbreak of the novel coronavirus and its disease COVID-19 present
an unprecedented challenge for humanity. Artificial Intelligence (AI) and robotics
may help fighting COVID-19. Potential applications of AI in this accelerating
pandemic include, but are not limited to, early detection and diagnosis, massive agent
modeling and simulation, data analytics, assistive robots, disinfection robots, public
awareness and patrolling, contactless delivery services, virtual healthcare assistants,
drug repurposing and vaccination discovery. This chapter sheds light on the roles
AI and robotics can play in fighting this disastrous pandemic, and possible future
ones, and highlights several potential applications to transform this challenge into
opportunities. This chapter also discusses the ethical implications of AI and robotics
during the pandemic and in the post-pandemic world.
Keywords COVID-19 pandemic · AI · Robotics · Data analytics · Contactless

delivery · Vaccination discovery
1 Introduction
Since the outbreak of the novel coronavirus, the AI and robotics community quickly
mobilized and gathered to offer solutions ranging from 3D printed masks1 to mass
ventilator systems2 and to contact tracing and AI driven social distancing apps.3
Figure 1 shows a non-exhaustive list of reported use of robots worldwide for COVID-
19 [1].
The WHO-China Joint Mission COVID-19 report also cited AI as a key element of
the efficient response.4 The European Commission launched an initiative (managed
by the European AI Alliance) to collect ideas about deployable AI and robotics
solutions, as well as information on other initiatives that could help solve the ongoing
coronavirus crisis: AI-Robotics vs COVID-19.5 The IEEE is also taking part in
the global response; a volunteer steering committee is working on applying the
lessons learned to COVID-19 in conjunction with the IEEE Robotics and Automation
Society Special Interest Group on Humanitarian Technology.6 The IEEE Robotics
and Automation Society (RAS) is providing a continuous coverage on emerging
COVID-19 related technologies via its online platforms.7
1 https://3dprintingindustry.com/news/3d-printing-community-responds-to-covid-19-and-corona
virus-resources-169143/.
2 http://massventil.org/.
3 https://www.iit.it/iit-vs-covid-19.
4 https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-
final-report.pdf.
5 https://ec.europa.eu/digital-single-market/en/news/join-ai-robotics-vs-covid-19-initiative-eur
opean-ai-alliance.
6 http://roboticsforinfectiousdiseases.org/index.html.
7 https://robohub.org/covid-19-robotics-resources-ideas-for-roboticists-users-and-educators/.
AI and Robotics in the Fight Against COVID-19 Pandemic 59
Fig. 1 Reported use of robots (ground, aerial) worldwide for COVID-19 as of April 12, 2020 [1]
AI is defined here as an evolving technology that aims at mimicking/reverse-

engineering and augmenting biological intelligence to build intelligent
systems/processes able to function and interact autonomously within struc-
tured/unstructured, static/dynamic and fully/partially observable environments [2].
It encompasses many sub-fields such as perception, knowledge representation,
cognitive reasoning, machine learning, data analytics, problem solving, distributed
AI and its embodiment, robotics [3]. This chapter describes a number of current and
potential future applications of AI and robotics in the battle against the novel coro-
navirus and its disease COVID-19. This chapter is organized as follows. Sections 2,
3, 4, 5, 6, 7, 8, 9 and 10 describe different applications of AI and robotics that a
number of countries used during the pandemic such as early detection and diagnosis,
massive agent modeling and simulation, data analytics, assistive robots, disinfection
robots, public awareness and patrolling, contactless delivery services, virtual
healthcare assistants and drug repurposing and vaccination discovery. Section 11
highlights the ethical implications of AI and robotics during the pandemic and in
the post-pandemic world. Finally, conclusions are drawn in Sect. 12.
2 Early Detection and Diagnosis
Early detection and early isolation are essential. Detecting and tracking transmission
on a large scale in a timely manner, and publishing the data of infected and suspected
infections are crucial in prevention and control measures, to minimize further trans-
mission. AI-driven smart wearable medical devices are used in personnel positioning,
contact tracing and alarms, and in early warning of areas with potential risks. In China,
some anti-epidemic methods focus on early detection and isolation. For example,
pandemic drones equipped with temperature and computer vision sensors are used
60 A. Khamis et al.
to detect symptoms of infective respiratory disease. Recently, drones are used to

monitor temperatures, heart and respiratory levels from a distance up to 10 m and
can detect coughing and sneezing. This can provide researchers with a clear view
of infections in public areas and other crowded places such as airports and health
care facilities. Detection of body temperature using drones is an effective method for
the non-contact detection of body temperature in China. A drone with an infrared
thermal imaging lens can take the temperature measurement of each resident in a
building without contact and send the data back to the disease control center. Once
an abnormal body temperature is detected, medical staff will pinpoint the location of
the suspected patient [4]. In addition to human body temperature monitoring, health
codes have been widely used since late February in China. Each citizen receives a
unique online electronic QR code (see Fig. 2) [5].
AI helmets and AI-powered glasses are used by the Chinese police to identify
faces of vehicle occupants and license plates. Alerts are triggered if the vehicle
occupant’s information can be found in the database of confirmed cases [6]. A smart
wearable medical device can be used in an early detection system. This device is
used to obtain a person’s body temperature, breathing and heartbeat status, whether
or not wearing a mask, and update the position information and infection/suspected
infection information in real time. At the same time, the precise position of the device
and the path of the terminal can be used to calculate a safe and low-risk travel path
for people traveling in real time.
Smart wearable medical devices can be useful in the early stage of major infectious
disease outbreaks, such as screening population with suspicious physical conditions,
quickly performing nucleic acid detection, leading to early detection and isolation.
The composition of such a wearable medical device is shown in Fig. 3, which is an
early concept and prototype developed under the National Nature Science Foundation
of China (NSFC) program No. 7204102194.
The three major functions of this wearable devices-based system are:
Fig. 2 Personal health QR-based system. The “health code” management information system is
based on real data, and connects to relevant databases such as key personnel’s dynamic control lists,
and issues “health codes” based on the verification and comparison results of the mass declaration
information and background data
Fig. 3 The composition of smart medical wearable devices, which can real-time grasp each person’s
current body temperature, heartbeat, breathing, confirmed infectious disease status, whether they are
in contact with a confirmed/suspected infectious case, whether a mask is worn during going out, the
epidemic situation during the period and so on. This information is uploaded to the terminal in real
time to generate a spatiotemporal map of the epidemic situation, which quickly, multi-dimensionally
and comprehensively displays the current body temperature, breathing, and heartbeat information
of the personnel
1. Outbreak Visualization: based on individual body temperature charts,

spatiotemporal dynamics of personnel mobility, people gathering heatmap,
spatiotemporal map of confirmed cases.
2. Early Detection and Early Warning: screen out suspicious cases in due time.
3. Pinpoint and Route Planning: propose safe travel paths for travelers.
In the early stage of major infectious diseases, people with suspicious physical
conditions detected by the smart wearable medical devices will be screened timely for
further CT examinations or nucleic acid tests. There are some data-driven approaches
using artificial intelligence to diagnose patients through chest scans. Li and Qin, et al.
[7] proposed a three-dimensional deep learning framework to detect COVID-19
using chest CT, named COVID-19 detection neutral network (COVNet). University
of Waterloo’s VIP Lab develops a COVID-Net: a convolutional neural network for
COVID-19 detection via chest radiography (13,800 chest X-Ray of 13,725 cases from
around the world.8 In China, there is a supercomputer that provides doctors around
the world with free access to an artificial intelligence diagnostic tool for early iden-
tification of Covid-19 patients based on a chest scan. The AI system on the Tianhe-1
computer can go through hundreds of images generated by computed tomography
8https://medium.com/@sheldon.fernandez/covid-net-an-open-source-neural-network-for-covid-
19-detection-48b8a55e6d44.
62 A. Khamis et al.
(CT) and give the diagnosis in about 10 s.9 What more, Wang et al. [8] propose an
innovative method that does not require specialized medical imaging equipment and
uses footage from Kinect depth cameras to identify respiratory patterns of patients.
They first apply a GRU neural network with bidirectional and attentional mechanisms
(BI-AT-GRU) to classify six clinically significant respiratory patterns.
3 Massive Agent Modeling and Simulation
Model prediction is to better understand the spatiotemporal transmission path of

major infectious diseases, to analyze the spatiotemporal transmission data of infec-
tious diseases, to timely prevent and control infectious diseases, and to analyze the
risks of various policies and measures during the epidemic. The system described in
the previous section combines smart wearable medical devices with infectious disease
prevention and control. It also combines data in geographic information systems to
construct a multi-dimensional, multi-scale infectious disease spatiotemporal frame-
work, and establish a model for the spatiotemporal spread of infectious diseases. The
system can be used to analyze the spatiotemporal spread of infectious diseases from
various perspectives, such as the natural meteorological environment, land use, and
population density, etc. The cellular automata models are used to simulate various
countries and regions. Various epidemic prevention policies and measures are used
to control the spread of infectious diseases and predict major infectious diseases.
The risks of various prevention and control policies and measures during the current
period provide theoretical basis for the prevention and monitoring of future infectious
diseases.
Using the data collected by wearable devices and the GIS technology, the temporal
and spatial transmission characteristics of infectious diseases are correctly described.
First, data mining is used to analyze the external environment that affects the occur-
rence and spread of infectious diseases, including regional economic conditions,
regional population density, regional ecological environment and other external
factors. Through geographic information and spatial analysis, spatial trends are
further analyzed, and statistical methods are used to determine the factors and their
effects. Combined with the data obtained from smart wearable medical devices, a
spatiotemporal spread model of infectious diseases is constructed, and the infectious
disease prediction model is obtained. Figure 4 is a spatiotemporal modeling flowchart
of infectious disease transmission based on the GIS technology and wearable device
data.
With the spatiotemporal spread model of infectious diseases, the GIS tech-
nology and wearable device data, external factors related to the spread of infec-
tious diseases are determined. The cellular automaton is used to model and simu-
late the spatiotemporal spread of infectious diseases. By choosing various external
factors, the spatiotemporal spread of infectious diseases is simulated, and the risks
9 https://www.thestar.com.my/tech/tech-news/2020/03/16/covid-19-chinese-supercomputer-uses-
artificial-intelligence-to-diagnose-patients-from-chest-scans.
Fig. 4 Spatiotemporal modeling flowchart of infectious disease transmission based on GIS

technology and wearable device data
under certain measures and policies are calculated and predicted. The simulation
results of the spread of infectious diseases in different countries and regions are
simulated. For example, after setting the population and geographical conditions
of different countries/regions and simulating the evolution of different epidemic
prevention measures, the spread of infectious diseases in different countries/regions
can be predicted. Suggestions can be made for different countries/regions to adopt
appropriate epidemic prevention measures. Figure 5 is a flowchart of the spread of
infectious diseases based on cellular automata.
Fig. 5 Modeling and simulation flowchart of spatiotemporal transmission of infectious diseases

based on cellular automaton
64 A. Khamis et al.
This system implements real-time early warning based on the following decision
rules.
1. Using wearable devices, when two people visit the same place at the same time,
if one of them becomes a confirmed case, the other person will be marked as a
suspected case.
2. If a person has never cross path with a confirmed infected person or suspected
case, this person is considered not infected.
3. If a person may encounter a confirmed or suspected case when if he travels, the
wearable device will advise him and prevent him from coming into contact with
the confirmed case or suspected case.
4. Wearable devices can accurately locate the infected person. Once the infected
person leaves, disinfection can be conducted immediately.
4 Data Analytics
AI-powered data analytics provides the ability to discover, recognize and predict
complex patterns and trends in different types of data at different levels of abstrac-
tions. During the pandemic of SARS-CoV-2, multimodal data is collected by robots,
cell phones and wearable devices. This data can be archived/steaming/live data, struc-
tured/unstructured data, numerical/non-numerical (text, image, audio, and video) and
multimodal data. Examples of the data include, but are not limited to, body temper-
ature, heart rate, breathing rate, SpO2, blood pressure, acoustic data, accelerom-
eter data, ultrasound, computerized tomography (CT) scans/chest radiography, depth
camera data and mobility data, to name just a few.
Insights are the new gold not the data, since data is worth very little unless the
insights are understood. In the context of coronavirus and COVID-19 pandemic, the
insights play a crucial role in the understanding, predicting, and decision-making
processes. Researchers use four main types of data analytics, namely, descriptive
analytics, predictive analytics, diagnostic analytics, and prescriptive analytics as
illustrated in Fig. 6 [9]. Descriptive data analytics provides insight into the past
and the present while predictive analytics forecasts the future. Diagnostic analytics
provides root-cause analysis and perspective analytics advises on possible outcomes
and their anticipated impacts.
Descriptive data analytics provides a better understanding of the data and its nature
and identifies patterns or relationships in the data. It provides insight into the past
and the present by answering questions like what has happened? what happens now?
what is the trend of a certain variable? what is the relationship between variables?
and how an item is performing with respect to other items or the benchmark? Various
web-based tools and mobile apps provide different forms of descriptive analytics for
COVID-19 such as the Johns Hopkins coronavirus resource center,10 worldometer,11
10 https://coronavirus.jhu.edu/map.html.
11 https://www.worldometers.info/coronavirus/.
Fig. 6 Data analytics [9]
covidvisualizer12 and DOMO coronavirus tracker.13 These tools summarize and

visualize descriptive statistics related to the number of confirmed COVID-19 cases
in every country, total number of deaths, number of recovered patients, number
of active causes, number of recovered cases, etc. This publicly available informa-
tion helps achieving public health measures advocated by WHO. Several wearable
devices with positioning are used in China and other countries to monitor coronavirus
patients, trace doctors, nurses and other clinicians who have contracted the disease
as quickly as possible and monitor the pandemic spread across the country. Some
tools were developed to facilitate contact tracing (Coronamap14 ), search for masks
(Maskmap15 ), visualize the disease transmission16 and show how the community is
responding differently due to COVID-19.17 Apple and Google are building a coro-
navirus tracking system into iOS and Android allows users to share data through
Bluetooth Low Energy (BLE) transmissions and approved apps from health orga-
nizations. Based on this system, Covid Watch18 contact trucing app is developed to
12 https://www.covidvisualizer.com/.
13 https://www.domo.com/coronavirus-tracking.
14 http://coronamap.site/.
15 https://maskmap.site/.
16 https://www.gisaid.org/epiflu-applications/next-hcov-19-app/.
17 https://www.google.com/covid19/mobility/.
18 https://www.covid-watch.org/.
66 A. Khamis et al.
empower people and protect their communities from COVID-19 using an anony-
mous exposure notification system. Other descriptive analytics tools are developed
as software-as-service19 for contact tracing, locating and conceptualizing infectious
disease spread by incorporating hundreds of thousands of multimodal data sources
such as statements from official public health organizations, digital media, global
airline ticketing data, livestock health reports, population demographics, etc.
Predictive models make prediction about future values of data and forecasts
new proprieties instead of just exploring data properties like in case of descriptive
analytics. These models answer questions like what would happen?; when would
it happen? and where would it happen? Despite the availability of several descrip-
tive analytics tools during the pandemic, there are much less predictive models.
Predicting future states using hand-crafted mathematical models or using data-
driven approaches depends on a number of factors such as targeted prediction (exact
values, reasonable range, trend, seasonality, etc.), type of data (stationary versus non-
stationarity), desired forecast window and availability of a priori knowledge. Gener-
ally speaking, predicting exact values of non-stationary variables for an extended
forecast window is challenging unless there is enough multimodal data and a priori
knowledge about the variables of interest. For example, COVID-19 cases cannot be
accurately predicted using only past and current case counts reported by WHO and
applying oversimplified data mining algorithms such as moving average, auto regres-
sive moving average, logistic regression, etc. Infectious disease models or epidemio-
logical models that incorporate transmission dynamics and clinical dynamics should
be considered. Existing infectious disease predictive models are oversimplified or a
repurposed version of similar disease models assuming that the novel corona virus
behaves like influenza or SARS-CoV. These models cannot be fully trusted to make
decisions. This is mainly due to lack of enough information about the novel coron-
avirus and COVID-19 such as self-mutation capability of the virus, incubation period,
how it spreads, what are all the different ways the virus can be transferred between
people? what is the transmission time or how long does it take to transmit the virus
to other person from the moment the virus enters a person’s body?, how temperature
and humidity can impact virus transmission, a priori knowledge and demographic
information like age, gender, blood type, other diseases, previous vaccination record,
etc.. For example, epidemic calculator20 implements a classical infectious disease
model—SEIR (Susceptible → Exposed → Infected → Removed) [10, 11]. This
model uses different transmission dynamics and clinical dynamics parameters such
as population size, number of initial infections, transmission times, case fatality rate,
hospitalization rate, etc. to simulate the disease’s progression. Robert Koch Institut21
developed a predictive model based on not only current case counts of WHO but also
using a novel epidemiological model that integrates the effect of population behavior
changes due to government measures and social distancing. This predictive model
can provide 6-day forecasts of COVID-19 case counts by country. The predictive
19 https://bluedot.global/.
20 http://gabgoh.github.io/COVID/.
21 http://rocs.hu-berlin.de/corona/docs/forecast/results_by_country/.
model of Institute for Health Metrics and Evaluation22 at the University of Wash-
ington has a wide range of projections for deaths from COVID-19 based on different
underlying assumptions and how they change, such as the effect of social distancing
or widespread testing. Due to lack of enough data, trustable predictive models need
to focus on predicting trends and reasonable ranges, rather than exact numbers. As
we collect more unbiased and consistent data and gain more information about this
novel virus, these predictive models will get better and more trustworthy.
Diagnostic analytics provides root-cause analysis and answers questions such as
why did a health-related problem happen? or why would a problem happen? Finally,
a prescriptive analytics model will process information about the current condition
of the patient or the population generated by descriptive analytics module, anomaly
detection and forecast from predictive analytics module, root-cause analysis gener-
ated by the diagnostic model and any other a priori knowledge that may be available
about the patient medical records and/or places recently visited. It then produces
timely recommendations for proactive actions or intervention plans to mitigate any
possible risk. This decision support or recommendation engine answers the following
questions, how would the predictions obtained from predictive models impact every-
thing else? what are the proactive decision/actions to be made? how we benefit from
predictions/recommendations? what are the best actions to make? what is the best
time to take this action? and what would be the impact of this action? Based on
the insights generated from the descriptive and predictive analytics models, different
strategies to flatten the outbreak curve, end the pandemic and bring life to normal are
recommended. For example, researchers at Imperial College concluded that there are
essentially three ways to end the pandemic, which are vaccination, herd immunity or
permanently change our behavior/society [12]. The consequences of doing nothing,
mitigation and the hammer & dance strategies were explained in [13].
5 Assistive Robots
Robots can perform many assistive tasks during the pandemic to mitigate the risk to
healthcare professionals. Applications of assistive robots include, but are not limited
to, medical care, nursing, patient monitoring, performing lab work, cooking and
serving medication, meal delivery to patients in isolation wards. Several assistive
telecare robots, community medical robots and telemedicine services are used during
the outbreak of the novel coronavirus. For example, doctors use the mounted iPad
on Spot to remotely interact with coronavirus patients, ask them question in order
22 https://covid19.healthdata.org/.
68 A. Khamis et al.
Fig. 7 Tommy, the robot nurse. Credit Flavio Lo Scalzo/Reuters
to assess the patients.23 Tommy helped Italian medical teams in treating COVID-19
patients24 (see Fig. 7).
Saskatchewan Remote Presence Robots (Fig. 8) are used to deliver health care to
rural and remote regions of Saskatchewan, Canada in order to protect physicians on
the front lines fighting the COVID-19 pandemic.25
The system illustrated in Fig. 9 uses artificial intelligence, big data, robots, the
Internet of Things, modern medical technology, cloud computing and other platforms
and methods. According to the users and scenarios, it can be divided into three parts,
namely, community robots, the monitoring data platform and the diagnostic platform
[14].
Each community entrance can be equipped with several robots, and the position
of each robot can be accurately obtained. For each person entering and leaving the
community, the identification is verified (for example, fingerprint identification, face
recognition, biometric identification), the body temperature is collected, the blood
pressure is monitored, the blood test can be performed to determine whether a face
mask is necessary. For suspected cases, one can further use the pneumonia test kit on
the community robot and take pictures of the corresponding disease location. At the
23 https://www.telegraph.co.uk/technology/2020/04/23/robot-dogs-used-help-doctors-remotely-
assess-coronavirus-patients/.
24 https://www.pri.org/stories/2020-04-08/tommy-robot-nurse-helps-italian-doctors-care-covid-
19-patients.
25 https://thestarphoenix.com/news/local-news/sask-ready-to-deploy-medical-robots-to-help-
fight-against-covid-19/.
Fig. 8 Saskatchewan remote presence robots. Credit University of Saskatchewan and Saskatchewan
Health Authority Remote Presence Robotic Program
Fig. 9 A composition framework diagram of community medical robots
same time, the medical staff connected to the remote diagnosis platform through the
voice dialogue system can communicate quickly. The robot will upload information
about the suspected patient to the monitoring data platform. The robot will record
and send data to the monitoring personnel. The robot can self-sterilize at regular
70 A. Khamis et al.
Fig. 10 Community medical robots
intervals and sterilize the air in the surrounding environment and effectively prevent
and reduce cross-infection.
The monitoring data platform collects information uploaded by medical robots in
various communities and stores data (time and location of examination for suspected
cases). Data mining (mines potential cases based on recorded data such as temper-
ature, reagents, pulse, blood routine, location, etc.), data analysis and calculation
(statistical analysis of the epidemic of the entire region) are performed. Forecasts of
the region in the next few days are given. Timely feedback is given to the epidemic
units and personnel to facilitate corresponding control decisions.
The diagnostic platform obtains real-time information through the monitoring
data platform. The information is mainly related to the disease. At the same time, it
can make video and voice calls with the suspects detected by the community robot.
It can also check and analyze the photos of the suspects in order to provide medical
care.
The Chinese Academy of Sciences developed a robot to remotely collect oropha-
ryngeal swabs from patients for testing, so the medical workers do not have to directly
swab the patients.26 Figure 10 shows the three major systems of community medical
robots.
Some more simplistic solutions (e.g., RoboAds) include only a mobile robot plat-
form for autonomous positioning of kiosks on the one hand to reach the target audi-
ence with interactive (touchless) billboards, while taking telemetry and collecting
data on people’s health condition (primarily body temperature).
26https://www.straitstimes.com/asia/east-asia/coronavirus-china-develops-robot-for-throat-swab-
sampling.
Fig. 11 Outdoor disinfecting robot from Siemens, the Chinese company Aucma working in the
joint laboratory for robot applications in Qingdao. The robot was designed using CAD and the
actual system was built in just a week. Credit SIPA Asia
6 Disinfection Robots
Disinfecting surfaces and the environment, performed routinely in hospitals, has

always been essential for infection prevention and control [15]. Beyond regular
surface wiping with highly efficient detergents, a key strategy has been to allow
the active ingredient to spread to all areas of the room, however this also needs
complete lockdown and heavy air ventilation. UV-C irradiation (200–280 nm) is
also an efficient disinfectant, if the radiation reaches all critical surfaces. Robots
are considered as an effective technology for disinfection, preventing any harm to
humans. There are two major types of applications: indoor and outdoor.
• Outdoor Disinfection usually means the spraying of an active material (NaClO,
sodium hypochlorite in a very low concentrate). While scientists argue that this
method has very limited effect on the spread of a virus [16], engineers have
developed both teleoperated and autonomous ground and aerial vehicles (see
Fig. 11). Several drone manufacturers have modified their agricultural models in
order to spray disinfectant over large areas [17]. These disinfecting drones have
been used for the first time in Europe. They have been deployed in China, Chile,
Indonesia, the Philippines, Colombia and the United Arab Emirates. XAG Robot
has deployed disinfectant-spraying robots and drones in Guangzhou, China.27
Nevertheless, safety of such systems remains a major concern.28
• Indoor Cleaning robots are available in the market for ward disinfection. The
LightStrike Germ-Zapping robots (XENEX, San Antonio, TX) became the first
disinfection system of its kind to deliver intense germicidal action from pulsed UV-
C at 200–315 nm29 over 12 years ago. The Danish UVD Robots ApS was founded
in 2016 by Blue Ocean Robotics and its solution offers indoor mobility to deliver
27 https://venturebeat.com/2020/03/03/how-people-are-using-ai-to-detect-and-fight-the-corona
virus/.
28 https://www.weforum.org/agenda/2020/03/three-ways-china-is-using-drones-to-fight-corona
virus/.
29 https://www.xenex.com/our-solution/lightstrike/.
72 A. Khamis et al.
Fig. 12 Indoor disinfecting robot UVD, consisting of a mobile base equipped with multiple LIDAR
sensors and an array of UV lamps mounted on top. Credit UVD Robots
the UV-C irradiation.30 It was the recipient of the IEEE/IFR 2019 Innovation and
Entrepreneurship Award (IERA)31 (see Fig. 12). Shenzhen-based YouiBot was
already making autonomous robots, and quickly equipped its existing mobile robot
base with thermal cameras and UV-C emitting bulbs.32 Akara Robotics, a spin-off
from Trinity College Dublin is testing and producing a new autonomous mobile
robot that is designed primarily to sterilize a room with UV light. The Indian
Milagrow offers its Indoor Disinfection RoboCop. The Turkish Milvus Robotics
calls its UV disinfecting robot SEIT-UV, with 360° disinfecting coverage, software
and sensor-based safety features. The Chinese WellWit Robotics offers its Pulsed
Light Germ-Killing Robot (WDR01A). The PBA Group announced the rollout
of their Sunburst UV Bots, UV-disinfecting autonomous mobile robots together
with Singapore based Frasers Property Group. A similar solution is developed by
Anscer Robotics in Bangalore, India.33 TIAGo robot equipped with UV-C sources
can be used for cleaning and disinfection at hospitals and other public areas.34 A
recent development from Rovenso targets directly offices and commercial spaces
with its focused UV-C disinfectant robot.35
7 Public Awareness and Patrolling
Drones have been widely used for the fight against COVID-19. Drones can be
equipped with high-power speakers at large gatherings. Warnings are broadcasted
to the crowd. Drones can be used to identify people not wearing masks. People are
reminded by drones to wear masks. At the same time, drones can detect people
quickly through thermal imaging and target recognition systems.
30 http://www.uvd-robots.com/.
31 https://spectrum.ieee.org/automaton/robotics/medical-robots/autonomous-robots-are-helping-
kill-coronavirus-in-hospitals.
32 https://www.bbc.com/news/business-51914722.
33 https://mobilerobotguide.com/2020/04/01/robotic-solutions-for-covid-19/.
34 http://blog.pal-robotics.com/how-to-build-a-solution-for-fighting-coronavirus-using-the-tiago-
base-robot/.
35 https://spectrum.ieee.org/automaton/robotics/industrial-robots/rovenso-uv-disinfection-robot.
Fig. 13 The Knightscope lineup of indoor and outdoor telepresence robots. Credit Knightscope
Robotics
Another example is Boston Dynamics’ Spot that is used at parks to remind visitors
of social distancing measures.36 Speech assistants are used for home isolation and
control. For residents who need to be isolated at home, the speech assistants will
provide appropriate advices. For example, “It is recommended that you and your
family undergo a 14-day medical observation at home. We will submit your infor-
mation to the neighborhood and community health service center. The center will
collect further information later. If you need any help, please contact the your commu-
nity center in time. Thank you!” [18]. Another example is Knightscope Robotics37
that can be used for patrolling corporate facilities. The robots are used for remote
monitoring of streets and corporate campuses (see Fig. 13).
8 Contactless Last-Mile Delivery Services
Fighting the coronavirus pandemic demands last-mile delivery robots. Last mile is a
term used in supply chain management and transportation planning to describe the
movement of people and goods from a transportation hub to the destination [19].
Various innovative solutions for last- mile delivery are currently being developed
or tested to reduce the delivery cost, increase customer satisfaction and minimize
the negative environmental impact. These solutions include, but are not limited to,
cargo-bikes, semi and fully autonomous last-mile delivery, delivery Droids (Bots), E-
Plaette, Postal delivery, driverless deliveries and privately-owned AV [20]. According
36 https://www.straitstimes.com/singapore/robot-reminds-visitors-about-safe-distancing-mea
sures-in-bishan-ang-mo-kio-park.
37 https://mobilerobotguide.com/2018/07/20/knightscope/.
74 A. Khamis et al.
Fig. 14 AIMBOT, an autonomous mobile robot. Credit UBTECH Robotics
to Makinsey, semi and fully autonomous last-mile delivery will reduce costs by
approximately 10–40% [21].
The highly contagiousness coronavirus results in one of the worst outbreaks.
Social distancing is the main measure taken to reduce the spread of the virus through
minimizing the contact between people. However, frontline workers who treat the
patients or deliver medicine or food for them and even people at home who order
essential goods like medication or grocery are still at risk. Contactless last-mile
delivery systems and services can result in avoiding physical contact between care-
givers and patients or between delivery workers and the recipients. These contactless
delivery systems benefit from the rapid proliferation of connected technologies and
the recent advancements in semi and fully autonomous delivery platforms which
revolutionize the urban logistics and provide a safe and efficient delivery methods
for medical supplies [22], medications [23], food, grocery and other goods [24, 25].
Figure 14 shows AIMBOT,38 an autonomous mobile robot developed by UBTECH
Robotics, performs disinfection tasks at Shenzhen Third Hospital.
The demand for food delivery facilities has never been higher as most restaurants
and cafés are closed and the public are advised to stay at home to prevent the virus
from spreading. However, despite COVID-19’s incredibly infectious nature, more
and more suppliers prefer contactless distribution solutions to reduce the risk to
38 https://www.weforum.org/agenda/2020/03/three-ways-china-is-using-drones-to-fight-corona
virus/.
Fig. 15 Nuro driverless vehicles. Credit Nuro
consumers and the delivery personnel. For example, Starship39 has hundreds of robots
delivering food to customers [26]. Drones are an ideal solution for contactless food
delivery to remote areas. Figure 15 shows Nuro driverless vehicle that has been
approved for delivery tests in California in April 2020 [25].
The spread of coronavirus has put tremendous pressure on health systems world-
wide. The virus has caused greater demand in laboratory testing as well as an urgent
need for personal protective devices to allow patients with milder symptoms to be
monitored remotely. Drone distribution is a valuable option as drones can easily carry
samples from hospitals to labs, provide simple security services, and bring medical
equipment to patients’ homes such that immediate control can be provided. Currently
some companies in China and Ghana are actively using this technology.
9 Virtual Healthcare Assistants and Chatbots
Since the beginning of the pandemic, many health care providers started to reduce
in-person visits for a variety of patients by providing consultations over the phone
or by video conference as a way to protect both patients and staff and to stop the
spread of COVID-19. Information and communication technologies (ICTs) have
great potential to address some of the challenges in this domain by providing acces-
sible, cost-effective, and high-quality health care services. The World Health Orga-
nization (WHO) recommends its member states to take steps towards developing
and implementing ICT based innovative solutions to reduce the need for personal
39 https://www.starship.xyz/.
76 A. Khamis et al.
contact between medical professionals and patients, and to increase accessibility

to health care services [27]. Virtual healthcare assistants and chatbots (VHAC) are
considered as one of the ICTs variants that aim to improve the conversation between
healthcare providers and patients and put more information in the hands of the end
users, to help healthcare organizations improve processes and reduce costs. VHAC
are AI and rule-based systems that interact with humans to perform various tasks,
to name a few, banking, answering phone calls, performing data entry, etc. These
assistants use cognitive technologies such as machine learning, natural language
processing (NLP), and neural networks to enable interactive communications with
the end-users. Virtual assistant technology in the healthcare industry can assist in
transforming various health processes and improve healthcare delivery worldwide. It
helps improving healthcare quality, patient care, patient safety and patient outcome at
lower costs [28]. VHAC can be considered as the optimum tool to provide healthcare
services to vulnerable groups such as the elderly with low immunity and comorbidity.
Recent reports claim that the global healthcare virtual assistant market is expected
to grow at a rate of 24.7% from 2018 to 2025 to reach $1.7 billion by 2025 [28].
With the increasing burden of communicable diseases, it is highly recommended
to utilize technological advancement to control and monitor critical situations and
decrease workload of healthcare workers. Technologies can facilitate receiving health
care services without the need of unnecessary visits to the doctors [29]. It is believed
that technological devices and ICT can be a great substitute for scarce human
resources in this domain in the years to come [29]. On the daily life basis, virtual
assistants can help providing reminders and motivational comments for medications,
food and exercises [30]. They can perform regular checkups and answer questions
regarding health issues [30]. They can be customized according to each person’s
interests and values in order to encourage people to participate in social interac-
tions and community activities [30]. They can also play a role as a mediator among
multiple experts from different fields [30]. The use of this technology to provide
online and real-time healthcare services includes tele-assessment, tele-diagnosis,
tele-interactions and tele-monitoring [30]. For instance, tele-monitoring (or remote
monitoring) records data obtained from specific sensors, sends the data to special-
ists, and assists in decision making. The specialists can then make decisions based
on other datasets and the patient’s medical history [30].
Virtual assistants have been employed as a communicative agent. Researchers
report that the usage of telemedicine increased between 2005 and 2017. The use of
this technology improved rapidly for primary care telemedicine in 2016 and 2017
[31]. Consistently, based on a review study, the popularity of using individualized
chat based system to deliver psychological therapies is increasing, although there are
some deficiencies in methodological procedures [32, 33]. There is a strong demand
of more robust and efficient methods and standards for evaluating these technologies
[33].
The need for implementing assistive technologies to fight COVID-19 has
increased. It is reported Chinese health specialists are considering to use virtual
technologies to provide consultation to patients [34]. During this difficult time, the
Centers for Medicare & Medicaid Services (CMS) has permitted people to use inter-
active applications to visit virtually their physician for a variety of purposes [34].
Canada, the UK, Italy, South Africa and India are some other countries that have
deployed virtual health services [34].
Researchers, however, suggest further enhancing the capabilities of technology.
“Virtual clinics” enables virtual visits with imaging data (e.g., chest X ray) to be
remotely examined [35]. Regarding the merits of this approach, it is expected that it
can help establishing equality among all people to receive a comprehensive examina-
tion and evaluation as well as reducing the number of patients in clinics and healthcare
centers [34]. Furthermore, this could reduce the burden of healthcare workers [35].
In addition, virtual healthcare assistants can play a major role in preventive
measures. “Chatbot” can help screen or identify early symptoms, teach and train
users essential hygienic practices such as handwashing and safe grocery shop-
ping [35]. Examples of the chatbots developed for COVID-19 are “Amplify.ai”,
and “Facebook’s Messenger for COVID-19 Program”. They provide information
regarding the coronavirus and the COVID-19 pandemic [35]. Amplify.ai aims to
create “interactive messenger experiences with support for both tapped and typed
responses viaadvanced Natural Language Processing (NLP)” [36]. Another chatbot
designed specifically for COVID-19 is “the Coronavirus Self-Checker” for those
who perhaps are sick [37]. This chatbot provides resources to protect people and
advices users whether or not they need to visit medical care centers. However, this
system is designed to provide information only to Americans [37].
During the fight against the pandemic, voice assistants are also widely used. A
voice assistant can complete 200 calls in 5 min and produce statistical results. Manual
calls, on the other hand, requires 2–3 min per call, plus the statistical analysis that
requires at least 3–4 h for processing. With the trial of voice robots, the efficiency
of epidemic investigation has been greatly improved. During the pilot process, a
voice assistant will automatically call the recipient’s phone, and multiple rounds of
interactive conversations with the recipient can be performed to collect and confirm
the information, including identity information, areas visited, recent contact groups,
and current symptoms. After confirming the information, the voice assistant will
automatically classify the statistics and promptly provide daily statistical results
[18].
10 Drug Repurposing/Discovery and Vaccination Discovery
AI can mimic the human decision-making process. Machines can learn from data
and human expertise. Science reports the most suitable tasks for AI include: learning
a function that maps well-defined inputs to well-defined outputs, large data sets exist
or can be created containing input–output pairs, the task provides clear feedback with
clearly definable goals and metrics, no long chains of logic or reasoning that depend
on diverse background knowledge or common sense, no need for detailed explanation
of how the decision was made, a tolerance for error and no need for provably correct
78 A. Khamis et al.
or optimal solutions, the phenomenon or function being learned should not change
rapidly over time, no specialized dexterity, physical skills or mobility required. The
unique properties of AI make it suitable for solving various medical problems, such
as drug repositioning and vaccination discovery.
The United Nations has been encouraging nations to develop technologies for
advanced health diagnostics through AI and big data, enhanced access to health care
through telemedicine, blockchain and AI optimized medical data. AI can improve
infectious disease monitoring, identify potential risks. AI has been used to classify bat
species likely to host filovirus that causes severe fevers like Ebola. The developed
model achieved 87% accuracy, which helped improve countries’ ability to handle
outbreaks. AI may surpass medical experts in diagnosis, analysis, and analytics for
drug development. Analytics models and data-sharing tools developed by DeepMind
have been utilized to identify deterioration by public health services in the UK and
US.
Traditionally, the solution to dangerous new bacterial and viral infections is to
create a mixture of different medicines. However, with the drug combinations sub-
optimally selected and doses selected through trial and error, this procedure is labo-
rious and time-consuming. This expensive and inefficient approach to create a cure is
complicated when a fast response to the global pandemic is necessary and resources
need to be maintained.
Conventional diagnosis collection involves the analysis of the virus or the devel-
opment of bacteria in reaction to various potential drugs. Drugs are administered
in growing doses to the bacteria or viruses before optimum growth suppression is
detected. To intensify the effect, additional medicines are added together. But when
many medications are tested concurrently as options, these approaches are not always
possible. These methods often yield promising effects but are not verified through
human trials [38, 39].
The effects of all potential drug formulations and the optimal mixture of drugs
are difficult to validate using conventional approaches. Moreover, if a drug from a
list of candidate drugs has not shown a significant impact on a pathogen, it typically
is no longer included in the conventional sampling.
Professor Ho and his staff, along with colleagues from Shanghai Jiao Tong Univer-
sity, have applied AI for drug development. The vesicular stomatitis virus (VSV)
infection was deliberately picked as 12 suitable candidates for diagnosis. Their devel-
opment also reduced the number of tests available to evaluate the full spectrum of
formulations and appropriate doses of these 12 drugs with IDentif. AI [38]. “This time
and precision in the discovery of new drug combination therapy is somewhat unpar-
alleled”, as Professor Ho states, “We spent three days to identify multiple optimized
medication schematics from thousands of possible combinations which reduced the
VSV infection to 1.5% without obvious negative consequences.” Most notably, the
team has seen the seven-fold higher effectiveness than sub-optimal doses in the
maximum dosage for the top-ranking drug mix. This shows that ideal dose detec-
tion is essential. Similarly, the mixture was 14 times less successful when a single
medication was supplemented by the medication mix and delivered at sub-optimal
doses.
The results of IDentif. AI prove it’s critical to think about how the medicine
develops and is subsequently given in a combination [38]. They concluded that
techniques like IDentif. AI, which can easily automate pharmaceutical use during
austere economic conditions in the midst of pandemics, would lead to improved
medical outcomes compared to traditional approaches. The team is now looking at
COVID-19, having proven the efficacy of IDentif. AI in providing care for infectious
diseases. Professor Ho said, “We will need a fast-clinical approach to combat VICs
that can evolve over time because of the current production of vaccines and antibody
therapies for COVID-19. Our strength is that we can run one trial and come up with
a list of drug combinations for therapy within days”. Prof. Ho concluded, “When a
disease enters an active outbreak, it would be important for a quick response and this
solution will continue to change as the pathogen evolves” [38].
Various businesses and start-ups have innovatively changed their work goals in
order to use AI to speed up the quest for a cure against COVID-19. To help researchers
easily synthesize and test new candidate molecules against COVID-19, the European
IA-centric starting Molecule.one has laid down a proprietary synthesis method for
open access to the scientific Community. IBM’s AI frameworks have been used
to cover three COVID-19 targets, and 3000 novel molecules have been developed.
Such molecules were published to the science community for synthesis, processing
and optimization, under the Creative Commons License (CCL). A list of 97 small
molecules candidates intended to inhibit the SARS-CoV-2 3CL protease has been
published by InSilico Pharmacy, a Hong Kong based drug development company.
A variety of fast virtual screening AI models with existing public and commercial
compound libraries as key repositories have been developed and evaluated against
COVID-19, respectively. Essentially, numerous research avenues have combined AI
models for future therapeutics to be produced at an unparalleled speed for COVID-19.
To date, both the bases and the proliferation of the COVID19 pathogenesis are
still unclear, and no vaccine nor proven treatment has yet been discovered. As a fast-
acting solution, in silico computational methods can be utilized for discovery and
even designing of novel drugs [39]. The short-time requirements of computational
methods are productive for high throughput screening of the currently known drugs
to define the significant drugs for newly emerging diseases, besides the prediction of
the negative impacts of novel drugs [40]. On the contrary, the development of novel
drugs via clinical approval requires several years of work, which is a time-consuming
process [41]. However, drug repositioning, also known as repurposing, is a potential
strategy to control the emerging diseases caused by infectious agents that are vastly
spreading [42]. Moreover, drugs that have been approved for a closely linked disease
or even sharing the same symptoms and/or complications, are safe for human use, but
only their efficacy against the COVID-19 is required to be re-examined, validated and
established [43]. In life-threatening cases, where there is no alternative medicine or
vaccine, such a drug repurposing strategy is particularly attractive. However, clinical
trials are essential to ensure that such proposed treatment is acting better than a
placebo [44]. Lopinavir and Ritonavir were mentioned in earlier literature to target
the Mpro of SARS virus. The protein sequences of COVID-19 Main protease (2019-
nCoV Mpro) and SARS-CoV Mpro are 96% identical [45]. In several early studies,
80 A. Khamis et al.
the similarities in the sequence of a potential target for COVID-19 to that of the
SARS Mpro were utilized to build a model for the structure of SARSCoV-2 Mpro
[45]. Homology based models were utilized to screen a library of compounds to
predict that Nelfinavir, an approved antiviral protease inhibitor, is a potential drug
for COVID-19 [46]. The sequence similarity of the SARS-CoV-2 Mpro to the SARS
Mpro is sufficiently high to build a good model for the structure of SARS-CoV-2
Mpro [42, 47]. However, the predictions of virtual screening studies and binding
energy calculations are generally more accurate if a high-resolution experimental
structure of the target is available.
Methods based on AI are emerging as exciting methods for exploration of the
enormous chemical space for sampling drug-like molecules. Models of AIs will test
characteristics based on current medical devices that can be used in the search for
more pharmaceuticals in the chemical area. The product design group has been able
to tackle a variety of issues, including the current antibiotic resistance epidemic.
Most notably, an AI strategy will minimize from many years to a few days the initial
process of medicament exploration.
11 Ethical Implication of AI and Robotics
Previous sections highlighted how important Artificial Intelligence and Robotics are
for addressing COVID-19. At same time these domains can bring a lot of benefits for
the humanity, they can pose serious risks for our fundamental rights ranging from
the impact on democracy to our right to life.
Currently, several Governments are establishing partnerships with private compa-
nies to get access and track people’s mobile. In [48], one can see a live index elabo-
rated by Top10PVN firm, about the use of mobile location per country which ranges
from processing anonymized data to the tracking of an individual person and her
contacts. Governments argue mobile location can provide invaluable information to
help understanding the dynamic of COVID-19 and, thus, elaborating public policies.
In fact, the data collected can be analyzed to identify patterns of movements which
can be used together with data on testing and diagnosis to inform how the virus is
being spread in a particular region or, even, at individual level, alert authorities if a
particular individual is obeying a home quarantine [49].
The main concern in these efforts is they can open the door to a further and
wider use of this kind technology to other domains increasing the surveillance of
the citizens under different and questionable justifications. This fact raises several
concerns about potential misuses that directly would impact our privacy, freedom of
expression and freedom of association accentuating, e.g., discrimination and further
harming marginalized groups. Recently, a joint statement [50] signed by different
organizations urged Governments ensure the use of digital technologies to address the
pandemic is in line with human rights. In this statement, the signatories listed several
conditions Governments should observe that include all surveillance measures must
be lawful, necessary and proportionate and all monitoring and surveillance powers
must be time-bound, and only continue for as long as necessary to address the current
pandemic. Considering the latter, Amnesty International [51], emphasizes “there is
a real danger surveillance measures become permanent fixtures. In the wake of the
attacks of 11 September 2001 (9/11), government surveillance apparatus expanded
significantly. Once these capabilities and infrastructure are in place, governments
seldom have the political will to roll them back”. Thus, what guarantees we have that
companies and Government will stop the surveillance or even discard all collected
and processed data once the pandemic ends?
Another relevant issue is if an AI-based system should ultimately decide who
should live or not, or simply if someone should receive or not a medical treatment.
This debate is not new, but it has increased those days during the Pandemic. The
world was not prepared for a Pandemic and some countries are facing some life
and death dilemmas due to resources limitation. The question is what are the data
should be used to provide an answer? Should age, gender, known diseases, race,
social status or other be considered? How should all these components be combined
and why? In China, some researchers developed an AI-based tool to assist doctors
to make choices about patient with COVID-19 using blood samples [52]. Systems
that provide support to human decisions are very welcome. However, they should
never undermine human agency, i.e., humans should not be obligated to use system
decisions blindly without having them scrutinised. The reason is simple. AI-based
systems are just math tools. They are neither intelligent nor neutral. They are fairly as
good as the quality of the data that is used in their training set. This fact is corroborated
with evidences presented in different reports that show gross errors produced by some
systems, which a human would never make [53].
A correlated problem is most of the people that will use AI-based systems does not
know their limitations. This has led to situations where some people in key positions
anthropomorphize and over-trust the technology, and using fallacious arguments,
impose the adoption of these systems in critical and sensitive tasks. Therefore, initia-
tives like IEEE Global Initiative on Ethics of Autonomous and Intelligent Systems
[54] and IEEE/MIT Global Council on Extended Intelligence [55] are very relevant.
While the former aims to educate and empower people to take ethics into considera-
tion during the life cycle of AI-based systems, the latter tries to shed some lights on
AI creating a new narrative for the domain to demystify the hype that surrounds it.
The risk for misusing technology is high. Organizations like ProPublica recently
pointed out people with disabilities may be denied from lifesaving care during the
Pandemic [56]. It cites some disasters preparedness plans in which people with
cognitive issues have lower priority for lifesaving treatment. In Brazil, the Ministry
of Health suggested in a press collective [57] that saving an elderly is more financially
expensive than saving a young. As the young has an entire life in front of her, she
would have preference to be saved. Information like those can be incorporated in an
AI-based system causing irreparable losses, and due to the opaqueness of the system,
this discriminatory information would never be uncovered and the responsible would
never be punished.
82 A. Khamis et al.
12 Conclusion
The global battle against the novel coronavirus and the COVID-19 pandemic has
seen AI and robotics playing extremely important roles in understanding the scope
of the pandemic, dealing with the contagious nature of the virus and decelerating
its spread. This chapter reviewed a number of AI and robotics applications in the
battle against COVID-19. These applications include early detection and diagnosis,
massive agent modeling and simulation, data analytics, assistive robots, disinfection
robots, public awareness and patrolling, contactless delivery services, chatbots for
medical care and drug repurposing and vaccination discovery. Ethical implications
of AI and robotics were also reviewed.
Many lessons are learnt from this unprecedented crisis that has profoundly
impacted human capital, including lives, well-being, learning, and productivity.
There is a need to fully understand the limitations of AI-based systems for not over-
trusting the technology and creating false arguments especially in critical health-
related tasks. Measures should be taken to protect digital rights, stop the surveil-
lance once the pandemic ends, ban new totalitarianism of surveillance technology
and digital totalitarian states. Robotics and AI in general have to be regulated and
smartly directed toward the benefit of humanity.
References
1. Yang, G.-Z., Nelson, B.J., Murphy, R.R,. Choset, H., Christensen, H., Collins, S.H. Dario, P.,
et al.: Combating COVID-19—the role of robotics in managing public health and infectious
diseases. Sci. Robot. 5(40). https://doi.org/10.1126/scirobotics.abb5589 (2020)
2. Khamis, A.: Biological versus non-biological/artificial intelligence. Medium (2019). Available
at: https://medium.com/@alaakhamis/biological-versus-non-biological-artificial-intelligence-
9dee32a1517d, last accessed 2 May 2020
3. Khamis, A., Meng, J., Wang, J., Azar, A.T., Prestes, E., Li, H., Hameed, I.A., Takács, A., Rudas,
I.J., Haidegger, T.: “Robotics and intelligent systems against a pandemic.” Acta Polytechnica
Hungarica 18(5). https://doi.org/10.12700/APH.18.5.2021.5.3 (2021)
4. Fan, W.: Epidemic promotes surge in demand for infrared temperature measuring instruments:
we “reunite families” and they “overtime”[N]. Sci. Technol. Board Daily. 2020.02.03
5. Shenzhen Municipal Affairs Service Data Administration: Epidemic Pass Reference Architec-
ture and Technical Guide. 2020.03.05
6. Sun, Q.: AR glasses check the car, induction disinfection, Zhongguancun resumed work using
these high-tech[N]. Beijing Daily. 2020.02.28
7. Li, L., Qin, L., Xu, Z.: Artificial intelligence distinguishes COVID-19 from community acquired
pneumonia on chest CT. Radiology. 2020.03.19
8. Wang, Y., Hu, M., Li, Q., Zhang, X.P., Zhai, G., Yao, N.: Abnormal respiratory patterns classifier
may contribute to large-scale screening of people infected with COVID-19 in an accurate and
unobtrusive manner. arXiv preprint arXiv:2002.05534 (2020)
9. Khamis, A.: Turning data into actionable insights. Medium (2019). Available at: https://
medium.com/@alaakhamis/turning-data-into-actionable-insights-c246969fa4c, last accessed
2 May 2020
10. Wu, J.T., Leung, K., Leung, G.M.: Nowcasting and forecasting the potential domestic and
international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling
study. The Lancet 395(10225), 689–697 (2020)
11. Kucharski, A.J., et al.: Early dynamics of transmission and control of COVID-19: a
mathematical modelling study. The Lancet Infectious Diseases (2020)
12. Gallagher, J.: Coronavirus: when will the outbreak end and life get back to normal? BBC
(2020), last accessed: April 25, 2020
13. Pueyo, T.: Coronavirus: the hammer and the dance. Available at: https://medium.com/@tom
aspueyo/coronavirus-the-hammer-and-the-dance-be9337092b56, last accessed: 25 April 2020
14. Han, S., Fan, Y.: Discussion on the application of logistics robot distribution in community
epidemic isolation. Digit. Commun. World 2020.02
15. Lehotsky, Á., Morvai, J., Szilágyi, L., Bánsághi, S., Benkó, A., Haidegger, T.: A kézhigiénés
technika vizsgálata elektronikus ellenőrző berendezés segítségével 26 magyarországi betegel-
látó intézményben. Orvosi Hetilap 158(29), 1143–1148 (2017)
16. Service, R.F.: Does disinfecting surfaces really prevent the spread of coronavirus? Sci. Mag.
(2020). https://doi.org/10.1126/science.abb7058
17. Zhao, J., Hong, X.: Application of disinfection robot in dealing with sudden unexplained
epidemic situation. In: The 16th Chinese Scientists Forum, Beijing 2019.09.08
18. Xu, B.: The current epidemic situation Yimi Yuntong’s intelligent voice robot is in place.
Comput. Netw. 2020.03
19. Goodman, R.: Whatever you call it, just don’t think of last-mile logistics, last. Glob. Logistics
Supply Chain Strat. 9(12), 46–51 (2005)
20. Khamis, A.: Smart mobility: Exploring foundational technologies and wider impacts. Apress
(Springer Nature), ISBN: 978-1-4842-7100-1, (2021)
21. Joerss, M., Schröder, J., Neuhaus, F., Klink, C., Mann, F.: Parcel Delivery: The Future of Last
Mile. McKinsey & Company (2016)
22. Niels, T., Hof, M.T., Bogenberger, K.: Design and operation of an urban electric courier cargo
bike system. In: 2018 21st International Conference on Intelligent Transportation Systems
(ITSC), pp. 2531–2537. https://doi.org/10.1109/ITSC.2018.8569606
23. Li, N.: How a Chinese drone delivery startup is capitalizing on COVID-19. Retrieved April
18, 20 from https://asia.nikkei.com/Business/Startups/How-a-Chinese-drone-delivery-startup-
is-capitalizing-on-COVID-19
24. Bangkok Post.: Robot to deliver meals, medication to Covid-19 patients in S’pore9. Retrieved
April 18, 20 from https://www.bangkokpost.com/world/1872349/robot-to-deliver-meals-med
ication-to-covid-19-patients-in-spore
25. Crowe, S.: Nuro driverless vehicles approved for delivery tests in California. Retrieved April
18, 20 from https://www.therobotreport.com/nurodriverless-delivery-vehicles-approved-califo
rnia/
26. Drexler, D.A., Takács, A., Nagy, T.D., Haidegger, T.: “Handover process of autonomous
vehicles-technology and application challenges.” Acta Polytechnica Hungarica 16(9), 235–255
(2019)
27. World Health Organization (WHO): Telemedicine: Opportunities and Developments in
Member States: Report on the Second Global Survey on eHealth. ISBN: 978-92-4-156414-
4 (2009). Available online PDF at: http://www.who.int/goe/publications/goe_telemedicine_
2010.pdf
28. Healthcare Virtual Assistant Market—Global Opportunity Analysis And Industry Forecast
(2018–2025). Retrieved May 9, 2020 from https://www.meticulousresearch.com/product/hea
lthcare-virtual-assistant-market/
29. Breen, G.-M., Matusitz, J.: An evolutionary examination of telemedicine: a health and
computer-mediated communication perspective. Soc. Work Public Health 25(1), 59–71 (2010).
https://doi.org/10.1080/19371910902911206
30. Kuziemsky, C., Maeder, A.J., John, O., Gogia, S.B., Basu, A., Meher, S., Ito, M.: Role of
artificial intelligence within the telehealth domain. Yearb. Med. Inform. 28(1), 35–40 (2019).
https://doi.org/10.1055/s-0039-1677897
84 A. Khamis et al.
31. Barnett, M.L., Ray, K.N., Souza, J., Mehrotra, A.: Trends in telemedicine use in a large commer-
cially insured population, 2005–2017. JAMA 320(20), 2147–2149 (2018). https://doi.org/10.
1001/jama.2018.12354
32. Hoermann, S., McCabe, K.L., Milne, D.N., Calvo, R.A.: Application of synchronous text-based
dialogue systems in mental health interventions: systematic review. J. Med. Internet Res. 19(8)
(2017). https://doi.org/10.2196/jmir.7023
33. Laranjo, L., Dunn, A.G., Tong, H.L., Kocaballi, A.B., Chen, J., Bashir, R., Surian, D., Gallego,
B., Magrabi, F., Lau, A.Y.S., Coiera, E.: Conversational agents in healthcare: a systematic
review. J. Am. Med. Inf. Assoc.: JAMIA 25(9), 1248–1258 (2018). https://doi.org/10.1093/
jamia/ocy072
34. Webster, P.: Virtual health care in the era of COVID-19. The Lancet 395(10231), 1180–1181
(2020). https://doi.org/10.1016/S0140-6736(20)30818-7
35. Ting, D.S.W., Carin, L., Dzau, V., Wong, T.Y.: Digital technology and COVID-19. Nat. Med.
26(4), 459–461 (2020). https://doi.org/10.1038/s41591-020-0824-5
36. Covid19—Amplify.ai.: (2020). Retrieved May 8, 2020, from http://amplify.ai/covid19/
37. COVID-19 Risk Screening Tool: (2020). Retrieved May 8, 2020, from https://covid19chat.cle
velandclinic.org/
38. Ho, D.: Addressing COVID-19 drug development with artificial intelligence. Adv. Intell. Syst.
(2020). https://doi.org/10.1002/aisy.202000070
39. Macalino, S.J.Y., Gosu, V., Hong, S., Choi, S.: Role of computer-aided drug design in modern
drug discovery. Arch. Pharmacal Res. 38(9), 1686–1701 (2015)
40. Talluri, S.: Computational protein design of bacteriocins based on structural scaffold of aureocin
A53. Int. J. Bioinform. Res. Appl. 15(2), 129–143 (2019)
41. Strømgaard, K., Krogsgaard-Larsen, P., Madsen, U.: (eds.): Textbook of Drug Design and
Discovery. CRC Press (2017)
42. Li, J., Zheng, S., Chen, B., Butte, A.J., Swamidass, S.J., Lu, Z.: A survey of current. Trends in
computational drug repositioning. Briefings Bioinform. 17(1), 2–12 (2016)
43. Hurle, M.R., Yang, L., Xie, Q., Rajpal, D.K., Sanseau, P., Agarwal, P.: Computational drug
repositioning: from data to therapeutics. Clin. Pharmacol. Ther. 93(4), 335–341 (2013)
44. Novac, N.: Challenges and opportunities of drug repositioning. Trends Pharmacol. Sci. 34(5),
267–272 (2013)
45. Liu, X., Zhang, B., Jin, Z., Yang, H., Rao, Z.: The crystal structure of 2019-nCoV main protease
in complex with an inhibitor N3. PDB ID 6LU7 dated 12-Feb-2020
46. Xu, X., Jiang, X., Ma, C., Du, P., Li, X., Lv, S., Li, Y.: Deep learning system to screen coronavirus
disease 2019 pneumonia. arXiv preprint arXiv:2002.09334 (2020)
47. Chen, L., Liu, W., Zhang, Q., Xu, K., Ye, G., Wu, W., Sun, Z., Liu, F., Wu, K., Zhong, B.,
Mei, Y., Zhang, W., Chen, Y., Li, Y., Shi, M., Lan, K., Liu, Y.: RNA based mNGS approach
identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan
outbreak. Emerg. Microbes Infect 9(1), 313–319 (2020)
48. COVID-19 Digital Rights Tracker: Available at https://www.top10vpn.com/news/surveillance/
covid-19-digital-rights-tracker/
49. Poland is making its citizens use a ‘selfie’ app during the coronavirus crisis. https://www.abc.
net.au/news/2020-04-25/coronavirus-poland-tracking-quarantine-selfie-app/12173884
50. Joint Civil Society Statement: States use of digital surveillance technologies to fight pandemic
must respect human rights. Available at https://www.hrw.org/news/2020/04/02/joint-civil-soc
iety-statement-states-use-digital-surveillance-technologies-fight
51. COVID-19, surveillance and the threat to your rights. Available at https://www.amnesty.org/
en/latest/news/2020/04/covid-19-surveillance-threat-to-your-rights/
52. Should AI help make life-or-death decisions in the coronavirus fight? Avail-
able at https://www.scmp.com/news/china/science/article/3076259/should-ai-help-make-life-
or-death-decisions-coronavirus-fight
53. Why deep-learning AIs are so easy to fool Artificial-intelligence—Researchers are trying to
fix the flaws of neural networks. Available at https://www.nature.com/articles/d41586-019-030
13-5
54. Ethics in Action: Available at https://ethicsinaction.ieee.org

55. CXI—Council on Extended Intelligence: https://globalcxi.org
56. People with Intellectual Disabilities May Be Denied Lifesaving Care Under These Plans as
Coronavirus Spreads. Available at https://www.propublica.org/article/people-with-intellectual-
disabilities-may-be-denied-lifesaving-care-under-these-plans-as-coronavirus-spreads?
57. (In Portuguese) Teich já sugeriu que salvar idoso em vez de jovem é mais caro à
Saúde. https://www.cartacapital.com.br/politica/teich-ja-sugeriu-que-salvar-idoso-em-vez-de-
jovem-e-mais-caro-a-saude/
A Model-Based Analysis to Predict and
Control the Dynamics of COVID-19
Manotosh Mandal, Soovoojeet Jana, Sayani Adak, Anupam Khatua,

and Tapan Kumar Kar
Abstract COVID-19 has become one of the most severe health issues of the twenty-
first century. More than 30 million people have been affected by this deadly disease
and more than nine lakh people have been died due to this disease worldwide. Gov-
ernment authorities are forced to impose lockdown in their respective countries. In
a word, COVID-19 has stopped the natural flow of life in worldwide. In this situa-
tion, scientists and researchers of different fields are trying to find out appropriate
mitigating measures for COVID-19. However, there is no approved pharmaceutical
measures like treatment or vaccination available to the health workers. So, the gov-
ernments are strengthening on the non-pharmaceutical measures like maintaining
social distance, use of face mask and sanitizer and on lockdown policy. In this sce-
nario, determining the dynamics of the disease can help governments, health workers,
scientists to decide future action to be taken in order to tackle the disease. In this
chapter, we have proposed and analyzed an SEAIR type fractional order epidemic
model in order to investigate the transmission mechanisms of the COVID-19. We
have studied the non-negativity and boundedness of the solutions, and the existence
and uniqueness of the solutions of the system. The explicit expression of the most
important parameter, namely the basic reproduction number is derived and the fur-
ther investigations of the system are performed in terms of the basic reproduction
number. Apart from studying the local dynamics of the fractional order system, we
have considered the environmental fluctuations in the deterministic system. We have
studied the stochastic stability of the infected equilibrium points. Finally, important
results are illustrated through numerical simulation works.
Keywords Fractional differential equation · Basic reproduction number ·

Stochastic stability · Sensitivity analysis · COVID-19 outbreak
M. Mandal
Department of Mathematics, Tamralipta Mahavidyalaya, Tamluk 721636, West Bengal, India
S. Jana (B) · S. Adak
Department of Mathematics, Ramsaday College, Amta, Howrah-711401, West Bengal, India
A. Khatua · T. K. Kar
Indian Institute of Engineering Science and Technology, Shibpur,
Howrah-711103, West Bengal, India
88 M. Mandal et al.
1 Introduction
It has been reported that the novel corona virus disease has been originated from the
city Wuhan of China in the month of December, 2019. After that, the disease has
spread to each part of the globe due to mainly air travel and unrestricted movement
of the people. Later, the world health organization (WHO) declared COVID-19 as a
global pandemic on 17th March, 2020. The main symptoms of this disease includes
fever, dry cough, tiredness, respiratory problems [31]. Although its symptoms are
similar to the other seasonal flu but the COVID-19 disease is more infectious in
nature. The severity of the virus can be easily observed from its statistics. The total
number of affected cases is 33,375,685 and 1,003,349 number of people have been
died worldwide due to this deadly virus. In a word, the COVID-19 disease has
became real threatening to the human mankind and the governments are desperately
looking for the mitigation strategies for the disease. However, due to the absence
of the proper pharmaceutical measures, governments agencies are thrusting on non-
pharmaceutical measures like lockdown, maintaining social distancing, use of face
mask and hand sanitizer etc. Although, lockdown policy has a great adverse effects
on the country’s economy but is being imposed almost in every affected countries to
flatten the epidemic curve. In this scenario, a qualitative study of COVID-19 is very
significant rather than the quantitative study. Therefore, a mathematical model based
study would certainly help to insight the overall scenario of the COVID-19 disease.
Mathematical modelling has been extensively used to study the dynamics of the
corona virus disease. There are many model-based articles addressing the short term
forecasting of the disease. Mandal et al. [29] performed a model based study on
the transmission dynamics of the COVID-19 disease. They studied the qualitative
behavior of the system and fitted their model to the some most affected states of India.
Wills et al. [47] presented a hybrid model with time varying disease transmission
rate to get a better insights about the dynamics of COVID-19. They also calibrated
their model with real data. While Bouchnita and Jebrane [10] formulated a multi-
scale hybrid model to assess the impacts of non-pharmaceutical interventions on the
transmission dynamics of corona virus disease. They showed that it is possible to
flattens the epidemic curve by restricting the movement of the individuals. Upadhyay
et al. [46] proposed an SIQR type age structured model to investigate the progression
of the pandemic in India, Italy and USA. They identified the most infected age groups
and analyzed the effectiveness of social distancing. Mishra et al. [33] studied the
global dynamics of a nonlinear epidemiological model for the SARS CoV-2 virus.
Amar et al. [7] predicted the final size of the COVID-19 pandemic using machine
learning approach. Some more interesting articles on corona virus can be found
in [18, 23, 41] and the references cited therein. Motivated by these works, in this
chapter, we propose a compartmental epidemic model for the COVID-19 disease.
Our aim is to study the qualitative behavior of the fractional order nonlinear model
for the COVID-19 disease.
Fractional Calculus is a new branch of classical calculus which is widely used in
many branches of science and technology. Also in last couple of decades, it is applied
A Model-Based Analysis to Predict and Control the Dynamics … 89
to many biological problems. The reasons of its wide usage is that the fractional order
derivatives has many interesting properties connected with any biological systems.
The fractional order derivatives are dependent on the previous states in addition to
the current state i.e. it has the capability to capture the memory effects of a system.
Also most of the biological systems are equipped with the memory phenomena.
Therefore it is more realistic to construct an epidemic model using the fractional
order derivatives rather the integer order derivatives. Moreover, the fractional order
derivatives has non-local property and the order of the fractional derivative provides
a better degree of freedom in fitting data. Due to these properties, fractional order
derivatives is being used widely in many epidemiological problems. Sardar et al.
[43] studied the dynamical aspects of an fractional order epidemic model for dengue
transmission. Mondal et al. [34] analyzed the dynamical behavior of a fractional order
eco-epidemiological model. El-Shahed [16] developed and analyzed a fractional
model for the transmission of Leptospirosis. Almeida et al. [6] presented a MSEIR
type epidemic model using Caputo fractional order derivatives. They also used a
case study of the varicella outbreak among Shenzhen school children, China. Also
many recent important articles on epidemic modelling using the fractional order
derivatives can be found in [17, 25, 27, 30, 36, 39] and the references therein.
Therefore, the recent trends of using fractional order derivatives in epidemiological
problems can be easily observed. Based on the above discussions, in this chapter we
formulate a compartmental model using fractional order derivatives for COVID-19
transmission. We study the qualitative dynamical behavior of the system in terms
of the basis reproduction number. Further we study the stochastic stability of the
infected steady state and performed the sensitivity analysis of the basic reproduction
number with respect to the system parameters.
The rest parts of this chapter is consisted with the following sections. Some related
works are listed in the Sect. 2. In Sect. 3, we have formulated the fractional order
mathematical model with the qualitative properties for the COVID-19 transmission.
Section 4 is composed with some basic definitions and fundamental results connected
to fractional calculus. Then the complete dynamical behavior of the system is ana-
lyzed in Sect. 5. Also the stochastic stability of the infected steady state is included
in Sect. 5. Some of the obtained theoretical results are illustrated through numerical
simulations in Sect. 6. Finally, last two chapters come to end with some concluding
remarks.
2 Related Works
Mathematical modelling technique is being extensively used since the occurrence

of the COVID-19 outbreak. In particular, different types of fractional order mod-
elling has came into literature to investigate the better transmission mechanism of
COVID-19. Ahmad et al. [2] studied a fractional order model for COVID-19 trans-
mission. They obtained the numerical solutions of the system and concluded that the
stability occurs for the smaller order of fractional derivatives. Alkahtani and Alzaid
90 M. Mandal et al.
[5] proposed and analyzed the dynamical behavior of a COVID-19 mathematical

model with fractional derivative. Atangana [8] investigated whether lockdown can
save the humans before the invention of vaccination by analyzing a fractional order
model. Shaikh et at. [44] formulated a fractional order mathematical model and sug-
gested some possible control measures to stop the outbreak of COVID-19. While
Rajagopal et al. [42] formulated a SEIRD-type epidemic model for the COVID-19
transmission. They discussed both the integer and fractional order models and esti-
mated the parameters using the real data of Italy. They pointed out that the fractional
model provides a better forecast to the real data. Yadav and Verma [48] presented the
numerical solutions of a fractional order COVID-19 model for Wuhan, China. By
using Caputo fractional derivative, Tuan et al. [45] studied the dynamical behavior
of the corona virus disease and also they estimated the value of the basic reproduc-
tion number. While Ahmed et al. [4] investigated the significance of lockdown in
eradicating the spread of corona virus by studying a five dimensional compartmental
fractional order model. Also some other types of fraction order models on corona
virus disease can be found in [1, 24, 35] and the references cited therein. Therefore,
the recent trends of studying the transmission dynamics and predicting the future of
corona virus through fractional order mathematical models can be easily observed.
3 Model Formulation
We take the following conditions to construct our COVID-19 epidemic model. In

this paper, we formulate a mathematical model which can be applied to insight the
dynamics of the COVID-19 outbreak. We divide the human population of a region
(it may be a country or a state or a district, etc.) into five mutually exclusive time-
dependent compartments, viz. susceptible population, S(t) (who are assumed to be
infected by COVID-19), exposed population, E(t) (who already have pathogen of
the disease), asymptomatic population, A(t) (who are exposed individuals but there
are no clinical signs of COVID-19), infected population, I (t) (who are infected
with the disease and they are either hospitalized or quarantined), and recovered
population, R(t) (who have released from the disease and no more infectious to the
community). We take η as a constant input to the susceptible class. The disease
transmission rates are taken as β1 and β2 . The natural death rate of each of the
classes is taken as d and disease induced death rate for the infected compartment
is taken as δ. We have assumed that the exposed people become infected at a rate
ωE, out of which a portion of people (θ ωE) joins to the asymptomatic class and the
rest portion ((1 − θ )ωE) directly joins to the infected class. The natural recovery
rates for the exposed, asymptomatic, and infected individuals are taken as ρ1 , ρ2
and ρ3 respectively. We have also considered the treatment for the infected people.
The positive constant u stands for the treatment control for the infected individuals
and σ denotes the effectiveness of the treatment control. The details of the system
parameters are provided in the Table 1 and the schematic model diagram of the disease
transmission is shown in Fig. 1.
Table 1 Description of model parameters

Parameters Description
η Recruitment rate to susceptible class
β1 Disease transmission rate for A
β2 Disease transmission rate for I
ρ1 The rate that E becomes R
ρ2 The rate that A becomes R
ρ3 The rate that I becomes R
ω Rate that E becomes I
θ The portions of E becomes A
d Natural mortality rate
δ Disease induced mortality rate for I
u Control parameter
σ Effectiveness of the control
Fig. 1 Model diagram for the disease transmission
By considering all these phenomenons, we construct COVID-19 epidemic model

in the following way:
⎧
⎪
⎪
dS
= η − (β1 A + β2 I )S − dS,
⎪
⎪ dt
⎪
⎪
⎨ dt = (β1 A + β2 I )S − (ρ1 + ω + d )E,
dE
dA
= θ ωE − (ρ2 + d )A, (1)
⎪
⎪
dt
⎪ dI = (1 − θ )ωE − ρ3 + σ u + d + δ I ,
⎪
⎪
⎩ dR = ρ E + ρ A + ρ + σ u I − dR.
⎪ dt 1+uI
dt 1 2 3 1+uI
The initial condition of the system (1) are S(0) > 0, E(0) ≥ 0, A(0) ≥ 0, I (0) ≥
0, R(0) ≥ 0. Note that all the parameters of the proposed model (1) are nonnegative
and δ > d as death rate due to the disease is higher than the natural death rate.
92 M. Mandal et al.
The commensurate fractional order form of the system (1) is given by

⎧
⎪
⎪
α
t0 Dt S(t) = η − (β1 A + β2 I )S − dS,
⎪
⎪
⎪
⎪ α
= (β1 A + β2 I )S − (ρ1 + ω + d )E,
⎨ t0 Dt E(t)
α
t0 Dt A(t) = θ ωE − (ρ2 + d )A, (2)
⎪
⎪
⎪ t0 Dtα I (t)
⎪ = (1 − θ )ωE − ρ3 + 1+uIσu
+ d + δ I,
⎪
⎪
⎩ Dα R(t) σu
= ρ1 E + ρ2 A + ρ3 + 1+uI I − dR.
t0 t
with initial conditions S(t0 ) = S0 ≥ 0, E(t0 ) = E0 ≥ 0, A(t0 ) = A0 ≥ 0, I (t0 ) =

I0 ≥ 0, R(t0 ) = R0 ≥ 0. Here α ∈ (0, 1] and t0 Dtα is the fractional derivative in the
sense of Caputo ([22, 38]).
The corresponding incommensurate fractional order form of the system (1) is
given by ⎧
α1
⎪
⎪ t0 Dt S(t) = η − (β1 A + β2 I )S − dS,
⎪
⎪
⎪
⎪ t0 Dtα2 E(t) = (β1 A + β2 I )S − (ρ1 + ω + d )E,
⎨
α3
t0 Dt A(t) = θ ωE − (ρ2 + d )A, (3)
⎪
⎪
⎪
⎪
α4 σu
t0 Dt I (t) = (1 − θ )ωE − ρ3 + 1+uI + d + δ I ,
⎪
⎩ Dα5 R(t) = ρ E + ρ A + ρ + σ u I − dR.
⎪
t0 t 1 2 3 1+uI
with initial conditions S(t0 ) = S0 ≥ 0, E(t0 ) = E0 ≥ 0, A(t0 ) = A0 ≥ 0, I (t0 ) =

I0 ≥ 0, R(t0 ) = R0 ≥ 0. Here α1 , α2 , α3 , α4 , α5 ∈ (0, 1].
4 Some Preliminaries of Fractional Calculus
In this section we state some definitions, lemmas a theorems for commensurate and
incommensurate fractional order system.
Definition 1 [38] The Caputo fractional order derivative of order α with α > 0 for
a function f : C n [t0 , ∞) → R is defined and denoted as follows:

α 1 t
f (n) (τ )
t0 Dt =

(n − α) t0 (t − τ )α−n+1
where C n [t0 , ∞) denotes the space of n times continuously differentiable functions

on [t0 , ∞),
(.) is the Gamma function, n is the positive integer such that n − 1 <
α < n and t > t0 .
Definition 2 [40] The Mittag-Lefflar function of one or two parameters for any
complex number z are defined and denoted by:
∞ zn ∞ zn
Eα (z) = n=0 and Eα1 ,α2 (z) = n=0 , α1 , α2 , α ∈ R+
αn + 1 α1 n + α2
Lemma 1 [37] Let, α ∈ (0, 1] and f (t), t0 Dα (t) ∈ C[a, b], if t0 Dtα ≥ 0 then f (t) is a
monotone increasing function for all t ∈ [a, b] and if t0 Dtα < 0 then f(t) is monotone
decreasing function for all t ∈ [a, b].
Lemma 2 [22] For α ∈ (0, 1), the solution for the following nonhomogeneous
Cauchy problem:
α
t0 Dt f (t) = μf (t) + g(t), f (a) = b, wherea, b, μ ∈ R
is the form:
t
f (t) = bEα [μ(t − a)α ] + (t − τ )α−1 Eα,α [μ(t − τ )α ]g(τ )d τ
0
The solution of the homogeneous Cauchy problem:

α
t0 Dt f (t) = μf (t), f (p) = q, where p, q, μ ∈ R
is of the form:
f (t) = qEα [μ(t − p)α ]
Lemma 3 [19] Let, f (t) : [t0 , ∞) → R be a continuous function such that

α
t0 Dt f (t) + μf (t) ≤ v, f (t0 ) = f0 , t0 ≥ 0, μ, v ∈ R, μ = 0 and α ∈ (0, 1).
Then we get the following inequality:

v v
f (t) ≤ x0 − Eα [−μ(t − t0 )α ] +
μ μ
for all t ≥ t0 .
Lemma 4 [38] Consider the following commensurate fractional order system for
α ∈ (0, 1]
α
t0 Dt x(t) = Mx, x(t0 ) = x0 > 0
where x ∈ Rn and M ∈ Rn×n . The system is asymptotically stable if and only if

|arg(λk )| > απ
2
for all the eigen values λk (k = 1, 2, ..., n) of the Jacobian matrix
J = ∂f
∂x
evaluated at the equilibrium points.
Lemma 5 [15] Let us assume the following incommensurate fractional order system
α
t0 Dt x(t) = f (x), x(t0 ) = x0 > 0
94 M. Mandal et al.
where α ∈ Rn with α = (α1 , α2 , ..., αn ) and αi ∈ (0, 1] for i = 1, 2, ..., n and x ∈ Rn .

Also let ξ = A1 where A = lcm(q1 , q2 , ..., qn ) and αi = pqii with pi and qi are relatively
primes for i=1,2,...,n. The equilibrium points of the system are locally asymptotically
stable if and only if |arg(λ)| > ξ2π for all the eigenvalues λ s of the matrix M-J
where M = diag(λAα1 , λAα2 , ..., λAαn ) and the Jacobian matrix J = ∂f ∂x
evaluated at
the equilibrium points.
Lemma 6 [3] Let, the characteristic equation of the Jacobian matrix about the
equilibrium point be
p(λ) = λ3 + b1 λ2 + b2 λ + b3 = 0 and
D(p) = 18b1 b2 b3 + (b1 b2 )2 − 4b21 b3 − 4b22 − 27b23
Then, the equilibrium point is locally asymptotically stable if any one of the fol-
lowing conditions hold
(i) D(p) > 0, b1 > 0, b3 > 0 and b1 b2 > b3

(ii) D(p) < 0, b1 ≥ 0, b2 ≥ 0, b3 > 0, and α < 23
(iii) D(p) < 0, b1 > 0, b2 > 0, b1 b2 = b3 , and α ∈ (0, 1).
Lemma 7 [28] Let us assume the fractional order differential equation:

α
t0 Dt x(t) = f (t, x), t0 > 0 and x(t0 ) = x0
α ∈ (0, 1], f : [t0 , ∞) × R → Rn , if f(t,x) satisfies Lipscitz condition with respect

to x then there exists a unique solution of the system on [t0 , ∞) × R.
5 Model Analysis
5.1 Equilibria
The system has two possible equilibria: disease free equilibria (DFE), P0 = ( dη , 0, 0,
0, 0) and endemic equilibria (EE), P∗ = (S ∗ , E ∗ , A∗ , I ∗ , R∗ ), where
η(1 − θ )(d + ρ2 )(1 + uI ∗ )
S∗ = ,
β1 θ I ∗ ((1 + uI ∗ )(d + δ + ρ3 ) + σ u) + (1 − θ )(d + ρ2 )(1 + uI ∗ )(d + β2 I ∗ )

∗ 1 σu
E = ρ3 + + d + δ I ∗,
(1 − θ )ω 1 + uI ∗

∗ θ σu
A = ρ3 + + d + δ I ∗,
(ρ2 + d )(1 − θ ) 1 + uI ∗

1 σu ρ1 [(1 + uI ∗ )(d + δ + ρ3 ) + σ u] θρ2 [(1 + uI ∗ )(d + δ + ρ3 ) + σ u] ∗
R∗ = ρ3 + ∗ + ∗ + ∗ I
d 1 + uI (1 − θ )ω(1 + uI ) (1 − θ )(d + ρ2 )(1 + uI )
and I ∗ is given by the following cubic equation
a0 I ∗ 3 + a1 I ∗ 2 + a2 I ∗ + a3 = 0 (4)
where
a0 = u2 (d + ρ2 )(d + δ + ρ3 )(d + ρ1 + ω)[β1 θ (d + δ + ρ3 )

+β2 (1 − θ )(d + ρ2 )]

a1 = u(d + ρ2 ) (d + ρ1 + ω)[(d + δ + ρ3 )[2β1 θ (d + δ + ρ3 + u) + (1 − θ )
(d + ρ2 )(2β2 + du)] + β2 (1 − θ )(d + ρ2 )σ u] + ηuω(1 − θ )[β1 θ (d + δ + ρ3 ) +
β2 (1 − θ )(d + ρ2 )]
a2 = (d + ρ2 ) − 2d 4 (1 − θ )u − d 3 (−β1 θ + β2 (1 − θ ) + (1 − θ )u(σ u + 2)
(δ + ρ1 + ρ2 + ρ3 + ω)) − d 2 (β1 θ (2δ + ρ1 + 2ρ3 + 2σ u + ω) + β2 (1 − θ )(δ +
ρ1 + ρ2 + ρ3 + σ u + ω) + (1 − θ )u(2(ρ1 + ω)(ρ2 + ρ3 ) + 2ρ2 ρ3 + (ρ1 + ρ2 +
ω)(2δ + σ u))) − d (β1 θ ((δ + ρ3 + σ u)((δ + 2ρ1 + ρ3 + σ u) + ω) − 2η(1 − θ )
uω) + (1 − θ )(β2 (δ(ρ1 + ρ2 + ω) − 2η(1 − θ )uω + (ρ1 + ω)(ρ 2 + ρ3 + σ u) +
ρ2 (ρ3 + σ u)) + ρ2 u(ρ1 + ω)(2(δ + ρ3 ) + σ u))) + β1 θ − ω σ 2 u2 + σ u(2δ +
2ρ3 − η(1 − θ )u) + (δ + ρ3 )(δ + ρ3 − 2η(1 − θ )u) − ρ1 (δ + ρ3 + σ u)2 − β2
(1 − θ )ρ2 ((ρ1 + ω)(δ + ρ3 + σ u) − 2η(1 − θ )uω)
a3 = (1 − θ )(d + ρ2 ) ω d 2 (d +ρ2 ) + d (δ + ρ3 + σ u)(d − ρ2 ) + ηβ2 (1 − θ )
(d + ρ2 ) + ηβ1 θ (d + δ + ρ3 + σ u) − d (d + ρ1 )(d + ρ2 )(d + δ + ρ3 + σ u) .
5.2 Basic Reproduction Number
The basic reproduction number is the most important epidemiological parameter for
any epidemic model to determine the nature of a disease. Usually, it is denoted by
R0 and is defined as the number of secondary infections made by a single infected
individual in contact with susceptible population during its whole infectious period.
Therefore, the dimensionless quantity, R0 refers as the expectation of the spreading
disease. To calculate it we need equilibria of the system. Generally disease persists
in a system if R0 is greater than unity and disease will dies out if R0 is less than
unity. The proposed system (1) has always possesses disease free equilibria and it
is given by P0 = dη , 0, 0, 0, 0 . We use the next generation matrix approach [12] to
determine R0 . The compartments which are directly engaged to spread the disease
are E, A, and I . Therefore, we consider the following three equations of the system
(1) to find the basic reproduction number.
96 M. Mandal et al.
⎧
⎪
⎨ dt = (β1 A + β2 I )S − (ρ1 + ω + d )E,
dE
dA
= θ ωE − (ρ2 + d )A,
⎪ dt
⎩ dI σu

dt
= (1 − θ )ωE − ρ3 + 1+uI +d +δ I
The above system can be written as dX

dt
= F(X ) − V(X ), where
⎛ ⎞ ⎛ ⎞
E (β1 A + β2 I )S
X = ⎝ A ⎠ , F(X ) = ⎝ 0 ⎠,
I 0
⎛ ⎞
(ρ1 + ω + d )E
and V(X ) = ⎝ −θ ωE + (ρ2 + d )A
⎠
σu
−(1 − θ )ωE + ρ3 + 1+uI +d +δ I
.
And the Jacobian⎛matrices of⎞F and V at the disease free equilibria are given by
0 βd1 η βd2 η
⎝
F = J (F|P0 ) = 0 0 0 ⎠ and
0 0 0
⎛ ⎞
ρ1 + ω + d 0 0
V = J (V|P0 ) = ⎝ −θ ω ρ2 + d 0 ⎠
−(1 − θ )ω 0 ρ3 + σ u + d + δ
respectively. The basic reproduction number, R0 is the spectral radius of the of the
matrix FV −1 and for the system (1) it is calculated as

ηω β1 θ β2 (1 − θ )
R0 = + . (5)
d (d + ρ1 + ω) d + ρ2 d + δ + ρ3 + σ u
5.3 Existence and Uniqueness of Solutions
The following theorem is stated and proved in connection to the existence and unique-
ness of solutions of the model system.
Theorem 1 For every initial point Xt0 = (St0 , Et0 , At0 , It0 , Rt0 ) ∈ R there exists a
unique solution Xt = (St , Et , At , It , Rt ) ∈ R of the system (2) for any time t > t0 .
Proof To prove the existence and uniqueness criterion of the system (2), we con-
sider the region [t0 , P] × R where R = {(x1 , x2 , x3 , x4 , x5 ) ∈ R5 : max{|S|, |E|, |A|,
|I |, |R|} ≤ Q}, where P, Q are two finite positive real numbers. Let, X = (S, E, A, I ,
R), Y = (S1 , E1 , A1 , I1 , R1 ) be two points in R and let us define the mapping
H : R → R5 by H (X ) = (H1 (X ), H2 (X ), H3 (X ), H4 (X ), H5 (X )) where
⎧
⎪
⎪ H1 (X ) = η − (β1 A + β2 I )S − dS,
⎪
⎪
⎪
⎪
⎨ H2 (X ) = (β1 A + β2 I )S − (ρ1 + ω + d )E,
H3 (X ) = θ ωE − (ρ2 + d )A,
⎪
⎪
⎪
⎪ H4 (X ) = (1 − θ )ωE − ρ3 + 1+uIσu
+ d + δ I,
⎪
⎪
⎩ H (X ) = σu
ρ1 E + ρ2 A + ρ3 + 1+uI I − dR.
5
For X , Y ∈ R, we have
||H (X ) − H (Y )||
= |H1 (X ) − H1 (Y )| + |H2 (X ) − H2 (Y )| + |H3 (X ) − H3 (Y )| + |H4 (X ) − H4 (Y )|

+|H5 (X ) − H5 (Y )|
= |η − (β1 A + β2 I )S − dS − η + (β1 A1 + β2 I1 )S1 + dS1 |

+|(β1 A + β2 I )S − (ρ1 + ω + d )E − (β1 A1 + β2 I1 )S1
−(ρ1 + ω + d )E1 | + |θ ωE − (ρ2 + d )A − θ ωE1 + (ρ2 + d )A1 |

σu σu
+|(1 − θ )ωE − ρ3 + + d + δ I − (1 − θ )ωE1 + ρ3 + + d + δ I1 |
1 + uI 1 + uI1
σu σu
+|ρ1 E + ρ2 A + ρ3 + I − dR − ρ1 E1 − ρ2 A1 − ρ3 + I1 − dR1 |
1 + uI 1 + uI
= |β1 (A1 S1 − AS) + β2 (I1 )S1 − IS) + d (S1 − S)| + |(β1 (AS − A1 S1 ) + β2 (IS − I1 S1 )
+ρ1 (E − E1 ) + ω(E − E1 ) + d (E − E1 )| + |θ ω(E − E1 ) − (ρ3 +

σ u(I − I1 )
δ + d )(I − I1 ) − |
(1 + uI )(1 + uI1 )
I − I1
+|ρ1 (E − E1 ) + ρ2 (A − A1 ) + ρ3 (I − I1 ) + σ u( − d (R − R1 )|
(1 + uI )(1 + uI1 )
≤ 2β1 |AS − A1 S1 | + 2β2 |IS − I1 S1 | + d |S1 − S| + (2ρ1 + ω + d + θ ω)|E1 − E|
I − I1
+2σ u| | + (2ρ3 + d + δ)|I − I1 | + ρ2 |A − A1 | + d |R − R1 |
(1 + uI )(1 + uI1 )
98 M. Mandal et al.
≤ 2β1 Q[|A − A1 | + |S − S1 |] + 2β2 Q[|I − I1 | + |S − S1 |] + d |S − S1 |

+(2ρ1 + ω + d + θ ω)|E − E1 |
+(2σ u + 2ρ3 + d + δ)|I − I1 | + ρ2 |A − A1 | + d |R − R1 |
≤ (2β1 Q + 2β2 Q + d )|S − S1 | + (2ρ1 + (1 + θ )ω + d )|E − E1 | + (2β1 Q + ρ2 )|A − A1
+(2β2 Q + 2σ u + 2ρ3 + d + δ)|I − I1 | + d |R − R1 |
≤ R||X − Y ||,
where R = max{(2β1 Q + 2β2 Q + d ), (2ρ1 + (1 + θ )ω + d ), (2β1 Q + ρ2 ), (2β2

Q + 2σ u + 2ρ3 + d + δ), d } Therefore, H (X ) satisfies the Lipscitz’s condition with
respect to X = (S, E, A, I , R) ∈ R. Hence from Lemma(7) we can conclude that the
system (2) possesses a unique solution with initial condition Xt0 = (St0 , Et0 , At0 , It0 , Rt0 ) ∈
R. Hence the theorem follows
5.4 Non-negativity and Boundedness of Solutions
In mathematical biology, we are concerned about the solutions which are non-
negative and bounded. Let us define R+ = {(St , Et , At , It , Rt ) ∈ R : S, A, E, I , R ∈
R5 } where R+ is the set of all non-negative real numbers.
Theorem 2 All the solutions of the system (2) starting in R+ 5 are non-negative and
uniformly bounded.
Proof (Non-negativity): Let us consider that Xt0 = (St0 , Et0 , At0 , It0 , Rt0 ) ∈ R+ be an
initial solution of the system (2). Assume T be a real number such that t0 ≤ t < T
and ⎧
⎪
⎨0 for t0 ≤ t < T
S(t) = 0 for t = T
⎪
⎩
< 0 for t = T +
From the the first equation of (2), we have t0 Dtα S(t)|S(T ) = 0. Then from Lemma
(1) we can say that S(T + ) = 0, which contradicts our assumption S(T + ) < 0.
Hence, for any t ∈ [t0 , ∞), we have S(t) ≥ 0. We can also prove E(t), A(t), I (t),
R(t) ≥ 0 for all t ≥ 0 ∀ t ∈ [t0 , ∞) in a similar way.
(Uniform boundedness)
To prove the uniform boundedness of the solutions we define the function F(t) =
S(t) + E(t) + A(t) + I (t) + R(t). Then,
α α α α α α
t0 Dt F(t) + F(t) = t0 Dt S(t) + t0 Dt E(t) + t0 Dt A(t) + t0 Dt I (t) + t0 Dt R(t)
+ d (S(t) + E(t) + A(t) + I (t) + R(t))
= η − δI (t)
≤ η as I (t) > 0
By Lemma 3, we have F(t) ≤ (F(t0 ) − ηδ )Eα [−δ(t − t0 )α ] + ηδ → ηδ as t → ∞.
Therefore all solution of the system (2) starting in the region R+ are lying in the
region = {(S, E, A, I , R) ∈ R+ : S + E + A + I + R ≤ ηδ }
5.5 Dynamical Behavior
Here we discuss about the stability of the DFE point P0 = ( dη , 0, 0, 0, 0) of the sys-
tem (2) and the endemic equilibrium point P∗ = (S ∗ , E ∗ , A∗ , I ∗ , R∗ ).
The Jacobian matrix at any point (S, E, A, I, R) is given by
J (S, E, A, I , R)
⎛ ⎞
−(β1 A + β2 I ) − d 0 −β1 S −β2 S 0
⎜ (β1 A + β2 I ) −(ρ + ω + d ) β S β2 S 0 ⎟
⎜ 1 1 ⎟
=⎜ ⎜ 0 θ ω −(ρ + d ) 0 0 ⎟
2
σu ⎟
⎝ 0 (1 − θ )ω 0 −(ρ3 + d + δ) − (1+uI )2
0 ⎠
σu
0 ρ1 ρ2 ρ3 + (1+uI )2 −d
η
At the DFE point d
, 0, 0, 0, 0 the Jacobian matrix is
⎛ ⎞
−d 0 −β1 dη −β2 dη 0
⎜ 0 ⎟
η
η ⎜ 0 −(ρ1 + ω + d ) β1 d β2 dη ⎟
J , 0, 0, 0, 0 = ⎜
⎜ 0 θω −(ρ2 + d ) 0 0 ⎟
⎟
d ⎝ 0 (1 − θ )ω 0 −(ρ3 + d + δ) − σ u 0 ⎠
0 ρ1 ρ2 ρ3 − σ u −d

The eigenvalues of the system (2) at E 0 = dη , 0, 0, 0, 0 are λ1 = −d , λ2 = −d
and the other three eigenvalues are obtained from the equation
p(λ) = λ3 + b1 λ2 + b2 λ + b3 = 0
where b1 = 3d + δ + ρ1 + ρ2 + ρ3 + σ u + ω,
b2 = 3d 2 + 2d δ + (2d + δ)ρ1 + (2d + δ) ∗ ρ2 + ρ1 ρ2 + 2d ρ3 + ρ1 ρ3 + ρ2 ρ3

+ 2duσ + u(ρ1 + ρ2 )σ + (2d + δ + ρ2 + ρ3 + σ u)ω + β2 η(θ−1)ω−β
d
1 ηθω
,
b3 = (1 − R0 ) (d + ρ2 ) (d + ρ1 + ω) (d + δ + ρ3 + σ u) .
100 M. Mandal et al.
Since all the parameters considered here are positive, from the expressions of
b1 , b2 , b3 we can conclude that
(i) b1 > 0
(ii) b3 > 0 if and only if R0 < 1.
Also we have D(p) = −27(1 − R0 )3 (d + ρ2 )3 (d + δ + ρ3 + σ u)3 (ρ + d + ω)3

− 4(1 − R0 )(d + ρ2 )(d + δ + ρ3 + σ u)(d + ρ1 + ω)(3d + δ + ρ1 + ρ3 + ω +
σ u)2 + 18d
(1 − R0 )(d + ρ2 )(d + δ + ρ3 + σ u)(d + ρ1 + ω)(3d + δ + ρ1 + ρ3 +
ω + σ u)[3d 3 + η{β2 (θ − 1) − β1 θ }ω + 2d 2 (δ + ρ1 + ρ2 + ρ3 + ω + σ u) + d {ρ2
ρ3 + uρ2 σ + ρ1 (ρ2 + ρ3 + σ u) + (ρ2 + ρ3 + σ u)ω + δ(ρ1 + ρ2 + ω)}] + d12 {−4
+ (3d + δ + ρ1 + ρ3 + σ u + ω)2 }[3d 2 + η{β2 (θ − 1) − β1 θ } + 2d 2 (δ + ρ1 + ρ2
+ ρ3 + σ u + ω) + d {(ρ2 ρ3 + uρ2 σ + ρ1 (ρ2 + ρ3 + σ u) + (ρ2 + ρ3 + σ u)ω + δ
(ρ1 + ρ2 + ω)}]2 defined in lemma (6).
(iii) b1 b2 − b3 = (−1 + R0 )(d + ρ2 )(d + δ + ρ3 + uσ )(d + ρ1 + ω)
+ d1 (((3d + δ + ρ1 + ρ3 + uσ + ω)(3d 3 + η(β2 (−1 + θ ) − β1 θ )ω + 2d 2 (δ +
ρ1 + ρ2 + ρ3 + uσ + ω)+
d (ρ2 ρ3 + uρ2 σ + ρ1 ρ2 + ρ3 + uσ ) + ρ2 ω + ρ3 ω + uσ ω + δ(ρ1 + ρ2 + ω))))
Hence, b1 b2 − b3 > 0 if and only if R0 > 1.
5.6 Existence of the Endemic Equilibrium Point
seen that a0 , a1 > 0 and

From equation (4) it can easily
a3 = (1 − θ )(d + ρ2 )(ω d 3 + d 2 (δ + ρ2 + ρ3 + σ u) + d (β1 ηθ + β2 η(1 − θ )
− ρ2 (δ + ρ3 + σ u)) + η(β2 (1 − θ )ρ2 + β1 θ (δ + ρ3 + σ u))
− d (d + ρ1 )(d + ρ2 )(d + δ + ρ3 + σ u))
= −(1 − θ )(d + ρ2 )[d (d + ρ1 )(d + ρ2 )(d + δ + ρ3 + σ u)(1 − R0 )
+ωd 2 (d + δ + ρ2 + ρ3 + σ u) − R0 d ω(d + ρ2 )(d + δ + ρ3 + σ u)

−ηωρ2 (δ + ρ3 + σ u)]
= (1 − θ )(d + ρ2 )[d (d + ρ1 )(d + ρ2 )(d + δ + ρ2 + ρ3 + σ u)(R0 − 1)

+ ωd {d (R0 − 1)(d + δ + ρ3 + σ u) + R0 ρ2 (δ + ρ3 + σ u)}]
It is easy to see that a3 > 0 for any R0 > 1. However, the sign of a2 is not fixed.
There are three possibilities. a2 > 0, a2 = 0, a2 < 0. If a2 ≥ 0, then by Descarte’s
rule of sign the equation (4) does not have any positive real solution. Hence, to analyze
the behavior of the system (2) we take the case a2 < 0. Then we can conclude that
the system (2) possesses two endemic equilibrium point for if a2 < 0. Further a2 < 0
is satisfied if and only if
1 δ(ρ1 + ρ2 + ω δ + ρ3
η< min{ , 2 ,
u(1 − θ ) 2(1 − θ )ω u(1 − θ )
δ + ρ3 (δ + ρ3 + σ u)(δ + 2ρ1 + ρ3 + σ u + ω) (ρ1 + ω)(δ + ρ3 + σ u)
, , }.
2u(1 − θ ) 2uω(1 − θ ) 2(1 − θ )uω
For R0 = 1, a3 > 0 hence, the same result follows. For R0 < 1, a3 takes positive
value. In both the cases we can see the existence of an EE point using Descatre’s rule
of sign.
Theorem 3 (i) There exists two endemic equilibrium points say (S ∗ , E ∗ , A∗ , I ∗ , R∗ )

of the system (2) provided
1 δ(ρ1 + ρ2 + ω δ + ρ3
R0 > 1 and eta < min{ , 2 ,
u(1 − θ ) 2(1 − θ )ω u(1 − θ )
δ + ρ3 (δ + ρ3 + σ u)(δ + 2ρ1 + ρ3 + σ u + ω)
, ,
2u(1 − θ ) 2uω(1 − θ )
(ρ1 + ω)(δ + ρ3 + σ u)
}.
2(1 − θ )uω
(ii) For R0 = 1, a3 > 0 and there exists an endemic equilibrium point for the sys-
tem (2).
(iii) For R0 < 1 the system (2) has an endemic equilibrium point for a2 < 0.
Thus we see from Theorem 3, the system (2) possesses endemic equilibrium point
even if R0 < 1. Thus we can say that the system undergoes a backward bifurcation.
The investigation of the existence of the backward bifurcation in any epidemic model
is very much demanding. Because the occurrence of the backward bifurcation indi-
cates that the system possesses an infected steady state together with the disease
free steady state when R0 < 1. Therefore, the condition R0 < 1 can not ensure the
disease will be removed from the population. So the further refinement of R0 and
additional restrictions are required. Fig. 2 depicts the backward bifurcation of the
system (2) with parameter values η = 5; β1 = 0.038; β2 = 0.082; σ = 0.84; u =
1; d = 0.2; δ = 0.25; ρ1 = 0.28; ρ2 = 0.38; ρ3 = 0.38; θ = 0.2; ω = 0.52.
5.7 Stability of the Endemic Equilibrium Point
The Jacobian matrix at the EE point (S ∗ , E ∗ , A∗ , I ∗ , R∗ ) is given by
J (S ∗ , E ∗ , A∗ , I ∗ , R∗ )
⎛ ⎞
−(β1 A∗ + β2 I ∗ ) − d 0 −β1 S ∗ −β2 S ∗ 0
⎜ (β1 A∗ + β2 I ∗ ) −(ρ + ω + d ) β S ∗ β2 S ∗ 0 ⎟
⎜ 1 1 ⎟
⎜ 0 θ ω −(ρ + d ) 0 0 ⎟
=⎜ 2 ⎟
⎜ 0 (1 − θ )ω 0 −(ρ + d + δ) − σu 0 ⎟
⎝ 3 (1+uI ∗ )2 ⎠
0 ρ1 ρ2 ρ3 + σ u −d
(1+uI ∗ )2
0.8
0.7
Stable EE
0.6
0.5
0.4
I
0.3
0.2
Unstable EE
0.1
Stable DFE Unstable DFE

0
0 0.5 1 1.5 2 2.5 3
R
0
Fig. 2 Backward bifurcation of the system (2)
The characteristic polynomial of the Jacobian matrix at the EE point is
λ4 + c1 λ3 + c2 λ2 + c3 λ + c4 = 0
where,
uσ
c1 = (4d + Aβ1 + I β2 + δ + ρ1 + ρ2 + ρ3 + + ω),
(1 + Iu)2
c2 = 6d 2 + 3 Ad β1 + 3dI β2 + 3d δ + Aβ1 δ + I β2 δ + 3d ρ1 + Aβ1 ρ1 + I β2 ρ1 +

δρ1 + 3d ρ2 + Aβ1 ρ2 + I β2 ρ2 + δρ2 + ρ1 ρ2 + 3d ρ3 + Aβ1 ρ3 + I β2 ρ3 + ρ1 ρ3 + ρ2
(3duσ )
ρ3 + (1+I 1u)2
+ (Auβ1σ )
(1+Iu)2
(Iuβ2 σ )
+ (1+Iu) (uρ1 σ ) (uρ2 σ )
2 + (1+Iu)2 + (1+Iu)2 + 3d ω + Aβ1 ω + I β2 ω + δω +
(uσ ω)
Sβ 2 (−1 + θ )ω + ρ 2 ω + ρ3 ω + (1+Iu) 2,
c3 = 4d 3 + 3d 2 (Aβ1 + I β2 + δ + ρ1 + ρ2 + ρ3 + ω) + 2Ad β1 (δ + ρ1 + ρ2 +
ρ3 + ω) + 2dI β2 (δ + ρ1 + ρ2 + ρ3 + ω) + 2dI β2 (δ + ρ1 + ρ2 + ρ3 + ω) + (2d +
Aβ1 )δ(ρ2 + ρ2 + ω) + (2d + Aβ1 + I β2 + δ)ρ1 ρ2 + (2d + Aβ1 + I β2 )ρ1 ρ3 + (2d
+ Aβ1 + I β2 + ω)ρ2 ρ3 + ρ1 ρ2 ρ3 + Sβ2 (θ − 1)ω(2d + ρ2 ) − Sβ2 (Aβ1 + I β2 ) +
3d 2 uσ 2 Aduβ1 σ 2dIuβ2 σ
(2d + Aβ1 + δ)ρ2 ω + ρ3 ω(2d + Aβ1 + I β2 + ρ2 ) + (1+Iu) 2 + (1+Iu)2 + (1+Iu)2 +
2duρ1 σ Auβ1 ρ1 σ Iuβ2 ρ1 σ 2duρ2 σ Auβ1 ρ2 σ I 1uβ2 ρ2 σ uρ1 ρ2 σ 2duσ ω
(1+Iu)2
+ (1+Iu)2
+ (1+Iu)2
+ (1+Iu)2
+ (1+Iu)2
+ (1+I 1u)2
+ (1+Iu)2
+ (1+Iu)2
+
Auβ1 σ ω Iuβ2 σ ω uρ2 σ ω
(1+Iu)2
+ (1+Iu)2
+ (1+Iu)2
,
c4 = d 4 + Ad 3 β1 + d 3 I β2 + d 3 δ + Ad 2 β1 δ + d 2 I β2 δ + λ4 + d 3 ρ1 + Ad 2 β1 ρ1
+ d 2 I β2 ρ1 + d 2 δρ1 + Ad β1 δρ1 + dI β2 δρ1 + d 3 ρ2 + Ad 2 β1 ρ2 + d 2 I β2 ρ2 + d 2 δρ2
+ Ad β1 δρ2 + dI 1β2 δρ2 + d 2 ρ1 ρ2 + Ad β1 ρ1 ρ2 + dI β2 ρ1 ρ2 + d δρ1 ρ2 + Aβ1 δρ1

ρ2 + I β2 δρ1 ρ2 + d 3 ρ3 + Ad 2 β1 ρ3 + d 2 I β2 ρ3 + d 2 ρ1 ρ3 + Ad β1 ρ1 ρ3 + dI β2 ρ1 ρ3 +
d 3 uσ
d 2 ρ2 ρ3 + Ad β1 ρ2 ρ3 + dI β2 ρ2 ρ3 + d ρ1 ρ2 ρ3 + Aβ1 ρ1 ρ2 ρ3 + I β2 ρ1 ρ2 ρ3 + (1+Iu) 2 +
Ad 2 uβ1 σ ) 2
Iuβ2 σ d 2 uρ1 σ Aduβ1 ρ1 σ dIuβ2 ρ1 σ d 2 uρ2 σ Aduβ1 ρ2 σ dIuβ2 ρ2 σ
(1+I 1u)2
+ d(1+Iu) 2 + (1+Iu)2 + (1+Iu)2 + (1+Iu)2 + (1+Iu)2 + (1+Iu)2 + (1+Iu)2 +
1 ρ1 ρ2 σ
duρ1 ρ2 σ
(1+Iu)2
+ Auβ
(1+Iu)2
+ Iuβ2 ρ)1 ρ2 σ (1 + Iu)2 + d 3 ω + Ad 2 β1 ω + d 2 I β2 ω + d 2 δω + Ad
β1 δω + dI β2 δω + d 2 Sβ2 (−1 + θ )ω + AdSβ1 β2 (−1 + θ )ω + dISβ22 (−1 + θ )ω −
dSβ2 (Aβ1 + I β2 )(−1 + θ )ω + dSβ1 (Aβ1 + I β2 )θ ω + Sβ1 (Aβ1 + I β2 )δθ ω + d 2 ρ2
ω + Ad β1 ρ2 ω + dI β2 ρ2 ω + d δρ2 ω + Aβ1 δρ2 ω + I β2 δρ2 ω + dSβ2 (−1 + θ )ρ2 ω +
ASβ1 β2 (−1 + θ )ρ2 ω + ISβ22 (−1 + θ )ρ2 ω − Sβ2 (Aβ1 + I β2 )(−1 + θ )ρ2 ω + d 2 ρ3
ω + Ad β1 ρ3 ω + dI β2 ρ3 ω + Sβ1 (Aβ1 + I β2 )θρ3 ω + d ρ2 ρ3 ω + Aβ1 ρ2 ρ3 ω + I β2
d 2 uσ ω Aduβ1 σ ω dIuβ2 σ ω Suβ1 (Aβ1 +I β2 )θσ ω 2σ ω 1 ρ2 σ ω
ρ2 ρ3 ω + (1+Iu) 2 + (1+Iu)2 + (1+Iu)2 + (1+Iu)2
+ duρ
(1+Iu)2
+ Auβ
(1+Iu)2
+
Iuβ2 ρ2 σ ω
(1+Iu)2
.
It is easy to see that c1 , c2 > 0,

c1 c2 c3 − (c32 + c12 c4 ) = (4d + Aβ1 + I β2 + δ + ρ1 + ρ2 + ρ3 + (1+Iu) uσ
2 + ω)
(6d + I β2 (δ + ρ1 + ρ2 + ρ3 + ω) + δ(ρ1 + ρ2 ) + (ρ1 ρ2 + ρ1 ρ3 + ρ2 ρ3 ) +

2
σ u(I β2 +ρ1 +ρ2 +ω) uσ ω
(1+Iu)2
+ −(Sβ2 + δ + Sβ2 θ + ρ2 + ρ3 )ω + (1+Iu) 2 + (Aβ1 + 3d )(δ +
ρ1 + ρ2 + ρ3 + (1+Iu)2 + ω) + 3d (Aβ1 + I β2 ))(4d + I β2 (δρ1 + δρ2 + ρ1 ρ2 + ρ1

uσ 3
ρ2 + ρ1 ρ3 + ρ2 ρ3 + δω + ρ2 ω + ρ3 ω + Sβ1 θ ω) + ρ1 ρ2 (δ + ρ3 ) +
Iuβ2 σ (ρ1 +ρ2 +ω)+uρ1 ρ2 σ +uρ2 σ ω
(1+Iu)2
+ ρ2 ω(δ − Sβ2 + Sβ2 θ + ρ3 ) + 3d 2 (Aβ1 + I β2 + δ +
uρ2 σ
ρ1 + ρ2 + ρ3 + (1+Iu)2 + ω) + Aβ1 (ρ2 ρ3 + (1+Iu)
uσ
2 + ρ1 (ρ2 + ρ3 + (1+Iu)2 + Sβ1 θ
uσ
uσ ω
ω + ρ2 ω + ρ3 ω + (1+Iu)2 + δ(ρ1 + ρ2 + ω)) + 2d (δρ1 + δρ2 + ρ1 ρ2 + ρ1 ρ3 + ρ2
u(ρ1 +ρ2 )σ uσ ω
ρ3 + (1+Iu)2
+ (1 − θ )Sβ2 ω + δω) + (ρ2 + ρ3 ) ω + (1+Iu) 2 + Aβ1 (δ + ρ1 + ρ2 +
ρ3 + uσ
(1+Iu)2
+ ω) + I β2 (δ + ρ1 + ρ2 + ρ3 + (1+Iu)
uσ
2 + ω))) − (4d 3 + I β2 (δρ1 + δ
Iuβ2 (ρ1 +ρ2 +ω)σ
ρ2 + ρ1 ρ2 + ρ1 ρ3 + ρ2 ρ3 + δω + Sβ1 + θ + ω + ρ3 ω) + (1+Iu)2
+
σ uρ2 (ω+ρ1 )
(1+uI )2
− ρ2 ω(2 + Sβ2 + δ + Sβ2 θ ) + δρ1 ρ2 + ρ2 ρ3 ω) + 3d (Aβ1 + I β2 + δ +
2
uρ2 σ
ρ1 + ρ2 + ρ3 + (1+Iu) uσ
2 + ω) + Aβ1 (ρ2 ρ3 + (1+Iu)2 + ρ1 (ρ2 + ρ3 + (1+Iu)2 + Sβ1 θ
uσ
uσ ω
ω + ρ2 ω + ρ3 ω + (1+Iu)2 + δ(ρ1 + ρ2 + ω)) + 2d (δρ1 + δρ2 + ρ1 ρ2 + ρ1 ρ3 + ρ2
uρ1 σ uρ2 σ uσ ω
ρ3 + (1+Iu) 2 + (1+Iu)2 − Sβ2 ω + δω + Sβ2 θ ω + ρ2 ω + ρ3 ω + (1+Iu)2 + Aβ1 (δ +
ρ1 + ρ2 + ρ3 + (1+Iu)2 + ω + I β2 (δ] + ρ1 + ρ2 + ρ3 + (1+Iu)2 + ω)))2 − (4d + A

uσ uσ
β1 + I β2 + δ + ρ1 + ρ2 + ρ3 + (1+Iu) uσ
2 + ω) (d + d (Aβ1 + I β2 + δ + ρ1 + ρ2 +
2 4 3
(ρ1 ρ2 +(Sβ1 θ+ ρ2 )ω)

ρ3 + (1+Iu)uσ
2 + ω) + ((Aβ1 + I β2 )((1 + Iu) δ + (1 + Iu) ρ3 + uσ )
2 2
(1+Iu)2
uρ1 σ uρ2 σ
+ d (δρ1 + δρ2 + ρ1 ρ2 + ρ1 ρ3 + ρ2 ρ3 + (1+Iu)2 + (1+Iu)2 − Sβ2 ω + δω + Sβ2 θ ω
2
uσ ω
+ ρ2 ω + ρ3 ω + (1+Iu) 2 + Aβ1 (δ + ρ1 + ρ2 + ρ3 + (1+Iu)2 + ω) + I β2 (δ + ρ1 +
uσ
ρ2 + ρ3 + (1+Iu)2 + ω)) + d (ρ2 (ρ1 (ρ3 + (1+Iu)2 + (Sβ2 (−1 + θ ) + ρ3 + σu )

uσ uσ
uρ2 σ
(1 + I 1u)2 ω + δ(ρ1 + ω)) + Aβ1 (ρ2 ρ3 + (1+I 1u)2
+ ρ1 (ρ2 + ρ3 + (1+Iu) uσ
2 + Sβ1 θ ω
uσ ω uρ2 σ
+ ρ2 ω + ρ3 ω + (1+Iu)2 + δ(ρ1 + ρ2 + ω)) + I β2 (ρ2 ρ3 + (1+Iu)2 + ρ1 (ρ2 + ρ3 +
uσ ω
uσ
(1+Iu)2
) + Sβ1 θ ω + ρ2 ω + ρ3 ω + (1+Iu) 2 + δ(ρ1 + ρ2 + ω))))
By Routh-Hurwitz’s criterion we can conclude that the endemic equilibrium point

is locally asymptotically stable.
5.8 Incommensurate Fractional Order System
Now we consider the incommensurate fractional order system (3), αi ∈ (0, 1] for
i = 1, 2, 3, 4, 5 and ζ = L1 where L = lcm(q1 , q2 , q3 , q4 , q5 ) and αi = pqii , where pi ,
qi are relatively prime for i = 1, 2, 3, 4, 5. Then by Lemma 5, an equilibrium point
of the system is locally asymptotically stable if and only if |arg(λ)| > ζ2π for all
roots λ’s of the characteristic equation
det(M − J ) = 0
where M = diag(λLα1 , λLα2 , λLα3 , λLα4 , λLα5 ) and J is the Jacobian matrix evaluated
at that equilibrium point (S ∗ , E ∗ , A∗ , I ∗ , R∗ ).
5.9 Stochastic Stability of Endemic Equilibrium Point
In this section, we will study our proposed model in the deterministic environment.
The dynamical behavior of the modified model coming up from white noise since
it provides a more realistic picture than its deterministic counterpart. In general the
modified version of the deterministic model is made by perturbing the deterministic
model with white noise that may be of two types. In the first way one or more impor-
tant parameters of the deterministic system are perturbed by white noise characterized
by a Gaussian distribution (see [26]) where as in the second way it is assumed that
the fluctuation affect the whole deterministic system rather than some parameters
(see [20]). In our present problem we consider that the fluctuation affects the whole
system and we want to examine its effect around the endemic equilibrium of the
system (1). It is assumed that a small perturbations around the endemic equilibrium
P∗ are directly proportional to the distances between S(t), E(t), A(t), I (t), R(t) and
(S ∗ , E ∗ , A∗ , I ∗ , R∗ ) . This type of approach is also considered by Beretta et al. [9].
Thus the system (1) can be written as:
⎧
⎪
⎪ dS = [η − (β1 A + β2 I )S − dS] dt + θ1 (S − S ∗ )dX1 ,
⎪
⎪
⎪
⎪ = [(β1 A + β2 I )S − (ρ1 + ω + d )E] dt + θ2 (E − E ∗ )dX2 ,
⎨ dE
dA = [θ ωE − (ρ2 + d )A] dt + θ3 (A − A∗ )dX3 , (6)
⎪
⎪
⎪
⎪ dI = (1 − θ )ωE − ρ3 + 1+uI σu
+ d + δ I dt + θ4 (I − I ∗ )dX4 ,
⎪
⎪
⎩ dR = σu
ρ1 E + ρ2 A + ρ3 + 1+uI I − dR dt + θ5 (R − R∗ )dX5 .
where, θi (i = 1, 2, 3, 4) are non-negative real intensities of environmental fluc-

tuations and X (t) = (X1 (t), X2 (t), X3 (t), X4 (t)) is a four dimensional Brownian
motion (white noise process) defined on a complete probability space. Thus dX =
(dX1 (t), dX2 (t), dX3 (t), dX4 (t)) is the required four dimensional white noise process
(see [32]). The system (6) has the same equilibrium as the deterministic one (1) and
for θi (i = 1, 2, 3, 4) the modified system (6) reduces to the original deterministic

model (1). Clearly, it makes us wonder that whether the dynamical behavior of our
deterministic model is robust with respect to such kind of a small perturbations of
white noise type by testing the asymptotic mean square stability behavior around the
endemic equilibrium E* of the modified differential equation system (6) and com-
paring the results with our deterministic system (1) (see [21]). The system of Eq. (6)
can be written as the Ito’ s differential system (see [32]) and this is of the form.
dY (t) = g(Y (t))dt + g(Y (t))dX (t), Y (t0 ) = Y0 , t ∈ [t0 , tg ]
Here the set of solutions due to Ito’s process is given by {Y (t) : t ∈ [t0 , tg ]}. We
translate the origin to the endemic equilibrium P∗ , (S ∗ , E ∗ , A∗ , I ∗ , R∗ ) and denote the
new variable as z1 = S − S ∗ , z2 = E − E ∗ , z3 = A − A∗ , z4 = I − I ∗ , z5 = R − R∗ .
The linearization of the system (6) around the endemic equilibrium P∗ is given
by
dz(t) = g(z(t))dt + g(z(t))dX (t) (7)
where z(t) = (z1 (t), z2 (t), z3 (t), z4 (t), z5 (t))T ,

⎡ ⎤ ⎡ ⎤
−c2 z1 0 −β1 S ∗ z3 −β2 S ∗ z4 0 θ1 z1 0 0 0 0
⎢−c1 z1 −c3 z2 −β1 S ∗ z3 −β2 S ∗ z4 0 ⎥ ⎢ 0 θ2 z2 0 0 0 ⎥
⎢ ⎥ ⎢ ⎥
g(z) = ⎢
⎢ 0 θ ωz2 −c z
4 3 0 0 ⎥
⎥ , h(z) = ⎢
⎢ 0 0 θ z
3 3 0 0 ⎥ ⎥
⎣ 0 (1 − θ )ωz2 0 0 0 ⎦ ⎣ 0 0 0 θ4 z4 0 ⎦
0 ρ1 z2 ρ2 z3 −c5 z4 −dz5 0 0 0 0 θ5 z5
and c1 = β1 A∗ + β2 I ∗ , c2 = c1 + d , c3 = ρ1 + ω + d , c4 = d + ρ2 , c5 = d + δ.
Clearly, the endemic equilibrium of the system (6) which is the trivial solution of the
system (7) i.e. (z1 , z2 , z3 , z4 , z5 ) = (0, 0, 0, 0, 0).
Assume = {t × R5 : t > t0 ∈ R+ }. Let U = C 2 () be a space for the twice con-
tinuously differentiable functions of z. With the help of the article [11], we only state
the following lemma.
Lemma 8 Let U (z, t) ∈ C 2 () be a function which satisfies the following inequal-
ities
M1 |z|k ≤ U (z, t) ≤ M2 |z|k and
LU (z, t) ≤ −M3 |z|k , where Mi > 0 for i = 1, 2, 3 and k > 0.
Then we have the following result: the trivial solution of the system (7) i.e.
(z1 , z2 , z3 , z4 , z5 ) = (0, 0, 0, 0, 0) is exponentially k-stable, whenever t ≥ 0, where
the differential operator is given by

∂U (z(t), t) T ∂U (z(t), t) 1 T ∂ 2 U (z(t), t)
LU (z(t), t) = + g (z(t), t) + Trace h (z(t)) h(z(t)) .
∂t ∂z 2 ∂2z
Particularly, for k = 2 the trivial solution (z1 , z2 , z3 , z4 , z5 ) = (0, 0, 0, 0, 0) of the

system (7) is called exponentially mean square stable. Also, the trivial solution is
globally asymptotically stable in probability.
We state and prove the following theorem.
Theorem 4 Let the following conditions be true:
1
θ12 < [5(β1 A∗ + β2 I ∗ ) + d ],
2
1
θ22 < 2(ρ1 + ω + d − − A22 ),
4
1
θ32 < 2(β1 S ∗ + ρ2 + d − − A29 ),
4
1
θ42 < 2(β2 S ∗ − − A28 ),
4
1
θ52 < 2(d − − A27 ).
4
where A2 = −(c1 + d + 4β1 S ∗ ) < 0, A7 = (1 − θ )ω, A8 = ρ2 − (β1 + β2 )S ∗ , A9 =
2ρ2 − β1 S ∗ .
Then the trivial solution of the system (7) and hence the positive solution of the
system (6) is asymptotically mean square stable.
Proof Let us define the following Lyapunov function
U (z, t) = b1 U1 (z, t) + b2 U2 (z, t) + b3 U3 (z, t) + b4 U4 (z, t) + b5 U5 (z, t),
where U1 (z, t) = 21 (z1 + z2 )2 , U2 (z, t) = 21 (z1 + z3 )2 , U3 (z, t) = 21 (z1 + z4 )2 , U4

(z, t) = 21 (z1 + z5 )2 , U5 (z, t) = 21 (z4 + z5 )2 and the five nonnegative constants bi ,
i = 1, 2, ..5 to be determined later.
Here,
1
LU1 (z, t) = (z1 + z2 )(−(c1 + c2 )z1 − c3 z2 − 2β1 S ∗ z3 − 2β2 S ∗ z4 ) + (θ12 z12 + θ22 z22 )

2
1 1
= − c1 + c2 − θ12 z12 − c3 − θ22 z22 − (c1 + c2 + c3 )z1 z2
2 2
− 2S ∗ (z1 + z2 )(β1 z3 + β2 z4 ).
1
LU2 (z, t) = (z1 + z3 )(−c1 z1 − θ ωz2 − (β1 S ∗ + c4 )z3 − β2 S ∗ z4 ) + (θ12 z12 + θ32 z32 )

2
1 2 2 1
= − c1 − θ1 z1 − β1 S ∗ + c4 − θ32 z32 − (c1 + β1 S ∗ + c4 )z1 z3
2 2
∗
− (z1 + z3 )(θ ωz2 + β2 S z4 ).
1
LU3 (z, t) = (z1 + z4 )(−c1 z1 − (1 − θ )ωz2 − β1 S ∗ z3 − β2 S ∗ z4 ) + (θ12 z12 + θ42 z42 )

2
1 2 2 ∗ 1 2 2 ∗
= − c1 − θ1 z1 − β2 S − θ4 z4 − (c1 + β2 S )z1 z4
2 2
∗
− (z1 + z4 )((1 − θ )ωz2 + β1 S z3 ).
LU4 (z, t) = (z1 + z5 )(−c1 z1 − ρ1 z2 + (ρ2 − β1 S ∗ )z3 − (c5 + β2 S ∗ )z4 − dz5 )

1 2 2 1 2 2 1 2 2
+ (θ1 z1 = +θ5 z5 ) − c1 − θ1 z1 − d − θ5 z5 − (c1 + d )z1 z5
2 2
2 2 2
∗ ∗
− (z1 + z5 )(ρ1 z2 + (β1 S − ρ2 )z3 + (β2 S + c5 )z4 ).
1
LU5 (z, t) = (z4 + z5 )((ρ1 + (1 − θ )ω)z2 + ρ2 z3 − c5 z4 − dz5 ) + (θ42 z42 + θ52 z52 )

2
1 1
= − c5 − θ42 z42 − d − θ52 z52
2 2
− (c5 + d )z4 z5 + (z4 + z5 )((ρ1 + (1 − θ )ω)z2 + ρ2 z3 ).
Therefore, by choosing bi = 1, i = 1, 2, ..5, we have

1 2 1 2 2
LU (z, t) = − 4 c1 − θ1 + c2 z1 − c3 − θ2 z22
2 2

∗ 1 2 2 ∗ 1 2 2
− β1 S + c4 − θ3 z3 − β2 S − θ4 z4
2 2

(8)
1
− 2 d − θ52 z52 + A1 z1 z2 + A2 z1 z3 + A3 z1 z4
2
+ A4 z1 z5 + A5 z2 z3 + A6 z2 z4 + A7 z2 z5
+ A8 z3 z4 + A9 z3 z5 + A10 z4 z5
where
A1 = −(c1 + c2 + c3 + ω + ρ1 ) < 0,
A2 = −(c1 + c4 + 4β1 S ∗ − ρ2 ) = −(c1 + d + 4β1 S ∗ ) < 0,
A3 = −(c1 + c5 + 5β2 S ∗ ) < 0,
A4 = −(c1 + d ) < 0,
A5 = −(θ ω + 2β1 S ∗ ) < 0,
A6 = ρ1 − 2β2 S ∗ ,
A7 = (1 − θ )ω,
A8 = ρ2 − (β1 + β2 )S ∗ ,
A9 = 2ρ2 − β1 S ∗ ,
A10 = −(c5 + β2 S ∗ ) < 0,
Equation (8) can be rewritten as

1 1 1
LU (z, t) ≤ − 4 c1 − θ12 + c2 z12 − c3 − θ22 z22 − β1 S ∗ + c4 − θ32 z32
2 2 2

1 1
− β2 S ∗ − θ42 z42 − 2 d − θ52 z52 + A6 z2 z4 + A7 z2 z5 + A8 z3 z4 + A9 z3 z5
2 2
(9)
Due to Cauchy’s inequality, we have
z42
A6 z2 z4 ≤ + A22 z22
4
z22
A7 z2 z5 ≤ + A27 z52
4
z32
A8 z3 z4 ≤ + A28 z42
4
z52
A9 z3 z5 ≤ + A29 z32 .
4
Applying these relations, the Eq. (9) reduces to

1 1 1 1
LU (z, t) ≤ −(4c1 + c2 − 2θ12 )z12 − c3 − θ22 − − A22 z22 − β1 S ∗ + c4 − θ32 − − A29 z32
2 4 2 4

∗ 1 2 1 2 2 1 2 1 2 2
− β2 S − θ4 − − A8 z4 − 2 d − θ5 − − A7 z5
2 4 2 4
≤ −(B1 z12 + B2 z22 + B3 z32 + B4 z42 + B5 z52 )
(10)
where
B1 = 4c1 + c2 − 2θ12 ,
1 1
B2 = c3 − θ22 − − A22 ,
2 2
1 1
B3 = β1 S ∗ + c4 − θ32 − − A25 ,
2 2
1 1
B4 = β2 S ∗ − θ42 − − A28 ,
2 4
1 1
B5 = 2(d − θ52 − − A27 ).
2 4
Now,
1
B1 > 0 =⇒ θ12 < [5(β1 A∗ + β2 I ∗ ) + d ],
2
1
B2 > 0 =⇒ θ22 < 2(ρ1 + ω + d − − A22 ),
4
1
B3 > 0 =⇒ θ32 < 2(β1 S ∗ + ρ2 + d − − A29 ),
4
1
B4 > 0 =⇒ θ42 < 2(β2 S ∗ − − A28 ),
4
1
B5 > 0 =⇒ θ52 < 2(d − − A27 ).
4
Assume that ξ = min{B1 , B2 , B3 , B4 , B5 }, then clearly ξ > 0. The equation (10) can
be written as
LU ≤ −ξ |z(t)|2 + o(|z(t)|2 ).
Hence, we can say that in a small neighborhood of trivial solution of (7) the Lyapunov
function LU (z(t), t) is negative definite. Hence according to the lemma (8) we may
conclude that the trivial solution of (7) i.e. the positive solution of the system (6) is
asymptotically mean square stable. This completes the proof.
6 Numerical Simulation
In this section, first we perform the numerical simulation of the commensurate

fractional-order system (2) with the following set of parameters:
S1 = {η = 50, β1 = 0.038, β2 = 0.082, σ = 0.84, u = 0.0011, d = 0.2, δ =
0.25, ρ1 = 0.28, ρ2 = 0.38, ρ3 = 0.38, θ = 0.2, ω = 0.52}.
Most of the parameter values are taken from [29, 31] and some values are simulated.
For the numerical simulation purpose, we apply the Predictor-Corrector P(EC)m E
(Predict, multi-term [Evaluate, Correct], Evaluate) method [13, 14] in the MAT-
LAB software. We have used implicit fractional linear multistep methods (FLMMs)
as the solver function for the system of fractional-order differential equations. The
method P(EC)m E is the modified iteration formula of the method, PECE (Predict,
Evaluate, Correct, Evaluate) and Adams-Moulton algorithm. In the Fig. 3, we present
the solutions of the system (2) with the parameter set S1 and the fractional-orders
α = 1, α = 0.95, α = 0.9, α = 0.85, α = 0.8 respectively.
56
55
α=1
α=1
54 α=0.95
α=0.95
50 α=0.9
α=0.9 α=0.85
52
α=0.85 α=0.8
45 α=0.8
50
40 48
E (t)
S (t)
35 46
44
30
42
25
40
20
38
15 36
0 20 40 60 80 100 0 20 40 60 80 100
t t
14
α=1
α=0.95
α=0.9
13 α=0.85
α=0.8
12
A (t)
11
10
8
0 20 40 60 80 100
t
30 140
120
25
100
20 α=1
α=0.95
80
R (t)
α=0.9
I (t)
15 α=1 α=0.85
α=0.95 60
α=0.8
10 α=0.9
α=0.85 40
α=0.8
5 20
0 0
0 20 40 60 80 100 0 20 40 60 80 100
t t
Fig. 3 Time series plot of the system (2)

120
100 α1=1(Susceptible)
α =0.8(Exposed)
2
α =0.6(Asymptomatic)
3
80 α4=0.5(Infected)
α =0.7(Recovered)
5
Population
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100
t
Fig. 4 Time series plot of the system (3) with parameter values S2
Now we consider the incommensurate fractional-order system (3). We choose the

following set of parameters:
S2 = {η = 50, β1 = 0.038, β2 = 0.082, σ = 0.84, u = 0.0011, d = 0.2, δ =
0.25, ρ1 = 0.28, ρ2 = 0.38, ρ3 = 0.38, θ = 0.2, ω = 0.52}
In the Fig. 4, we present the solutions of the system (3) with the parameter set S2
and the fractional-orders α1 = 0.9, α2 = 0.8, α3 = 0.6, α4 = 0.5, α = 0.7. As
the determinant of the matrix M − J determined at the endemic equilibrium point
(S ∗ , E ∗ , A∗ , I ∗ , R∗ ) = (17.7842, 54.5923, 9.776, 27.298, 29.3795) gives a polyno-
mial of degree 35. The minimum value of all the arguments of the roots is 0.3409
which is greater than απ 2
= 0.157. Hence, by Lemma (5) the equilibrium point is
asymptotically stable.
Next, we present simulations based on the stochastic model (6). We take a
set of parameters S1 . In the deterministic part we have seen that for this param-
eter set the system is always locally stable around its interior equilibrium point
P∗ = (S ∗ , E ∗ , A∗ , I ∗ , R∗ ) = (17.7842, 54.5923, 9.776, 27.298, 29.3795). Let P1 =
(θ1 , θ2 , θ3 , θ4 , θ5 ) = (20.9, 31.6, 36.3, 16.5, 9.2) represent the intensities of white
noise. Now for P1 , we see that the differential equation system (6) is unstable at
the interior equilibrium. Again if we take P2 = (θ1 , θ2 , θ3 , θ4 , θ5 ) = (0.009, 0.006,
0.003, 0.005, 0.002) then we see that the differential equation system (6) is asymp-
totically mean square stable around the trivial equilibrium point of the system (7).
Fig. 5 Instability for the 250

S(t)
parameter set S1 and P1 E(t)
A(t)
200 I(t)
R(t)
150
Populations
100
50
0
0 5 10 15 20
Time
Fig. 6 Stability for the 150

parameter set S1 and P2
S(t)
E(t)
A(t)
I(t)
100 R(t)
Populations
50
0
0 5 10 15 20
Time
These consequences are presented in the Fig. 5 (Instability for the parameter set S1
and P1 ) and Fig. 6 (Stability for the parameter set S1 and P2 ) respectively. Therefore,
the stability of the deterministic system may be transformed to unstable due to dif-
ferent intensities of white noise. Thus, the modified model i.e. stochastic model (6) is
more practical than the deterministic model in the sense that it covers more realistic
behaviour than the deterministic model. Furthermore, for simulation of the stochas-
tic model, we use the Euler’s method and also the noise increments are assumed as
the independent distributed random variables and these are produced by using the
pseudo-random number in the numerical sense.
6.1 Sensitivity Analysis of R0
In this section we perform sensitivity analysis of the basic reproduction number R0 .

Sensitivity is performed in order to check the significance of the dependent variables
on the independent variable. From (5) we see that the basic reproduction number R0 is
a function of different parameters namely η, ω, d , ρ1 , ρ2 , ρ3 , β1 , β2 , θ, σ, δ, u.
To check the effect of these parameters we use normalized sensitivity index.
Definition 3 The normalized forward sensitivity index of a function f (x1 , x2 , ..., xn )
f ∂f xi
with respect to the parameter xi , (1 ≤ i ≤ n), is defined as
xi = ∂xi f
.
∂R0 ρ1
To check the sensitivity of R0 with respect to the parameter ρ1 we compute ∂ρ1 R0
=
ρ1 ∂R0 β2 (1−θ) β2
− d (d +ρ 1 +ω)
. Similarly for the parameter δ, ∂β2 R0
= d +δ+ρ3 +σ u β1 θ β (1−θ ) . Fol-
d +ρ2 + d +δ+ρ
2
3 +σ u
lowing this process we can find the impact of the rest of the parameters on the
basic reproduction number R0 . We now take the values η = 50; β1 = 0.038; β2 =
0.082; σ = 0.84; u = 0.0011; d = 0.2; δ = 0.25; ρ1 = 0.28; ρ2 = 0.38; ρ3 =
0.38; θ = 0.2; ω = 0.52; to compute the values of the sensitivity index (Table 2).
We see from Table 2 some values of the index are positive and some are negative.
Positive index implies that R0 is an increasing function of that parameter and negative
index implies that R0 is a decreasing function of that parameter.
From Table 1 it is observed that
dR0 = −1.3760. That means when d is increased
by 10 %, R0 will decrease by 13.7 %. Also,
θR0 = 0.0626 which implies if θ is
increased by 10 % then R0 will increase by 0.6 %. Now we plot some contour maps
of the basic reproduction number with respect to several parameters.
Figure 7a represents the change of R0 with respect to θ and ω. In this figure we
see that with increasing ω, R0 increases. We can see from the figure that R0 does
not depend on θ , the rate at which exposed class goes to asymptomatic class. Rather
the rate of infection has more significance on the value of R0 . From Fig. 7(b) we see
the change of R0 with respect to d and ρ1 i.e. the death rate and natural recovery
rate of exposed class. We see that the value of R0 is high when recovery is slow.
This is a very obvious thing. Fig. 7(b) represents this natural phenomena. Also when
the death rate is high the value of R0 is low. Figs. 7c, d represents the change of R0
with respect to d and ρ2 and d and ρ3 respectively, where ρ2 represents the natural
recovery of asymptomatic class and ρ1 represents the natural recovery of infected
class. These figures shows the same change of R0 as of Fig. 7b. We see the change of
R0 with respect to ω and σ where σ measures the effectiveness of treatment control
in Fig. 7(e). When ω is low i.e. the rate of infection of exposed population is less, the
value of R0 is low. This is very much the normal case. When σ is high, R0 is low i.e. the
Table 2 Sensitivity index

Para meters d ρ1 ω η β1 θ ρ2 β2 δ ρ3 σ u
Sensitivity −1.3760 −1.4 0.48 1 0.2501 0.0626 −0.1638 0.7498 −0.1122 −0.1706 −0.3771 −0.3771
index
0.2 6.5 0.28 20
8
2.5
3
3.5
4.5
5.5
4
6.5
6
0.19 6 0.26
16
14
12
18
10
0.18
5.5 0.24
0.17 16
5 0.22
0.16
8
0.2
6.5
2.5
3.5
4.5
5.5
5
3
6
4.5 14
ρ1
θ
0.15
18
16
14
12
10
0.18
4
0.14 12
0.16
0.13 3.5
10
0.14
0.12 3
8
6.5
5.5
2.5
6
4.5
5
3
3.5
4
0.11 0.12
2.5 8
18
10
14
12
16
20
0.1 0.1
0.1 0.2 0.3 0.4 0.5 0.1 0.12 0.14 0.16 0.18 0.2
ω d
(a) (b)
22 18
8
0.35 0.35 17
20
16
14
12
10
16
14
8
12
10
16
18 15
0.3 0.3
14
16
13
8
0.25 0.25
2
3
ρ
14 12
16
14
12
10
16
14
8
12
10
18
0.2 0.2 11
12
10
10 9
0.15 0.15
8
8
18
8
20
14
16
10
12
10
16
12
14
18
8
22
0.1 0.1 7
0.1 0.12 0.14 0.16 0.18 0.2 0.1 0.12 0.14 0.16 0.18 0.2
d d
(c) (d)
10 2.4 2.4
0.08
4
0.8 2.2
5
3
2.2
9 2.2 2.2
7
0.07
0.7 2
2
8 2 2
0.06 1.8
0.6
1.8
1.8 1.8
7
6
5
0.05
4
1.6
7
0.5
3
8 1.6
2
1.6
σ
1.6
β
0.4 0.04 1.4

1.4 1.4
1.4
5
9
0.3 0.03 1.2 1.2
1.2 1.2
4
8
6
7
5
4
0.2 0.02 1 1 1
1
10 3
9
0.1 0.01 08 0.8 0.8 0.8
0.1 0.2 0.3 0.4 0.5 0.1 0.15 0.2 0.25
ω δ
(e) (f)
Fig. 7 a. Contour plot of R0 with respect to θ and ω. b Contour plot of R0 with respect to d and
ρ1 . c Contour plot of R0 with respect to d and ρ2 . d Contour plot of R0 with respect to d and ρ3 . e
Contour plot of R0 with respect to ω and σ . f Contour plot of R0 with respect to δ and β2
treatment is effective, R0 decreases. Lastly, Fig. 7f represents the contour map of R0

with respect to β2 and δ. Here δ represents death due to disease and β2 represents rate
of disease transmission. When β2 is low, the value of R0 is low in spite of any value of
δ. Hence, we can conclude that β2 plays a significant role in controlling the disease.
7 Discussions
This chapter deals with a fractional order epidemic model to investigate the trans-
mission dynamics of the COVID-19 disease. It is very much clear that the disease
COVID-19 has left an uncompensated loss to the socio-economic status of almost
every country throughout the globe. Government agencies and policy makers are des-
perately trying to invent the mitigation strategies for this disease. In this perspective,
mathematical modelling tool can be very much useful to predict the future charac-
teristics of the disease and to find out the possible control strategies. Motivated by
the real need, here we come up with a model based study to analyze the transmission
dynamics of the disease. We use fractional order derivatives to construct the mathe-
matical model. Fractional derivatives are used due to its superior properties that are
equipped with biological systems. Based on the nature of the disease, we have devel-
oped an SEAIR type five dimensional compartmental model. Both the commensurate
and non-commensurate systems are considered. Some fundamental definitions and
theorems regarding fractional calculus are provided for a better understanding. The
basic biological properties like positivity and boundedness are checked. The exis-
tence and the uniqueness of the solutions of the system are established. The dynamical
behavior of the system is studied in terms of the basic reproduction number, which
acts as a key threshold quantity for any epidemic model. The numeric value of this
quantity decides the upcoming trends of the disease. The existence of the infection
free equilibrium and the infected equilibrium is discussed under different parametric
conditions. The local stability analysis of all the existing steady states are studied.
The occurrence of backward bifurcation is observed in the model system. This is a
very typical phenomena which indicates that the disease still persist even when the
basic reproduction is below unity. Therefore, additional efforts is required to achieve
a refinement of the basic reproduction number. In addition, since each systems is
consisted with some sort of uncertainties, so it is very useful to study the stochastic
behavior of the system. So, we have studied the stochastic stability of the infected
steady state. In addition, since the estimation of the system parameters are equipped
with some sort of uncertainties, so we have performed the sensitivity analysis of the
basic reproduction number with respect to the model parameters. Finally, we have
verified the results for both the commensurate and the non-commensurate system
through numerical simulations.
8 Conclusions
Here we have presented a compartmental mathematical model to analyze the trans-

mission dynamics of the corona virus disease. Fractional order derivatives are used
to build the model. However, we have not considered any type of delay in the disease
transmission which is very much related with the corona virus disease. Also, the
age dependent infection and recovery rate is very much interesting topic should be
studied for the case of COVID-19. Network and multi-patch modelling of corona
virus is also very much demanding. Moreover, one can fit the real world data to this
fractional order system and estimate the system parameters. We left all these topics
for our future research works.
Acknowledgements The work of S. Jana is partially supported by Dept of Science & Technology
and Biotechnology, Govt. of West Bengal (vide memo no. 201 (Sanc.)/ST/P/S&T/16G-12/2018
dt 19-02-2019). A. Khatua is financially supported by Department of Science and Technology-
INSPIRE, Government of India (No. DST/INSPIRE Fellowship/2016/IF160667, dated: 21st Septem-
ber, 2016). Also the authors would like to acknowledge Prof. Ahmad Taher Azar, the editor of the
book, for his constant and unconditional support regarding the improvement of the chapter.
References
1. Abdo, M.S., Shah, K., Wahash, H.A. and Panchal, S.K., 2020. On a comprehensive model of
the novel coronavirus (COVID-19) under Mittag-Leffler derivative. Chaos, Solitons Fractals
109867 (2020)
2. Ahmad, S., Ullah, A., Al-Madlal, Q.M., Khan, H., Shah, K., Khan, A.: Fractional order math-
ematical modeling of COVID-19 transmission. Chaos Solitons Fractals 110256 (2020)
3. Ahmed, E., El-Sayed, A.M.A., El-Saka, H.A.A.: On some Routh-Hurwitz conditions for frac-
tional order differential equations and their applications in Lorenz, Rossler, Chua and Chen
systems. Phys. Lett. A 358, 1–4 (2006)
4. Ahmed, I., Baba, I.A., Yusuf, A., Kumam, P., Kumam, W.: Analysis of Caputo fractional-order
model for COVID-19 with lockdown. Adv. Difference Equat. 2020(1), 1–14 (2020)
5. Alkahtani, B.S.T., Alzaid, S.S.: A novel mathematics model of covid-19 with fractional deriva-
tive. Stability and numerical analysis. Chaos Solitons Fractals 138, 110006 (2020)
6. Almeida, R., da Cruz, A.M.B., Martins, N., Monteiro, M.T.T.: An epidemiological MSEIR
model described by the Caputo fractional derivative. Int. J. Dyn. Control 7(2), 776–784 (2019)
7. Amar, L.A., Taha, A.A. and Mohamed, M.Y.: Prediction of the final size for COVID-19 epi-
demic using machine learning: a case study of Egypt. Infectious Disease Modelling (2020)
8. Atangana, A.: Modelling the spread of COVID-19 with new fractal-fractional operators: can
the lockdown save mankind before vaccination? Chaos Solitons Fractals 136 (2020)
9. Beretta, E., KolmanovskiiV, Shaikhet L.: Stability of epidemic model with time delays influ-
enced by stochastic perturbations. Math. Comput. Simul. 45, 269–277 (1998)
10. Bouchnita, A, Jebrane, A.: A hybrid multi-scale model of COVID-19 transmission dynamics
to assess the potential of non-pharmaceutical interventions. Chaos Solitons Fractals 109941
(2020)
11. Cai, L., Li, X.: A note on global stability of an SEI epidemic model with acute and chronic
stages. Appl. Math. Comput. 196, 923–930 (2008)
12. Diekmann, O., Metz, J.A.J., Heesterbeek, J.A.P.: On the definition on the computation of
the basic reproduction number ratio R0 in models for infectious diseases in heterogeneous
population. J. Math. Biol. 28, 365–382 (1990)
13. Diethelm, K. Braunschweig: Efficient solution of multi-term fractional differential equations

using P(EC)m E methods. Computing 71, 305–319 (2003)
14. Diethelm, K., Ford, N.J., Freed, A.D.: A predictor-corrector approach for the numerical solution
of fractional differential equations. Nonlinear Dyn. 29, 3–22 (2002)
15. El-Saka, H.A.A., Lee, S. and Jang. B.: Dynamic analysis of fractional-order predator-prey
model biological economic system with Holling type II functional response. Nonlinear Dyn.
(2019)
16. El-Shahed, M.: Fractional order model for the spread of leptospirosis. Int. J. Math. Anal. 8(54),
2651–2667 (2014)
17. El-Shahed, M., El-Naby, F.A.: Fractional calculus model for childhood diseases and vaccines.
Appl. Math. Sci. 8(98), 4859–4866 (2014)
18. Hellewell, J., Abbott, S., Gimma, A., Bosse, N.I., Jarvis, C.I., Russell, T.W., Munday, J.D.,
Kucharski, A.J., Edmunds, W.J., Sun, F., Flasche, S.: Feasibility of controlling COVID-19
outbreaks by isolation of cases and contacts. The Lancet Global Health (2020)
19. Li, H.L., Zhang, L., Hu, C., Jiang, Y.L., Teng, Z.: Dynamical analysis of a fractional of a
fractional order predator prey model incorporating a prey refuge. J. Appl. Math. Comput.
(2016). /DOIurl10.1007/s12190-016-1017-8
20. Huang, Z., Yang, Q., Cao, J.: Complex dynamics in a stochastic internal HIV model. Chaos,
Solitons Fractals 44, 954–963 (2011)
21. Jana, S., Haldar, P., Kar, T.K.: Complex dynamics of an epidemic model with vaccination and
treatment controls. Int. J. Dyn. Control 4, 318–329 (2016)
22. Kilbas, A., Srivastava, H., Trujillo, J.: Theory and Application of Fractional Differential Equa-
tions. Elsevier, New York (2006)
23. Kucharski, A.J., Russell, T.W., Diamond, C., Liu, Y., Edmunds, J., Funk, S., Eggo, R.M., Sun,
F., Jit, M., Munday, J.D. Davies, N.: Early dynamics of transmission and control of COVID-19:
a mathematical modelling study. The lancet infectious diseases (2020)
24. Kumar, S., Cao, J., Abdel-Aty, M.: A novel mathematical approach of COVID-19 with non-
singular fractional derivative. Chaos Solitons Fractals 139 (2020)
25. Kumar, R., Kumar, S.: A new fractional modelling on susceptible-infected-recovered equations
with constant vaccination rate. Nonlinear Eng. 3(1), 11–19 (2013)
26. Lahrouz, A., Omari, L., Kiouach, D.: Global analysis of a deterministic and stochastic nonlinear
SIRS epidemic model. Nonlinear Anal. Model Control 16(1), 69–76 (2011)
27. Latha, V.P., Rihan, F.A., Rakkiyappan, R., Velmurugan, G.: A fractional-order delay differential
model for Ebola infection and CD8 T-cells response: stability analysis and Hopf bifurcation.
Int. J. Biomath. 10, 1750111 (2017)
28. Li, Y., Chen, Y., Podlubny, I.: Stability of fractional-order nonlinear dynamic systems: Lya-
punov direct method and generalized Mittag-Leffler stability. Comput. Math. Appl. 59(5),
1810–1821 (2010)
29. Mandal, M., Jana, S., Nandi, S.K., Khatua, A., Adak, S., Kar, T.K.: A model based study on the
dynamics of COVID-19: prediction and control. Chaos Solitons Fractals 136, 109889 (2020)
30. Mandal, M., Jana, S., Nandi, S.K., Kar, T.K.: Modelling and control of a fractional-order
epidemic model with fear effect. Energy Ecol. Environ. 5(6), 421–432 (2020)
31. Mandal, M., Jana, S., Khatua, A., Kar, T.K., Modeling and control of COVID-19: a short-term
forecasting in the context of India. Chaos Interdisc.J. Nonlinear Sci. 30(11), 113119 (2020)
32. Mao X(2007) Stochastic differential equation and application (2nd edn)
33. Mishra, A.M., Purohit, S.D., Owolabi, K.M. and Sharma, Y.D.: A nonlinear epidemiological
model considering asymptotic and quarantine classes for SARS CoV-2 virus. Chaos Solitons
Fractals 109953 (2020)
34. Mondal, S., Lahiri, A., Bairagi, N.: Analysis of a fractional order eco-epidemiological model
with prey infection and type 2 functional response. Math. Methods Appl. Sci. 40(18), 6776–
6789 (2017)
35. Mohammad, M., Trounev, A.: On the dynamical modeling of COVID-19 involving Atangana-
Baleanu fractional derivative and based on Daubechies framelet simulations. Chaos Solitons
Fractals 140 (2020)
36. Mouaouine, A., Boukhouima, A., Hattaf, K., Yousfi, N.: (2018) A fractional order SIR epidemic
model with nonlinear incidence rate. Adv. Differ. Equ. 1, 160 (2018)
37. Odibat, Z., Shawagfeh, N.: Generalized Taylors formula. Appl. Math. Comput. 186, 286–293
(2007)
38. Petras, I.: Fractional-order Nonlinear Systems: Modelling Analysis and Simulation. Higher
Education Press, Beijing (2011)
39. Pinto, C.M.A., Carvalho, A.R.N.: A latency fractional order model for HIV dynamics. J. Com-
put. Appl. Math. 312, 240–256 (2017)
40. Podulubny, I.: Fractional Differential Equations. Academic Press, San Diego (1999)
41. Prem, K., Liu, Y., Russell, T.W., Kucharski, A.J., Eggo, R.M., Davies, N., Flasche, S., Clifford,
S., Pearson, C.A., Munday, J.D. and Abbott, S., 2020. The effect of control strategies to reduce
social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study.
The Lancet Public Health
42. Rajagopal, K., Hasanzadeh, N., Parastesh, F., Hamarash, I.I., Jafari, S., Hussain, I.: A fractional-
order model for the novel coronavirus (COVID-19) outbreak. Nonlinear Dyn. 101(1), 711–718
(2020)
43. Sardar, T., Rana, S., Chattopadhyay, J.: A mathematical model of dengue transmission with
memory. Commun. Nonlinear Sci. Numer. Simul. 22(1–3), 511–525 (2015)
44. Shaikh, A.S., Shaikh, I.N. and Nisar, K.S., 2020. A mathematical model of covid-19 using
fractional derivative: Outbreak in India with dynamics of transmission and control
45. Tuan, N.H., Mohammadi, H., Rezapour, S.: A mathematical model for COVID-19 transmission
by using the Caputo fractional derivative. Chaos, Solitons Fractals 140 (2020)
46. Upadhyay, R.K., Chatterjee, S., Saha, S., Azad, R.K.: Age-group targeted testing for COVID-19
as new prevention strategy (2020)
47. Willis, M.J., Díaz, V.H.G., Prado-Rubio, O.A. and von Stosch, M.: Insights into the dynamics
and control of COVID-19 infection rates. Chaos, Solitons Fractals 109937 (2020)
48. Yadav, R.P., Verma, R.: A numerical simulation of fractional order mathematical modeling of
COVID-19 disease in case of Wuhan China. Chaos, Soliton Fractals 140 (2020)
Long Tails of Mean-Field COVID-19
Epidemic Curves: Implications
of a Hidden Metapopulational Dynamics
Eugene B. Postnikov
Abstract This chapter addresses the problem of a possible complex origin of the
observable country-wide epidemic data detected for a number of epidemic curves
of COVID-19. The key idea is the actual existence of decomposition into several
approximate solutions within the mean-field compartmental approach of mathemat-
ical epidemiology and the direct summation of outbreaks localized within weakly
connected socio-geographic areas. It is argued that the type of a multiscale distri-
bution of such components can be estimated using the interrelations between the
analytical invariant-based solution of the susceptible–infected–recovered/removed
(SIR) model and the continuous wavelet transform based on the Derivative of Gaus-
sian wavelet. The analysis is illustrated and verified by the comparison between
the principal SIR-based mode decompositions and geographically spread outbreaks,
which made their input in the full epidemic curve for countries, where COVID-19
dynamics demonstrated a long tail in the time course of registered cases.
Keywords COVID-19 · Metapopulations · Wavelet transform · SIR ·

Compartmental models
1 Introduction
The recent outbreak of COVID-19 disease, which is officially designated by the

World Health Organization as the pandemics [1], is a serious challenge not only
for the public health system and worldwide economics but also for the research
community involved in the research in the field of mathematical epidemiology and
data analysis [2–6].
The most natural primary attempt to this problem is the usage of compartmen-
tal models of mathematical epidemiology, which have a long story dated back to
the works of Kermack and McKendrik (SIR model) [7] and have demonstrated a
E. B. Postnikov (B)
Department of Theoretical Physics, Kursk State University,
Radishcheva st., 33, Kursk 305000, Russia
120 E. B. Postnikov
long series of successful practical application during almost a century [8, 9]. This
type of models is build in analogy with chemical reactions in a well-mixed medium
considering the full population as a mixture of susceptible and infected/infectious
individuals whose contacts lead to the growth of number of the latter and respec-
tive diminishing the number of the former. Naturally, a finite duration of an illness
induces the introduction of the third kind of variable, recovered or removed (e.d.
dead) individuals, which can not be immediately reinfected again. Such scheme can
be also extended by additional categories such as exposed individuals (those who
are infected but not yet infectious; the resulting system is called the SEIR model),
by taking into account processes of recovering and dying separately, by considering
asymptomatic carriers, etc.
Under the conditions of uncertainty in the determination of accurate character-
istics of social contacts, transmission ways and local geographic specificity when
addressing the country-wide epidemic dynamics, the simplest SIR model remains
an adequate tool for the primary model estimations of the outbreak since it con-
tains the minimum of parameters (note that the more realistic SEIR model can be
also approximated by some effective SIR model with specially rescaled parame-
ters [10]). In addition, the SIR model can be easily modified to take into account
additional processes related, e.g. quarantine measures, etc. This is confirmed by a
number of successful research, which only not reproduce the COVID-19 outbreak
but also analyse results of governmental measures undertaken to fight the epidemics
[4, 11–13].
At the same time, the obtained reproducibility of realistic epidemic curves by the
SIR model is not universal and in a number of cases, especially related to countries
with a wide geographic spread and/or highly regional specificity, is far from the
observed situation (see more detailed review and reference in the next section). This
situation motivates to advert to more sophisticated modern approach, which takes
into account a complex socio-geographical interactions, namely, the metapopulation
approach. It considers a locally multi-patch system, for which local dynamics within
each patch is supplied with additional interactions between them originated, e.g.
from the network of contacts or migration [14, 15]. Such as microscopically complex
structure can lead to the macroscopic dynamics qualitatively distinct from the one
expected within the epidemiology of well-mixed populations, in particular, disease
persistence [16] that is recently under discussion respectively to the emergent effect
of the linear growth of the cumulative number of revealed infected persons (or,
equivalently, long periods of the almost constant numbers of daily cases) in several
countries [17]. From the point of view of mathematical modelling, the respective
data analysis demands for methods, which realise decoupling complicated spatio-
temporal dynamics into a set of the characteristic modes more suitable for analysis
by means of the classic epidemiological models [18, 19].
Thus, the main goal of this work is to discuss the phenomenon of “long tails” in the
daily reports of the COVID-19 epidemic curves using their multiscale decomposition
via the continuous wavelet transform. The wavelet function under consideration
should be specially adjusted to the solution of the classic epidemiological SIR model
Long Tails of Mean-Field COVID-19 Epidemic Curves: Implications … 121
with the subsequent analysis of decoupled and coupled modes within the frame of
the metapopulation approach.
The chapter is organized as follows: after a review of related work, which noted the
existence of the multimodal character of COVID-19 outbreak in different countries,
the detailed mathematical introduction into the topic of approximate solutions of
epidemic compartmental models and the wavelet functions having a similar shape is
given. The next section applies this formalism to the analysis of the spring-summer
outbreaks in the countries, which demonstrate three qualitatively different cases
revealed by the wavelet transform. The last case (an almost constant magnitude
of the infected persons’ number) is discussed from the point of view of Kendall’s
travelling waves. Finally, appendices provide the program code codes used for the
models considered and an additional analytic discussion of the more sophisticated
SIR-X model in comparison with the classic SIR model.
2 Related Works
As it is proven in the work [20], the compartmental SIR model in the form analyti-
cally reduced to Verhulst’s logistic equation under some well-definite mathematical
conditions gives the description adequate to epidemic dynamics in different countries
during the first stage of the outbreak’s course up to the first main maxima and slightly
after it. However, more substantial studies of the logistic fitting of the cumulative
number of infected persons had revealed deviations that induced a demand for its
modification or extension [21, 22].
In particular, the observation that a single logistic curve cannot reproduce the
COVID-19 outbreak in Italy with high accuracy has been done in the works [23, 24]
and, a phenomenological decomposition into the combination of two logistic curve
was carries out using the data available at the ends of March and April, respectively.
Later [25], the study [24] was updated up to the middle of May with an addition of the
third logistic component and supplied with analysis of data for Brazil and the USA
including summertime data. On the contrary, the work [26], although more limited
in the time interval, made an attempt to consider the observed bi-logistic situation as
influence of the sum of input from different regions, in particular Lombardy region
and the rest of the country. The phenomenological bi-logistic curve approach was
also considered in details of uncertainty estimations for the case of Austria although
again for the time, when the main outbreak was not finished yet [27].
Two works gave a more detailed consideration of reasons for multi-logistic dynam-
ics within the context of country-wide data: [28] operates by a set of independent SIR
systems, where solutions are approximated by individual curves related to the choice
of the required number of such systems with a characteristic longevity of a country,
[29] considers summation of logistic curves for weakly coupled subpopulations with
a restricted mobility, while [30] started directly from the logistic function solutions
considered as local ones and introduced the country-wide dynamics as a statistical
averaging of multiple logistic distributions.
122 E. B. Postnikov
Thus, more fine-level model picture, which considers the spread of COVID-19 out-
breaks across spatially-distributed unavoidably meets the conditions of the metapop-
ulation approach of mathematical epidemiology. The latter includes both spatial
(including networks of either travel or intra-social connections) and population-
structure aspects. In particular, it is argued that the different rate of revealing infected
persons within the general community may lead to the double-peak structure of the
summed data in Spain [31]. On the contrary, the shielding effect created by recovered
persons who belong to the same sub-community as still susceptible may reduce the
global spread [32]. Fine-scale studies of effects of the disease spread as a conse-
quence of the complex network connectivity, the travel traffic and its reduction is
explored, e.g. in [33–35].
Finally, the wavelet transform, which is a powerful tool for periodic and multiscale
analysis of time series, has found an application in the problems of mathematical
epidemiology too. However, the main focus of such applications is on recurrent
epidemics when the complex continuous wavelet transform is used to trace the non-
stationarity of outbreaks including both temporal and spatial factors, see e.g. [36–38].
On the other hand, the use of wavelet-based numerical techniques addressed to
the analysis and forecast of individual outbreaks is sufficiently less developed area
of research emerged only recently. Some of them use the discrete wavelets simply
as a formal decomposition basis for an application of data-driven autoregressive
models; in particular, there are known such works devoted to the possibility of pro-
jecting COVID-19 dynamics using the actually reported one [39, 40]. An approach
more related to the interplay of the SI (susceptible-infected) compartmental mod-
els of mathematical epidemiology and the revealed number of infected persons was
proposed in [41, 42] and applied to the initial peak data of COVID-19 outbreak in
different countries. It should be pointed out, however, that the Mayer wavelet used
by the authors, was chosen due to its mathematical properties (orthonormality, com-
pactness in the Fourier space and good localisation in time) but not due to any special
closeness of an individual basic function to the model’s functional solution.
3 Mathematical Background
3.1 SIR System and Its Kink-Like Solution
The celebrated Kermack–McKendrick’s three-compartment SIR model [8, 9] subdi-

vides the full population of N individuals into three groups: susceptible S, infected
I , and recovered/removed R. The last group includes persons who have got immu-
nity after suffering form a disease and those who died. In both these outcomes the
individuals who belong to R group cannot be infected again. The total population is
assumed constant S + I + R = N = const. At the same time, for the convenience of
calculations, it is possible to consider relative values S/N → S, I /N → I , R/N → R
that leads to the rescaled condition
S + I + R = 1. (1)
Respectively, the kinetic schemes of transitions between the states of persons are
the following:
• the contact of a susceptible person with an infected one results in the transition of
the former to the infected state with some probability, which defines the transmis-
sion rate k:
k
I + S → 2I ,
• during the average characteristic time τ , the infected person recovers or die, i.e.
the rate of transition from the infected state to the recovered/removed one is equal
to τ −1 , and:
τ −1
I → R.
On the macroscopic (mean-field) level, these kinetic two-component scheme leads

to the SIR system of ordinary differential equations
dS
= −kSI , (2)
dt
dI
= kSI − τ −1 I , (3)
dt
dR
= τ −1 I . (4)
dt
The sum of Eqs. (2)–(4) confirms that their system satisfies the conservation law
(1) since
d
(S + I + R) = 0.
dt
•> Important
The system (2)–(4) corresponds either to a well-mixed population or to a set of
synchronized sub-populations. The latter means that each of them is characterised by
the same infection spread rate k and, simultaneously, the processes of outbreaks start
approximately at the same initial time from the approximately the same initial ratio
of infected persons to the same total number of people in the sub-population. Such
a situation can be already realised when a completely new infection is introduced to
a wide region via, say, a large transport hub with the fast dissemination of primary
infected persons over the whole region. In this case, the outbreak starts and will go in
several location practically simultaneously whence the sum of epidemic curves will
behave like in the well-mixed population even when several regions are disjointed.
The violation of these conditions leads to the perturbations in the shape and time
124 E. B. Postnikov
course of the cumulative epidemic curve that may play a role of an indicator of
existence such asynchronous sub-populations.
The relatively simple forms of the right-hand sides of Eqs. (2)–(4) make it pos-
sible to immediately describe the qualitative behaviour of solutions for all three
functions. Since all of them are positive, k, τ (also positive by their meaning and def-
inition) dS/dt < 0, and dR/dt > 0, i.e. the number of the susceptible persons always
decreases monotonically and the number of those who get sick and recovered/died
always increases monotonically.
On the contrary, the speed of change of the infected sub-population size can havea
different sign that is demonstrable if to rewrite Eq. (3) in the form
dI
= τ −1 I (R0 S − 1) , (5)
dt
where R0 = kτ is called the basic reproduction number (or, equivalently, the basic
reproduction ratio) [43, 44].
Note that R0 is completely defined by the properties of the infection agent, social
contact structure, etc. They defines in complex the transmission rate k, and the dura-
tion of the illness τ . In the absence of the changes of the first factor, e.g. due to a
quarantine measures, R0 = const, and serves as an important parameter characteris-
ing a particular disease.
If R0 S < 1 then dI /dt < 0 always, i.e. the quantity of infected persons diminishes
at any time moment from the initial time of the introduction of an infected person into
the population. If R0 S > 1 then dI /dt > 0 and outbreak develops. Since 0 ≤ S ≤ 1,
the boundary value of the basic reproduction number, which separates two scenarios,
R0 = 1.
It should be pointed out also that R0 should be distinguished from the instant
reproduction number Rt = 1 + τ −1 IdI /dt, which characterises the instant (growing
or decaying) dynamics of the outbreak’s course. As it seen from the right-hand side
of Eq. (5) It depends not only a disease’s properties and transmission possibilities
but also on the variable number of still accessible part of the susceptible population.
To get further quantitative conclusions, it is required to take into account that
the conservation law (1) is not the unique invariant in the SIR system. Dividing
(2) by −kS and (4) by τ −1 , we get equations with the same right-hand sides, and,
consequently, their left-hand sides are equal too:
1 dS 1 dR
− = −1 . (6)
kS dt τ dt
Collecting the terms of Eq. (6) in the left-hand side and representing them as a
derivative,
d
log(S) + kτ R = 0,
dt
we get the second invariant
log(S) + kτ R = log(S0 ), (7)
where S0 is the initial condition for the susceptible subpopulation, when R(0) = R0 =
0; the initial condition R0 should not be mixed with the basic reproduction number
R0 .
Eq. (7) can be also rewritten as

S
log + kτ R = 0. (8)
S0
Thus, the number of equations in the system (2)–(4) is already excessive and it
can be reduced to one equation due to existence of two invariants, (1) and (8).
This procedure can be carried out substituting I = 1 − R − S from Eq. (1) into
Eq. (4) and taking the exponential function from Eq. (8). The resulting unique equa-
tion written with respect to one variable is
dR
= τ −1 1 − R − S0 e−kτ R , (9)
dt
where R(0) = 0 is the initial condition.
Equation (9) has the formal implicit analytic solution obtained by the method of
variable separations:
R
dR
= τ −1 t. (10)
1 − R − S0 e−kτ R
0
Two other quantities characterising the outbreak can be calculated subsequently

expressing S from Eq. (8), and, further, I from Eq. (1).
Although the integral (10) cannot be expressed via standard analytic functions,
there exists an important case, which can be treated analytically as a reasonable
approximation. It is the case of not very large R0 when the exponential function can
be effectively fitted by the three first terms of its expansion into Taylor’s series (note
that R is always bounded from above as R < 1 by the normalization and Eq. (1)):
R20 2
e−R0 R ≈ 1 − R0 R + R . (11)
2
Substituting the polynomial (11) instead of the exponential function in Eq. (10)
we get the integral
R
dR
R2
= τ −1 t,
0
(1 − S0 ) + (S0 R0 − 1)R − S0 20 R2
126 E. B. Postnikov
which can be written also as,
R
dR S0 R20 τ −1
= t. (12)

2 2 2 2
2(1−S0 ) S0 R0 −1 S0 R0 −1
0
S0 R20
+ S0 R20
− R− 2S0 R20
Now, Eq. (12) contains the standard integral representing the hyperbolic tangent

dξ 1 ξ
= tanh−1 ,
A −ξ
2 2 a A
where the notations ξ = R − B and

2
2(1 − S0 ) S0 R0 − 1 S0 R0 − 1
A= + , B=
S0 R20 S0 R20 2S0 R20
are introduced.
Thus, the solution reads as

AS0 R20 τ −1 B
R = B + A tanh t − tanh−1 (13)
2 A
and has a form analogous to the Kink solution known in a wide range of problems
described by non-linear differential equations [45].
Although the final size of the epidemics (the total ratio of suffered population)
follows from Eq. (13) approximately as R(∞) = R∞ = A + B, it is possible to get
this quantity exacly using (8) under the condition I (∞) = 0:

1 − R∞
log + R0 R∞ = 0,
S0
where the terms can be regrouped as
R0 (R∞ − 1) eR0 (R∞ −1) = −S0 R0 eR0 . (14)
Taking into account that the right-hand side of Eq. (14) uses the functional equation
defining the Lambert W function [46] f (W ) = W exp(W ), the desired final size is
expressed as
1
R∞ = 1 + W −S0 R0 e−R0 . (15)
R0
Note here that Lambert’s W-function of negative argument is negative, and W (−ξ )
is non-linear negative functions tending to zero for positive ξ → ∞; W (−ξ ) = −ξ
for 0 ≤ ξ ≤ 1 only. The last fact is coordinated with the meaning R0 as the boundary
of the outbreak’s emergence (it is clear is to take S0 ≈ 1).
Finally, using Eq. (4) and differentiating (13), it is easy to get the formula, which
describes the dynamics of the infected individuals number:
2 −1
S0 R20 A2 2 AS0 R0 τ −1 B
I (t) = sech t − tanh . (16)
2τ 2 2 A
Note also that such kind of invariant-based analysis can be also applied to the case
of modified model, so-called SIR-X system proposed recently [11] for taking into
account strong quarantine measures in China; the respective derivations are provided
in Appendix B.
3.2 Kink Solution and Integral of the Gaussian Function
To take the next step, i.e. the wavelet-based decomposition of epidemic curves, it
is useful to note that there is a well-known and extensively mathematically studied
[45] approximation of the Kink-like solution taken in the form of hyperbolic tangent
as the integral of the Gaussian function:
t
2 2 (t−β)2 dt
tanh √ (t − β) + tanh √ β ≈2 e− 2σ 2 √ , (17)
2π σ 2 2π σ 2 2π σ 2
0
where the inflection points located at the time moment t = β are coordinated to
each other as well their derivatives at this point; σ is the standard deviation of the
Gaussian function. Due to this fact, the difference between functions in the both
sides of Eq. (17) is minimal in the vicinity of the inflection point. They both are
considered at the time moment t = 0 while there is difference at t → ∞ although it
can be practically negligible for β > 2σ .
Comparing Eqs. (17) and (13), it is seen that one can apply to the analysis of
epidemic time series methods specially developed for revealing parameters of the
Gaussian function via the wavelet analysis as it will be described in the next subsec-
tion.
For the sake of demonstrability, let us derive explicit expressions for the param-
eters β and σ for the case, when an infection is introduced into a population by a
small number of its carriers, i.e. S0 ≈ 1. Then Eqs. (13) and (16) take the forms

R0 − 1 R0 − 1 R0 − 1 −1 1
R= + tanh t − tanh (18)
2R20 R20 2τ 2R0
and
128 E. B. Postnikov
2
2 R0 − 1 R0 − 1 2τ −1 1
I (t) = 2 sech 2
t− tanh . (19)
R0 2τ 2τ R0 − 1 2R0
As it follows from Eq. (17),
(t−β)2
1 2 e− 2σ 2
√ sech 2
√ (t − β) ≈ √ , (20)
2π σ 2 2π σ 2 2π σ 2
whence
8τ 2
σ = . (21)
π (R0 − 1)2
Thus, the next question is how to reveal appropriate Gaussian components in the
time series under consideration. It can be answered applying the continuous wavelet
transform with a wavelet, which is itself build on the base of the Gaussian function.
3.3 Gaussian Wavelets
The continuous wavelet transform (CWT) of a function f (t) is defined as the convolu-
tion, which maps the one-dimensional transformed function into the two-dimensional
+∞
t − t
w(t, a) = f (t )ψ dt , (22)
a
−∞
where ψ(·) is the wavelet (an appropriate norm is included into this notation here), a
is called the scale (this variable define the characteristic range the time (when t is con-
sidered as the instant time variable), within of which the function ψ(·) significantly
differs from zero.)
Among a large variety of wavelet functions, the particular case, which is the most
suitable for the goals posed in this work, is taken from the family of wavelets defined
as derivatives of the Gaussian function.
Let us considered the Gaussian function centred in the time point t and having
the standard deviation a:

t − t 1 (t−t )2
G = √ e− 2a2 . (23)
a a 2π
Then its scaled first derivative

d t − t t − t 1 t − t − (t−t2 )2
a G ≡ψ =− √ e 2a (24)
dt a a a 2π a
is the wavelet, which satisfies all properties required from the wavelet functions: (i) it
is a well-localised function with tails fast tending to zero beyond the distances larger
than a from its centre; (ii) it is a square integrable function and, moreover, satisfies
the admissibility condition
+∞
t − t
ψ dt = 0, (25)
a
−∞
that also implies that the respective wavelet-transform of any constant is equal to
zero, and iii) has the amplitude norm
+∞

ψ t − t dt = 2 . (26)
a π
−∞
Note that there exits also a popular energy norm, which keeps constant the integral
from the absolute value of the wavelet function squared but the amplitude-based
variant (26) is more convenient in the problems related to the edge detection [47]
that is close to that one, which will be considered in this work. The same reason of
interpretation makes it useful to keep the non-unitary norm in Eq. (26). Namely, the
convolution of the transformed function with the Gaussian (23),
+∞
(t−t )2 dt
fa (t) = f (t )e− 2a2 √ (27)
a 2π
−∞
results in the usual Gaussian-filtered (smoothed, de-noised) function fa , where a

is the smoothed window’s length. In turn, the derivative of this de-noised function
multiplied by the window’s width
dfa (t)
a = w(t, a) (28)
dt
is the desired wavelet transform keeping in mind that the derivative and the integral
are taken with respect to different variables (t and t ) and Eqs. (22), (24).
•> Important
An important example within the contest of application to the epidemics data process-
ing is the wavelet transform of the Gaussian function, i.e. Eq. (22) with f(t) = g(t),
where G a0 (t) is the function given by Eq. (23) with t = 0 and a0 , and ψ (t − t )/a
defined by Eq. (24).
Since the convolution of two Gaussians is a Gaussian too,
130 E. B. Postnikov
t2
1 −
2(a02 +a2 )
fa (t) = e (29)
2π a02 + a2
and, taking into account Eq. (28),

2
at − 2t 2
2(a0 +a )
wG a0 (t, a) = − 3 e . (30)
2π a0 + a
2 2
Whence, the two-dimensional function (30) is equal to zero at all scales at the
point of instant time corresponding to the location of the maximum of the analysed
Gaussian bell-shaped function. In addition, wG a0 (t, 0) = 0 and wG a0 (t, ∞) = 0. In
between, there exist two extrema (the line of positive maximum and the line of
negative minimum) determined via the equality dwG a0 /dt = 0,
t 2 = a02 + a2 (31)
and, via dwG a0 /da = 0,

3a2 t 2 a2
− 2 = 1. (32)
a02 + a2 a02 + a2
Using also Eq. (31) it is easy to conclude that the transform of the Gaussian has
two points of extrema at the scale ae = a0 symmetric in time with respect√to the zero
line corresponding to the Gaussian’s maximum on the distance te = ±a0 2 from it.
The Fourier transform of the (zero-centred, t = 0) Derivative-of-Gaussian wavelet

has the simple analytic form
+∞
t − (t−t2 )2 iωt dt (aω)2
=−
ψ e 2a e √ = −iaωe− 2 (33)
a a 2π
−∞
that allows the computation of the continuous wavelet transform (22) using the con-
volution theorem as
+∞
−1 (aω)2
w(t, a) = f (ω)aωe− 2 e−iωt d ω, (34)
2π
−∞
where f (ω) is the Fourier transform of the analysed function, which can be found
in practice applying the Fast Fourier Transform (FFT), and the CWT (34) will be
carried out by the Inverse FFT of the element-by-element product of the found Fourier
coefficients and the function (33).
4 The Wavelet Transform of Outbreaks
4.1 Test Example: Wavelet Transform of the Gaussian

Function
As the first example intended to illustrate the method for revealing maxima proposed
in the previous section, let us consider the purest example—the Gaussian function
t2
−
2a02
e
f (t) = √ (35)
a0 2π
and its continuous wavelet transform with the wavelet, which is built on the base of
the first derivative of the Gaussian function, see Fig. 1. The program code applied
for the data processing is given and discussed in Appendix A.
It is visible that the obtained picture exactly corresponds to the analytical results
of Eq. (30): the “two-hamped” function is antisymmetric respectively to the line
t = 0 at which the maximum of the function (35) is located. The value of the wavelet
transform at this point is equal to zero. Both humps have √ clear expressed point-
wise exprema: the maximum
√ at the point (t, a) = (−2 2, 2) and the minimum at
the point (t, a) = (2 2, 2). Therefore, such symmetric picture makes possible the
conclusions about the location of the maximum of the analysed bell-shaped function
and the characteristic width of this function. Symmetry of the extrema indicates the
symmetry of the analysed function.
4.2 A “perfect Outbreak”: The Case of South Africa
Figure 2 demonstrates the result of applying the the method described about not to
an artificial curve but to the real time series representing the COVID-19 outbreak in
South Africa (the data of daily registering cases according to the aggregation and
analytic system “Our World in Data” [48]). One can see that the picture of the wavelet
transform’s magnitude in Fig. 2 looks quite similar to the picture in 1: there are two
extrema placed symmetrically with respect to the vertical white line, which denotes
w(t, a) = 0. Its position marks the the day of July 18, 2020, i.e. the maximum of the
outbreak. The scales, at which the extrema take places, is aextr = 17 days.
The important feature of the wavelet transform’s plot is that the bright “spots” cor-
responding to its maximum and minimum, are sufficiently smooth although the plot
of the transformed function I (t) contains weakly variations. However, the period of
these oscillations is more than twice shorter that the characteristic scale of the more
slow bell-shaped outbreak. This feature directly illustrates the operational definition
of the transform (28) as a derivative of the Gaussian-smoothed time series (27).
Whence, the method based on the application of the continuous wavelet transform,
132 E. B. Postnikov
Fig. 1 The zero-centred Gaussian function with a0 = 2 shown as the dashed (blue) line in the upper
panel and its two-dimensional wavelet transform with the derivative of Gaussian wavelet depicted
as a two-dimension intensity map of magnitudes (lower panel); the thin white dotted line highlights
the values w(a, t) = 0); the solid (red) line in the upper panel highlights the values of w(a, t) for
the scale a = 2 corresponding to the extrema of the function w(a, t) with respect to the variable a
Fig. 2 The daily registered COVID-19 infection cases in South Africa shown from May 21, 2020
till September 22, 2020 (upper panel) and its wavelet transform with the Derivative of Gaussian
wavelet depicted as a two-dimension intensity map of magnitudes (lower panel); the white dotted
lines highlight the values w(a, t) = 0. The day t = 0 corresponds here to March 6, 2020
has an advantage of the automatic choice of an appropriate de-noising and the deter-
minations of the parameters of a bell-shaped outbreak simultaneously. At the same
time, the two-dimensional character of the function w(a, b) provides an opportunity
to explore small-scale features of the signal too, if it would be needed. In particular,
the small-scale periodicity is reflected by the series of spots near the abscissa axes
in Fig. 2.
4.3 Asymmetric Wavelet Extrema: The Case of Italy
The next example based now on the real-world data concerns the COVID-19 outbreak
in Italy, which starts to be a prototypic case for this disease, see the discussion in the
section “Related works” above. Figure 3 presents the time course of the main COVID-
19 outbreak (registered cases) in Italy considered as a whole and its wavelet transform.
The zero magnitude lines of the transform are highlighted as white dotted curves. The
most left of them (days 0 − 20) should be excluded from the consideration because
it originates from the boundary effect (the characteristic widths of the wavelet is
comparable with the distance to the left boundary of the actual finite sample). The
series of of semi-closed arcs during the second half of the time interval (starting from
the day 50 up to the end of the time considered) reflects the weakly variability (such
an effect as also noticed in [13]).
Fig. 3 The daily registered COVID-19 infection cases in Italy from January 31, 2020 till July 8,
2020 (upper panel) and its wavelet transform with the derivative of Gaussian wavelet depicted as
a two-dimension intensity map of magnitudes (lower panel); the white dotted lines highlight the
values w(a, t) = 0
134 E. B. Postnikov
The main region of interest is located in the centre of the plot. Although at the
first sight, there is one principal maximum for the analysed curve, and the wavelet
transform picture with two extrema looks similar to Fig. 1, they differ in details.
First of all, the zero wavelet magnitude line is not a vertical straight line but a
curve, which starts from the the day # t=53 (March 24, 2020), have a significant
curvature at small scales and tends to the vertical straight line corresponding to the
day # 66 (April 5, 2020). Respectively, the extrema locations are asymmetric too: the
maximum is located (with respect to the (t, a) co-ordinate plane, both variables have
the dimensionality of days) at the point (t1 , a1 ) = (40, 12) and (t2 , a2 ) = (92, 20).
These time moments correspond to the dates March 12, 2020 and May 2, 2020.
The work [24] indicated the maxima of two components of Italian outbreak with
maxima located at the dates March 27, 2020 and April 17, 2020. Whence, one can
note that the small-scale beginning of the principal wavelet zero line is three days
before the first cited data. Moreover, using the difference between the location of the
wavelet extreme and√the peak of the bell-shaped analysed function derived above,
we get t1∗ = t1 + a1 2 that (being rounded) corresponds to the day of March 27,
2020, i.e. there is the exact correspondence between the maxima localisation of the
first component determined by two independent methods.
The case of the second wavelet extreme is less straightforward. It correspond to
the zero line at the date, which is almost two weeks earlier that the second maximum
revealed in the work [24]. At the same time, it should be pointed out that the wavelet
surface shown in Fig. 3 does not show the righ-hand side minimum for the first (with
the scale a1 ) and the left-hand side maximum for the second (with the scale a2 )
extrema, and these missing extrema are a maximum and a minimum, respectively.
Thus, it is possible to conclude that this behaviour originates from overlapping these
two component. The original analysed plot, which does not have two distinct maxima,
confirms this conclusion. As a result, the time co-ordinate of large-scale zero wavelet
transform line can be considered as the left boundary determining the positive part
of two-humped wavelet transform of the second component. The midpoint of these
extrema (April 5, 2020 and May 2, 2020) gives the location of the maximum of the
second component around April 18, 2020 that is well corresponded with the value
given in the work [24], April 17, 2020.
4.4 Sloped Wavelet Transform Magnitude Zero Line: The

Case of Russia
Figure 4 demonstrates a more complicated example, which allows discussing an

origin of the extremely weakly decaying epidemic curve of COVID-19 in Russia.
Looking on the analysed curve I (t), one can see several stages: the initial exponential
growth tending to the maximum (as it is shown in the work [20] is accurately satisfies
the conventional SIR model) followed by a well-expressed peak in the middle of May,
and two further almost plateau, one with the magnitude about 7000 registered persons
Fig. 4 The daily registered COVID-19 infection cases in Russia from February 1, 2020 till Septem-
ber 2, 2020 (upper panel) and its wavelet transform with the Derivative of Gaussian wavelet depicted
as a two-dimension intensity map of magnitudes (lower panel); the white dotted lines highlight the
values w(a, t) = 0
per day and another about 5000 registered persons per day. To the date of analysis
there is no a visible significant further decay (due to this fact, the time series was
extended with the same value out of the right boundary to avoid significant boundary
disturbances during the wavelet transform; in the final representation of w(a, t) in
Fig. 4 this extrapolation was deleted).
As a consequence of such shape of the analysed curve I (t), the plot of the wavelet
transform magnitude in Fig. 4 demonstrates drastic asymmetry. In contrast not only
to Fig. 1 but even to Fig. 3, there is no a time-scale distribution with a maximum and a
minimum with comparable magnitudes even located at different scales. There is one
very expressed maximum and a very week minimum with the magnitude comparable
to zero.
The exact wavelet magnitude zero line highlighted in Fig. 4 with white colour
behaves also in the way different from the cases considered above. It is sloped and
has the almost constant slope for a wide range of scales (except very small scales,
where the local peak of I (t) is visible and the very large scales, where the wavelet’s
window width is comparable with the considered time interval, i.e. the finite-size
effect affects the result).
The initial growth and peak can be mainly associated in the outbreak in Moscow
and Moscow region (see the primary regional analysis of the outbreak’s time course
in [28]), which contains approximately 10.3 % of the Russian population on 0.0047 %
of the country’s area, i.e. the problem can be considered as a local and admits the
136 E. B. Postnikov
straightforward ODE modelling. This part of epidemic curve serves also as the source
of the large maximum in the wavelet transform plot.
In turn, the region to the left from the wavelet transform magnitude zero line is
filled almost uniformly with quite small values. On the one hand, this follows formally
from Eq. (25): the wavelet transform of the slightly varying (almost constant) function
is also almost zero. On the other hand, as it is discussed above for the case of Italy, the
epidemiological origin of such vanishing has the interpretation as a composition of
several outbreaks of comparable intensity separated by some time delay. In the case
of such spacious country as Russia, the origin of time delays between long-separated
locations is natural.
This effect can be illustrated by a simplified example. Let us consider three inde-
pendent outbreaks (say, the primary infections carriers arrived to the respective cities
with the times separated by ) with the same parameters. Then, the cumulative curve
is the sum of three solutions (13)

R = 3B+
A [tanh (α(t − tm − t)) + tanh (α(t − tm )) + tanh (α(t − tm + t))] , (36)
where α and tm are introduced for a shortened notation.

The expansion of (36) in the vicinity of the inflection point t = tm of the second
outbreak up to the first non-linear term is equal to,

1

Rt∼tm = 3B + A α(t − tm − t) − α 3 (t − tm − t)3
3
1
+α(t − tm ) − α 3 (t − tm )3
3

1 3
+ α(t − tm + t) − α (t − tm + t) ,
3
3
(37)
that is simplified to

Rt∼tm = 3B+A α 3 − 2 tanh(α t)2 (t − tm )−

1 3
α (3 − 8 tanh(α t)2 + 6 tanh(α t)4 (t − tm )3 . (38)
3
Eq. (38) contains the same first and third powers with respect to t but different
√
coefficients. The minimal value of the factor at t 3 is reached for tanh(α t) = α t
and equal to 1/3. Therefore, the expansion of the three outbreaks summed,

5 1 α2

Rt∼tm = 3B + A α(t − tm ) − · (t − tm ) ,
3
(39)
3 3 3
has three time smaller cubic term, i.e. the curve

R(t) is more flat in this region
than each individual R(t). Respectively, due to Eq. (4), the curve
I (t) defined as
the time derivative of
R(t), has less sharp maximum at this point than I (t).
Larger number An appropriate choice of a number of the epidemic with appro-
priate coefficients and time delays can, in principle, form the detected unique curve
of the metapopulation formed by the summation of epidemic curves for (almost)
independent individual populations.
On the other hand, the effect of a “long tail” can be considered also not neglecting
the epidemic spread between the contacting regions or sub-population completely.
The next section will discuss this approach.
5 Discussion: Summation of the Contact Epidemic

Spread Solutions
In order to discuss the revealed “long tail”, almost horizontal, with a small negative
slope, which is most demonstrable in the case of COVID-19 in Russia (although it
is seen for a number of other countries too, see, e.g. small but stable non-zero tail
in the case of Italy, Fig. 3), one can address the predecessor of modern sophisticated
metapopulation models proposed by D.G. Kendall [49] who replaced the system
(2)–(4) by the following one
dS
= −kS Ĩ , (40)
dt
dI
= kS Ĩ − τ −1 I , (41)
dt
dR
= τ −1 I , (42)
dt
where
Ĩ =
−1 I (x, y)dxdy (43)

is not a point-wise variable but the one averaged over some neighbourhood
.
In the case of contacts restricted by area with the characteristic size δ, the integral
representation (43) can be replaced by the differential form
δ2 2
Ĩ = I + ∇ I, (44)
2d
where d = 1 for the chain coupling and d = 2 for the symmetric two-dimensional
spatial coupling.
138 E. B. Postnikov
Fig. 5 The illustrative example of travelling spatio-temporal Kendall’s wave (upper panel) and
the respective time-dependent cumulative outbreak curve formed by the summation over the whole
spatial region (lower panel)
For example, the system (40)–(42) in one-dimensional case takes the from

∂S δ 2 ∂I
= −kS I + , (45)
∂t 2 ∂x

∂I δ 2 ∂I
= kS I + − τ −1 I , (46)
∂t 2 ∂x
∂R
= τ −1 I . (47)
∂t
This system was extensively studied in the works [50, 51], where it has been
shown that its solution forms a travelling wave spreading with the stable speed

v = kδ 2 1 − R−1 0 . An example of such wave is shown in Fig. 5.
It should be pointed out that in this case (under the same normalization of the
variables as in Eq. (1), there exists also and the second invariant written now with
respect to the travelling wave variable x = x − vt as
S δ2 τ d 2 R
log( ) + kτ R + = 0, (48)
S0 2 dx2
i.e. the second derivative is added to Eq. (8).

Respectively, the travelling wave solution satisfies the ordinary differential equa-
tion
dS δ2 d 2 S
v = kS(1 − S) + τ −1 S log(S) − S 2 , (49)
dx 2 dx
where S0 ≈ 1 is taken for simplicity. Equation (49) has an approximate analytical
solution, see the details in [51]. Two other variables can be expressed from this
solution using Eqs. (1) and (48) and have the mathematical structure close to the
solution of the conventional SIR system discussed above. The main difference is that
the outbreak of the stable bell-shaped form spreads in time and space.
However, since the main purpose of this discussion is not the consideration
of the quantitative properties of such spread (that can be found in [51]) but the
demonstration, how this effect leads to the emergence of a long tail in the time-
dependent epidemic curve cumulative for the whole space, let us consider the direct
numerical solution of the system (45)–(47). The corresponding program code is
given in AppendixB. As the initial conditions the Gaussian function I (x, 0) =
√
0.1 exp(−x2 /(2δ 2 ) 2π δ 2 is taken; R(x, 0) =, S(x, 0) = 1 − I (x, 0) − R(x, 0)
assuming the normalisation of the whole population to the unity. The parameters
are equal to δ = 0.25, k = 0.5, τ = 5 in arbitrary units (a.u.).
The upper panel in Fig. 5 demonstrates the travelling wave solution of a finite
characteristic width spreading with a constant speed in time and space that is indicated
by the constant slope of the bright stripe of high magnitude after some short transient
time interval. But the key point is that the summation of all data on I (x, t) detected
at every spatial point at the given time moment, I (t) = x I (x, t) shown in the
lower panel of Fig. 5. It clearly demonstrates that such summation results in the
sigmoid curve, which tends to the some constant saturated plateau for the generalised
population not separated with respect to the habitat of each local sub-population.
That is also important to note that the infection spread described by the system (45)–
(47) (and, in the general case, the system (40)–(42)) does not require an extensive
mobility of infected persons in contrast to the reaction-diffusion models like Fisher-
Kolmogorov’s one, see the discussion in [50]. All what is needed is a presence of
contacts between neighbouring low-mobile local sub-populations.
Thus, qualitatively the saturated tail Fig. 5 is similar to the long tail in Fig. 4.
Certainly, this correspondence is qualitative only since the real intra-country contacts
have rather networking structure, the spatial distribution of the susceptible population
is not uniform, the measures preventing the infection spread should be taken into
account, etc. But at least the concept of Kendall’s wave gives a hint, why such a slow
decay of the COVID-19 outbreak is observed for such a spatially extended country
as Russia when one consider the summary time-dependent statistics only.
140 E. B. Postnikov
6 Conclusion and Outlooks
The main points of this work can be summarized as follows. The analysis of the
epidemic curves for diseases, which affect whole countries as the recent pandemics
of COVID-19 requires the consideration of more complicated underlying spatial
structure reflected in the unified time-dependent curve. Therefore, modelling this
curve may require not more sophisticated purely time-dependent models based on
the ordinary differential equations but some combination of simple multiple solutions
of classic models of mathematical epidemiology, i.e. the metapopulation approach.
The question is how many such components are required?
The continuous wavelet transform can help answering this question. As it is shown,
even the widespread conventional wavelet, namely the wavelet constructed as the
derivative of the Gaussian function is coordinated under some reasonable simpli-
fying assumption with the solution of the well-studied SIR model. The exploration
of the two-dimensional plot, which represents the magnitude distribution for such
wavelet transform allows to conclude, how many components should be taken as a
first approximation. This quantity can vary from one to several components. One
component corresponds to the case with a high localisation of the populations, when
the mean-filed approach based on the ordinary differential equations. More spatially
spread countries as well as countries with some socio-geographic difference (e.g.
North Italy and South Italy) exhibits more complicated dynamics. It includes a vari-
ety from two almost coexisting (with some time displacement) components, as it is
illustrated with the case of Italy up to the necessity to consider the country-wide data
as a cumulative quantity obtained via integration of the travelling wave solution of
the epidemiological partial differential equation written with respect either to the real
spatial spread or the sub-populations or a combination of the both ones. The demon-
strable example of this complicated behaviour is the case of Russia characterised by
the extremely “long tail” of the epidemic curve.
Finally, it should be pointed out that the this work provides only the mathematical
route to such studies and presents first results on this way. The further research direc-
tions can be listed as follows: more detailed investigations of specificity of either
mono- or multimodal dynamics of COVID-19 outbreaks in different countries (due
to the pandemic spread of the disease, a large variety of patterns is observed) with
the subsequent analysis of socio-geographic backgrounds, which lead to the revealed
features; the coordinated explorations of local regional outbreaks and the country-
wide dynamics intended for building microscopic hierarchy of epidemic processes
within the metapopulation approach and the procedure of coarse-graining realising
the transition from spatio-temporal (including contact networks-based models) to a
mean-field time-dependent models; usage of the wavelet-based analysis for testing
agent-based simulations, which may be developed to mimic the disease spreading
process and effectiveness of the interventions aimed in its control and prevention. In
addition, the analytical approximations discussed within this work are still approx-
imations, therefore, their improvement is possible. This relates to the search for a
wavelet, which is better coordinated with the solutions representing the epidemic
curves as well as to the consideration of model approaches, which are better adjusted
to the way of obtaining the available medical records, i.e. taking into account the latent
time of infections, asymptomatic and not revealed cases, etc. As for the latter, some
hints may be provided extending the invariant-based approach, which demonstrated
its powerfulness for the classic SIR approach on the more sophisticated modifica-
tions. A possible example of such generalisation is provided in Appendix B.
Appendix A: practical computation of the CWT with

the Gaussian wavelet
The practical computing the continuous wavelet transform of the equispaced sample
of the daily registered data on the number of infected persons can be carried out using
the FFT-based algorithm based on the convolution theorem as a discretization of the
explicit formula (34). For the practical implementation in this work, the program
code was written in MATLAB language using its special possibility of the parallel
element-by-element multiplication and functions’ computations discussed in details
in [52]. The function, which calculates the CWT with the wavelet (24) reads as
Program Code
function w=fftGau(t,f,a);
% Sampling lengths in time and scale

N=length(t);
Na=length(a);
% Fourier transform of the processed function
F=fft(f);
% Centred and scaled sample of frequencies
nrm=2*pi/(t(end)-t(1));
omega=([0:floor(N/2),-ceil(N/2)+1:-1])*nrm;
% Convolution of Fourier images of the signal and the wavelet
AA=repmat(a’,1,N);
OMEGA=repmat(omega,Na,1);
FF2=repmat(F,Na,1);
OMEGAa=OMEGA.*AA;
WINDOW=i*OMEGAa.*exp(-OMEGAa.ˆ2/2);
CNV2=WINDOW.*FF2;
% Inverse FFT
w=ifft(CNV2,N,2,’symmetric’);
142 E. B. Postnikov
The processed data were taken from the aggregation and analytic system “Our
World in Data” [48]; the program code used for data downloading is provided in
https://github.com/postnicov/owid_loglet_interface!.
Appendix B: Simulation of Kendall’s wave
The data used to plot Fig. 5 were obtained by the numerical solutions of the system of
partial differential equations (45)–(47) via the specialised software FlexPDE 5.0.22
(https://www.pdesolutions.com/) using the following program code (it
is practically self-explanatory because of the closeness of the FlexPDE syntax to the
common mathematical notation):
Program Code
TITLE ’Kendall‘s wave’

COORDINATES cartesian1 { coordinate system: 1D }
VARIABLES { system variables }
S(threshold=0.1)
I(threshold=0.1)
R(threshold=0.1)
DEFINITIONS { parameter definitions }
kappa=0.5
tau=5
delta=0.25
INITIAL VALUES
I=0.1*exp(-xˆ2/(2*deltaˆ2))/sqrt(2*pi*deltaˆ2)
R=0
S=1-I
EQUATIONS { PDE’s, one for each variable }
S: dt(S)=-kappa*S*(I+deltaˆ2*dxx(I)/2)
I: dt(I)=kappa*S*(I+deltaˆ2*dxx(I)/2)-I/tau
R: dt(R)=I/tau
BOUNDARIES { The domain definition }
REGION 1
START(0) LINE TO (25)
TIME 0 TO 150
PLOTS { save result displays }
for t=0 by 0.5 to 150
elevation(I) from (0) to (25) export
END
The exported data were imported to MATLAB for plotting using the function
fpreade from the special interface package [53].
Appendix C: global analytical properties of the SIR-X system
Recently, B.F. Maier and D. Brockmann within the context of COVID-19 modelling
proposed [11] a modification of the classical SIR system, which is called SIR-X
model. It answers two valuable challenges of the respective mathematical modelling:
(i) in fact, nobody knows the real number of infected persons, the epidemic curves
deals with the reported cases, which are only the part of the total infected population;
(ii) the outbreak of COVID-19 in Mainland China demonstrated a subexponential
(power-law in time) increase of confirmed cases during the initial stage of epidemics
(instead of the conventional exponential time dependence, which follows from the
SIR model).
The new variant of a compartment model introduced by Maier&Brockmann reads
as
dS
= −αSI − κ0 S, (50)
dt
dI
= αSI − βI − κ0 I − κI (51)
dt
dR
= βI + κ0 S (52)
dt
dX
= (κ + κ0 ) I , (53)
dt
where α and β are the conventional transmission and recovery rates, respectively, but
κ0 and κ are the coefficients, which characterise the containment rate and removal
of symptomatic infected persons. In addition, new variable X proportional to the
empirically confirmed and reported cases, is introduced. The analysis carried out by
the authors of this model is based on the linearisation under the condition of large k0
and numerical fitting the obtained solution to the medical records. It demonstrates
that the model (50)–(53) can catch the desired dynamical behaviour.
The key idea, which leads to revealing principal global features of the classic
SIR system is reducing dimensionality of the system due to existence of algebraic
invariants, which simplify the system considered in (S, I ) phase plane in the same
way as it is discussed above for the SIR model and its spatio-temporal extension. As
it will be shown below, it is possible to follow this way for the Eqs. (50)–(53) due to
the specific introduction of the containment and removal terms.
First of all, the considered system is supplied by its construction with the conser-
vation law for the full population N :
S + I + R + X = N. (54)
144 E. B. Postnikov
Note that it is convenient to put N = 1 as denoting the full accessible population; in

this case, all variables will have the meaning of the respective relative part of the full
population.
Further, the right-hand sides of the both Eqs. (50) and (51) has a common multiplier
(S and I , respectively), which can be taken out, and both sides of the equations can
be divided by these multipliers. Applying the standard formula of the derivative of a
natural logarithm, Eqs. (50) and (51) can be rewritten as
d ln(S)
= −α exp(ln(I )) − κ0 , (55)
dt
d ln(I )
= α exp(ln(S)) − (β + κ0 + κ), (56)
dt
where the remaining variables at right-hand sides are expressed as I = exp(ln(I ))
and S = exp(ln(S)) to get the uniform variable alteration.
Considered together, Eqs. (55) and (56) result in the equation
d ln(S) α exp(ln(I )) + κ0
= , (57)
d ln(I ) (β + κ0 + κ) − α exp(ln(S))
which can be easily solved analytically by the separation of variables.

However, it is important to take into account the principal difference between the
time course of S and I . While S is a monotonically decaying function that is obvious
from Eq. (50) since its right-hand side is always negative, the variable I has one
maximum corresponding to the peak of epidemics. This value Imax is determined by
the condition dI /dt = 0 that gives the equality
(β + κ0 + κ)
Sm = ≡ R−1
0,eff , (58)
α
where S = Sm when I = Imax , and R0,eff is the effective basic reproduction number
of the SIR-X model.
Thus, within the intervals I ∈ [I0 , Imax ], S ∈ [S0 , Sm ] both functions, I and S
are monotonous and the integration from the initial to the current values gives the
algebraic expression, which defines a unique curve on the (S, I ) phase plane:

κ0 I S
(I − I0 ) + ln = Sm ln − (S − S0 ).
α I0 S0
It is convenient to rewrite this equality in the form

S0 S − SS0 SS S0 1 κ0 I S0
− e m 0 = − exp (I − I0 ) + ln − ,
Sm S0 Sm Sm αSm I0 Sm
which indicates that the number of susceptible persons on the time interval of growing
I can be exactly analytically expressed via the Lambert W-function:
αSκ0
S0 S0 I m (I −I0 )
S = −Sm W − e− Sm × e Sm . (59)
Sm I0
For I = I0 , the argument of the Lambert function in Eq. (59) is its reciprocal, −Sm
cancel each other and S = S0 . On the other hand, this form allows the exact determin-
ing the maximal number of infected persons since in this case the Lambert function
should be equal to −1 = W (−e−1 ), i.e.
αSκ0
S0 − S0 Imax m (Imax −I0 ) 1
e Sm × e Sm = . (60)
Sm I0 e
This algebraic equation again is exactly solvable:

− αSκ m
κ0 αI0 S0 0
− κα (S0 +I0 −Sm )
Imax = W e 0 . (61)
α κ0 Sm
Subsequently, both functions I (t) and S(t) are also monotonous when I ∈
[Imax , 0], S ∈ [Sm , Smax ]; the former decays to zero while the latter grows to the
saturation. Integrating Eq. (57) within these intervals but starting now from I = Imax ,
S = Sm and repeating similar procedures, it is possible to get the expression for the
second stage of the outbreak again as the Lambert W-function:
αSκ0
1 I m (I −Imax )
S = −Sm W − e Sm . (62)
e Imax
Therefore, substituting either (59) or (62) into Eq. (51), it is possible to obtain
the unique solution for the number of infected persons as an implicit quadrature
expression
I
dI
t=
αSκ0 (I −I0 ) (63)
S
S0 − Sm0
αI −Sm W − Sm e × I0 − Sm
I m
0 e S m
for t ∈ [0, tm ], where tm is the time moment corresponding to I (tm ) = Imax , and
I
dI
t = tm +
αSκ0 (I −Imax ) (64)
αI −Sm W − e Imax − Sm
1 I m
Im e S m
for t ∈ [tm , ∞].

Respectively, having I (t) found by this way, the time evolution of the number of
susceptible persons will be found via the algebraic equations (59) and (62), and the
146 E. B. Postnikov
rest of variables—by the simple integration of the obtained two functions of time
substituted into Eqs. (52) and Eqs. (53) with the lower bounds of integration equal
to R(0) = X (0) = 0 when starting from the very beginning of the outbreak.
Note that all singularities in (63) and (64) are weak and the integrals do not diverge.
For t → 0 and t → ∞ the denominators ∝ I , i.e. the integration gives logarithm
leading to the standard exponential growth and decay of the number of infected
in the vicinity of the initial and asymptotically large times. In the vicinity of the
maximum point, using the known asymptotic expansion [54]

W (ξ ) + 1 ≈ 2(1 + eξ ),
and the equality (60), the denominator tends to zero as the power-law function ∝ (1 −
I /Imax )κ0 /(2αSm ) , i.e. also sufficiently slowly to avoid a divergence of the respective
integral.
Note also that the complete procedure can also be carried out using S instead of
I due to the symmetry of Eq. (57) respectively to both variables; in this case, I (S)
will be expressed via the Lambert W-function too. However, the form of solution
given above is more convenient from the point of view that the main X (t) can be
obtained by the direct integration of I (t) that makes possible to reveal the origin of
the replacement of an exponential growth immanent for the classic SIR model by
the power-law growth, for which the system (50)–(53) was invented in [11].
Now let us consider the growth’s properties at the first stage of an outbreak. First
of all, it should be pointed out that all derivations and equations for I and S are valid
for the standard SIR model too if simply put κ0 = 0 that eliminates the second term
in Eq. (50). The functional form of Eq. (51) will not be affected, the only difference
is in the value of Sm . The solution in quadratures (63) takes the form
I
dI
t= S (I −I0 )

. (65)
− SSm0 e− Sm
0
0
αI −Sm W ×e Sm − Sm
For small (I − I0 )/Sm , when the exponential function in the Lambert W function’s
argument is close to unity, it naturally reduces to
I
dI
t=
I α (S0 − Sm )
0
that gives the standard exponential growth of the epidemic beginning within the SIR
model:
I (t) = I0 e[α(S0 −Sm )t] . (66)
On the contrary, one can not neglect the factor (I /I0 )κ0 /(αSm ) in Eq. (63) even for
small (I − I0 )/Sm , which eliminates the exponential factor, since the growth of the
former affects the integral directly, not as a small addition to unity. The respective
influence far from the outbreak’s peak, when the absolute values of an argument of
Lambert W function are sufficiently smaller than 1/e, can be estimated using Taylor’s
expansion taking into account the equality
1 W (z)
W (z) =
z 1 + W (z)
as

αSκ0 − S0 αSκ0
S0 − S0 I m S0 Sm I m
W − e Sm × ≈− + −1 .
Sm I0 Sm 1 − SSm0 I0
Respectively, the integral (63) takes the form
I
dI
t=
κ0 ,
αS
I α [S0 − Sm ] − S0
−1
I m
0 S0
Sm −1
I0
which can be taken analytically and the resulting solution is

αSκ m α S0 −Sm +
S0
t
0 S0
I0 S0 − Sm + S0
S0 e Sm −1
−1
I (t) = ⎡ ⎤ αSκ0m .
Sm
(67)
S0 κ0
α S0 −Sm + αSm t
⎣S0 − Sm + ⎦
S0
S0
e Sm −1
S0
Sm−1
Thus, it is seen that the growth of infected persons under the same conditions, when
the standard SIR model gives pure exponential growth, is slower. Except for the very
first moment, when the time-dependent part of the denominator in Eq. (67) (that
corresponds to the initial conditions in Eq. (51)) vanishes, the exponential function
is divided by relatively fast-growing time-dependent denominator. Interestingly, the
solution (67) has a form of the power-law function of the solution of the logistic
equation, which slows down from the exponential to linear growth (the further tending
to saturation will be out of the considered time interval corresponding to the active
growth stage only, where the SIR model exhibit the exponential growth). The rate
of this slowing depends directly on the value of κ0 , which is the main controlling
factor. In the limit κ0 → 0, Eq. (67) will be reduced to the pure exponential solution,
Eq. (66) that can be easily demonstrated by the expansion of the exponential function
in the denominator up to the linear function of time with the subsequent transition
to
the exponential function (due to the exponent 1/k0 ), which eliminates exp α S0
S0 t
Sm−1
from the nominator as well as the amplitude multiplier additional to I0 .
148 E. B. Postnikov
Now, the last step: calculating the dynamics of symptomatic, quarantined infected
persons X (t) from Eqs. (53) and (67). Fortunately, Eq. (67) can be integrated in an
analytic form that results in the desired explicit formula
αSκ m −1
0 ⎧
(κ + κ0 ) I0 S0 − Sm + S0
S0
⎨ α S0 −Sm + S S0 t
Sm −1 0
X (t) = e Sm −1 ×
α [S0 − Sm ] ⎩
⎡ ⎤1− αSκ0m
S0 κ0
S0 α S0 −Sm + αSm t
⎣S0 − Sm + ⎦
S0
e Sm −1 × (68)
S0
Sm
−1
⎛ ⎞
S0 κ0
αSm S0 α S0 −Sm + αSm t
⎝ ⎠−
S0
2 F1 1, 1; 1 + ,− e Sm −1
κ0 Sm
1− αSκ m ⎫
0 ⎬
S0
S0 − Sm + S0
−1 ⎭
Sm
Since three terms in the curly braces are combined multiplicatively, it is obvious
that two of them, being time-dependent, heavily affect the dynamics and lead to its
deviation from the exponential growth provided by the first multiplier. Note finally,
that linearisation route described in the work [11] also showed the deviation of X (t)
dynamics from the exponential growth expressed as emergence of an additional mul-
tiplicative time-dependent factor. But in the case of Eq. (68) such influence is derived
within the non-linear route based on the exact (S, I ) phase space representation.
References
1. WHO: (2020). https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-

reports
2. Cobey, S.: Modeling infectious disease dynamics. Science 368, 713–714 (2020). https://doi.
org/10.1126/science.abb5659
3. Currie, C.S.M., Fowler, J.W., Kotiadis, K., Monks, T., Onggo, B.S., Robertson, D.A., Tako,
A.A.: How simulation modelling can help reduce the impact of COVID-19. J. Simul. 14, 83–97
(2020). https://doi.org/10.1080/17477778.2020.1751570
4. Roda, W.C., Varughese, M.B., Han, D., Li, M.Y.: Why is it difficult to accurately predict
the COVID-19 epidemic? Infect. Dis. Mod. 5, 271–281 (2020). https://doi.org/10.1016/j.idm.
2020.03.001
5. Metcalf, C.J.E., Morris, D.H., Park, S.W.: Mathematical models to guide pandemic response.
Science 369, 368–369 (2020). http://orcid.org/10.1126/science.abd1668
6. Buchanan, M.: The limits of a model. Nature Phys. 605, 16 (2020). http://orcid.org/10.1038/
s41567-020-0934-5
Proc. Roya. Soc. Lond. A 115, 700–721 (1927). http://orcid.org/10.1098/rspa.1927.0118
8. Murray, J.D.: Mathematical Biology: I. An Introduction. Springer Science & Business Media
(2007)
9. Brauer, F., van den Driesche, P.V., Wu, J. (eds.): Mathematical epidemiology. Springer, Berlin
(2008)
10. Guirao, A.: The Covid-19 outbreak in Spain. A simple dynamics model, some lessons, and
a theoretical framework for control response. Infect. Dis. Modell. (2020). https://doi.org/10.
1016/j.idm.2020.08.010
11. Maier, B.F., Brockmann, D.: Effective containment explains subexponential growth in recent
confirmed COVID-19 cases in China. Science 368, 742–746 (2020). https://doi.org/10.1126/
science.abb4557
12. Cooper, I., Mondal, A., Antonopoulos, C.G.: A SIR model assumption for the spread of COVID-
19 in different communities. Chaos Solitons Fractals 139 (2020). https://doi.org/10.1016/j.
chaos.2020.110057
13. Dehning, J., Zierenberg, J., Spitzner, F.P., Wibral, M., Neto, J.P., Wilczek, M., Priesemann, V.:
Inferring change points in the spread of COVID-19 reveals the effectiveness of interventions.
Science 369, eabb9789 (2020). https://doi.org/10.1126/science.abb9789
14. Grenfell, B., Harwood, J.: (Meta) population dynamics of infectious diseases. Trends Ecol.
Evol. 12, 395–399 (1997). https://doi.org/10.1016/S0169-5347(97)01174-9
15. Colizza, V., Vespignani, A.: Epidemic modeling in metapopulation systems with heterogeneous
coupling pattern: theory and simulations. J. Theoret. Biol. 251, 450–467 (2008). https://doi.
org/10.1016/j.jtbi.2007.11.028
16. Hess, G.: Disease in metapopulation models: implications for conservation. Ecology 77, 1617–
1632 (1996). https://doi.org/10.2307/2265556
17. Thurner, S., Klimek, P., Hanel, R.: A network-based explanation of why most COVID-19
infection curves are linear. Proc. Natl. Acad. Sci. USA (2020). https://doi.org/10.1073/pnas.
2010398117
18. Lloyd, A.L., Jansen, V.A.A.: Spatiotemporal dynamics of epidemics: synchrony in metapopu-
lation models. Math. Biosci. 188, 1–16 (2004). https://doi.org/10.1016/j.mbs.2003.09.003
19. Ball, F., Britton, T., House, T., Isham, V., Mollison, D., Pellis, L., Tomba, G.S.: Seven challenges
for metapopulation models of epidemics, including households models. Epidemics 10, 63–67
(2015). https://doi.org/10.1016/j.epidem.2014.08.001
20. Postnikov, E.B.: Estimation of COVID-19 dynamics “on a back-of-envelope”: Does the sim-
plest SIR model provide quantitative parameters and predictions? Chaos Solitons Fractals 135,
(2020). https://doi.org/10.1016/j.chaos.2020.109841
21. Kaxiras, E., Neofotistos, G.: Angelaki,: The first 100 days: modeling the evolution of the
COVID-19 pandemic. Chaos Solitons Fractals 138 (2020). https://doi.org/10.1016/j.chaos.
2020.110114
22. Pelinovsky, E., Kurkin, A., Kurkina, O., Kokoulina, M., Epifanova, A.: Logistic equation and
COVID-19. Chaos Solitons Fractals 140 (2020). https://doi.org/10.1016/j.chaos.2020.110241
23. Dattoli, G., Di Palma, E., Licciardi, S., Sabia, E.: On the Evolution of Covid-19 in Italy: A
Follow up Note. arXiv:2003.12667 (2020)
24. Vannucci, V., Vannucci, L.: Estimation of the ending time of Covid-19 emergence in Italy: a
2-waves model as sum of logistics (2020). https://doi.org/10.13140/RG.2.2.26675.58403
25. Vannucci, V., Vannucci, L.: Somme di logistiche per stimare la durata di Covid-19 in Italia,
Stati Uniti e Brasile (10.13140/RG.2.2.14172.62085) (2020). https://doi.org/10.13140/RG.2.
2.14172.62085
26. Dattoli, G., Di Palma, E., Licciardi, S., Sabia, E.: A Note on the Evolution of Covid-19 in Italy.
arXiv:2003.08684 (2020)
27. Chruściel, P.T., Szybka, S.J.: A phenomenological algorithm for short-range predictions of the
Covid-19 pandemics 2020. medRxiv p. doi.org/10.1101/2020.05.22.20098350 (2020). https://
doi.org/10.1101/2020.05.22.20098350
28. Postnikov, E.B.: Reproducing country-wide COVID-19 dynamics can require the usage of a
set of SIR systems. PeerJ 9, (2020). https://doi.org/10.7717/peerj.10679
150 E. B. Postnikov
29. Kaxiras, E., Neofotistos, G.: Multiple epidemic wave model of the COVID-19 pandemic:
modeling study. J. Med. Internet Res. 22(7) (2020). https://doi.org/10.2196/20912
30. Roberts, D.H.: Two New Models for Epidemics with Application to the COVID-
19 Pandemic in the United States, Italy, and the United Kingdom. medRxiv p.
doi.org/10.1101/2020.07.13.20152686 (2020). https://doi.org/10.1101/2020.07.13.20152686
31. Huang, J., Qi, G.: Effects of control measures on the dynamics of COVID-19 and double-peak
behavior in Spain. Nonlinear Dyn. (2020). https://doi.org/10.1007/s11071-020-05901-2
32. Weitz, J.S., Beckett, S.J., Coenen, A.R., Demory, D., Dominguez-Mirazo, M., Dushoff, J.,
Leung, C.Y., Li, G., Măgălie, A., Park, S.W., Rodriguez-Gonzalez, R., Shivam, S., Zhao, C.Y.:
Modeling shield immunity to reduce COVID-19 epidemic spread. Nature Med. 26, 849–854
(2020). https://doi.org/10.1038/s41591-020-0895-3
33. Peixoto, P.S., Marcondes, D., Peixoto, C., Oliva, S.M.: Modeling future spread of infections
via mobile geolocation data and population dynamics. An application to COVID-19 in Brazil.
PloS One 15, e0235732 (2020). https://doi.org/10.1371/journal.pone.0235732
34. Linka, K., Peirlinck, M., Sahli Costabal, F., Kuhl, E.: Outbreak dynamics of covid-19 in europe
and the effect of travel restrictions. Comput. Methods Biomech. Biomedical Eng. 2, 710–717
(2020). https://doi.org/10.1080/10255842.2020.1759560
35. Ruktanonchai, N.W., Floyd, J.R., Lai, S., Ruktanonchai, C.W., Sadilek, A., Rente-Lourenco, P.,
Ben, X., Carioli, A., Gwinn, J., Steele, J.E., Prosper, O., Schneider, A., Oplinger, A., Eastham,
P., Tatem. A., J.: Assessing the impact of coordinated COVID-19 exit strategies across Europe.
Science (2020)
36. Grenfell, B.T., Bjørnstad, O.N., Kappey, J.: Travelling waves and spatial hierarchies in measles
epidemics. Nature 414, 716–723 (2001). https://doi.org/10.1038/414716a
37. Cazelles, B., Chavez, M., de Magny, G.C.d., Guégan, J.F., Hales, S.: Time-dependent spectral
analysis of epidemiological time-series with wavelets. J. Royal Soc. Interface 4, 625–636
(2007). https://doi.org/10.1098/rsif.2007.0212
38. Chavez, M., Cazelles, B.: Detecting dynamic spatial correlation patterns with generalized
wavelet coherence and non-stationary surrogate data. Sci. Rep. 9, 1–9 (2019). https://doi.org/
10.1038/s41598-019-43571-2
39. Chakraborty, T., Ghosh, I.: Real-time forecasts and risk assessment of novel coronavirus
(COVID-19) cases: a data-driven analysis. Chaos Solitons Fractals 135 (2020). https://doi.
org/10.1016/j.chaos.2020.109850
40. Singh, S., Parmar, K.S., Kumar, J., Makkhan, S.J.S.: Development of new hybrid model of dis-
crete wavelet decomposition and autoregressive integrated moving average (ARIMA) models
in application to one month forecast the casualties cases of COVID-19. Chaos Solitons Fractals
135 (2020). https://doi.org/10.1016/j.chaos.2020.109866
41. Krantz, S.G., Polyakov, P., Rao, A.S.R.S.: True epidemic growth construction through harmonic
analysis. J. Theoret. Biol. 494 (2020). https://doi.org/10.1016/j.jtbi.2020.110243
42. Krantz, S.G., Rao, A.S.R.S.: Level of underreporting including underdiagnosis before the first
peak of COVID-19 in various countries: Preliminary retrospective results based on wavelets
and deterministic modeling. Infect. Control Hosp. Epidemiol. 41, 857–861 (2020). https://doi.
org/10.1017/ice.2020.116
43. Heffernan, J.M., Smith, R.J., Wahl, L.M.: Perspectives on the basic reproductive ratio. J. Roy.
Soc. Interface 4, 281–293 (2005). https://doi.org/10.1098/rsif.2005.0042
44. van den Driessche, P.: Reproduction numbers of infectious disease models. Infect. Dis. Mol.
3, 288–303 (2017). https://doi.org/10.1016/j.idm.2017.06.002
)
45. Bassett, B.: e−x dx and the Kink Soliton. Comput. Math. Appl. 36, 37–45 (1998). https://
2
doi.org/10.1016/S0898-1221(98)00139-4
46. Corless, R.M., Gonnet, G.H., Hare, D.E., Jeffrey, D.J., Knuth, D.E.: On the Lambert W function.
Adv. Comput. Math. 5(1), 329–359 (1996). https://doi.org/10.1007/BF02124750
47. Mallat, S.: A Wavelet Tour of Signal Processing: The Sparse Way. Academic (2009)
48. Roser, M., Ritchie, H., Ortiz-Ospina, E., Hasell, J.: Coronavirus Pandemic (COVID-19). Our
World in Data (2020). https://ourworldindata.org/coronavirus
49. Kendall, D.G.: Mathematical models of the spread of infection. In: Mathematics and computer
science in biology and medicine. H.M. Stationery Off, London (1965)
50. Postnikov, E.B., Sokolov, I.M.: Continuum description of a contact infection spread in a SIR
model. Math. Biosci. 208, 205–215 (2007). https://doi.org/10.1016/j.mbs.2006.10.004
51. Naether, U., Postnikov, E.B., Sokolov, I.M.: Infection fronts in contact disease spread. Eur.
Phys. J. B 65, 353–359 (2008). https://doi.org/10.1140/epjb/e2008-00291-9
52. Postnikov, E.B., Tsoy, M.O., Postnov, D.E.: A fast method for the detection of vascular structure
in images, based on the continuous wavelet transform with the Morlet wavelet having a low
central frequency. In: Proceedings of SPIE 10337, 103370X (2017). https://doi.org/10.1117/
12.2268427
53. Rahmani, M.: FPMat: FlexPDE MATLAB Interface. https://www.mathworks.com/
matlabcentral/fileexchange/6723-fpmat-flexpde-matlab-interface
54. Veberič, D.: Lambert W function for applications in physics. Comput. Phys. Commun. 183,
2622–2628 (2012). https://doi.org/10.1016/j.cpc.2012.07.008
Prediction of Confirmed, Recovered
and Casualties’ Cases of COVID-19
in India by Autoregressive Integrated
Moving Average (ARIMA) Models
Sarbjit Singh, Kulwinder Singh Parmar, Jatinder Kumar,

and Jatinder Kaur
Abstract Fast spreading coronavirus disease 2019 (COVID-19), originated in the

Wuhan city, China in December 2019, is a contagious disease caused by Severe
Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Within a short period,
COVID-19 infections spread over large geographical area affecting millions of people
and declared a pandemic by the World Health Organization (WHO). The fast and
quick spread of the virus across the globe resulted in thousands of casualties. COVID-
19 prevalence in India was reported in the late of January 2020 and the number
of infections increased sharply by the end of March. In such a troublesome situ-
ation, time series analysis proves very much helpful in monitoring and assessing
the growth curve of COVID-19 infections. In the present study, autoregressive inte-
grated moving average (ARIMA) models are developed for the time series data of
cumulative confirmed, recovered and causalities cases of COVID-19 in India. The
data set under study is broken up into two subsets, modelling and testing data sets.
After analysing the input data for stationarity using autocorrelation function (ACF)
and partial correlation function (PACF) plots, different ARIMA models are esti-
mated for confirmed, recovered and causalities’ cases of COVID-19 in India for
modelling phase. ARIMA Model outputs are then compared with observed values
of confirmed, recovered and casualties’ cases for the testing phase using error anal-
ysis. It has been found that ARIMA (0, 2, 3), ARIMA (0, 2, 5) and ARIMA (1, 2, 1)
models are appropriate with the lowest mean absolute percentage error (MAPE)
S. Singh (B)
Department of Mathematics, Guru Nanak Dev University College, Narot Jaimal Singh, Pathankot,
Punjab, India
e-mail: sarbjit.narot@gndu.ac.in
K. S. Parmar (B)
Department of Mathematics, I.K. Gujral Punjab Technical University, Kapurthala, Punjab, India
e-mail: dr.kulmaths@ptu.ac.in
S. Singh · J. Kumar
Department of Mathematics, Guru Nanak Dev University, Amritsar, Punjab, India
J. Kaur
Department of Mathematics, Guru Nanak Dev University College, Verka, Amritsar, Punjab, India
154 S. Singh et al.
values for the data of confirmed cases, recovered cases and casualties’ cases respec-
tively. Finally, the developed ARIMA models are used to forecast one-month ahead
values of confirmed, recovered and casualties’ cases of COVID-19 in India. The
predictions indicate rise in confirmed COVID-19 cases and speedy recoveries as
well, whereas the casualties continue to show a constant trend in future. Based on
these future trends of COVID-19 outbreak, governments and policymakers can take
preventive measures to break the ongoing chain of COVID-19 infections and make
necessary arrangements in the wake of an emergency.
Keywords COVID-19 · Time series modelling · ARIMA model · Confirmed

cases · Recovered cases · Casualties’ cases · Forecasting
1 Introduction
1.1 Background
“The pandemic is a once-in-a-century health crisis, the effects of which will be

felt for decades to come” (WHO). An epidemic possibly linked to seafood and
the live animal market was witnessed in the Wuhan city of China in December
2019. The entire country was engulfed in just 30 days and then the entire globe
within two months. This fast-spreading virus was called as COVID-19 and declared
a pandemic by World Health Organization (WHO) on January 30, 2020 [21, 51,
72]. COVID-19 (Coronavirus Disease-2019) is a disease caused by Severe acute
Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) [4, 15, 26, 27, 31, 32]. High
fever, dry cough, life-threatening pneumonia with acute respiratory distress syndrome
etc. are the characteristic symptoms of COVID-19 [20]. Old age people and those with
medical problems like cardiovascular disease, diabetes, chronic respiratory disease,
and cancer are more vulnerable to get infected by this virus [3]. The rapidly spreading
nature of COVID-19 resulted in posing a great threat to public health and thereby
devastating the whole world. As on 8:15 am CEST, 12th July 2020, there have
been 12,401,262 confirmed cases of COVID-19, including 559,047 deaths globally
reported to WHO. The total number of death count associated with COVID-19 is
much more than the previously detected coronavirus strains namely SARS-CoV and
MERS-CoV. The outbreak of this deadly disease reminds us of the 1918 Influenza
pandemic in the United Kingdom. The COVID-19 pandemic in India is part of the
worldwide pandemic. The coronavirus is spreading its roots in India very fast. As
a result, India has now become the epicentre of this worldwide pandemic, ranking
just behind U.S. and Brazil. It is highly likely that India will end up being with the
maximum number of cases in the world. The state-wise data related to COVID-19
confirmed, recovered and casualties’ cases in India as on 30th July 2020 has been
given in Table 1 (Source: https://www.covid19india.org).
Unlike America, India reacted quickly to the pandemic by imposing a nationwide
lockdown at the great economic cost which effected the entire 1.3 billion population
Prediction of Confirmed, Recovered and Casualties’ Cases … 155
Table 1 State-wise COVID-19 confirmed, recovered and casualties’ cases in India

S. No. State name Confirmed cases Recovered cases Casualties’ cases
1 Andaman and Nikobar 428 201 2
2 Andhra Pradesh 120,390 55,406 1213
3 Arunachal Pradesh 1410 677 3
4 Assam 36,295 27,832 92
5 Bihar 46,080 30,320 278
6 Chandigarh 978 611 14
7 Chhattisgarh 8539 5636 48
8 Dadra and Nagar Haveli 1026 648 2
9 Delhi 133,310 118,633 3907
10 Goa 5489 3784 39
11 Gujarat 59,126 43,195 2396
12 Haryana 33,631 26,420 413
13 Himachal Pradesh 2403 1332 14
14 Jammu and Kashmir 19,419 11,322 348
15 Jharkhand 9861 4035 98
16 Karnataka 112,504 42,901 2147
17 Kerala 21,797 11,365 68
18 Ladakh 1347 1080 6
19 Lakshadweep 0 0 0
20 Maharashtra 400,651 239,755 14,463
21 Manipur 2458 1639 0
22 Meghalaya 784 207 5
23 Mizoram 398 215 0
24 Madhya Pradesh 30,134 20,934 843
25 Nagaland 1513 595 5
26 Odisha 29,175 18,939 159
27 Puducherry 3177 1874 47
28 Punjab 14,946 10,213 361
29 Rajasthan 38,964 27,569 650
30 Sikkim 596 198 1
31 Tamil Nadu 234,114 172,883 3741
32 Telangana 58,906 43,751 492
33 Tripura 4485 2678 21
34 Uttar Pradesh 77,334 45,807 1530
35 Uttarakhand 6866 3811 72
36 West Bengal 65,258 44,116 1490
156 S. Singh et al.
of India. A 14-h voluntary public curfew was observed throughout the country on
22 March 2020 on the call of the Prime Minister. Keeping in mind the severity of
the viral infection compulsory lockdowns was imposed in all the major cities having
COVID-19 hotspots. To control the fast spread of disease and build the necessary
healthcare infrastructure, a nationwide lockdown of 21 days was imposed in the
country by the orders of the Prime Minister on 24 March 2020 which was extended
on April 14, May 3 and May 17 respectively. Like all over the world, Airports in
India were put to screening mechanisms for the people returning from abroad and
placed them in isolation for 14 days and testing them for COVID-19. Maharashtra
is the worst-hit state of India in this pandemic. In Maharashtra, there is a place
Dharavi which is the largest slum in Asia. Earlier, it seemed Dharavi would almost
certainly suffer an exponential rise in cases and thus would be badly affected. But it
did not happen, Dharavi managed to flatten the curve with the help innovative staff
of clinics and manpower from non-government organizations. COVID-19 infections
knocked India on 30 January 2020 in Kerala and it spread in almost all parts of the
country within six months. As per data available with the Ministry of Health and
Family Welfare (MoHFW) on 30th July 2020, a total of 1,583,792 confirmed cases,
1,020,582 recoveries and 34,968 deaths were reported in the country which put India
in the first rank in COVID-19 data tally for the highest number of confirmed cases
in Asia and third-highest number in the world. United States of America and Brazil
being the top two worst-hit countries. On 19 May India crossed the 100,000 marks
and 200,000 on 3 June. However, on 6th July 2020, a low fatality rate of 2.80%
was reported in India as compared to the global fatality rate of 4.7%. Mumbai,
Delhi, Ahmedabad, Chennai, Pune, Kolkata, Hyderabad and Bengaluru accounted
for around half of all reported cases in India as on 31 July 2020, 8:00 IST (Table 2).
Hindustan Times, a prominent newspaper of India, analysed the active coron-
avirus cases in the country and found that urban areas, or city districts, are more
affected by the virus and accounts for the majority of the active cases in the country.
Due to the looming economic crisis and considering the plight of daily wagers and
migrant labours, the government decided to relax the lockdown in phases from June
Table 2 COVID-19 confirmed, recovered and casualties’ cases in Mumbai, Delhi, Ahmedabad,
Chennai, Pune, Kolkata, Hyderabad and Bengaluru
S. No. State/city Total cases Recovered cases Confirmed cases Casualties’ cases
1 Mumbai 117,406 90,089 20,528 6493
2 Delhi 137,694 124,524 9420 4020
3 Ahmedabad 26,969 21,801 3559 1689
4 Chennai 102,985 88,826 11,986 2173
5 Pune 96,669 52,719 41,664 2286
6 Kolkata 23,888 16,197 6801 820
7 Hyderabad 39,991 305 39,663 23
8 Bengaluru 60,998 23,603 36,210 1104
2, 2020. Contrary to the claims of the government regarding the availability of health
infrastructure and diagnostics, the number of COVID-19 patients continues to rise
with each passing day breaking the previous day’s records. With little known about
this disease, its rapid escalation has caused an alarming situation in every country.
With educated guesses all around mathematical modelling and simulation can help
researchers to provide scientific answers to all the urgent queries [12]. To prevent
community transmission of this life-threatening disease, governments are taking
some extreme steps like complete lockdown/curfew, quarantine, travel restrictions
and contact tracing of the infected or suspected people based on the predictions and
forecasting of mathematical models [13, 47, 19, 33]. Studies at large scale are in
progress to access the outbreak characteristics of COVID-19 [5, 28, 66].
1.2 Problem Statement
The main target of the present study is the development of appropriate ARIMA
models for the time series data of confirmed, recovered and casualties’ cases of
COVID-19 in India which help in making one-month ahead predictions of the input
data. The development of appropriate ARIMA prediction models can be a vital
tool in understanding the growth pattern of the virus and thus help to contain the
spread of the disease [30, 46, 66, 70, 71]. So, to deal with such a problem, time-
series data consisting of daily observations from 30th January 2020 to 26th July
2020 of confirmed cases, recovered cases and casualties’ cases of COVID-19 in
India is selected for the study (Data Source: https://www.covid19india.org). The
development of ARIMA models for different time series of confirmed, recovered and
casualties’ cases of COVID-19 helps in better understanding the future growth of the
pandemic. The future estimates obtained by these models will help the government
to plan well in advance. This study will also help in the estimation and preparation
of the number of hospitals, ventilators, quarantine centres and the other necessary
infrastructure needed by the patients soon.
1.3 Motivation and Incitement
Keeping in view the severity of the COVID-19 pandemic, there is the constant need
for data analysis. Mathematical modelling can be of great help to study the future
growth and spread of the disease [1]. Time series analysis is an indispensable tool to
predict future values using the past relationship between the variables. The predic-
tions of the study can help governments, administrative officers and public health
officials for the timely management of health and other necessary facilities needed
to surmount the prevailing crisis [36, 69]. Time series analysis deals with modelling
and forecasting of time series data by studying the variables and relationship among
them. Autoregressive Integrated Moving Average (ARIMA) model is a statistical
158 S. Singh et al.
model based on Box-Jenkins [7] method which is a commonly used time series anal-
ysis model. ARIMA includes the wide range of patterns such as stationarity, linearity,
seasonality etc. of the data set [6, 34, 35, 41–44, 55–57, 62].
1.4 Contribution and Organisation
The proposed study is undertaken to forecast the confirmed, recovered and causal-
ities cases of COVID-19 in India using autoregressive integrated moving average
(ARIMA) models of time series analysis. Based on Box-Jenkins methodology, the
ARIMA models have great tendency to predict future values of time series accu-
rately. In this study, appropriate ARIMA models are developed to forecast one-
month ahead values of confirmed, recovered and causalities’ cases of COVID-19 in
India. The future trends estimated by these models help in making suitable arrange-
ments to control the situation. The present study is organised into following sections.
Section 2 deals with the earlier studies related to mathematical and statistical tech-
niques of forecasting the spread of infectious diseases. The detailed methodology of
ARIMA modelling and forecasting has been discussed in Sect. 3. The application
of developed models to input data and the results obtained have been discussed in
Sect. 4. Section 5 highlights conclusions of the present study.
2 Related Study
The last two decades have witnessed a shift of research on data-based issues related
to prior identification of the eruption and fatal spread of epidemics. In this scenario,
it’s a herculean task to detect the disease and its trajectory of transmission as early as
possible to contain its spread. Hence, accurate forecasting is the need of the hour to
take suitable measures. The problems of understanding and controlling the disease
present a range of mathematical challenges. Various mathematical and statistical
techniques of time series analysis such as multivariate linear regression, grey fore-
casting models, backpropagation neural networks and simulation models have been
employed earlier to forecast the spread of infectious diseases [25, 29, 38, 39, 48, 59,
65, 67, 68]. Also, many different mathematical and machine-learning-based fore-
casting models have been used to date to predict the outbreaks of epidemics and find
out their global effects [52] and for specific countries such as India [40], the USA
[49], China, Italy [58], Spain [14], Japan, France [45], among others. Simple struc-
ture and fast application to the data set makes ARIMA a successful model among
many baseline time series approaches for implementation in the field of health and
medicine [9]. The other salient feature of ARIMA is that it is user friendly as it does
not involve too much mathematics or statistics making it convenient for the decision-
maker to interpret for implementation in real practices. Therefore, ARIMA model
has been widely used for analysing infectious diseases outbreaks, and more precisely
for estimation and prediction of various diseases such as influenza, malaria, dengue
fever, tuberculosis, HEV, HFRS, Pertussis, Hepatitis, SFTS, HBV, Brucellosis and
many more. Several researchers have published their work on time series modelling
of infectious disease particularly COVID-19 [17, 22, 50, 60, 63, 64]. Kumar et al. [24]
predicted the growth pattern of COVID-19 in the worst-hit 15 countries with the help
of the ARIMA model. Monllor et al. [37] carried their study on Spain and Italy and
the results were predicted with high precision for the daily figures of COVID19 cases
in both the countries. Ceylan [10] applied ARIMA to help authorities to take essen-
tial measures to combat this pandemic in Italy, Spain, and France and concluded
that ARIMA (0, 2, 1), ARIMA (1, 2, 0), and ARIMA (0, 2, 1) were the best fit
respectively for these countries. This indicates that predicting the growth patterns of
epidemics is essential for the authorities to take effective measures to control it. Chen
et al. [12] developed a Bats-Hosts-Reservoir-People transmission network model and
concluded that the transmissibility of SARS-CoV-2 was higher than MERS in the
Middle East countries, similar to the severe acute respiratory syndrome, but lower
than MERS in the Republic of Korea. Their study concluded that there is vivid
proof in favour of community transmission in Wuhan and that the number of persons
infected increased to twofold in just 7.4 days. Kucharski et al. [23] developed a time-
based stochastic model to study the transmission of COVID-19 over a certain period.
There was a decline in reproduction number from 2.35 to earlier 1.05 after imposing
travel restrictions in other areas outside Wuhan. Singh et al. [54] studied ARIMA and
LS-SVM models for the prediction of SARS-CoV-2 confirmed cases in Italy, France,
Spain, UK and USA. Italy. Wang et al. [63, 64] proposed an algorithm called Patient
Information Based Algorithm (PIBA) for approximating the casualties’ occurred
during an outbreak of the epidemic. Zhao et al. [70, 71] predicted the spread of the
COVID-19 in South Africa, Egypt, Algeria, Nigeria, Senegal and Kenya using the
modified SEIR model. Tomar and Gupta [61] used LSTM (long short-term memory)
techniques and curve fitting methods for the advanced 30 days prediction of COVID-
19 cases in India. For Spain, [2] concluded that Sutte-ARIMA method gave more
accurate and reliable daily predictions of confirmed cases of COVID19. Singh et al.
[53] made 30 days of advanced predictions of death counts due to COVID-19 by
developing a novel coupled model of discrete wavelet decomposition and ARIMA
model.
Most of the previous studies discussed above deal with mathematical modelling
of COVID-19 infections data sets belonging to the most affected countries across the
globe. Different methodologies and algorithms have been developed in these studies
to model and forecast the COVID-19 data sets. The proposed work is novel study for
multivariate COVID-19 time series data of India, which aims at developing econo-
metric ARIMA models for estimating the future trends for the data of confirmed,
recovered and casualties’ cases in India. Besides the development and best fitting
of time series data with appropriate ARIMA models, the developed models have
tendency to generate one-month ahead accurate future values together with 95%
forecast intervals with least errors.
160 S. Singh et al.
3 Methodology
3.1 Autoregressive Integrated Moving Average (ARIMA)

Model
Time series is defined as the set of observations that are listed in time order. Analysis
of time series helps in examining the performance pattern of the series to derive
useful statistical information of the data. The major aim of time series analysis in
statistics is forecasting. ARIMA is a very well-known flexible and commonly used
time series model. It is more or less like a regression model. ARIMA model is a
combination of two models: autoregressive model (AR) and moving average (MA)
model, which make use of past observations for finding future values. In an ARIMA
( p, d, q) model, p stands for the order autoregressive terms, the number of times the
series has to be differenced to make it stationary is denoted by d, and q denotes the
order of moving average terms. An ARIMA ( p, d, q) models can be represented by
the following mathematical equation:

p

q
Yt = θ0 + φ j Yt− j + at − θi at−i (1)
j=1 i=1
where Yt is the actual value of the time series and at is the random error at time t which
are independent identically distributed variables following a normal distribution with
zero mean, and θi and φ j are the coefficients [8].
Autocorrelation function (ACF) and Partial Autocorrelation function (PACF) plots
are used to determine the orders of AR terms or MA terms or both. If the ACF plots
decay towards zero and PACF plot cuts off quickly towards zero, then AR terms
are included in the model. Similarly, MA terms are included in the model when an
ACF plot drops sharply after a few lags and PACF plots decrease more gradually
[11, 35, 62].
An ARIMA model involves model identification, parameter estimation, diagnostic
checking and forecasting. In the identification stage, we identify the ARIMA model to
be used appropriately for our problem. The values of p, d and q are identified at this
stage using the autocorrelations, inverse autocorrelations, partial autocorrelations,
cross-correlations and unit root tests. We also need to determine whether the time
series contains a seasonal component or not. The seasonal component determines
the fluctuations in the series during the season. Seasonality can be determined by
autocorrelation, seasonal subseries and spectral plots. If the process is non-stationary
i.e. the mean of a series is changing with time, then differencing is needed to make it
stationary. The value of d is determined by the number of times differencing required
to make time-series stationary. After making time series stationary, ACF and PACF
plots enables to identify the orders of AR and MA terms.
For the estimation step, the method of moments, maximum likelihood estimators
(MLE) and Ordinary Least Squares (OLS) are commonly used methods. For diag-
nostic testing, residuals of estimated ARIMA model are checked. The model with
well-behaved residuals is generally the best. The validity of the estimated model is
tested by using mean absolute per cent error (MAPE). If the diagnostic tests indi-
cate problems with the estimated model, the above steps for model estimation are
repeated until an appropriate model is obtained [53, 54].
Since the model for the outbreak of one disease cannot be automatically applied to
another, therefore utmost care is needed while applying any model. Every time model
identification is the primary step in every forecasting. The conventional ARIMA
models require quite a reasonable number of parameters to detect autocorrelations.
Practically, the hierarchical model is recommended for the short length time series as
it can detect the eruption of epidemics more rapidly than the lab-based exceedance
system [16, 18].
3.2 Performance of Prediction
The performance of prediction of the developed ARIMA model for COVID-19 data of
confirmed, recovered and casualties’ cases in India can be evaluated by mean absolute
error (MAE), mean square error (MSE), root mean square error (RMSE), mean abso-
lute percentage error (MAPE) and coefficient of determination (R2 ). The observed
and predicted values of COVID-19 data from these states are used to measure the
accuracy of prediction. MAE, MSE, RMSE and MAPE are defined by
n
1 ∧
MAE = Y (t) − Y (t) (2)
n t=1
1 2
n
MSE = Y (t) − Y (t) (3)

n t=1

n 2
1
RMSE =

Y (t) − Y (t) (4)

n t=1

100 Y (t) − Y (t)

n
MAPE = (5)
n t=1 Y (t)

where Y (t) is the estimated value of Y (t).

162 S. Singh et al.
4 Application, Results and Discussion
Since January 2020, COVID-19 infections were prevalent in India which engulfed
almost all the states of India within a month. Maharashtra is the most affected state
of India with more than 4 lakh cases and 15 thousand causalities approximately. The
rate of the pervasiveness of COVID-19 confirmed cases in Andhra Pradesh, Delhi,
Karnataka and Tamil Nadu is very much high as compared to the other states of India.
But the recovery rate for the capital city Delhi is highest as compared to other states
of India. To predict the data of confirmed, recovered and casualties’ cases of COVID-
19, appropriate ARIMA models are developed separately for confirmed, recovered
and casualties’ cases with 179 sample points ranging from 30th January 2020 to 05th
August 2020. In the modelling phase, 150 sample points of the data are utilised for the
development of ARIMA models separately for the data of confirmed, recovered and
casualties’ cases and the validity of the developed models is tested by the rest of 29
sample points in the model testing phase. Mean absolute error (MAE), mean square
error (MSE), root mean square error (RMSE) and mean absolute percentage error
(MAPE) are used as indicators to ascertain the performance of the developed ARIMA
models. The developed ARIMA models are finally used to make the one-month ahead
predictions of the data of COVID-19 confirmed, recovered and casualties’ cases in
India.
Descriptive Analysis of COVID-19 data of confirmed, recovered and casualties’
cases in India has been given in Table 3. The mean of daily confirmed cases in India
is more than 2 lakhs which reflects the dangerous spread of COVID-19 infection in
India. But the mean recovered cases are more than 1.25 lakhs and mean casualties’
cases are 600 per day approximately. The time series plot of COVID-19 confirmed,
recovered and casualties’ cases in India has been shown in Fig. 1.
In the present study, appropriate ARIMA models are developed for the modelling
and prediction of the time series of confirmed, recovered and casualties’ cases of
COVID-19 in India. The input dataset for modelling, validation and prediction
purposes is comprised of the time series of confirmed, recovered and casualties’
cases of COVID-19 in India. In time series analysis using ARIMA methodology,
the input data is first checked for stationarity. The constancy of mean, variance and
ACF implies stationarity in time series, which is necessary for accurate prediction
of future values. Stationarity in time series data can be either be located by ACF and
PACF plots or augmented Dickey-Fuller (ADF) test. ACF and PACF plots for input
data of confirmed, recovered and casualties’ cases of COVID-19 in India have been
Table 3 Descriptive Analysis of the data of confirmed, recovered and casualties’ cases of COVID-
19 in India
COVID-19 data Mean Standard deviation Skewness Kurtosis Variance
Confirmed cases 2.2032 × 105 3.4800 × 105 1.7859 5.2951 1.2111 × 1011
Recovered cases 1.2769 × 105 2.1949 × 105 1.9247 5.7780 4.8176 × 1010
Casualties’ cases 6.0345 × 103 8.9230 × 103 1.4793 3.9665 7.9620 × 107
Fig. 1 Time series plot of confirmed, recovered and casualties’ cases due to COVID-19 in India
shown in Figs. 2a, 3a and 4a respectively. These ACF plots exhibit non-stationarity in
the time series of confirmed, recovered and casualties’ cases of COVID-19 in India.
To develop appropriate ARIMA models, non-stationarity has to be removed by the
application of differencing transformation. After taking first differences of the time
series of confirmed, recovered and casualties’ cases, ACF and PACF plots are regen-
erated which have been shown in Figs. 2b, 3b and 4b respectively. A slow decaying
pattern of these plots once again reflects non-stationarity; therefore, the differencing
transformation is applied again. Figures 2c, 3c and 4c show ACF and PACF plots
for the second differenced time series of confirmed, recovered and casualties’ cases
respectively. At this stage, stationarity of the time series of confirmed, recovered and
casualties’ cases has been attained. The ACF and PACF plots are shown in Figs. 2c, 3c
and 4c help in estimating parameters p, d and q of ARIMA models. As a second-order
differencing transformation makes the time series stationary, so different ARIMA
models are developed for the time series with the value of parameter d as 2 and mean
absolute percentage error (MAPE) is calculated for each of these models, given in
Table 4. ARIMA models with least MAPE values are appropriate for modelling and
testing time series; which are ARIMA (0, 2, 3), ARIMA (0, 2, 5) and ARIMA (1, 2,
1) respectively for confirmed, recovered and casualties’ cases. The model residuals
are obtained after fitting confirmed, recovered and casualties’ cases of COVID-19 in
India with these ARIMA models whose ACF and PACF plots as shown in Fig. 5. The
modelling phase of the time series of confirmed, recovered and casualties’ cases with
these ARIMA models have been shown in Fig. 6. MAE, MSE, RMSE and MAPE
164 S. Singh et al.
Fig. 2 ACF and PACF plots of a confirmed cases b the first difference c the second difference of
COVID-19 in India
Fig. 2 (continued)
values (Eqs. 2–4 and 5) are used to test the validity of developed ARIMA models by
comparing the observed and predicted values, which are given in Table 5. The MAPE
values for the data of confirmed, recovered and casualties’ cases of COVID-19 in
India are found to be 3.1184, 5.0857, and 1.7151 respectively which are the least
values as compared to other ARIMA models fitted to the same data (Table 4). The
graphical comparison between observed and predicted values for the testing phase
has been shown separately for the time series of confirmed, recovered and casualties’
cases in Fig. 7. ARIMA model forecasts with 95% forecast confidence intervals for
confirmed, recovered and casualties’ cases have been shown in Fig. 8. Finally, the
developed ARIMA models generate one-month ahead predictions of the time series of
confirmed, recovered and casualties’ cases of COVID-19 in India shown by different
coloured lines in Fig. 9. Moreover, the time series of one-month ahead predictions
of confirmed, recovered and casualties’ cases of COVID-19 in India generated by
ARIMA models has been given in Table 6. One-month ahead predictions indicate the
sharp increasing trend of confirmed as well as recovered cases, but casualties’ cases
remain constant. Approximately 50,000 confirmed cases are expected to appear daily
whereas speedy recovery is also predicted which is about 30,000 in number per day.
As far as the casualties’ cases are concerned, about 600–800 deaths per day will be
expected. It means that the recovery rate is about 60% of confirmed cases, while the
death rate is about 2% of confirmed cases. With this numerical evidence obtained
by ARIMA modelling, governments may take effective strategies to control the rise
166 S. Singh et al.
Fig. 3 ACF and PACF plots of a recovered cases b the first difference c the second difference of
COVID-19 in India
Fig. 3 (continued)
of the curve of COVID-19 confirmed cases. With the increasing trend estimated by
ARIMA models for confirmed cases of COVID-19 in India, there is an urgent need
of necessary facilities like mass testing, quarantine centres and life support systems
to control the growth curve of COVID-19 infections.
168 S. Singh et al.
Fig. 4 ACF and PACF plots of a casualties’ cases b the first difference c the second difference of
COVID-19 in India
Fig. 4 (continued)
Table 4 Mean absolute percentage error (MAPE) values of different ARIMA models for the data
of confirmed, recovered and casualties’ cases of COVID-19 in India
Confirmed cases Recovered cases Casualties’ cases
Model MAPE Model MAPE Model MAPE
ARIMA (0, 2, 1) 3.1334 ARIMA (0, 2, 1) 5.2743 ARIMA (0, 2, 1) 1.7556
170 S. Singh et al.
Fig. 5 ACF and PACF plots of appropriately fitted ARIMA model residuals for confirmed,
recovered and casualties’ cases due to COVID-19 in India
Fig. 6 ARIMA modelling

phase for data of
a confirmed, b recovered,
c casualties’ cases of
COVID-19 in India
Fig. 6 (continued)
Table 5 Performance of prediction of ARIMA models for data of (a) confirmed (b) recovered (c)
casualties’ cases of COVID-19 in India
Data and fitted model MAD MSE RMSE MAPE R2
Confirmed cases 3.2001e+04 2.0597e+09 4.5384e+04 3.1184 0.9894
ARIMA (0,2,3)
Recovered cases 3.6844e+04 2.9536e+09 5.4347e+04 5.0857 0.9928
ARIMA (0,2,5)
Casualties’ Cases 479.0912 5.7394e+05 757.5907 1.7151 0.9940
ARIMA (1,2,1)
172 S. Singh et al.
Fig. 7 ARIMA model

testing phase for data of
a confirmed, b recovered
COVID-19 in India
Fig. 7 (continued)
174 S. Singh et al.
Fig. 8 ARIMA model

Forecast and 95% forecast
intervals for data of
a confirmed, b recovered,
COVID-19 in India
Fig. 8 (continued)
Fig. 9 One-month ahead prediction of confirmed, recovered and casualties’ cases of COVID-19
cases
176 S. Singh et al.
Table 6 Time series data of one-month ahead ARIMA model predictions of confirmed, recovered
and casualties’ cases of COVID-19 cases in India
S. No. Date Confirmed cases Recovered cases Casualties’ cases
1 27-07-2020 1,485,203 950,389 33,554
2 28-07-2020 1,534,807 982,196 34,298
3 29-07-2020 1,584,617 1,014,155 35,045
4 30-07-2020 1,634,648 1,046,266 35,796
5 31-07-2020 1,684,974 1,078,530 36,552
6 01-08-2020 1,735,561 1,110,946 37,312
7 02-08-2020 1,786,396 1,143,515 38,075
8 03-08-2020 1,837,495 1,176,236 38,844
9 04-08-2020 1,888,857 1,209,109 39,616
10 05-08-2020 1,940,477 1,242,134 40,392
11 06-08-2020 1,992,357 1,275,315 41,173
12 07-08-2020 2,044,498 1,308,643 41,958
13 08-08-2020 2,096,899 1,342,125 42,747
14 09-08-2020 2,149,560 1,375,760 43,540
15 10-08-2020 2,202,482 1,409,547 44,338
16 11-08-2020 2,255,663 1,443,487 45,139
17 12-08-2020 2,309,105 1,477,579 45,945
18 13-08-2020 2,362,807 1,511,823 46,755
19 14-08-2020 2,416,769 1,546,220 47,569
20 15-08-2020 2,470,991 1,580,769 48,388
21 16-08-2020 2,525,473 1,615,471 49,211
22 17-08-2020 2,580,216 1,650,324 50,037
23 18-08-2020 2,635,219 1,685,330 50,868
24 19-08-2020 2,690,482 1,720,489 51,704
25 20-08-2020 2,746,005 1,755,800 52,543
26 21-08-2020 2,801,788 1,791,263 53,387
27 22-08-2020 2,857,832 1,826,879 54,235
28 23-08-2020 2,914,136 1,862,647 55,087
29 24-08-2020 2,970,700 1,898,567 55,943
30 25-08-2020 3,027,524 1,934,639 56,803
5 Conclusions
The present study was aimed at developing ARIMA models for the time series
of daily confirmed, recovered, and casualties’ cases of COVID-19 in India which
were then applied to predict one-month ahead confirmed, recovered, and casualties’
cases. The input dataset of 179 daily confirmed, recovered, and casualties’ cases
was divided into two datasets; modelling and testing datasets. The modelling dataset
consisted of 150 observations which were used as input to ARIMA models and
rest 29 observations were used for testing purpose to validate these models. The
performance of prediction of the developed ARIMA models for the time series of
confirmed, recovered, and casualties’ cases was evaluated by comparing 29 predicted
and observed values. On the basis of prediction performances of developed ARIMA
models, one-month ahead predictions of daily confirmed, recovered, and casualties’
cases of COVID-19 in India. It was found that the approximate errors for confirmed,
recovered, and casualties’ cases were 3%, 5% and 1% respectively. The coefficients of
determination for confirmed, recovered, and casualties’ cases were found to 0.9894,
0.9928 and 0.9940 which revealed the closeness of observed and predicted data for
the time series data of recovered and casualties’ cases using the developed ARIMA
models. Moreover, the large incidence of COVID-19 confirmed cases and the speedy
recovery rate of approximately 60% in India was estimated by one-month ahead
predictions. But the death rate remained fixed in one-month ahead predictions which
was observed to be around 2 to 3%. These prediction results can help the governments
and administrative officers in India to plan well in advance and take preventive
measures to break down the ongoing chain of the incidence of COVID-19 confirmed
cases.
References
1. Abdirizak, F., Lewis, R., Chowell, G.: Evaluating the potential impact of targeted vaccination
strategies against severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East
respiratory syndrome coronavirus (MERS-CoV) outbreaks in the healthcare setting. Theor.
Biol. Med. Model. 16(1), 16 (2019)
2. Ahmar, A.S., del Val, E.B.: Sutte-ARIMA: short-term forecasting method, a case: Covid-19
and stock market in Spain. Sci. Total Environ. 138883 (2020)
3. Anon.: EACS and BHIVA statement on risk of COVID-19 for people living with HIV (PLWH)
1 April 2020 (2020a). https://eacsociety.org/home/covid-19-and-hiv.html
4. Baldwin, R., di Mauro, B.W.: Mitigating the COVID Economic Crisis: Act Fast and Do
Whatever It Takes. CEPR Press London, UK (2020)
5. Binti Hamzah, F., Lau, C., Nazri, H., Ligot, D.V., Lee, G., Tan, C.L., Bin Mohd Shaib,
M.K., Zaidon, U.H.B., Abdullah, A.B., Chung, M. H.: CoronaTracker: worldwide COVID-19
outbreak data analysis and prediction. Bull. World Health Organ. 1, 32 (2020)
6. Box, G.E.P., Jenkins, G.M.: Time Series Analysis, Forecasting and Control. Holden Day, San
Francisco, CA (1976)
7. Box, G. E. P., Jenkins, G. M.: Control. Halden-Day, San Francisco (1970)
8. Brockwell, P.J., Davis R.A.: Introduction to Time Series and Forecasting. Springer Texts in
Statistics (2002)
178 S. Singh et al.
9. Cao, L.T., Liu, H.H., Li, J., Yin, X.D., Duan, Y., Wang, J.: Relationship of meteorological factors
and human brucellosis in Hebei province, China. Sci. Total Environ. 703, 135491 (2020)
10. Ceylan, Z.: Estimation of COVID-19 prevalence in Italy, Spain, and France. Sci. Total Environ.
138817 (2020)
11. Chatfield, C.: The Analysis of Time Series: An Introduction, 5th edn. Chapman and Hall, CRC,
London (1996)
12. Chen, T.M., Rui, J., Wang, Q.P., Zhao, Z.Y., Cui, J.A., Yin, L.: A mathematical model for
simulating the phase-based transmissibility of a novel coronavirus. Infect. Dis. Poverty 9(1),
1–8 (2020)
13. Choi, S., Ki, M.: Estimating the reproductive number and the outbreak size of COVID-19 in
Korea. Epidemiol. Health 42 (2020)
14. Costagliola, D.: When is the epidemic warning cut-off point exceeded? Eur. J. Epidemiol.
10(4), 475 (1994)
15. Daniels, J.P.: Venezuelan migrants “struggling to survive” amid COVID-19. 395(10229), 1023
(2020)
16. Diebold, F.V.: Elements of Forecasting. South-Western College, Cincinnati (1998)
17. Ghosal, S., Sengupta, S., Majumder, M., Sinha, B.: Prediction of the number of deaths in India
due to SARS-CoV-2 at 5–6 weeks. Diab. Metabol. Syndr.: Clin. Res. Rev. (2020)
18. Guerrero, V.M.: ARIMA forecasts with restrictions derived from a structural change. Int. J.
Forecast. 7(3), 339–347 (1991)
19. Hellewell J, Abbott S, Gimma A, Bosse NI, Jarvis CI, Russell TW, Mun- day JD, Kucharski
AJ, Edmunds WJ, Sun F, Flasche S (2020) Feasibility of controlling COVID-19 outbreaks by
isolation of cases and contacts. Lancet Global Health 8, e488–96
20. Heymann, D.L., Shindo, N.: COVID-19: what is next for public health? The Lancet 395(10224),
542–545 (2020)
21. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng,
Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo,
L., Xie, J.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
The Lancet 395(10223), 497–506 (2020)
22. Kotwal, A., Yadav, A.K., Yadav, J., Kotwal, J., Khune, S.: Predictive models of COVID-19 in
India: a rapid review. Med. J. Armed Forces India 76(4), 377–386 (2020)
F., Jit, M., Munday, J.D., Davies, N., Gimma, A., van Zandvoort, K., Gibbs, H., Hellewell,
J., Jarvis, C.I., Clifford, S., Quilty, B.J., Bosse, N.I., Abbott, S., Klepac, P., Flasche S.: Early
dynamics of transmission and control of COVID-19: a mathematical modelling study. The
Lancet Infect. Dis. (2020)
24. Kumar, P., Kalita, H., Patairiya, S., Sharma, Y.D., Nanda, C., Rani, M., Rahmani, J., Bhaga-
vathula, A.S.: Forecasting the dynamics of COVID-19 pandemic in Top 15 countries in April
2020: ARIMA model with machine learning approach. medRxiv (2020)
25. Kurbalija, V., Radovanović, M., Ivanović, M., Schmidt, D., von Trzebiatowski, G.L., Burkhard,
H.D., Hinrichs, C.: Time-series analysis in the medical domain: a study of Tacrolimus
administration and influence on kidney graft function. Comput. Biol. Med. 50, 19–31 (2014)
26. Lai, C.C., Shih, T.P., Ko, W.C., Tang, H.J., Hsueh, P.R.: Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and
the challenges. Int. J. Antimicrob. Agents, p.105924 (2020)
27. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K.S., Lau, E.H., Wong,
J.Y., Xing, X.: Early transmission dynamics in Wuhan, China, of novel coronavirus–infected
pneumonia. N. Engl. J. Med. 382, 1199–1207 (2020)
28. Lin, Q., Zhao, S., Gao, D., Lou, Y., Yang, S., Musa, S.S., Wang, M.H., Cai, Y., Wang, W.,
Yang, L., He, D.: A conceptual model for the coronavirus disease 2019 (COVID-19) outbreak
in Wuhan, China with individual reaction and governmental action. Int. J. Infect. Dis. 93,
211–216 (2020)
29. Liu, Q., Li, Z., Ji, Y., Martinez, L., Zia, U.H., Javaid, A., Lu, W., Wang, J.: Forecasting the
seasonality and trend of pulmonary tuberculosis in Jiangsu Province of China using advanced
statistical time-series analyses. Infect. Drug Resist. 12, 2311 (2019)
30. Ma, Z.E., Zhou, Y.C., Wang, W.D., Jin, Z.: Mathematical Modeling and Research of Infectious
Disease Dynamics. Science Press (2004)
31. Ma, Z.: Spatiotemporal fluctuation scaling law and metapopulation modeling of the novel
coronavirus (COVID-19) and SARS outbreaks. arXiv preprint arXiv:2003.03714 (2020)
32. Mandal, S., Bhatnagar, T., Arinaminpathy, N., Agarwal, A., Chowdhury, A., Murhekar, M.,
Gangakhedkar, R.R., Sarkar, S.: Prudent public health intervention strategies to control the
coronavirus disease 2019 transmission in India: a mathematical model-based approach. The
Indian J. Med. Res. 151(2–3), 190 (2020)
33. Mandal, S., Bhatnagar, T., Arinaminpathy, N., Agarwal, A., Chowdhury, A., Murhekar, M.,
Gangakhedkar, R.R., Sarkar, S.: Prudent public health intervention strategies to control the
coronavirus disease 2019 transmission in India: a mathematical model-based approach. Indian
J. Med. Res. (2020). https://doi.org/10.4103/ijmr.IJMR_504_20
34. McNeil, A.J., Frey, R., Embrechts, P.: Quantitative Risk Management: Concepts, Techniques
and Tools-Revised Edition. Princeton University Press (2015)
35. Melard, G., Pasteels, J.M.: Automatic ARIMA modeling including interventions, using time
series expert software. Int. J. Forecast. 16(4), 497–508 (2000)
36. Ming, W., Huang, J., Zhang, C.J.P.: Breaking down of healthcare system Mathematical
modeling for controlling the novel coronavirus (COVID-19) outbreak in Wuhan, China. bioRxiv
(2020)
37. Monllor, P., Su, Z., Gabrielli, L., & Taltavull de La Paz, P.: COVID-19 infection process in
Italy and Spain: Are data talking? Evidence from ARMA and vector autoregression models.
Front. Public Health 8, 784 (2020)
38. Nsoesie, E.O., Beckman, R.J., Shashaani, S., Nagaraj, K.S., Marathe, M.V.: A simulation
optimization approach to epidemic forecasting. PloS One 8(6), e67164 (2013)
39. Orbann, C., Sattenspiel, L., Miller, E., Dimka, J.: Defining epidemics in computer simulation
models: how do definitions influence conclusions? Epidemics 19, 24–32 (2017)
40. Parker, R.A.: Analysis of surveillance data with Poisson regression: a case study. Stat. Med.
8(3), 285–294 (1989)
41. Parmar, K.S., Bhardwaj, R.: Wavelet and statistical analysis of river water quality parameters.
Appl. Math. Comput. 219(20), 10172–10182 (2013)
42. Parmar, K.S., Bhardwaj, R.: Water quality management using statistical and time series
prediction model. Appl. Water Sci. 4(4), 425–434 (2014)
43. Parmar, K.S., Bhardwaj, R.: Statistical, time series and fractal analysis of full stretch of River
Yamuna (India) for water quality management. Environ. Sci. Pollut. Res. 22(1), 397–414 (2015)
44. Parmar, K.S., Soni, K., Singh, S.: Prediction of River Water Quality Parameters Using Soft
Computing Techniques. In: Intelligent Data Analytics for Decision-Support Systems in Hazard
Mitigation, pp. 429–440. Springer, Singapore (2020)
45. Pelat, C., Boëlle, P.Y., Cowling, B.J., Carrat, F., Flahault, A., Ansart, S., Valleron, A.J.: Online
detection and quantification of epidemics. BMC Med. Inform. Decis. Mak. 7(1), 29 (2007)
46. Peng, Y., Lei, M., Li, J.-B., Peng, X.-Y.: A novel hybridization of echo state networks and
multiplicative seasonal ARIMA model for mobile communication traffic series forecasting.
Neural Comput. Appl. 24, 883–890 (2014)
47. Prem, K., Liu, Y., Russell, T. W., Kucharski, A. J., Eggo, R. M., Davies, N., Jit, M., Klepac,
P., Flasche, S., Clifford, S., Pearson, C.A.B., Munday, J.D., Abbott, S., Gibbs, H., Rosello,
A., Quilty, B.J., Jombart, T., Sun, F., Diamond, C., Gimma, A., van Zandvoort, K., Funk, S.,
Christopher, I., Abbott, S.: The effect of control strategies to reduce social mixing on outcomes
of the COVID-19 epidemic in Wuhan, China: a modelling study. The Lancet Public Health
(2020)
48. Ren, H., Li, J., Yuan, Z.A., Hu, J.Y., Yu, Y., Lu, Y.H.: The development of a combined math-
ematical model to forecast the incidence of hepatitis E in Shanghai, China. BMC Infect. Dis.
13(1), 421 (2013)
49. Rolka, H.R.: Comments on Some methodological issues in biosurveillance. Stat. Med. 30(5),
416–419 (2011)
50. Roy, A., Kar, S.: Nature of transmission of Covid19 in India. medRxiv (2020)
180 S. Singh et al.
51. Shen, M., Peng, Z., Xiao, Y., Zhang, L.: Modelling the epidemic trend of the 2019 novel
coronavirus outbreak in China. BioRxiv (2020)
52. Shmueli, G., Burkom, H.: Statistical challenges facing early outbreak detection in biosurveil-
lance. Technometrics 52(1), 39–51 (2010)
53. Singh, S., Parmar, K.S., Kumar, J., Makkhan, S.J.S.: “Development of new hybrid model
of discrete wavelet decomposition and autoregressive integrated moving average (ARIMA)
models in application to one month forecast the casualties’ cases of COVID-19. Chaos, Solitons
& Fractals 109866 (2020a)
54. Singh, S., Parmar, K.S., Makkhan, S.J.S., Kaur, J., Peshoria, S., Kumar, J.: Study of ARIMA
and least square support vector machine (LS-SVM) models for the prediction of SARS-CoV-2
confirmed cases in the most affected countries. Chaos, Solitons & Fractals 110086 (2020b)
55. Soni, K., Parmar, K.S., Kapoor, S.: Time series model prediction and trend variability of aerosol
optical depth over coal mines in India. Environ. Sci. Pollut. Res. 22(5), 3652–3671 (2015)
56. Soni, K., Parmar, K.S., Kapoor, S., Kumar, N.: Statistical variability comparison in MODIS
and AERONET derived aerosol optical depth over Indo-Gangetic plains using time series. Sci.
Total Environ. 553, 258–265 (2016)
57. Soni, K., Kapoor, S., Parmar, K.S., Kaskaoutis, Dimitris G.: Statistical analysis of aerosols over
the Gangetic-Himalayan region using ARIMA model based on long-term MODIS observations.
Atmos. Res. 149, 174–192 (2014)
58. Stroup, D.F., Wharton, M., Kafadar, K., Dean, A.G.: Evaluation of a method for detecting
aberrations in public health surveillance data. Am. J. Epidemiol. 137(3), 373–380 (1993)
59. Thomson, M.C., Molesworth, A.M., Djingarey, M.H., Yameogo, K.R., Belanger, F., Cuevas,
L.E.: Potential of environmental models to predict meningitis epidemics in Africa. Trop. Med.
Int. Health 11(6), 781–788 (2006)
60. Tiwari, A.: Modelling and analysis of COVID-19 epidemic in India. medRxiv (2020)
61. Tomar, A., Gupta, N.: Prediction for the spread of COVID-19 in India and effectiveness of
preventive measures. Sci. Total Environ. 138762 (2020)
62. Valenzuela, O., Rojas, I., Rojas, F., Pomares, H., Herrera, L.J., Guillen, A., et al.: Hybridization
of intelligent techniques and ARIMA models for time series prediction. Fuzzy Sets Syst. 159(7),
821–845 (2008)
63. Wang, L., Li, J., Guo, S., Xie, N., Yao, L., Cao, Y., Day, S.W., Howard, S.C., Carolyn Graff,
J., Gu, T., Ji, J.: Real-time estimation and prediction of mortality caused by COVID-19 with
patient information-based algorithm. Sci. Total Environ. 138394 (2020a)
64. Wang, L.S., Wang, Y.R., Ye, D.W., Liu, Q.Q.: A review of the 2019 Novel Coronavirus (COVID-
19) based on current evidence. Int. J. Antimicrobial Agents 105948 (2020b)
65. Wang, Y.W., Shen, Z.Z., Jiang, Y.: Comparison of ARIMA and GM (1, 1) models for prediction
of hepatitis B in China. PloS One 13(9), e0201987 (2018)
international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling
study. The Lancet 395(10225), 689–697 (2020)
67. Zhang, L., Wang, L., Zheng, Y., Wang, K., Zhang, X., Zheng, Y.: Time prediction models
for echinococcosis based on gray system theory and epidemic dynamics. Int. J. Environ. Res.
Public Health 14(3), 262 (2017)
68. Zhang, X., Liu, Y., Yang, M., Zhang, T., Young, A.A., Li, X.: Comparative study of four time
series methods in forecasting typhoid fever incidence in China. PloS One, 8(5), e63116 (2013)
69. Zhang, X., Ma, R., Wang, L.: Predicting turning point, duration and attack rate of COVID-19
outbreaks in major Western countries. Chaos, Solitons & Fractals 109829 (2020)
70. Zhao, S., Lin, Q., Ran, J., Musa, S. S., Yang, G., Wang, W., Lou, Y., Gao, D., Yang, L., He, D.,
Wang, M.H.: Preliminary estimation of the basic reproduction number of novel coronavirus
(2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the
outbreak. Int. J. Infect. Dis. 92, 214–217 (2020a)
71. Zhao, S., Musa, S.S., Lin, Q., Ran, J., Yang, G., Wang, W., Lou, Y., Yang, L., Gao, D., He, D.,
Wang, M.H.: Estimating the unreported number of novel coronavirus (2019-nCoV) cases in
China in the first half of January 2020: a data-driven modelling analysis of the early outbreak.
J. Clin. Med. 9(2), 388 (2020b).
72. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R.,
Niu, P.: A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med.
(2020)
Dynamical Modeling and COVID-19
Pandemic
Muhammad Shahzad, Faisal Sultan, Mehboob Ali, and Soma Mustafa
Abstract The world health organization (WHO) has declared the Coronavirus
(COVID-19) a pandemic in 2020. Considering this ongoing global issue, different
health and safety measure has been recommended by the WHO to ensure the proac-
tive, comprehensive, and coordinated steps to bring back the whole world into a
normal situation. There are around 100 plus research groups across the world trying
to develop a vaccine for previous and new versions of coronavirus. All the work is
at an early stage, contains huge uncertainties and a long list of unanswered ques-
tions however, continuous efforts lead to success. Therefore, the quantitative and
qualitative analysis of the COVID–19 pandemic is needed for the identification
and controlling the spread of COVID-19. Mathematical models with computational
simulations are the effective tools that help global efforts to estimate key transmis-
sion parameters and further improvements for controlling this disease. This is an
infectious disease and can be modeled as a system of non-linear differential equa-
tions with reaction rates. In this chapter, we develop two simple models for coron-
avirus disease spreading within a mathematically/biologically feasible region, i.e.,
positively invariant for the model and boundedness solution of the system. So that
the system becomes well-posed mathematically and epidemiologically for sensitive
(stability) analysis. Then computational results show the occurrence of a forward
bifurcation when the basic reproduction number is equal to unity. The proposed
method gives a major step forward to evaluate the models and identify the key crit-
ical parameters, i.e., recovery factors. These critical model-parameters allow the
biologist/chemist to specify/distinguish control strategies to adopt further precau-
tion measures with improvements. This is another way of controlling the individuals
from the spreading called control monitoring strategy.
Keywords Epidemic disease modeling · Influence mechanism · Model reduction ·

Sensitivity analysis · COVID-19 outbreak
M. Shahzad (B) · F. Sultan · M. Ali · S. Mustafa

Department of Pure and Applied Mathematics, The University of Haripur, Haripur, KP, Pakistan
e-mail: shahzadmaths@uoh.edu.pk
184 M. Shahzad et al.
1 Introduction
In January 2020, the spreading of COVID-19 isolated the people of Wuhan province
in China to observe the home quarantine. While spreading in Italy, and France the
WHO declared the COVID-19 a pandemic. After this, the COVID-19 becomes an
international issue, and this virus is spreading very quickly. Millions of confirmed
cases were reported in infected countries (USA, Italy, Spain, India, etc.). Therefore,
in an affected area of the region, an emergency has been affirmed by the world health
organization WHO, and a serious health concern has been paid by the WHO. All the
countries are making all-out efforts to deal with a rapidly evolving situation which
is a challenge for the whole world.
Mathematical modeling is an effective tool that can be used to present COVID-19
transmissions to analyze the basic imitation numbers and serial intervals. Although
many mathematical models are available online for the prediction of coronavirus
disease but still need improvement for better control of its spreading. Mathematical
models with computational simulations help global efforts to identify the critical-
model transmissions and model-dynamics. Such computational approach gives more
suggestions to estimate the model parameters and to predict this spreading. To model
the COVID-19, it is necessary to carefully analyze the model dynamics and identify
key critical parameters more accurately and widely. Some proposed theoretical and
computational approaches help international efforts for controlling this disease, like
[1] describes the interaction between all populations. This study has also proposed
the estimation of the model parameters. Then, for the suggested model for the new
confirmed cases in China, the improved model [2] with more explanations were
introduced along with that the idea of sensitivity analysis has been proposed for
the COVID-19 to identify the model sensitive parameters [3, 4]. The application of
mathematical modeling and fractional derivatives in systems biology and infectious
disease problems were given by [5–17] and non-singular fractional derivative for
immune and tumor cells are given in [18]; an important numerical approach for
fractional model of HIV-1 infection of CD4+ T-cells models presented in [19]; using
Haar wavelet and Adams-Bashforth-Moulton methods for fractional Lotka-Volterra
population model is shown in [20]; fractional predator–prey dynamical system with
Chaotic behaviour is given in [21]; an efficient numerical method for fractional SIR
epidemic model of infectious disease presented in [22]; a nonlinear fractional model
to describe the population dynamics of two interacting species expressed in [23];
numerical approximation for HIV infection of CD4+ T cells mathematical model
shown in [24]; an analysis for heat equations arises in diffusion process presented
in [25]; a new Rabotnov fractional-exponential function-based fractional derivative
for diffusion equation is given in [26]; using nonsingular derivative for propagation
of classical optical solitons is given in [27]; a fractional derivative with two singular
kernels is shown in [28].
Many mathematical models conclude that lockdown is the best way to reduce
the spread of COVID-19 effectively among all the control strategies. However, lock-
down interventions are very risky for a country’s economic stability. Therefore, as a
Dynamical Modeling and COVID-19 Pandemic 185
step to prevent the increasing number of infections, social distancing interventions to

minimize the successful contact of infections and the rapid test is the better option in
various countries, instead of implementing lockdown in the countries. Underdevel-
oped countries like Pakistan has adopted the “smart lockdown” strategy according
to the country’s top health officials to control the coronavirus hotspots across the
country and targeted in 3-steps, i.e.,
1. Identify,
2. Target to smart lockdown then,
3. Medical help to recover the patient through its task force based on young volun-
taries across the country, known as ‘Corona Relief Tiger Force (CRTF) of
volunteers’.
Along with that various healthcare strategies have also been conducted by the
governments to suppress the spread of COVID-19 in the country, such as with social
distancing, international travel restrictions, rapid-test, and even lockdown. They have
used many theoretical and practical tools to prevent this from spreading in their
countries. Overall, the first set of measures taken by the governments seem to have
an immediate (although heterogeneous) effect.
Here we will address two simple models of disease spreading and control strate-
gies. Our models are based on the Mass-Action Law with reaction rate constants and
measuring the sensitivities for each model-state relating to model-parameters that
improve the outcome. Through reduction techniques, each patient will be character-
ized into different routes to treat them according to its recovery pattern. The health
factor increases with the increases in the recovery factor introduced at different steps.
This will increase the survival of infected and serious patients. In this study, three
different techniques of sensitivity are also applied in computational simulations [4].
Also, some transmission parameters have been added to update the previous model
of the COVID-19. Then the model key critical parameters were investigated and
discussed.
This whole chapter is organized into six sections. Section one presents the impor-
tance of mathematical modeling and computational approaches for monitoring and
controlling the spreading of diseases along with the contributions of different coau-
thors in the same area. Section two comprises the methods proposed to study the
problem, i.e., mathematical modeling for the physical problem in the form of differen-
tial equations to be approximated numerically/computationally. Results and discus-
sion are revealed in section three by applying the techniques over the multi-route
problem. Then the sensitive analysis through three different normalization tech-
niques has been applied in section four and finally, the comparison of obtained
results along with another possible (multi-route) spreading model of the disease has
been addressed in section five.
2 Proposed Method
To reduce the spreading of coronavirus disease, governments have implemented

successive measures to encourage social distancing. However, it remained unclear
how effective measures reduced the spread of the virus. We examined how the
effective-contact rate, the mean number of daily contacts for an infectious individual
to transmit the virus, among other citizens evolved over the period with imple-
mented measures, regarding a priori information on governmental measures. We
propose a model involving multi-routes of the COVOD-19 spreading and measure and
compare the spreading of the disease and virus transmission dynamically. The idea
of graph theory uses to show the model population transmissions. Another novelty
in this work is that the proposed models of COVID-19 have been simplified with the
help of “model reduction techniques”, MRT. This will help to measure and specify
further control/spreading with the recommendation and improvement. Accordingly,
the dynamical models for model states are investigated based on computational simu-
lations. Furthermore, some key critical transmission parameters are identified using
three techniques of sensitivity analysis.
A detailed mechanism may occur through a series of distinct steps, known as a
complex mechanism. Each of these steps can be written as an equation, i.e., if we
have ith species (patients) Ai , participating in any model and the process is going
on in uni-direction (forward or irreversible) then sth basic forward stoichiometric
mechanisms can be written as:

N
N
α Si Ai <=> i∓ => β Si Ai . (1)
i=1 i=1
Here, in the first step, several reversibility factors are involved

Nbefore approaching
the irreversible condition, i.e., the final stage. The formal sums i=1 α Si Ai = (α S , A)
appearing on both sides of Eq. (1) are the subgroups i∓ while α, β are the constants
and are corresponding stoichiometric coefficients, the stoichiometric vectors γs : γs =
βs − αs are obtained through their difference at each point. In matrix form, the above
equation will take a form

= γ1 γ2 . . . γi
If there exist any other intermediates between the subgroups, i.e., between the
healthy and infected patient’s groups, there exist any subgroups of patients having
mild symptoms of a virus that can either recover towards the healthy or become a
part of an infected patient, such that any intermediate auxiliary states ∓
s (patients
having mild symptoms). Thus, the extended form of the reaction mechanism may be
represented as

N N
i∓
α Si Ai <=> ∓ => β Si Ai (2)
s
i=1 i=1
i.e., the interaction between the healthy and mildly than in between the mildly then
between the mildly and healthy. The detail will be mentioned in the next section with
an example. If the system is open (such that with no social distance or without isolated
patients) the concentration Ai will become an intensive variable Ai are xi = V olume
Ni
,
where V >. 0 is volume. This implies the volume of the system is not constant, then
there exist V and we have a different form. Whereas in the case of constant volume
we have ci = Ai . The polynomial form of the reaction rate function is provided by
the Mass-Action Law:
s (c) = + −
s (c) − s (c);

n
n
β
+ +
s (c) = K s (T ) ciαi , − −
s (c) = K s (T ) ci i (3)
i=1 i=1
here c Ai , c Bi are the concentration of initial and final (product) substances.

ki+ , ki− are the coefficient for the direct and reverse reactions and their ratio
ki /ki− = keq represents equilibrium constants.ki will be related to any increasing
+
exponential factor but now we will take any constant. When there is a reversibility
factor involved in the mechanism then we have an equilibrium such that + ∗
s (c ) =
− ∗
s (c ) .
Thus Eq. (3) along with the stoichiometric vectors provides the kinetic equations,
i.e.,
dc
ċ = = J (c) = s s (c); (4)
dt
Some other linear constraints also take part during the spreading, i.e., the balancing
equations \or involved balancing matrix.
M c = bc , bc = b A . . . bl , (5)
M represents the molecular balanced matrix. The relation between them is M ×

= 0.
The system of Eq. (4) can be written as follows:
dc
ċ = = s (c, α); (6)
dt
Here c ∈ R m , α ∈ R n . Now, the above system (6) can be further analyzed
with the help of sensitivity analysis. This approach allows us to investigate the
sensitivity of each concerning variable parameter. That can be represented as

∂ci ci α p , α p − ci α p
ċ p = = lim ; (7)
∂t α p →0 α p
Equation

(7) implies the time-dependent sensitivities
of each involve vari-
ables c j , j = 1, 2, . . . , m relating to all parameter values α p , p = 1, 2, . . . , n .
Further, the sensitivity of the coefficients can be measured through their differentials,
i.e.,

∂ci p ∂ ∂ci ∂ ∂ci ∂
ċ p = = = = (i (c(t), α)); (8)
∂t ∂t ∂α p ∂α p ∂t ∂α p
Equation (8) is used to identify the local sensitivity of model elements concerning
model parameters in systems biology. It means this approach is used to determine
which variable or parameter is sensitive to a specific condition that is defined by a
variable or parameter.
Differentiate with the help of chain rule, Eq. (8) will become more driven and the
Jacobian matrix further takes the sensitivity equations, i.e.,
Ṡ = Hα p + J . S, p = 1, 2, . . . , n (9)
here the above matrices S, Hα p and J are defined by

⎛ ∂c1 ⎞ ⎛ ∂1 ⎞
∂α p
⎛
∂α p
⎞
∂1
⎜ ⎟∂c2 ⎜ ⎟ ∂2∂c1
, . . . ∂1
∂cm
⎜ ⎟∂α p ⎜ ⎟ ⎜ .
∂α p . ⎟
S=⎜ ⎟ ⎜ ⎟ ⎜
⎜ .. ⎟, Hα p = ⎜ .. ⎟, J = ⎝ .. . . . .. ⎠
⎟ (10)
⎝ . ⎠ ⎝ . ⎠ ∂m ∂m
∂cm ∂m ∂c1
, . . . ∂cm
∂α p ∂α p
Equation (9) provides the local sensitivity values through the ‘Simbiology’ in
MATLAB by using three different normalization techniques, i.e., half-normalization,
full-normalization, and non-normalization. These normalization techniques become
more important when we have a complex model of COVID-19 spreading, especially
when spreading is in a different direction, i.e., adopting different routes. In that
case, we need to apply the model reduction techniques over the multi-routes COVID
spreading. This will help to identify the critical parameters of the model to improve
the dynamic model. For further details, readers are referred to [29–40].
3 Result and Discussion
To discuss the different kinetics patterns in detail, let us consider an updated model
for Coronavirus Disease. The graphical representation of the COVID-19 model helps
us to understand infectious diseases.
From the above system, the number of reaction route is two. Now it is important
to know the impact of the species in each route and reversibility factors. To answer
these questions, we will separately deal with both reaction routes.
3.1 HID-MODEL (1st Route)

In a group of people if some healthy person group (H ) gets infected k1+ , this new
group will become an infected
person
group (I ). Then, either an infected individual
or a group will get recover k1− and become healthy or after some time die (D),
denoted by (k2 ). The model diagram is given below.
The model chemical reactions of Fig. 1 can be simply expressed as follows:
K 1+ K2
H ←→
−
I −→ D. (11)
K1
For convenience, we consider the concertation of a healthy person H as c H ,

infected I as c I and died people D as c D here, the following parameters are defined
as their initials:
k1+ = 0.1, k2+ = 0.2, c H = 0.8, c I = 0.2, c D = 0.4

eq eq eq
(12)
By using the above system (4) the time derivatives of concentrations will become,
d
c·H = c H = −k1 c H + k1− c I + vin cin
H − vout c H ,
dt
Fig. 1 The HID model

diagram of the spreading
COVID-19
d
c·I = c I = −k1 c H − (k1− + k2 )c I + vin cin
I − vout c I ,
dt
d
c·D = c D = k2 c I + vin cin
D − vout c D , (13)
dt
H − vout c H , depends upon the specified area chosen for study, i.e.,
While the vin cin
closed, or open. Here we will consider a closed system for a case study, i.e., constant
volume. Solving the system (13), we observe that as the number of healthy people
decreases the death graph increases, while the infected people contribute on both
sides. Some of the infected people get recovers while some infected people die per
day (Fig. 2).
In the tabulated form we can also observe that with the decrease in health the
number of death increases (Table 1).
In Fig. 3 and Table 2. We have observed within a week that with time the death
graph overlaps the infected graph if the number of healthy people gets infected with
Fig. 2 The complete behavior of the involved species in the system (13) in computational simula-
tions using initial populations H (0) = 0.8, I (0) = 0.2, D(0) = 0.04. Time is represented in the
day
Table 1 First ten iterative values results during the initial three days
H 0.8000 0.8000 0.7998 0.7996 0.7994 0.7990 0.7986 0.7982 0.7977 0.7971
I 0.2000 0.1985 0.1972 0.1959 0.1947 0.1936 0.1926 0.1916 0.1906 0.1898
D 0.0400 0.0415 0.0430 0.0445 0.0459 0.0474 0.0488 0.0503 0.0517 0.0531
Fig. 3 The complete behavior of the involved groups (species) for a system (13) after one week
Table 2 Ten iterative results measured near the completion of one week
H 0.7257 0.7230 0.7204 0.7177 0.7151 0.7124 0.7098 0.7072 0.7059 0.7046
I 0.1647 0.1641 0.1635 0.1628 0.1622 0.1616 0.1610 0.1605 0.1602 0.1599
D 0.1496 0.1529 0.1562 0.1594 0.1627 0.1659 0.1692 0.1724 0.1740 0.1756
the same ratio. While the time will come within a month when the death graph also
overlaps the group of healthy people graph, Fig. 4 and Table 3.
The results and graph obtained through the model indicate that the spreading of
the disease is very fast, and this situation is possible when no precaution measure has
been adopted. Another possibility is that the infected patient may lose their willpower
very fast and its recovery factor is very slow, i.e., old people above seventy years.
Now, the important thing is to reduce the second step of our model. This can be done
either by introducing the recovery factors at each stage. Either it can be achieved
with the proper medication or with the social distances and quarantine techniques,
or small lockdown but it will affect the dynamical spreading.
Now, after one month the graphs between healthy people and the death rate are
shown in Figs. 5 and 6.
Here, from the above results and graphs, we have seen that the number of healthy
people reduces fast after getting infected. This is because there is only one recovery
factor/stage inserted in the model, i.e., reversibility of the first step. Now, we will see
that by inserting one more step/factor of recovery how the model behaves.
Fig. 4 The complete behavior of the involved groups (species) for a system (13) near one month
Table 3 Ten iterative results measured near the completion of one month
H 0.5328 0.5254 0.5182 0.5111 0.5040 0.4971 0.4902 0.4844 0.4787 0.4730 0.4673
I 0.1209 0.1192 0.1176 0.1159 0.1143 0.1128 0.1112 0.1099 0.1086 0.1073 0.1060
D 0.3864 0.3954 0.4042 0.4130 0.4216 0.4302 0.4386 0.4457 0.4528 0.4597 0.4666
3.2 HISD-MODEL (2nd Route)
Consider another model for the spreading of disease, if some healthy and infected
people are living together. Among them, some healthy person H gets infected I and
get recover but some of them reach to the serious conditions S, i.e., ventilator but
still have some chances to get recover otherwise dies D. The model diagram here is
given below:
The model chemical reactions of Fig. 7 can be simply expressed as follows:
K 1+ K2
H + I ←→
−
S −→ D. (14)
K1
The time derivatives of concentrations are given by (4):
d
ċ H = c H = −k1 c H c I + k1− c S + k2 c S + vin cin
H − vout c H ,
dt
Fig. 5 The complete behavior of the involved groups (species) health-death for a system (13) after
ten days
Fig. 6 When health decreases the death and infected graph will increase over time
Fig. 7 The HISD model

diagram of the spreading
COVID-19
d
ċ I = c I = −k1 c H c I + k1− c S + vin cin
I − vout c I ,
dt
d
ċ S = c S = k1 c H c I − k1− c S − k2 c S + vin cin
S − vout c S ,
dt
d
ċ D = c D = k2 c S + vin cinD − vout c D . (15)
dt
At here following parameters are defined for the case of a two-step mechanism
k1+ = 1, k2+ = 0.4,

eq eq eq eq
c1 = 0.4, c2 = 0.2, c3 = 0.1, c4 = 0.04
The balance (bold letters) of healthy and the infected patients can be seen among
its different stages, i.e.,
Balance Healthy Infected Serious Death

H-balance H – H –
I-balance – I I I
Now, mathematically speaking we can measure the behavior of every involved

species along with the impact of one species over the other.
⎡ ⎤
c

H
1010 ⎢ ⎥
⎢ c I ⎥ = b1
M.c = const. ⇒
0 1 1 1 ⎣ cS ⎦ b2
cD
Here we have,
C H + C S = b1 ,
C I + C S + C D = b2 . (16)
Through this system of linear Eq. (16), we can get the finalized reduced form of
the system. Now, let us check the behavior of the species in its reduced form with
the help of model reduction techniques (Fig. 8; Table 4).
Fig. 8 Comparison of healthy, infected, and serious patient rates during the initial three days
H 0.4000 0.4019 0.4038 0.4054 0.4070 0.4092 0.4112 0.4130 0.4146 0.4162
I 0.2000 0.2000 0.1998 0.1996 0.1993 0.1987 0.198 0.1972 0.1962 0.1952
S 0.1000 0.0981 0.0962 0.0946 0.0930 0.0908 0.0888 0.0870 0.0854 0.0838
The above result and graph indicate that from the very initial we obtain some
good results, i.e., H is inversely proportional to the I and S. Increase in the health
sector with the decrease in an infected and serious condition of the patients. That is
due to the recovery factor involved in serious condition patients as well as in infected
patients (Table 5).
Table 5 Ten iterative results measured near the completion of one week
H 0.4557 0.4567 0.4576 0.4585 0.4594 0.4603 0.4612 0.4621 0.4631 0.4640 0.4648
I 0.1060 0.1035 0.1010 0.0985 0.0962 0.0938 0.0916 0.08920.0868 0.0845 0.0823
S 0.0443 0.0433 0.0424 0.0415 0.0406 0.0397 0.0388 0.0379 0.0369 0.0360 0.0352
Fig. 9 Comparison of healthy, infected, and serious condition patient rates
Similarly, Fig. 9 indicates that with time there is further improvement in the system
and will remain controllable as compared to the previous model. Note here, both the
affected and the serious patients are participating in the recovery sector due to which
the health graph increases with time (Fig. 10; Table 6).
From the above results and graph, it is clear that if the situation remains under
controllable for the whole month then we can completely recover all the infected
and serious condition patients, i.e. when both the curves of I and S touch the zero
surface.
Figure 11 indicates that increasing the recovery factor at any stage will increase the
life of the patients, just like here patients are also recovering from serious conditions
other than the infected recovering pattern.
4 Sensitivity Analysis
Equation (7) represents the time-dependent sensitivity analysis of the COVID-19

model [4]. Measuring the sensitivity of the HID-model for a given system (13)
Fig. 10 Comparison of healthy, infected, serious patients in the first month
H 0.4964 0.4966 0.4968 0.4970 0.4972 0.4974 0.4975 0.4975 0.4976 0.4976 0.4976
I 0.0078 0.0073 0.0069 0.0065 0.0061 0.0057 0.0054 0.0053 0.0053 0.0052 0.0052
S 0.0036 0.0034 0.0032 0.0030 0.0028 0.0026 0.0025 0.0025 0.0024 0.0024 0.0024
Fig. 11 As the number of

healthy persons increases the
number of infected and
serious patients decreases
(using initial populations H (0) = 10,000, I (0) = 200, D(0) = 25 and param-
eters k1+ = 0.2, k1− = 0.8, k2 = 0.1 (a) N on − N or mali zation sensitivit y,
(b) H al f − N or mali zation sensitivit y, (c) Full − N or mali zation sensitivit y)
given in Fig. 12.
The sensitivity analysis for HISD-model (using initial populations H (0) =
10,000, I (0) = 200, S(0) = 50, D(0) = 10 and parameters k1+ =
1, k1− = 0.8, k2 = 0.4 (a) N on − N or mali zation sensitivit y, (b) H al f −
N or mali zation sensitivit y, (c) Full − N or mali zation sensitivit y) are given in
Fig. 13.
Fig. 12 The computational simulations for sensitive analysis of the HID model along with the
concerning parameters for the (COVID–19) disease
Fig. 13 The computational simulations for sensitive analysis of the HISD model along with the
concerning parameters for the coronavirus disease (COVID–19)
5 Conclusions and Further Directions
Here, we have developed two simple models of the COVID-19 spreading to incorpo-
rate the impact of a single individual over the others along with the different recovery
factors. These models are presented as a set of mathematical equations. The dynamics
of model equations are simplified with the help of “model reduction computational
simulations techniques” for the initial populations and parameters, to evaluate the
spreading with the dynamical view of the virus transmission. To measure the stability
of the system, the idea of local sensitivity is applied with three different techniques,
i.e., half, and full normalization sensitivity and then the non-normalization sensitivity.
They provide us the sensitivity of each variable relating to the model parameters.
The suggested methods give a major step forward to evaluate and identify the key
critical parameters for the multi-route spreading model, i.e.,
The above model indicates the spreading of the disease in two different patterns
(routes) at the same time. The second route is much better as compared to the first
one in which two recovery factors are involved to increase the survival of infected
and serious patients and fewer the death rate. This is another way of controlling the
individuals from the spreading called control monitoring strategy will be addressed
later.
Acknowledgements The authors extend their appreciation to ‘The University of Haripur, KP,
Pakistan’ for providing a feasible research environment, motivational and encouraging behavior
during the COVID-19 lockdown. We are also thankful to Dr. Sarbaz H. A. Khoshnaw for his
valuable remarks and discussion during the studies.
Authors’ contributions
All authors interpreted the results, contributed to writing the article, and approved the final
version for submission.
Funding
Not applicable.
Availability of data and materials
Data used in this study is obtained from publicly available sources that are referred to in the
main text.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
We declare no competing interests.
References
Med. 9(2), 462 (2020)
2. Tang, B., Bragazzi, N.L., Li, Q., Tang, S., Xiao, Y., Wu, J.: An updated estimation of the risk
of transmission of the novel coronavirus (2019-nCov). Infect. Dis. Model. 5, 248–255 (2020)
3. Khoshnaw, S.H., Salih, R.H., Sulaimany, S.: Mathematical modelling for coronavirus disease
(COVID-19) in predicting future behaviours and sensitivity analysis. Math. Model. Nat.
Phenom. 15, 33 (2020)
4. Khoshnaw, S.H., Shahzad, M., Ali, M., Sultan, F.: A quantitative and qualitative analysis of
the COVID–19 pandemic model. Chaos, Solitons & Fractals 138, 109932 (2020)
F., Jit, M., Munday, J.D., Davies, N.: Early dynamics of transmission and control of COVID-19:
a mathematical modelling study. The Lancet Infect. Dis. 20, 553–558 (2020)
6. Mohd, M.H., Sulayman, F.: Unravelling the myths of R0 in controlling the dynamics of COVID-
19 outbreak: a modelling perspective. Chaos, Solitons & Fractals 138, 109943 (2020)
7. Volpert, V., Banerjee, M., Petrovskii, S.: On a quarantine model of coronavirus infection and
data analysis. Math. Model. Nat. Phenom. 15, 24 (2020)
8. Kochańczyk, M., Grabowski, F., Lipniacki, T.: Dynamics of COVID-19 pandemic at constant
and time-dependent contact rates. Math. Model. Nat. Phenom. 15, 28 (2020)
9. Roda, W.C., Varughese, M.B., Han, D., Li, M.Y.: Why is it difficult to accurately predict the
COVID-19 epidemic? Infect. Dis. Model. 5, 271–281 (2020)
10. Tuite, A.R., Fisman, D.N., Greer, A.L.: Mathematical modelling of COVID-19 transmission
and mitigation strategies in the population of Ontario Canada. CMAJ 192(19), E497–E505
(2020)
Kucharski, A.J., John Edmunds, W., Sun, F., Flasche, S.: Feasibility of controlling COVID-19
outbreaks by isolation of cases and contacts. The Lancet Glob. Health 8, e488–e496 (2020)
12. Liu, Y., Gayle, A.A., Wilder-Smith, A., Rocklöv, J.: The reproductive number of COVID-19
is higher compared to SARS coronavirus. J. Travel Med. 27(2), 1–4 (2020)
13. Cakir, Z., Savas, H.B.: A mathematical modelling approach in the spread of the novel 2019
coronavirus SARS-CoV-2 (COVID-19) pandemic. Electron. J. Gen. Med. 17(4), em205 (2020)
14. Bouchnita, A., Jebrane, A.: A multi-scale model quantifies the impact of limited movement of
the population and mandatory wearing of face masks in containing the COVID-19 epidemic
in Morocco. Math. Model. Nat. Phenom. 15, 31 (2020)
15. Utkucan, Ş., Tezcan, Ş.: Forecasting the cumulative number of confirmed cases of COVID-19
in Italy, UK and USA using fractional nonlinear grey Bernoulli model. Chaos, Solitons &
Fractals 138, 109948 (2020)
16. Chaves, L.F., Hurtado, L.A., Rojas, M.R., Friberg, M.D., Rodríguez, R.M., Avila-Aguero,
M.L.: COVID-19 basic reproduction number and assessment of initial suppression policies in
Costa Rica. Math. Model. Nat. Phenom. 15, 32 (2020)
17. Roosa, K., Lee, Y., Luo, R., Kirpich, A., Rothenberg, R., Hyman, J.M., Yan, P., Chowell, G.:
Real-time forecasts of the COVID-19 epidemic in China from February 5th to February 24th,
2020. Infect. Dis. Model. 5, 256–263 (2020)
18. Ghanbari, B., Kumar, S., Kumar, R.: A study of behaviour for immune and tumor cells
in immunogenetic tumour model with non-singular fractional derivative. Chaos, Solitons &
Fractals 133, 109619 (2020)
19. Kumar, S., Kumar, R., Singh, J., Nisar, K.S., Kumar, D.: An efficient numerical scheme for
fractional model of HIV-1 infection of CD4+ T-cells with the effect of antiviral drug therapy.
Alex. Eng. J. 59(4), 2053–2064 (2020)
20. Kumar, S., Kumar, R., Agarwal, R.P., Samet, B.: A study of fractional Lotka-Volterra population
model using Haar wavelet and Adams-Bashforth-Moulton methods. Math. Methods Appl. Sci.
43(8), 5564–5578 (2020)
21. Kumar, S., Kumar, R., Cattani, C., Samet, B.: Chaotic behaviour of fractional predator-prey
dynamical system. Chaos, Solitons & Fractals 135, 109811 (2020)
22. Kumar, S., Ahmadian, A., Kumar, R., Kumar, D., Singh, J., Baleanu, D., Salimi, M.: An efficient
numerical method for fractional SIR epidemic model of infectious disease by using Bernstein
wavelets. Mathematics 8(4), 558 (2020)
23. Kumar, S., Kumar, A., Odibat, Z.M.: A nonlinear fractional model to describe the population
dynamics of two interacting species. Math. Methods Appl. Sci. 40(11), 4134–4148 (2017)
24. Srivastava, V.K., Awasthi, M.K., Kumar, S.: Numerical approximation for HIV infection of
CD4+ T cells mathematical model. Ain Shams Eng. J. 5(2), 625–629 (2014)
25. Kumar, S., Ghosh, S., Samet, B., Goufo, E.F.D.: An analysis for heat equations arises in
diffusion process using new Yang-Abdel-Aty-Cattani fractional operator. Math. Methods Appl.
Sci. 43(9), 6062–6080 (2020)
26. Kumar, S., Nisar, K.S., Kumar, R., Cattani, C., Samet, B.: A new Rabotnov fractional-
exponential function-based fractional derivative for diffusion equation under external force.
Math. Methods Appl. Sci. 43(7), 4460–4471 (2020)
27. Veeresha, P., Prakasha, D.G., Kumar, S.: A fractional model for propagation of classical optical
solitons by using nonsingular derivative. Math. Methods Appl. Sci. (2020)
28. Baleanu, D., Jleli, M., Kumar, S., Samet, B.: A fractional derivative with two singular kernels
and application to a heat conduction problem. Adv. Differ. Equ. 2020(1), 1–19 (2020)
29. Khoshnaw, S.H.A.: Model reductions in biochemical reaction networks (Doctoral dissertation,
University of Leicester) (2015)
30. Khoshnaw, S.H.: A mathematical modelling approach for childhood vaccination with some
computational simulations. AIP Conf. Proc. 2096(1), 020022 (2019)
31. Akgül, A., Khoshnaw, S.H., Mohammed, W.H.: Mathematical model for the Ebola virus
disease. J. Adv. Phys. 7(2), 190–198 (2018)
32. Khoshnaw, S.H.: Reduction of a kinetic model of active export of importins. In: Conference
Publications, vol. 2015, No. special, p. 705. American Institute of Mathematical Sciences
(2015)
33. Shahzad, M., Sultan, F., Ali, M., Khan, W.A., Mustafa, S.: Modeling multi-route reaction
mechanism for surfaces: a mathematical and computational approach. Appl. Nanosci. 1–8
(2020)
34. Sultan, F., Ali, M., Mustafa, S., Shahzad, M., Iqbal, A.: The impact of the rate coefficient over
the reaction mechanism. Appl. Nanosci. 1–7 (2020)
35. Shahzad, M., Sultan, F., Ali, M., Khan, W.A., Irfan, M.: Slow invariant manifold assessments
in multi-route reaction mechanism. J. Mol. Liq. 284, 265–270 (2019)
36. Shahzad, M., Sultan, F., Ali, M., Tauseef, I., Ahmed, S.: Numerical simulations for the equi-
librium state and solution behaviors in the multi-phase catalytic reaction mechanism. Int.
Commun. Heat Mass Transf. 118, 104818 (2020)
37. Shahzad, M., Shah, S.I.A., Sultan, F., Ali, M.: The C-matrix augmentation in a multi-route
reaction mechanism. Appl. Nanosci. 1–8 (2020)
38. Shahzad, M., Ali, M., Sultan, F., Azeem Khan, W.: Computational analysis of the slow invariant
manifold for single and multi-route reaction mechanisms. Sci. Iranica 27(3), 1293–1299 (2020)
39. Shahzad, M., Abdel-Aty, A.H., Attia, R.A., Khoshnaw, S.H., Aldila, D., Ali, M., Sultan, F.:
Dynamics models for identifying the key transmission parameters of the COVID-19 disease.
Alex. Eng. J. (2020)
40. Ali, M., Shahzad, M., Sultan, F., Khan, W.A.: Physical assessments on the invariant region in
multi-route reaction mechanism. Phys. A: Stat. Mech. Its Appl. 545, 122499 (2020)
SARS-CoV-2: Potential Drug Targets
and Its Virtual Screening
Raghvendra Dubey and Kushagra Dubey
Abstract The well-established structure of SARS-CoV-2 proteins has opened the

door for the drug development of the potent inhibitors. The interaction of spike
proteins of the virus with human angiotensin converting enzyme (ACE-2) via receptor
binding domain start the journey of the virus in the host cell. The entry of corona
virus by endocytosis is followed by genomic replication, transcription and formation
of the positive sense RNA. The assembling of genomic material with viral structure
proteins, endoplasmic reticulum & golgi intermediate forms mature viron, which
on exocytosis completes the SARS-CoV-2 life cycle. The entire cycle highlights
the importance of different proteins involved in functioning and virulence of the
virus. Targeting some of these proteins such as spike proteins, 3C like protease (3CL
pro), papaine like protease (PL pro), helicase, RNA dependent RNA polymerase
(RdRp) and N protein plays important role in the development of the antiviral drugs.
Using computational approach the researchers are investigating important targets
interaction with ligands (novel or existing) for the development of potent antiviral
drugs. Number of existing FDA approved drug molecules are repurposed against
3CL pro, PL pro, RdRp and few of them, e.g. remdisivir, favipiravir and lver-
mectin, are currently used in clinical application against SARS-CoV-2. Numbers
of small molecules libraries are also high through output screened for the identifi-
cation of novel ligand molecule for new drug development. In the present chapter
various approaches and strategies for the development of antiviral drugs using the
computation tools has been highlighted for the main targets of SARS-CoV-2.
Keywords SARS-CoV-2 · Computation approach · RNA dependent RNA

polymerase (RdRp) · 3CL pro · PL pro · Spike protein
R. Dubey (B)
Matoshri Institute of Pharmacy, Dhanore, Yeola, Nashik, Maharashtra, India
K. Dubey
Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India
204 R. Dubey and K. Dubey
1 Introduction
In December 2019, the deadly pandemic novel corona virus COVID-19 was reported
in Wuhan City, China resulting term epidemic respiratory syndrome suffering the
large number of people throughout the world [73, 103, 193]. This has changed the
health policies, lifestyle and economy of entire world. In the few months the infection
has become the main causative agent for life threatened pandemic disease world-
wide. The fatal condition of the disease has locked down the whole human race. The
entire healthcare system and researchers have engaged in identifying the treatment of
deadly pandemic [70, 132]. The available marketed drugs are repurposed, the small
molecule and phytoconstituents are investigated for the identifying and developing
the treatment of the coronavirus COVID-19 [58, 178].
The COVID-19 virus also known as severe acute respiratory syndrome coro-
navirus 2 (SARS-CoV-2) belong the family of coronaviridae family, subfamily
cornairinae, order Nidovirales of zoonotic virus which same as SARS-CoV and
the middle East respiratory syndrome coronavirus (MERSCoV). The virus has the
ability to cause severe respiratory infection in human beings. There has been a lot
of work done in identifying the genomic sequence of the corona virus. The basic
components of the CoVs are spikes; envelope protein, membrane protein, struc-
ture proteins, non-structure proteins, positive sense single strand RNA and several
assessor proteins [57, 148]. The coronaviruses are enveloped structured viruses with
pleomorphic or spherical shape, which consists of single strand large RNA genomes
with open reading frames (ORFs) in the range six to ten. The genomes are positive
in size ranges between 26.2 and 341.7 kb. The outer surface of corona virus consists
of club shaped spike glycoprotein projections [57].
Looking into the necessity of development for safe and effective drugs for the
treatment of the COVID-19 there is an utter requirement to understand the func-
tion and role of various proteins and enzymes in the lifecycle of the SARS-CoV-2.
Hence in the current chapter an effort is made to illustrate the role of the various key
proteins and enzymes and their targeting for the development of the antiviral drugs.
The role of spike protein in binding with the receptor binding protein of host cells
using the receptor angiotensin converting enzyme-2, followed by entry in the cell via
endocytosis has significantly provided the opportunity to the researcher to develop
inhibitors to block the virus access in human cells. The ligands which are screened
for spike protein were studied in the content. In the present chapter the noteworthy
drug development work done on various proteins such as 3C like protease (3CL pro),
papain like protease (PL pro), helicase and RNA dependent RNA polymerase (RdRp)
which are playing important role in replication, transcription, and new virion gener-
ation were also reviewed. The overview on the computational approaches employed
for the development of the novel drugs using protein ligand interaction were high-
lighted in the chapter. The approaches for the drug development for the antiviral
therapy and the strategies to achieve the same are significantly placed. The content
are presented with aim to give brief insight about the SARS-CoV-2, it’s lifecycle, key
protein involved in virulence and the computation approach used for development
SARS-CoV-2: Potential Drug Targets and Its Virtual Screening 205
of inhibitors. The chapter consists of significant inhibitors which are identified and
proved to be active against specific targets. The sequence analysis indicates that the
new corona virus is closely related to SARS-CoV.
2 Background
2.1 The Life Cycle of SARS-CoV-2
The entry mechanism of SARS-CoV-2 is still controversial but the basic pathway
followed by corona virus is the same as cornaviridae family. The coronavirus SARS-
CoV-2 enters in the host cell by interaction of its spike glycoproteins with host cells,
ACE-2 (angiotensin converting enzyme-2) receptor. The virus then enters in the host
cell by fusion. Once the host cell’s Trans membrane serine protease 2 (TMPRSS2)
cleaved the S protein present in the cornona virus, the spherical corona virus then
fused the viral cores into the cytoplasm of host cells [57, 148, 162, 168].
Till date seven different strains of human CoVs including Covid-19 has been
identified. The highly pathogenic three strains SARS-CoV, MERS CoV and Covid-
19, cause common infections to the upper respiratory tract. Although some other
symptoms were also observed in the few infectious cases.
The most important structural proteins of CoV are spike (S) protein (trimeric),
membrane (M) protein; envelope (E) protein, and the nucleocapsid (N) protein, shown
in Fig. 1. Apart from main structural protein some of the viruses such as beta-CoVs
also have hemagglutinin esterase (HE) glycoprotein [196].
Fig. 1 Important structural proteins of CoV are spike (S) protein (trimeric), membrane (M) protein;
envelop (E) protein, and the nucleocapsid (N) protein
The life cycle of the corona virus in the host cells usually undergoes major eight
critical steps, Fig. 2. The first and most important step is the entry of the virus in the
host cell, which involves the attack of virus spike protein S1 subunit on the host cell
membrane. The interaction of spike protein with host receptor angiotensin converting
enzyme 2 binding site, results in tight binding at receptor binding domain of the host
cell membrane. The virus gets entered in the host cell by endocytosis. The virus
enters by proteolytic cleavage of S protein into two subunits S1 and S2 by cathepsin,
Fig. 2 The life cycle of corona virus. The various steps are (1) The spike proteins of corona virus
attach to the host cell receptor binding protein and enter the cell by endocytosis (2) The virus releases
the positive sense RNA in the cytoplasm. (3) The viral genomes translate in polyproteins using
viral polymerase. (4) The viral genome replicates and transcripts by viral polymerase to produce
subgenomic RNA and positive sense RNA. (5) The subgenomic RNA, viral structure proteins
(spike protein, Envelope Protein, Membrane) are translated and get assembled with endoplasmic
reticulum (ER). The N protein translated to neuclocapsid with the use of non-structure proteins. (6)
The neuclocapsid, endoplasmic reticulum with structure proteins and glogi body assembled to form
endoplasmic reticulum-Golgi intermediate compartment. (7) The virus get full structured in Golgi
Vesicle to form matured viron. (8) The mature virus fuses the membrane and releases the virus by
exocytosis
furin, TMPRSS2 or another protease. Once the virus enters the host cell, the positive
sense RNA enters in the cytoplasm of the host cell. The RNA entered in the host cell
and uses the host machinery for its genomic development [162, 168, 196].
The viral genomes translate in the polyproteins using the viral polymerase. The
viral RNA synthesis, replication and transcription take place in presence of viral
polymerase to produce small pieces of viral RNA known as subgenomic RNA
and genomic positive sense RNA. The non-structure protein helps the virus to
protect from host defense mechanisms so that successful replication and transcription
processes take place.
The structural subgenomic RNA such as Spike (S), Membrane (M) and Envelope
(E) were translated and assembled and inserted in the endoplasmic reticulum. The
Nucleocapsid is translated and binds with non-structure protein to form genomic
RNA. The endoplasmic reticulum is assembled with Nucelocapsid genomic RNA
and forms the endoplasmic reticulum golgi intermediate compartment (ERGIC)
[168, 196].
The virus gets matured in the in the Golgi vesicle to form matured virion. The
vesicle containing the mature virions reaches to the outer cell membrane and merges
to release the viral copy outside the cell by exocytosis.
2.2 Approach’s for Viral Treatment
Number of different approaches was highlighted in the current situation for over-
coming the pandemic situation. The scientific therapies which were used are broadly
classified in two categories:
(a) Drug Acting on Host Cell and Immune System
It was observed that the predefined medicaments, nutrients and vitamins playing
important role in boosting the immune response of host cells and are used for the
prevention and treatment of infection. Boosting the immunity helps in the controlling
various metabolic and enzymatic process for normal function in host cells, which
helps in reducing the trigger impact of corona infection.
The virus interaction with the host cell involve binding of angiotensin converting
enzyme-2 (ACE 2) with the receptor which has also opened the gate for developing
the inhibitor drugs which can directly act on the host cell receptor to prevent the
interaction of virus with host cells.
(b) Drug Acting on the Corona Virus
The second approach which was widely accepted involves the drug action on the
corona virus. This includes novel ligand identification, repurposing and inhibitors
from natural resources. The available antivirals are the first line drugs which were
used for the treatment. Due to difference in the receptor’s shape and binding poten-
tial in virus targets, the potential target identification is required for the successful
treatment of viral infection [143, 152].
2.3 Strategies for SARS-CoV-2 Drug Development
The lifecycle and potent component of the corona virus has helped in identification
of the potent targets and their role in the infection. Each component plays important
role in the integrity, function and virulence of the virus. Knowing the structure of the
CoV-2 virus (available in Protein data Bank) & its components, various strategies
have been planned using virtual screening methods.
The following strategies were planned to develop the potent drugs [152] (Fig. 3):
(a) Repurposing of Exiting Drugs
The available antiviral drugs or FDA approved drugs were virtually screened with
various potential targets of corona virus. The repurposing is selected as the best
approach, as drugs that are being tested have already developed a pharmaceutical,
therapeutic and toxicological history. The drug dose, dosage form, ADMET, side-
effects and important interactions studies have already been carried out, proven &
safe for human use. The advantage of the approach is that the drug candidate for
research has been well established for safety and efficacy, which helps to reduce the
time needed to bring the drug into the market. The approach is basically concentrated
on broad spectrum drugs, which has disadvantages of major and minor side effects.
(b) Screening the Database Libraries
Number of database libraries which include chemical database, drug database, herbal
database, nucleotide database etc. were used and screened over potent targets of
corona virus identified from Protein data bank. The small molecule database libraries
such as Zinc-15, Asinex, Chembl, PubChem, MolProt, Enamine, CAS antiviral,
Enamine libraries, Timbal, chemDiv, Coconut Libraries, ESCOP, HerbMedPro,
Phytochem Lib, TIPdb and IMPPAT were used for screening the small molecule
against the targets. The approach is helpful in identification of new drug molecules
for the treatment of corona infection. The High throughput virtual screening of the
database libraries will bring the good number of molecules effectively act on the
Fig. 3 Strategies for SARS-CoV-2 drug development

targets. The specific libraries will help in identification of agonist, antagonist or inhi-
bition of potential molecules for the targets. The identified molecule needs to go
through efficacy and safety evaluation in preclinical and clinical trials.
(c) Identification of Novel Targets in Virus
The novel targets were identified by genomic information, interaction studies and
pathological characteristics of the coronavirus. The approach is time consuming and
costly as compared to the other two methods. The approach is significant and will
lead to efficient drug identification. It involves bioinformatics analysis of protein
and its interaction with the host cell. The identification of targets will lead to specific
attacks of the drug which can prevent the unwanted side effects of the drug. The
identification of novel targets and drugs for the same required more than a decade of
time.
3 Drug Discovery and Development on Potential Targets
The virtual ligand screening of various corona virus targets was conducted using
number of approaches:
1. Screening the ligands on the structure proteins of the virus, or on protein binding
to the host cell.
2. Screening the ligands over the enzymes and functional proteins which are
important for virus growth, replication and synthesis.
3. Screening the ligands over enzymes involved in virulence factor.
The positive sense RNA is found in human coronaviruses are basically of two
types, which characterizes as structural proteins [Spike (S), Membrane (M), Envelope
(E) and Nucleocapsid (N)] and non-structural proteins (nsp-1–nsp-12). The non-
structural protein has wide importance in developing the novel drugs e.g. [nsp-12
known as RNA dependent RNA polymerase (RdRp)] which plays a potential role in
drug development.
The possible targets which are involved in the drug discovery by computation
approach are:
3.1 Spike Protein
The spike protein is a glycoprotein tran’s-membrane which is essential for the entry
to the host cell. The S protein has two functional subunits denoted as S1 & S2.
The structure of the spike S protein is clove shaped and has three major sections,
which form trimer, which are ectodomain, TM region and intracellular domain. The
ectodomain region also called as ED [15, 75, 102].
Fig. 4 The S-protein consist

of S1 & S2 domain
ED region is comprised of receptor binding S1 domain, membrane fusion subunit

S2 together on C-terminal. The crow appearance of the corona virus is due to the
homo-trimeric form on the outer surface of the virion. The S1 domain basically
involved interaction with the host cells i.e. with angiotensin converting enzyme2
(ACE2) and act as receptor binding domain and also helps to anchor the S2 domain
which helps in the fusion of the virus and RNA genomes in the host. Due to the
essential role of the receptor binding domain, it plays important role in the targeting
the drug for virus entry in host cells [15, 46, 68]. There are two important domain of
the S protein S1 & S2 domain showed in Fig. 4.
3.1.1 S1 and S2 Domain and Drug Design Strategies
The well-defined structure of S1 domain has two parts which are termed as N-terminal
Domain represented as NTD and C-terminal domain represented as CTD, which
forms receptor binding domain. In terms of interaction via RBD, the 14 amino acids
of the virus interact with 18 residues of host ACE2 receptor. The structure of S1 & S2
domains of SARS-CoV-2 showed ~99% similarity of S2 subunit and 70% similarity
of S1 subunit with Bat SARS-CoV with human SARS-CoV and the residues of
S-RBD of SARS-CoV-2 are highly conserved while comparing with SARS-CoVs
from bats and human. The scientific evidence showed that the SARS-CoV-2 viral S-
receptor binding domain and the host ACE2 receptor has affinity ten times higher
than SARS-CoV virus with host membrane. The key residues in the receptor binding
domain pocket of SARS-CoV are Tyr442, Leu472, Asn479, Asp480, and Thr487,
which are important for targeting the novel entry inhibitor. Simultaneously the host
ACE 2 receptor residue Lys31 and Lys353 plays an important role in the virus binding
using salt bridge between Lys31-Glu35 and Lys353-Asp38, which are surrounded
by the hydrophobic environment. The Lys 31 and Lys 353 are represented as hot
spots for the receptor binding domain. The molecular interactions of human ACE2
receptor hotspot 31 with SARS-CoV-2 are supported by residues Gln 493 and Leu
455. Some key residues of S protein of SARS-CoV-2 such as Leu455, Phe486, Ser494
also provide supports for hotspot 31. For hotspot 353 the residue serine 494 helps in
binding and providing structure stability [15, 46, 68, 74, 75, 100, 123, 173, 180].
The above identified interactions and key residues were used for the computational
screening of the novel entry of inhibitors for SARS-CoV-2. The insilico approaches
were used for the screening of the molecule for the ACE2 host receptor and hotspots
31 & 353.
Number of drugs has been screened for the S proteins & its interaction. The
starting research showed that the antimalarial drug hydroxylchloroquine [124] 28
inhibits entry of SERS-CoV-2 by acting on the RBD and elevating the endosomal
pH and hence altering the terminal glycosylation of ACE-2. Some inhibitors iden-
tified with the proposed targets such as Apilimod [74], ABPD25Y [82], CR3022
mAb [23], Ergoloids [23], Darifinacin [23], 2-(3,4-dhydroxyphenyl)-3,7-dihydroxy-
4H chromen-4one (fisetin) [124], 2-(3,4-dihydroxyphenyl)-3,5,7-trihydoxy-4H-
chromen-4-one (quercetin) [124], quercetin 3-O-galactosyl-rhamnosyl-glucoside
[33], MI1851 [179], Bisoxatin (DB09219) [170], SSAA09E1, SSAA09E2 and
SSAA09E3 [2] have inhibited S1 or S2 subunit or host protease cathepsin L, S-
ACE2 interaction, and prevents fusion of host and viral cell membrane. Number of
small molecules has also showed significant inhibition at the target. The peculiar
furin like cleavage site which is S1 & S2 sites plays an essential role in develop-
ment of the inhibitor of furin cleavage site of the spike proteins which also plays an
important role in the drug development and blocking viral entry process.
3.2 Envelope Protein (E)
The E protein is a transmembrane structure protein found in CoV Family. It is

the smallest protein with size ranging 8.4–12 kDa size. The E protein consists of
hydrophobic and charged cytoplasmic tail. E protein plays a central role in the viral
morphogenesis and assembly. E protein is found to be responsible for virulence of the
virus. The E protein forms pentameric protein lipid pores in the host membrane that
allows the ion transport and helps in induction of apoptosis. The E protein also helps
in activation of host nucleotide-binding domain and leucine-rich repeat containing
proteins (NLRP3) inflammation which leads to the overproduction of Interleukin 1
beta (IL-1 β) and results in acute repiratory distress syndrome [47, 110, 139, 144,
145, 171] (Fig. 5).
In absence of E protein the virus is immature showing lower viral titer and inef-
ficient progenies. The E protein is one of the targets in the CoV drug design as it
is important protein potentially involved in ion channel activity [47, 110] and high
Fig. 5 The E protein

structure of CoV-2
impact on the postsynaptic density protein 95 (PDZ)-binding motif (cytoplasmic β-

barrel or β-sandwich fold and an N-terminal secretory-pathway signal peptide) that
induces virulence. The FDA approved four potent inhibitors observed for E protein
were Artemther, ondansetron, mefenamic acid and tretinoin [44]. The Gliclazide and
memantine [153] has been proved to inhibit the E protein linked ion channel. Hexa
methylene amiloride blocks E protein associated ion channel [61]. There is only three
substitutions and one deletion in the E proteins from SARS-CoV-2 and SARS-CoV
and hence it is expected that in both the proteins will act in the same way. Amino
acid VAL 25 & PHE 26 has shown significant involvement in the interaction with E
protein inhibitors vibsanol B, Belachinal and Macaflavanone [32].
3.3 Membrane Protein (M)
The membrane protein is a very important component which provides shape to the
virus. The M protein maintains the function of viral envelope and helps by inter-
acting with other corona protein and incorporating Golgi complex into new virions
and stabilizes neucleocapsid protein. The M protein is involved in protein protein
interaction and plays an important role in viral intracellular homeostasis. The interac-
tion between M proteins with other proteins plays an important role in viral assembly.
The Membrane and spike protein interaction is critical for new viral progenies while
the membrane protein and nucleotide complex has an important role in formation
Fig. 6 M protein of
SARS-CoV-2
of viral core by stabilization of Nucleocapsid-RNA Complex [21, 72, 80, 118, 130,
154].
The Membrane protein is also considered for the screening of the small
molecule drugs and phytoconstituents to identify the potent inhibitor. The
phenylpolypropanoids caffeic acids, rutin and ferulic acid have shown significant
binding towards the M protein [20] (Fig. 6).
3.4 Nucleocapsid Protein (N)
The N protein is an important component of viral protein which consists of three

intrinsically disordered regions (IDRs). The regions are characterised as N-arm,
central linker (CL), and the C-tail. The N protein has an important role in function in
RNA binding and dimerization. The central linker region contains a large number of
phosphorylation site and is rich in arginine and serine residue. The genetic process
replication and transcription in viruses is regulated by N protein. The protein is also
involved in altering the host cells metabolism, cell cycle and apoptosis process. The N
protein also involved in inhibiting cell proliferation through inhibition of cytokinesis
in human peripheral blood [49, 90, 109].
The Nucleocapsid protein is an important protein which consists of RNA binding
sites which interact with ribonucelotide 5 monophosphates such as AMP, UMP, CMP
and GMP. The information about the interactions between ribonucleotides helps in
designing the potent inhibitors [27, 49, 90, 109, 115] (Fig. 7).
Number of potent inhibitors have been developed using RNA binding site inhibi-
tion strategies, example N-(6-oxo-5,6-dihydrophenanthridine-2-yl) (N, N dimethyl
Fig. 7 Nucleocapsid protein

(N) of SARS-CoV-2
amino) (PJ34) [115], H3 (6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-

5,8-dione) [97], Some herbal products such as catechingallate and gallocatechin-
gallate were also showed significant inhibitory potential action against corona
virus.
There is significant inhibition in viral titer observed with decrease in oligomer-
ization process occurring due to inhibition of N Protein as it plays an important role
in oligomerization at C terminal end. The N protein peptide also activates the T cells
in humans as it binds significantly with human MHC-1 in T2 cells. Two significant
inhibitors simeprevir and grazoprevir show high affinity for neucleocapsid proteins
[20].
3.5 Non-structural Proteins
The replicase gene is one of the important components of genomic sequences of

CoV, which encodes a number of non-structural proteins termed as nsp’s.
The nonstructural proteins (nsp1–nsp 16) plays an important role in SARS-CoV-2
virus replication and virulence. Targeting such protein will affect the RNA reproduc-
tion and overall virulence hence the targets are considered for computation studies.
There are some important nonstructural proteins which are considered in computa-
tional studies as the target proteins, these are nsp1, nsp2, nsp4, nsp6, nsp 7, nsp 8,
nsp 9, nsp 10, nsp 12 & nsp 16 [57, 148].
The NSP’s are found in two large PP’s in which the C terminal end PPs is known as
Mpro or 3C like protease which are cleaved by chymotrypsin like cysteine protease
and the N terminal end protease is also known as papain like protease PL pro. In PPs,
the PLpro cuts the first three cleavage sites and the rest 11 sites are cut by CL pro.
The non-structure proteins have direct or indirect significant role.
3.5.1 Non-structure Protein 1 (Nsp1)
The nsp 1 plays an important role as virulence of the SARS-CoV-2. It helps in

inhibiting the host translation mechanism by binding with a 40S ribosome unit along
with 43S pre-initiation complex and 80S ribosome. The complex forms degrade the
host mRNA by inducing the endonucleolytic activity. It binds with mRNA while
entering the C-terminal domain. It helps in viral gene expression in infected cells
by inhibiting host gene expression by targeting type I interferon expression and
antiviral signaling pathway. Due to the inhibition potential of nsp1 toward host’s
innate immune system it is considered as host shutoff factor [88, 89, 113, 116, 161,
166, 167].
The non-structural protein 2 is also known as RNA Binding Protein. The replicase
polyprotein was cleaved by PL protein at N terminal to release Nsp1, Nsp2 and
Nsp3. The Nsp2 is found in complex with Nsp1 and Nsp3 and suppresses the gene
expression in host cells. In SARS-CoV-2 the Nsp2 binds with prohibiting 1 and
prohibitin 2 binding proteins produced by open reading frames (ORF1 a & ORF
1 b) genes. The nsp2 helps in inhibition of the intracellular host signaling during
infection which helps in increasing the infection virulence. The genomic replication
in SARS-CoV-2 is promoted by nsp2. The Nsp1 and Nsp2 also helps maintain the
mitochondria functional integrity and protect viral cells from various stresses [8, 24,
35, 36, 59, 185].
3.5.3 Non-structure Protein 3 (Nsp3) (Papain Like Protease PLpro)
The non-structure protein nsp3 is integral to viral replication. It has two transmem-
brane regions and its domain acts as an essential component in RNA replication
including single strand (ss) RNA binding and unwinding domain. It is known as
papain like protease [76, 101].
PL pro is one of the most significant targets for the drug discovery in CoV-2.
During the viral replication in virus, the non-structure protein nsp1, nsp2 & nsp3
which were released by cleavage of N terminus of replicas polyprotein, act as an
essential component to correct the virus replication. Pl pro has been the important
indispensable target for eliciting the potent inhibition activity.
SARS-CoVPLpro belongs to the CA (family C16) peptidase clan. The active
site comprises a typical catalytic triad of Cys112-His273-Asp287, which is well-
aligned, functional and located at the thumb and palm sub-domain interface. The
catalytic cysteine (Cys112) is located in the thumb domain at the foot (N-terminus)
of alpha-helix alpha. Cys112’s side chain sulphur atom is situated 3.7 Å from the
catalytic histidine (His273) pros (π)-nitrogen atom located at the foot of the palm
domain and adjacent to the versatile loop BL2 (also referred to as the G267-G272
loop or β-turn) or β-turn. At the foot of the palm domain, one of the oxygen atom
of the catalytic aspartic acid side chain (Asp287) is situated 2.7 Å from the tele(er)-
nitrogen of the catalytic histidine. Within the oxyanion hole, the side chain of Trp107
is located and the indole-ring nitrogen is participating in the stabilisation of nega-
tively charged tetrahedral intermediates formed during catalysis. Cellular ubiquitin
specific proteases (USP) like USP14 and USP7 (or HAUSP) are strikingly close to
the overall tertiary configuration of PLpro. However, the catalytic triad of PLpro
aligns structurally well only with the catalytic triad of USP14 and not USP7 in their
unbound states. In order for the USP7 catalytic triad to have the right orientation for
catalysis, a substrate-induced alignment must occur when interacting with ubiquitin
or other regulatory domains. PLpro’s finger domain, which contains a tetrahedrally
coordinated zinc ion with four cysteines, is important for catalysis because it retains
PLpro’s structural integrity [12] (Fig. 8).
Currently, CoV-2 PLpro’s crystal structure 6 is available and shows that
CoV-2 PLpro has three domains identical to those in CoVPLpro which are the
catalytic cysteine cleavage domain, putative labile Zn-binding domain, and ubiq-
uitin domain.The catalytic site represents a classic amino acid triad, Cys111-His272-
Asp286, which plays a crucial role for viral replication. The ZnII ion is labile and
tetrahedrally coordinated at the Zn site by four retained Cys residues (Cys189-X-X-
Cys192-Xn-Cys224-X-Cys226) and is also essential for catalysis because it retains
CoV-2 PLpro’s structural integrity. In addition, PLpro has an additional domain, an
ubiquitin domain that activates the innate immune responses of the host. All domains
in a single protein, CoV-2 PLpro, are also likely to be promising therapeutic targets
[107].
For PLP activity, a yeast-based assay was developed that relies on PLP’s ability to
induce a pronounced slow-growth phenotype when added in S. cerevisiae. From the
NIH diversity set library, five chemical suppressors of the slow-growth phenotype
Fig. 8 Papain like protease SARS-CoV-2

were identified. The NSC158362 & NSC158011 were found to be most active to
inhibit CoV replication and PLP protease activity respectively [54].
6MP and 6TG were identified as reversible and slow-binding SARS-CoVPLpro
inhibitors. Both kinetic measurements and molecular docking are used for inves-
tigation of inhibition mechanisms. Both compounds are found to be competitive,
selective, and reversible inhibitors of the PLpro. The thiocarbonyl moiety present in
6MP or 6TG is an active pharmacophore is essential for the inhibitions concluded
from structure-function relationship [30, 34].
Seven isolated tanshinone natural compounds showed good inhibitory activity
for both cysteine proteases. All the isolated compounds function as time-dependent
PL(pro) inhibitors and noncompetitive enzyme isomerization inhibitors except
rosmariquinone, which showed a mixed-type simple reversible slow-binding inhibi-
tion [125].
The isolated diarylheptanoids compounds from Alnus japonica were evaluated
against PL(pro). Hirsutenone was found to be the most potent inhibitor. Structure-
activity study shows that catechol and , β-unsaturated carbonyl moiety in the
molecule were essential requirements for inhibition of SARS-CoV cysteine protease
[125].
The geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin
D, tomentin E which contain a 3,4-dihydro-2H-pyran moiety found to be potent
inhibitor. fromfluorogenic inhibitor-screening platform, it was found that, zinc ion
and its conjugates potentially inhibit the enzymatic activity of SARS-CoV PLP2
[93].
Library of 50,080 compounds for PLpro inhibitors was studied and a non-covalent
lead inhibitor was obtained. In Vero E6 cells, a compound GRL0617 inhibited SARS-
CoV viral replication with no cytotoxicity. From a high-throughput screening of a
diverse chemical library, a new lead compound 3 (6,577,871) was identified [66].
A series of noncovalent inhibitors generated by structure-guided design with
nanomolar potency against the papain-like protease (PLpro) was studied. Selec-
tivity and cytotoxicity studies have identified a more than 100-fold preference for
coronaviral enzymes over homologous human deubiquitinating enzymes (DUBs)
[136].
Human enzymes have been greatly inhibited up to concentrations as high as
100 μM by naphthalene-based PLpro inhibitors.
The FDA approved drugs in silico screened and docked in S3/S4 pockets of the
enzyme’s active site. Sixteen FDA-approved drugs have been shown to bind the target
enzyme with considerable affinity and strong geometry, including chloroquine and
formoterol, indicating their ability to be used against the virus.
Numbers of inhibitors showed potent affinity toward PLpro some are ribavirin,
remdesivir, riboflavin, ipromide, valganciclovir, leodropropizine, b Thymidine,
Aspartame, doxycycline, reproterol, Chrysin, Sugetriol-3,9-diacetate, Baicalin,
Neohesperidin, Phaitanthrin D, (e)-Epigallocatechin [10].
The nsp4 is found in combination with nsp3 and is required for viral replication by
inducing double membrane cytoplasmic vesicles. The nsp4 is engaged in homtypic
and heterotypic interactions [9, 65, 122]. The nsp4 & nsp 3 proteins are essential for
membrane rearrangement. The amino acid residues of nsp4 interact with nsp 3 which
results in relocalization of proteins from the endoplasmic reticulum [64, 122, 142].
3.5.5 Non-structure Protein 5 (Nsp5) {3C Like Proteinase (3CL Pro)}
The nsp5 is also known as 3 CL pro, the main protease with 306 amino acids which
cleaves the polyprotein to release nsp4 to nsp16.
SARS-CoV encodes two proteases, a papain-like cysteine protease (PLpro)
and a chymotrypsin-like cysteine protease known as 3C-like protease (3CLpro).
There were three types of SARS-CoV which are active dimer which is wild-type,
monomeric forms that consists of G11A, S139A or R298A mutation on the dimer
interface, and a super active octamer.
The SARS-CoV 3CLpro forms a dimer with the two promoters (denoted as “A”
and “B”) that are oriented almost at right angles to each other. The SARS-CoV
3CLpro crystal structure consists of three domains, domain I consists of residues
8–101 and domain II consists of residues 102–184, the β-barrels that form the
chymotrypsin structure that are present, whereas in domain III (residues 201–306)
α-helices are present.
The structure also contains a Cys-His catalytic dyad and the substrate or inhibitor
binding site is situated in a cleft between domains I and II. For the residue of the
P1-Gln substrate on the enzyme, the substrate-binding subsite S1 specificity of a
CoV protease in protomer A confers absolute specificity. Each of the N-terminus
residue (also known as N -finger) are squeezed between domain II and domain III
of the parent monomer and domain II of the other monomer. This plays a vital role
in formation and dimerization of the active site of 3CLprol.The SARS-CoV 3CLpro
monomer is mostly inactive while the dimer is strongly active. 3CLpro breaks down
11 specific sites in a polyprotein and produces various non-structural proteins that
are necessary for viral replication. In comparison to structural/accessory protein-
encoding genes, 3CLpro is situated at the 3 end that exhibits extreme heterogeneity
and plays an important role in viral replication. It is thus a potential target for the
screening of anti-coronaviruses inhibitors [3, 26, 85, 133, 181, 182] (Fig. 9).
The 3CLpro sequences of SARS-CoV-2 and SARS-CoV have 96% similarity
of the 306 residues and 12 residues are found different, namely T35V, A46S,
S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L.
The 3CLpro structure of the novel coronavirus (COVID 19) is a contact dimer,
which is the same as the 3CLpro structure of SARS-CoV. When overlapping is done
between 3CLpro structures of SARS-CoV-2 (PDB ID: 6M03) and SARS-CoV (PDB
ID: 2C3S). it was observed that, all the residues are oriented in almost the same direc-
tion that surrounds both active sites, with the exception of Ala46 in place of serine
Fig. 9 CL pro main protease

SARS-CoV-2
(SARS-CoV 3CLpro) in Subsite S2 of SARS-CoV-2 3CLpro [60, 67, 69, 71, 105,
160].
Another striking difference is observed on the dimer interface. Another difference
is that, a hydrophobic interaction is formed between Thr285 and Ile286 in the SARS-
CoV 3CLpro dimer, but Thr285 and Ile286 are substituted by alanine and leucine in
SARS-CoV-2 3CLpro dimer.
3CL pro inhibitors can be categorised as peptoids and non-peptidomimetics.
Peptidomimetics that resemble natural peptide substrates forms a noncovalent
complex with 3CL pro, and to catalyse the formation of cysteine-participating
covalent bonds the warhead group undergoes a nucleophilic attack [149].
For the inhibitory effect, the warheads (consists of Michael receptors, aldehydes
and different types of ketones, covalently bind to the Cys145 residue in S1’ pocket
of 3CLpro . Numerous 3CLpro inhibitors have been reported which are based on
the crystal structure of 3CLpro, like peptide mimetics and small molecules mostly
through virtual screening methods [56].
The computational method and cell-based assays indicate were carried out on
synthesized the Phe-Phe dipeptide inhibitors that are anti-SARS agent which was
obtained by condensation of the Phe-Phe dipeptide α,β-unsaturated ester with 4-
(dimethylamino)cinnamic acid [184].
The inhibitor bound to SARS-CoV 3CLpro, a series of peptidomimetic 3CL
protease inhibitors were identified. Boc-Ser as the P4 -ligand was incorporated which
was involved in important hydrogen-bonding interactions in the S 4-subsite and this
resulted in increase in SARS-CoV 3CLpro inhibitory activity [39].
A potent 3CLprosynthetic inhibitor TG-0205221 with different functional groups
at the P1–P4 sites has tightly binding between TG-0205221 and the 3CLpro enzyme
through a covalent bond, hydrogen bonds, and unprecedented hydrophobic inter-
actions. In covalent inhibitors, aldehyde groups covalently bound to Cys145 of
Mpro. The dipeptidyl N,N-dimethyl glutaminyl fluoromethyl ketones (fmk) were
observered to be severe acute respiratory syndrome coronovirus (SARS-CoV)
inhibitors [188].
The trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors were commer-

cially introduced. In the P1-position three different amino acids were explored and
varying amino acids and long alkyl chain were incorporated in the P2-P4 positions
[147].
A series of keto-glutamine analogues showed reversible inhibitiors against SARS
3CL(pro) with a phthalhydrazido group at the alpha-position. It was found that to
these glutamine-based “warheads” if tripeptide (Ac-Val-Thr-Leu) attached then they
was served as better inhibitors [81].
The low-molecular weight peptidic SARS-CoV 3CL protease inhibitors were
designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-
benzothiazole in which the P3 valine unit was substituted with a variety of distinct
moieties [165].
All the dipeptide- type inhibitors showed moderate to good inhibitory activi-
ties against 3CL(pro). The peptidomimetic α-ketoamides foundas inhibitors of main
and 3C proteases. P2 substituent of the α-ketoamides was optimized and found
near-equipotent, broad-spectrum antivirals against alpha coronaviruses, betacoro-
naviruses, and enteroviruses [189].
The α-ketamine inhibitor complexed with the unliganded found active SARS-
CoV-2M pro inhibitor. P3-P2 amide bond incorporated into a pyridone ring to
enhance the half-life of the compound in plasma. On the basis of the unliganded
structure, the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro was
developed [190].
The non peptidicdecahydroisoquinolin scaffold was designed and the methy-
lene linker was used for connecting the P2 site cyclohexyl group of the substrate-
based inhibitor with the α-nitrogen atom of the P2 position. All the synthesized
decahydroisoquinolin inhibitors exhibit clear inhibitory activities for 3CL(pro) [150].
For the incorporation of a necessary non-prime site substituent, the synthesis
of decahydroisoquinolin inhibitors was carried out and the incorporation of amino
functionality on the decahydroisoquinolin scaffold was performed and the scaffold
was built by Pd(II) catalysed diastereoselective ring formation. The synthesized
decahydro isoquinoline inhibitors were found to become more potent inhibitors of
SARS 3CLpro when paired with a non-prime site substituent [121].
Sample processing and subsequent optimization of the lead dipeptide-like
sequence of major protease (3CLpro) inhibitors of severe acute respiratory syndrome
(SARS) resulted in the identification of probe compound ML188 (16-(R), (R)-
N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl) furan-
2-carboxamide, Pubchem CID: 46897844. 16-(R) is a noncovalent inhibitor of
SARS-CoV 3CLpro, having moderate MW, a strong enzyme and antiviral inhibitor
[108].
The fused 1,2,3-triazole derivatives found to have antiviral activity against human
coronavirus 229E. For identification of molecular interactions between synthesized
compounds and the 3-chymotrypsin-like protease in silico studies were carried out
[91].
A structure-guided design and evaluation of a novel class of MERS-CoV 3CL
protease inhibitors with a piperidine moiety as a starting element has been carried
out. The mechanism of action of the compounds and the binding-related structural
determinants were illuminated using X-ray crystallography [55].
Synthesis of 40 novel unsymmetrical aromatic disulfides were performed and
evaluated in vitro against SARS-CoV M pro. From the Preliminary studies it was
observed that these synthesized disulfides are reversible and competitive inhibitors.
Molecular docking simulation was used for generating the possible binding mode
and structure-activity relationships were understand by constructing a comparative
field analysis (CoMFA) model [174].
The phenylisoserine derivatives which are connected with the essential func-
tional groups against SARS-CoV 3CL protease have synthesized. The GOLD soft-
ware was used and from the structure activity relationship study it was found that
phenylisoserine derivatives gave SK80 that was active against SARS-CoV 3CL
R188I mutant protease [95].
Serine derivatives are designed (based on the tetrapeptide aldehyde and
Bai’scinnamoly inhibitor), for their inhibitory activities using SARS 3CL R188I
mutant protease. Structure activity relationship studies of the candidate compounds
were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant
protease. These inhibitors showed protease selectivity and no cytotoxicity [96].
Novel approach to aldehyde conversion mediated by N-bromosuccinimide using
thioacetal was devised. In order to have a tetrapeptide aldehyde, structural optimiza-
tion was performed which was based on X-ray crystallographic studies of the R188I
SARS 3CL protease that was in a complex with each inhibitor. There was no substrate
sequence in the resulting compound, except for a P(3) site directed toward the outside
of the protease [6].
The cinanserin analogs for the inhibitory activities against SARS-coronavirus
(CoV) 3CL protease was performed by using fluorescence resonance energy transfer
(FRET) assay. It was found that four analogs show significant activities [183].
A series of pyrazolone compounds were evaluated by in vitro protease assay
using fluorogenic substrate peptide as possible SARS-CoV 3CL protease inhibitors,
in which several showed potent inhibition against 3CL protease [135].
The author synthesised and identified low micromolar inhibitory activity
compounds from analogues against SARS-CoV and MERS-CoV3CL(pro). Docking
experiments indicate that the oxyanion hole in the 3CL(pro) is destabilised by
carboxylate present in either R(1) or R(4) [99].
Quercetin, epigallocatechingallate and gallocatechingallate (GCG) showed to
exhibit strong 3CL (pro) inhibition. GCG showed a binding energy of −
14 kcal mol(−1) to the 3CL(pro) active site and the galloyl moiety was needed
for 3CL(pro) inhibition activity at the 3-OH position [119].
Fluorescence resonance energy transfer analysis was used to isolate and test eight
diterpenoids and four biflavonoids for SARS-CoV 3CL (pro) inhibition. From the
isolated compounds, biflavoneamentoflavone demonstrated the most active 3CL(pro)
inhibitory activity consistent with the presence of apigenin moiety in flavone C-3
[140].
The inhibitory activities of nine alkylated chalcones and four coumarins from
Angelica keiskei, against SARS-CoV proteases (3CL(pro) and PL(pro) were deter-
mined (cell-free/based) and it was found that chalcone that contains the perhydroxyl
group, showed most potent 3CL(pro) and PL(pro) inhibitory activity [127].
The flavonoid library was analysed by means of induced-fit docking analysis
which suggested that the sites S1, S2 and S3 were involved in binding with flavonoids.
Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzy-
matic activity of SARS-CoV 3CLpro and the interaction of the three flavonoids
was confirmed using a tryptophan-based fluorescence method [86].
Self-quenched fluorogenic peptide substrate mrethod was used for a quantitative
high throughput screen (qHTS), an assay was performed on 10,755 compounds
including approved drugs, clinically investigated drug candidates, and bioactive
compounds. 27 3CLpro inhibitors were identified and the most potent 3CLpro
inhibitors were found to be Walrycin B, Hydroxocobalamin, Suramin sodium,
Z-DEVD-FMK and LLL-12 [195].
Computation molecular docking screening method for prediction of inhibitory
potential of narcissoside for COVID-19 protein 6W63 and found that the narcis-
soside showed high affinity and high inhibitory potential than standard inhibitor
X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)
ethyl]-1H-imidazole-4-carboxamide) [48]
The N-Substituted isatin derivatives were prepared and evaluated. It was found that
some of these compounds are potent and selective inhibitors but isatin 4o exhibited
more potent inhibition. A number of isatin derivatives have been evaluated using fluo-
rogenic peptide in vitro protease assays. Of all the compounds, 8k1 demonstrated the
most potent inhibitory action against 3CL(pro). These findings suggested that these
inhibitors could theoretically be incorporated as anti-SARS medications [29, 105].
The tanshinones were isolated from Salvia miltiorrhiza and found to be
specific and selective inhibitors for the SARS-CoV3CL(pro) and PL(pro), viral
cysteine proteases. All of the tanshinones exceptro smariquinone have been
described as noncompetitive enzyme isomerization inhibitors. The Quinone-
methidetriterpenes, celastrol, pristimerin, tingenone, and iguesterin from Tritery-
giumregelii and synthesis of dihydrocelastrolby hydrogenation under palladium cata-
lyst were performed. The SARS-CoV 3CL(pro) inhibitory activities and showed
potent inhibitory activities [126].
The sixty two bioactive alkaloids and hundred terpenoids of plants native to Africa
were docked with the novel SARS-CoV-2 3CLpro and compared with the reference
inhibitors Lopinavir and Ritonavir. From the predictive ADME/tox and Lipinski
filter analysis, four non-toxic, drug-induced alkaloids (10-Hydroxyusambarensine
and Cryptoquindoline) and terpenoids (6-Oxoisoiguesterin and 22-Hydroxyhopan-
3-one) were found that bind to the SARS-CoV-2 3CLpro receptor binding site and
catalytic dyad [63, 141].
With the aid of in silico techniques wide range of natural active compounds,
including glycyrrhizin, bicylogermecrene, tryptanthrine, β-sitosterol, indirubin,
indican, indigo, hesperetin, crysophanic acid, rhein, berberin and β-caryophyllene,
were used as possible herbal candidates for anti-viral action against SARS-CoV-2
and found that glycyrrhizin, tryptanthrine, rhein and berberine have high affinity with
viral protease, followed by the lowest binding energy with drugs [117].
The sixty five bioactive molecules present in Tea plant were docked with
molecular dynamics (MD) simulations. The docking scores of three bioac-
tive molecules (Oolonghomobisflavan-A, Theasinensin-D, and Theaflavin-3-O-
gallate) were compared with repurposed drugs (Atazanavir, Darunavir, and
Lopinavir) for SARS-CoV-2 during the time of simulation, and It was found that
Oolonghomobisflavan-A molecule have a good number of hydrogen bonds and
higher MM-PBSA binding energy. Also MD simulations and MM-PBSA studies
was performed and it was reveal that Oolonghomobisflavan-A found to be a potential
inhibitor for the Mpro of SARS-CoV-2 [19].
The 113 quinoline-drugs, elvitegravir and oxolinic acid are capable of interfering
with the NTP entry-channel and thus interfere with the RNA-directed 5 -3 poly-
merase action of SARS-CoV-2 RdRp. The result reveals that rilapladib is the only
quinoline capable of interrupting the Spike-RBD-ACE2 complex. Quinoline, 1,2,3,4-
tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI), saquinavir, elvitegravir,
oxolic acid and rilapladib are recommended for the treatment of COVID-19 [7].
The library of 1900 clinically safe drugs and identified 108 effective drugs and
found that masitinib, a tyrosine-kinase inhibitor used in cancer therapy, significantly
inhibited the function of SARS-CoV-2 main protease 3CLpro. From X-ray crystal-
lography it was observed that masitinib binds directly to the active site of 3CLpro, thus
is a potential candidate in clinical trials for the treatment of SARS-CoV-2 infection
[45].
Herein, the SARS-CoV-2 Mpro fluorescence-based protease assay was developed
to test for possible inhibitors. In addition, molecular simulation experiments have
been performed to further illustrate the relationship of Mpro with GC376. GC376 or
its optimised analogues are very promising to evolve in humans with SARS-CoV-2
infection, alone or with other antiviral drugs. It was found that GC376 is a promising
inhibitor of Mpro for SARS-CoV-2. GC376 is a dipeptidyl bisulfite-adduct salt with
excellent inhibitory activity against many picornaviruses and coronaviruses [77].
The murine coronavirus, the mouse hepatitis virus (MHV) was used as a model
system for the research of the phenotype, genotype, and pathogenicity of the broad-
spectrum 3CLpro inhibitor virus, GRL-001. GRL-001 is a 5-chloropyridyl ester-
derived compound that has been shown to inhibit 3CLpro enzymatic action of SARS-
CoV and MERS-CoV and to block the replication of SARS-CoV, MERS-CoV and
bat coronavirus HKU5. GRL-001 is therefore a possible lead compound for growth
[43].
Repurposing of drugs was reviewed by author that identifies the new field of
application and use of well-known and commonly used chemical molecules. Antiviral
drugs, cardiovascular drugs, drug candidate from traditional Chinese medicines with
perspective, main molecular parameters and preliminary bioactivity and potential
bioactivity analysis were reviewed.
The virtual method is used to find the interaction of the COVID-19 main protease
(Mpro) and SARS spike glycoprotein-human angiotensin-converting enzyme II
(ACE2) with antiviral and antimalarial drugs currently on the market. It was found
that oseltamivir, ritonavir, remdesivir, ribavirin, and favipiravir are potentially inhibit
SARS-CoV-2.Chloroquine and hydroxychloroquine showed high binding interac-
tion with the SARS spike glycoprotein-human ACE2 complex [28, 128]. Numbers
of inhibitors showed potent affinity toward PLpro some are ribavirin, remde-
sivir, riboflavin, ipromide, valganciclovir, leodropropizine, b Thymidine, Aspartame,
doxycycline, reproterol, Chrysin, Sugetriol-3,9-diacetate, Baicalin, Neohesperidin,
Phaitanthrin D, (e)-Epigallocatechin.
3.5.6 Non-structure Protein 6 (Nsp 6)
The nsp6 has trans membrane domains, also known as multi pass membrane protein
which consist of 290 amino acids. It binds with nsp3 and nsp4 and induces double
membrane vesicle in host infected cell. It interferes with the autophagosome delivery
of the viral factors to lysosomes for destruction [13, 16, 37, 38].
The Nsp 7 consist of 83 amino acids which bind with Nsp 8 to form hexadecamers
which act as a cofactor for RNA dependent RNA polymerase. The hexadecamer is a
doughnut shape structure which consists of two copies of nsp7 and one of nsp8. The
nsp7 interacting with nsp8 to form multiple functional quaternary stable structure
[98, 129, 131, 164, 187].
There are three helics in nsp7 which forms flat up down up antiparallel alpha
helix sheet. The alpha helix has two turns at the N terminal segment of residues and
packed in the surface of other two alpha proteins in the helix sheet [94, 129, 131,
157, 164, 187].
The Nsp 8 has about 198 amino acids as usually forms hexadecamer with nsp7. It acts
as a cofactor for RNA-dependent RNA polymerase. The complex of Nsp 8 &sp 7 act
as cofactor which have capabilities to stimulate polymerase activity as nsp12 itslef
is not efficiently capable of executing the polymerase reaction. Due to importance
of nsp7–nsp8–nsp12 complex it is known as minimal core component for mediating
RNA synthesis in SARS-CoV-2 virus [94, 129, 157, 169, 187].
Numbers of drugs have been screened for this complex and it was reported that
Vitamin D binds at nsp7 & np8 complex and inhibit binding with RNA dependent
RNA polymerase nsp12. The binding causes potential inhibition of the functional
activity of SARS-CoV-2 [94, 129, 157, 169, 187].
The Nsp9 has about 113 amino acids and functions in the viral replication as a dimeric
single strand binding protein. The Nsp 9 interacts with the RNA helicase 5 and forms
a complex which is important for virus replication, virulence and RNA production.
The SARS-CoV-2 and other Corona Nsp 9 structures are highly conserved.
The Nsp 9 is one of choice for the drug targets and the number of FDA approved
drugs has been repurposed on the protein. Based on highest binding energy the an
arginine vasopressin, conivaptan was observed to have highest binding with Nsp 9
and has stable interaction with its amino acids in the residue [25, 50, 78, 104, 112,
158].
The Nsp 10 has about 139 amino acids, which forms dodecamer by binding with
Nsp14 & Nsp 16. Thecomplex excites 3 -5 exoribonuclease and 2 O methyltrans-
ferase activity involved in the formation of SARS-CoV-2 viral mRNA capping
machine. The Nsp 14 plays an important role in the function of S-adenosylmethionine
(SAM)-dependent (guanine N7) methyl transferase (N7-MTase).
The Nsp10 subunit contains two zinc fingers which interact with Nsp14 & Nsp16.
The surface interaction of nsp10 with Nsp14 overlaps with surface interaction in
nsp16. The surface of Nsp 10 which interacts with nsp14, nsp16 and other subunits
involved in viral replication complexes is important for novel drug development [22,
87, 92, 106, 155, 156, 176].
The Nsp 11 has 13–23 amino acids which form by cleavage of the protein phosphatase
which is metal dependent and aspartate base serine–threonine phosphatase. The first
nine amino acids of nsp11 are identical to nsp12 [41, 185, 191].
The nonstructural protein identified as NSP12 in corona virus is termed as RNA

dependent RNA polymerase (RdRp). The nsp12 catalytic subunits have two acces-
sory subunit nsp7 and nsp8.The enzyme plays a vital role in the replication and
transcription complex in corona virus. The enzyme RNA dependent RNA poly-
merase (RdRp) is an important for life cycle of RNA virus and is most conserved
across different viral species such as zika virus, hepatitis C virus, influenza virus and
corona virus [94, 129].
The nsp12 subunit of corona virus contains an interface domain known as N
terminal nidovirus RdRp aasociated nuclotidyl transferase (NiRAN) and C- terminal
RdRp domain. The RNA dependent RNA polymerase (RdRp) is identified at C-

terminus and preserves the ser-asp-asp motif. The nonspecific protein nsp8 and nsp7
helps in binding of Nsp 12 to the RNA for enhancing the RNA dependent RNA
polymerase (RdRp) activity. In COVID-19 RNA dependent RNA polymerase (RdRp)
is one of the potent targets selected for discovery of virus inhibitors.
The SAR-CoV has large polycistronic genomes which 5 capped and 3 polyadeny-
lated RNA. The 5 and 3 end translate viral; replicasepolyproteins and viral struc-
tural protein repectively. The viral mRNAs consist of particular sequences that are
noncontiguous in viral genomes. The RNA dependent RNA polymerase (RdRp) has
special properties which can be observed with the complexity of CoVs viral RNA and
gneome size. The core protein is single chain with approx. 900 amino acids which
show minimal activity and the unprecedented size of viral RdRp contains 500–600
amino acids. A cupped right hand shape was observed for core protein which further
subdivided into sub domain with finger and palm domain [5, 83, 84, 134, 163].
In viral genomic RNA synthesis two molecules are observed by RdRp which
include primer independent (denovo) & primer dependent RNA synthesis. Both
the RNA synthesis are different in which denovo synthesis involves the formation
of phosphodiester bonds between 3 hydroxyl and 5 phosphate group while it was
observed that in primer dependent base pairing occur by protein primer. The template
substrates are provided for the synthesis by riboneucleotide triphosphates (ATP, UTP,
CTP & GTP). The metal ions Manganese (Mn) and Magnesium (Mg) act as important
cofactor for the polymerization reaction (Fig. 10).
The catalytic process in RdRp is due to its immobile structural motif arrange-
ment. The template RNA, double stranded RNA and rNTP entered though the three
pivotal channels. The template RNA & rNTPs participate in release of pyrophosphate
moiety after polymerization when they are allowed to enter though charged residue
lined entry tunnels into catalytic cavity. The formation of template channel is via
intertwined fingers and flexible thumb which is further extended to fingers surface
for nucleotide entry. During the replication process the variable conformation of
the template channel. The palm & thumb subdomains form central channel which
exports double starnd RNA (dsRNA). The two replication modes differs in the size
of RdRp thumb domain, the primer depended initiation is small and bacteriophage
polymerase is larger. The finger and the palm subdomain are bounded by bridge
connection which includes polypeptide chain containing C terminal region which is
an important function element for rNTP positioning to catalysis. The palm domain
contains active site region α- helices, catalytic aspartates, β strands and RNA recog-
nizing motif. With the help of metal ions the RdRps selectively binds with rNTps
and catalysephosphoryl transfer reaction. The 3 hydroxyl group of the RNA primer
strand is positioned by Motif E at palm & thumb subdomains tightloop and helps
in catalysis of rNTP. The template RNA is stabilized by finger domains two motif,
motif G with entrance channel and motif with conserved arginine residue. The RdRps
helps in the escaping the virus from host defence mechanism [51, 83, 134, 159, 175,
194].
Fig. 10 RNA dependent

RNA polymerase (NSP 12)
SARS-CoV-2
The remdisivir is found to be active against RdRps [84]. Docking studies has also
showed potent binding of remdesivir, omipressin, lyressin, exanorelin, polymxcin B,
Narcocin, cisatracurium and cistinexine [5].
The computer assisted screening also confirms the potent binding of quinupris-
tion [134], milbemycin [83], lvermectin [83] and baloxavir [83] in the cavity. The
neuclotide analoges Galidesivir, sofosbuvir, Favivir, remdesiir, ribavirin, dosabvir,
pimodivir, and belcabuvir also showed potent inhibition against RNA dependent
RNA polymerase (RdRp) [174, 195].
The docking studies has showed that MAW-22 [51], pitavastin [11], ridogel [11],
rosoxacin [11], femotidine [137], hesperidine [137], comostat mesylate [137], sotes-
bmivir [52], cefuroxime [53], hydroxychloroquine [53], tenofovir [53], glidesavir
[4] and number of small molecule drugs [194] showed potent binding in the cavity
of RNA dependent RNA polymerase (RdRp).
3.5.13 Non-structure Protein 13 (Nsp 13) (Helicase Enzyme)
The Nsp 13 is helicase enzymes which unwinds duplex RNA in SARS-CoV-2.

Helicase enzyme plays an important role in the virus replication, transcription and
translation process. It is a non-structural protein (Nsp13) which includes terminal
metal binding domain (MBD) and helicase domain(Hel). The zinc binding domain
Fig. 11 Genomic structure

of helicase enzyme
SARS-CoV-2
is formed at N terminal which consist of twenty six cysteine residues and the heli-
case domain with conserved motif at C terminus. The enzyme hydrolyses ATP,
dATP&dCTP [79, 192].
The nsp13 also possesses 5 triphosphatase activity which is responsible for intro-
duction of 5 terminal cap of viral m RNA. The 5 terminal cap is mainly responsible
for recognizing sites for translation. The 5 terminal capping also plays important
role in splicing, translation, nuclear export and stability of mRNA.
The helicase can become one of the important targets for the ligands but the
toxicity due to non-specificity of inhibitors reduces its recognition. Despite toxicity
helicase is chosen in some disease as a potent target for drug discovery and reported
for antiviral drug discovery [1, 79, 172] (Fig. 11).
The helicase proteins were screened for a number of drugs such as
itraconazole, rolitetracycline, cefsulodine, lymecycline, dabigatran, saquinavir
and canrenoic acid. The naturally available phytochemicals such as rutin,
hesperidin, triptexanthoside-D, 3,5-dimethoxy-1-[(6-O-b-D- xylopyranosyl-b-D-
glucopyranosyl)oxy]-9H-xanthen-9-one, quercetagetin 6-O-b-D-glucopyranoside,
homovitexin„ kouitchenside A, 8,2-dihydroxy-3,4,5-trimethoxy-1- [(6-O-b-D-
xylopyranosyl-b-D-glucopyranosyl)oxy]-9H-xanthen-9- one, simeprevir, pari-
taprevir, grazoprevir and kouitchenside D [62, 114, 138, 151, 177].
The Nsp 14 is an important enzyme which is responsible for two main activities
3 -5 exoribonuclease activity and N7 methyltransferase activity. The introduction
of 5 -capping to the virus is catalyzed by methyltransferase enzymes. The process
of introducing 5 cap is multiple steps which involve removal gamma phosphate
of mRNA by RNA triphosphate, the guanosine monophosphate transfer to mRNA,
methylation of G Cap Guanine methyl ttransferase and methylation of adenine to
result cap-1 structure.
The Nsp 14 plays an important role in intial and intermediate life cycle of virus.
The Nsp14 usually forms complex with Nsp 10, which plays important role in viral
RNA proofreading at its N- terminal exonuclease domain. The proofreading helps in
preventing from mutagenesis. The proofreading activity is stimulated and stabilized
by the interaction of one molecule of nsp10 with exonuclease domain of the nsp14,
in the presence of the two zinc fingers of nsp14 [14, 31, 106, 120, 186].
The Nsp 15 is an important enzyme which is responsible for endoribonuclease

activity. The endoribonuclease activity is performed by cleaving ribonucleic acid
at uridylates 3 position which results in the formation products of 2 -3 cyclic phos-
phodiesterase. The Nsp 15 is a very important regarding misguiding the host immune
system to recognize and detect the virus. For the same Nsp15 protein targets viral
polyuridine sequence and degrades them so that the host sensor should not recog-
nise the viral protein. The endoribonuclease activity of Nsp 15 is activated by the
manganese as co-factor [17, 18, 41, 42, 146].
The Nsp 16 is always observed in complex with Nsp10 in which the nsp16 monomer
rests on the top of the nsp 10 molecule. The Nsp 16 composed of twelve beta strands,
seven alpha helices and five omega helices. The Nsp16 using S-adenosylmethionine
as methyl source plays an important role in methylation of 2 hydroxy groups
of adenine. The methylation protects the degradation mRNA by exoribonucleases
and promotes mRNA translation. It also helps in preventing recognition from the
host immune system. It can be concluded that in the absence of the nsp16 there
will decrease in the viral replication process and simultaneously reduce the repose
towards the immune sensing factors RIG-I (retinoic acid induced gene-I) and MDA-5
(melanoma differentiation associated gene 5).
Targeting the nsp16 protein for drug design will help in the inhibiting methylation
activity to restrain the viral replication and reinstating the host immune system for
the recognition of viral protein [40, 111].
4 Conclusion and Perspectives
Humans have always been the victims of virus attacks. Every new virus attack
changes the entire lifestyle, health policy and economy of the world. Hence the
treatment of viral infection is an utter need for the global community. The covid-19
viral infection has become a severe lethal pandemic worldwide and the drug devel-
opment has been a bottleneck for the researchers. There is an utter need to have a
robust cure for the SARS-CoV-2 treatment.
The most critical need is to known the entire life cycle of the SARS-CoV-2 in
the host cell. Knowing the lifecycle of the SARS-CoV-2 provides detailed insight
about its functioning and virulence. The virus enters the host cell via endocytosis by
interaction of virus spike proteins with host angiotensin converting enzyme 2 binding
site. Number of enzymes cleaves the viral protein in small segments and positive
sense RNA which uses the host cell machinery for their genomic development and
efficiently performs replication, transcription and translation. The genomic material,
structure proteins [Spike (S), Membrane (M) and Envelope (E)] assembled and binds
with N protein, endoplasmic reticulum and golgi bodies to form ERGIC (endoplasmic
reticulum golgi intermediate compartment), which carries the matured virion ready
for attacking the new cells.
The study of the life cycles highlighted the importance of structural and nonstruc-
tural proteins which have a significant role in the viral entry and growth. The
researcher has targeted such proteins for the development of the antiviral drugs. The
present chapter has included the role of the important structure proteins and their
selection as a target protein for the development of novel inhibitors for SARS-CoV-2.
The Computation drug design has been observed as the important tool for the
identification & prediction of potent ligand protein interaction. The fastest way for
identification of potent molecules for treatment of SARS-CoV-2 was from the market
drug using repurposing, as once the efficient drug is identified, the approval time will
be saved for quick clinical treatment. It will be effective and cost sensitive approach
for the identification of effective drug for the viral treatment.
The main targets of viral proteins were also screened for a number of small
molecule libraries to identify the potent novel molecule for SARS-CoV-2. The
computation high through virtual screening method is employed for the screening of
libraries. The research in computational drug development has showed paramount
importance in prediction of reliable drugs with potent therapeutic action.
The structure and non-structure proteins have been used as important target recep-
tors for ligand screening. The positive sense RNA consist of potent targets which
are S spike (S) protein, Envelope (E) protein, Membrane (M) protein, Nucleocapsid
(N) protein and non-structural proteins such as papain like protease (PL pro), Main
Protease (3CL pro), RNA Dependent RNA polymerase, helicase enzyme which plays
important role in virulence and integrity of virus. Knowing the role of the structure
and nonstructural proteins has helped in planning the viral treatment by inhibiting
the entry in host cell, preventing the cleavage in genomic strand for replication,
transcription or transition process, inhibiting the genomic machinery by inhibiting
the viral enzymes for replication & transcription and inhibiting the assembling of
the structural protein the cytoplasm for new virion formation. As the viral protein
interacts with the host cell, there are chances to develop the drugs by targeting both,
but amongst the choice of drug targeting between virus cell and host cell, the safe
and effective approach was to target the viral proteins. Targeting host enzymes may
also alter the metabolic and genetic process in the host cell hence the toxicity and
safety studies are of prime importance in such cases.
The computational approach has given a number of drugs for the treatment of
SARS-CoV-2 which are in clinical trials. Few FDA approved drugs were identified
from the repurposing using the Insilco approaches have been used in the treatment of
SARS-CoV-2. The remedisvir was significantly identified against RNA Dependent
RNA polymerase (RdRps) which is brought in the clinical treatment of the patients
worldwide. Ivermectin, ribavirin and favivir are also repurposed drugs identified by
docking and simulation for the effective drugs against the SARS-CoV-2. In future
the identified protein structure from the bioinformatics tools can be screened against
the small molecule libraries from synthetic, nucleotide and herbal database for the
identification and predication of potent inhibitors of the Covid-19 virus. The high
through virtual screening of such libraries will speed up the drug discovery process
in identification of safe, effective and stable anticovid-19 molecule.
References
1. Adedeji, A.O., Marchand, B., Te Velthuis, A.J.W., Snijder, E.J., Weiss, S., Eoff, R.L., Singh,
K., Sarafianos, S.G.: Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS
One 7(5) (2012). https://doi.org/10.1371/journal.pone.0036521
2. Adedeji, A.O., Severson, W., Jonsson, C., Singh, K., Weiss, S.R., Sarafianos, S.G.: Novel
inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct
mechanisms. J. Virol. 87(14), 8017–8028 (2013). https://doi.org/10.1128/jvi.00998-13
3. Adem, S., Eyupoglu, V., Sarfraz, I., Rasul, A., Ali, M.: Identification of Potent COVID-19
Main Protease (Mpro) Inhibitors from Natural Polyphenols: An in Silico Strategy Unveils a
Hope Against CORONA (2020). https://doi.org/10.20944/preprints202003.0333.v1
4. Aftab, S.O., Ghouri, M.Z., Masood, M.U., Haider, Z., Khan, Z., Ahmad, A., Munawar, N.:
Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug
target using a computational approach. J. Transl. Med. 18(1), 1–15 (2020). https://doi.org/10.
1186/s12967-020-02439-0
5. Ahmad, J., Ikram, S., Ahmad, F., Rehman, I.U., Mushtaq, M.: SARS-CoV-2 RNA dependent
RNA polymerase (RdRp)—a drug repurposing study. Heliyon 6(7), e04502 (2020). https://
doi.org/10.1016/j.heliyon.2020.e04502
6. Akaji, K., Konno, H., Mitsui, H., Teruya, K., Shimamoto, Y., Hattori, Y., Ozaki, T., Kusunoki,
M., Sanjoh, A.: Structure-based design, synthesis, and evaluation of peptide-mimetic SARS
3CL protease inhibitors. J. Med. Chem. 54(23), 7962–7973 (2011). https://doi.org/10.1021/
jm200870n
7. Alexpandi, R., De Mesquita, J.F., Pandian, S.K., Ravi, A.V.: Quinolines-based SARS-CoV-2
3CLpro and RdRp inhibitors and Spike-RBD-ACE2 inhibitor for drug-repurposing against
COVID-19: an in silico analysis. Front. Microbiol. 11(July), 1–15 (2020). https://doi.org/10.
3389/fmicb.2020.01796
8. Angeletti, S., Benvenuto, D., Bianchi, M., Giovanetti, M., Pascarella, S., Ciccozzi, M.:
COVID-2019: the role of the nsp2 and nsp3 in its pathogenesis. J. Med. Virol. 92(6), 584–588
(2020). https://doi.org/10.1002/jmv.25719
9. Angelini, M.M., Akhlaghpour, M., Neuman, B.W., Buchmeier, M.J.: Severe acute respiratory
syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles.
MBio 4(4), 1–10 (2013). https://doi.org/10.1128/mBio.00524-13
10. Arya, R., Das, A., Prashar, V., Kumar, M.: Potential Inhibitors Against Papain-Like Protease
of Novel Coronavirus (SARS-CoV-2) from FDA Approved Drugs (2020). https://doi.org/10.
26434/chemrxiv.11860011.v2
11. Baby, K., Maity, S., Mehta, C.H., Suresh, A., Nayak, U.Y., Nayak, Y.: Targeting SARS-CoV-
2 RNA-dependent RNA polymerase: an in silico drug repurposing for COVID-19. F1000
Research 9, 1166 (2020). https://doi.org/10.12688/f1000research.26359.1
12. Báez-santos, Y.M., John, S.E.S., Mesecar, A.D.: The SARS-coronavirus papain-like protease:
structure, functionand inhibition by designed antiviral compounds COVID-19 resource centre
is hosted on Elsevier Connect, the company’s public news and information website. Elsevier
hereby grants permission. Antiviral Res. 115(January), 21–38 (2015)
13. Baliji, S., Cammer, S.A., Sobral, B., Baker, S.C.: Detection of nonstructural protein 6 in
murine coronavirus-infected cells and analysis of the transmembrane topology by using bioin-
formatics and molecular approaches. J. Virol. 83(13), 6957–6962 (2009). https://doi.org/10.
1128/jvi.00254-09
14. Becares, M., Pascual-Iglesias, A., Nogales, A., Sola, I., Enjuanes, L., Zuñiga, S.: Mutagenesis
of coronavirus nsp14 reveals its potential role in modulation of the innate immune response.
J. Virol. 90(11), 5399–5414 (2016). https://doi.org/10.1128/jvi.03259-15
15. Belouzard, S., Millet, J.K., Licitra, B.N., Whittaker, G.R.: Mechanisms of coronavirus cell
entry mediated by the viral spike protein. Viruses 4(6), 1011–1033 (2012). https://doi.org/10.
3390/v4061011
16. Benvenuto, D., Angeletti, S., Giovanetti, M., Bianchi, M., Pascarella, S., Cauda, R., Ciccozzi,
M., Cassone, A.: Evolutionary analysis of SARS-CoV-2: how mutation of Non-structural
Protein 6 (NSP6) could affect viral autophagy. J. Infect. 81(1), e24–e27 (2020). https://doi.
org/10.1016/j.jinf.2020.03.058
17. Bhardwaj, K., Guarino, L., Kao, C.C.: The severe acute respiratory syndrome coronavirus
Nsp15 protein is an endoribonuclease that prefers manganese as a cofactor. J. Virol. 78(22),
12218–12224 (2004). https://doi.org/10.1128/jvi.78.22.12218-12224.2004
18. Bhardwaj, K., Liu, P., Leibowitz, J.L., Kao, C.C.: The coronavirus endoribonuclease Nsp15
interacts with retinoblastoma tumor suppressor protein. J. Virol. 86(8), 4294–4304 (2012).
https://doi.org/10.1128/jvi.07012-11
19. Bhardwaj, V.K., Singh, R., Sharma, J., Rajendran, V., Purohit, R., Kumar, S.: Identification
of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors. J. Biomol.
Struct. Dyn. 1–10. https://doi.org/10.1080/07391102.2020.1766572
20. Bhowmik, D., Nandi, R., Jagadeesan, R., Kumar, N., Prakash, A., Kumar, D.: Identification
of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope
formation and virion assembly using docking based virtual screening, and pharmacokinetics
approaches. Infect. Genet. Evol. 84(June), 104451 (2020b). https://doi.org/10.1016/j.meegid.
2020.104451
21. Bianchi, M., Benvenuto, D., Giovanetti, M., Angeletti, S., Ciccozzi, M., Pascarella, S.: Sars-
CoV-2 envelope and membrane proteins: structural differences linked to virus characteristics?
Biomed. Res. Int. 2020 (2020). https://doi.org/10.1155/2020/4389089
22. Bouvet, M., Lugari, A., Posthuma, C.C., Zevenhoven, J.C., Bernard, S., Betzi, S., Imbert,
I., Canard, B., Guillemot, J.C., Lécine, P., Pfefferle, S., Drosten, C., Snijder, E.J., Decroly,
E., Morelli, X.: Coronavirus Nsp10, a critical co-factor for activation of multiple replicative
enzymes. J. Biol. Chem. 289(37), 25783–25796 (2014). https://doi.org/10.1074/jbc.M114.
577353
23. Cabezón, E., Arechaga, I.: Drug weaponry to fight against SARS-CoV-2. Front. Mol. Biosci.
7(August), 1–11 (2020). https://doi.org/10.3389/fmolb.2020.00204
24. Chakraborty, A.K.: Virology & mycology corona virus ORF1ab-derived Nsp9 and
Nsp10 non-structural proteins have homologies to S8/S10 ribosomal proteins as well as
RlmG/ErmDrRNA methyltransferases and may inhibit host mitoribosome assembly and
protein synthesis. Virol. Mycol. 9(186), 1–6 (2020). https://doi.org/10.35248/2161-0517.20.
09.186
25. Chakraborty, A.K.: Coronavirus Nsp2 Protein Homologies to the Bacterial DNA Topoiso-
merase I and IV Suggest Nsp2 Protein is a Unique RNA Topoisomerase with Novel Target for
Drug and Vaccine Development, vol. 9(185), pp. 1–8 (2020). https://doi.org/10.31219/osf.io/
tc9us
26. Chandel, V., Raj, S., Rathi, B., Kumar, D.: In silico identification of potent FDA approved
drugs against coronavirus Covid-19 main protease: a drug repurposing approach. Chem. Biol.
Lett. 7(3), 166–175 (2020)
27. Chang, C.K., Jeyachandran, S., Hu, N.J., Liu, C.L., Lin, S.Y., Wang, Y.S., Chang, Y.M.,
Hou, M.H.: Structure-based virtual screening and experimental validation of the discovery of
inhibitors targeted towards the human coronavirus nucleocapsid protein. Mol. Biosyst. 12(1),
59–66 (2016). https://doi.org/10.1039/c5mb00582e
28. Cheke, R.S.: The molecular docking study of potential drug candidates showing anti-COVID-
19 activity by exploring of therapeutic targets of SARS-CoV-2. Eurasian J. Med. Oncol. 4(3),
185–195 (2020). https://doi.org/10.14744/ejmo.2020.31503
29. Chen, L.R., Wang, Y.C., Yi, W.L., Chou, S.Y., Chen, S.F., Lee, T.L., Wu, Y.T., Kuo, C.J.,
Chen, T.S.S., Juang, S.H.: Synthesis and evaluation of isatin derivatives as effective SARS
coronavirus 3CL protease inhibitors. Bioorg. Med. Chem. Lett. 15(12), 3058–3062 (2005).
https://doi.org/10.1016/j.bmcl.2005.04.027
30. Chen, X., Chou, C.Y., Chang, G.G.: Thiopurine analogue inhibitors of severe acute respiratory
syndrome-coronavirus papain-like protease, a deubiquitinating and deISGylating enzyme.
Antivir. Chem. Chemother. 19(4), 151–156 (2009). https://doi.org/10.1177/095632020901
900402
31. Chen, Y., Cai, H., Pan, J., Xiang, N., Tien, P., Ahola, T., Guo, D.: Functional screen reveals
SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc.
Natl. Acad. Sci. USA 106(9), 3484–3489 (2009). https://doi.org/10.1073/pnas.0808790106
32. Chernyshev, A.: Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: The
Screening for Inhibitors in Approved Drugs (2020). https://doi.org/10.26434/chemrxiv.122
86421
33. Chikhale, R.V., Gurav, S.S., Patil, R.B., Sinha, S.K., Prasad, S.K., Shakya, A., Shrivastava,
S.K., Gurav, N.S., Prasad, R.S.: Sars-cov-2 host entry and replication inhibitors from Indian
ginseng: an in-silico approach. J. Biomol. Struct. Dyn. 1–12 (2020). https://doi.org/10.1080/
07391102.2020.1778539
34. Chou, C.Y., Chien, C.H., Han, Y.S., Prebanda, M.T., Hsieh, H.P., Turk, B., Chang, G.G., Chen,
X.: Thiopurine analogues inhibit papain-like protease of severe acute respiratory syndrome
coronavirus. Biochem. Pharmacol. 75(8), 1601–1609 (2008). https://doi.org/10.1016/j.bcp.
2008.01.005
35. Clementz, M.A., Kanjanahaluethai, A., O’Brien, T.E., Baker, S.C.: Mutation in murine coron-
avirus replication protein nsp4 alters assembly of double membrane vesicles. Virology 375(1),
118–129 (2008). https://doi.org/10.1016/j.virol.2008.01.018
36. Cornillez-Ty, C.T., Liao, L., Yates, J.R., Kuhn, P., Buchmeier, M.J.: Severe acute respiratory
syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved
in mitochondrial biogenesis and intracellular signaling. J. Virol. 83(19), 10314–10318 (2009).
https://doi.org/10.1128/jvi.00842-09
37. Cottam, E.M., Maier, H.J., Manifava, M., Vaux, L.C., Chandra-Schoenfelder, P., Gerner, W.,
Britton, P., Ktistakis, N.T., Wileman, T.: Coronavirus nsp6 proteins generate autophagosomes
from the endoplasmic reticulum via an omegasome intermediate. Autophagy 7(11), 1335–
1347 (2011). https://doi.org/10.4161/auto.7.11.16642
38. Cottam, E.M., Whelband, M.C., Wileman, T.: Coronavirus NSP6 restricts autophagosome
expansion. Autophagy 10(8), 1426–1441 (2014). https://doi.org/10.4161/auto.29309
39. Dai, W., Zhang, B., Jiang, X.-M., Su, H., Li, J., Zhao, Y., Xie, X., Jin, Z., Peng, J., Liu, F., Li,
C., Li, Y., Bai, F., Wang, H., Chen, X., Cen, X., Hu, S., Yang, X., Wang, J., Liu, X., Xiao, G.,
Jiang, H., Rao, Z., Zhang, L.-K., Xu, Y., Yang, H., Liu, H.: Structure-Based Design, Synthesis
and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug
Candidates Targeting the SARS-CoV-2 Main Protease (2020). https://doi.org/10.1101/2020.
03.25.996348
40. Decroly, E., Imbert, I., Coutard, B., Bouvet, M., Selisko, B., Alvarez, K., Gorbalenya, A.E.,
Snijder, E.J., Canard, B.: Coronavirus nonstructural protein 16 is a Cap-0 binding enzyme
possessing (Nucleoside-2 O)-methyltransferase activity. J. Virol. 82(16), 8071–8084 (2008).
https://doi.org/10.1128/jvi.00407-08
41. Deng, X., Baker, S.C.: An “Old” protein with a new story: coronavirus endoribonuclease is
important for evading host antiviral defenses. Virology 517(October 2017), 157–163 (2018).
https://doi.org/10.1016/j.virol.2017.12.024
42. Deng, X., Hackbart, M., Mettelman, R.C., O’Brien, A., Mielech, A.M., Yi, G., Kao, C.C.,
Baker, S.C.: Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and
limits apoptosis in macrophages. Proc. Natl. Acad. Sci. USA 114(21), E4251–E4260 (2017).
https://doi.org/10.1073/pnas.1618310114
43. Deng, X., StJohn, S.E., Osswald, H.L., O’Brien, A., Banach, B.S., Sleeman, K., Ghosh,
A.K., Mesecar, A.D., Baker, S.C.: Coronaviruses resistant to a 3C-like protease inhibitor are
attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness
cost of resistance. J. Virol. 88(20), 11886–11898 (2014). https://doi.org/10.1128/jvi.01528-14
44. Dey, D., Borkotoky, S., Banerjee, M.: In silico identification of tretinoin as a SARS-CoV-2
envelope (E) protein ion channel inhibitor. Comput. Biol. Med. 127(August):104063 (2020).
https://doi.org/10.1016/j.compbiomed.2020.104063
45. Drayman, N., Jones, K.A., Azizi, S.-A., Froggatt, H.M., Tan, K., Maltseva, N.I., Chen, S.,
Nicolaescu, V., Dvorkin, S., Furlong, K., Kathayat, R.S., Firpo, M.R., Mastrodomenico,
V., Bruce, E.A., Schmidt, M.M., Jedrzejczak, R., Muñoz-Alía, M.Á., Schuster, B., Nair,
V., Botten, J.W., Brooke, C.B., Baker, S.C., Mounce, B.C., Heaton, N.S., Dickinson, B.C.,
Jaochimiak, A., Randall, G., Tay, S.: Drug repurposing screen identifies masitinib as a 3CLpro
inhibitor that blocks replication of SARS-CoV-2 in vitro. bioRxiv Prepr. Serv. Biol. 1–32
(2020). https://doi.org/10.1101/2020.08.31.274639
46. Du, L., He, Y., Zhou, Y., Liu, S., Zheng, B.J., Jiang, S.: The spike protein of SARS-CoV—a
target for vaccine and therapeutic development. Nat. Rev. Microbiol. 7(3), 226–236 (2009).
https://doi.org/10.1038/nrmicro2090
47. Duart, G., García-Murria, M.J., Grau, B., Acosta-Cáceres, J.M., Martínez-Gil, L., Mingarro, I.:
SARS-CoV-2 envelope protein topology in eukaryotic membranes. Open Biol. 10(9), 200209
(2020). https://doi.org/10.1098/rsob.200209
48. Dubey, K., Dubey, R.: Computation screening of narcissoside a glycosyloxyflavone for poten-
tial novel coronavirus 2019 (COVID-19) inhibitor. Biomed. J. 43(4), 363–367 (2020). https://
doi.org/10.1016/j.bj.2020.05.002
49. Dutta, N.K., Mazumdar, K., Gordy, J.T.: The nucleocapsid protein of SARS–CoV-2: a target
for vaccine development. J. Virol. 94(13), 1–2 (2020). https://doi.org/10.1128/jvi.00647-20
50. Egloff, M.P., Ferron, F., Campanacci, V., Longhi, S., Rancurel, C., Dutartre, H., Snijder,
E.J., Gorbalenya, A.E., Cambillau, C., Canard, B.: The severe acute respiratory syndrome-
coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the
RNA virus world. Proc. Natl. Acad. Sci. USA 101(11), 3792–3796 (2004). https://doi.org/10.
1073/pnas.0307877101
51. El Hassab, M.A., Shoun, A.A., Al-Rashood, S.T., Al-Warhi, T., Eldehna, W.M.: Identification
of a new potential SARS-CoV-2 RNA-dependent RNA polymerase inhibitor via combining
fragment-based drug design, docking, molecular dynamics, and MM-PBSA calculations.
Front. Chem. 8(October), 1–11 (2020). https://doi.org/10.3389/fchem.2020.584894
52. Elfiky, A.A.: Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life. Sci.
248(January) (2020a). https://doi.org/10.1016/j.lfs.2020.117477
53. Elfiky, A.A.: SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico
perspective. J. Biomol. Struct. Dyn. 1–9 (2020b). https://doi.org/10.1080/07391102.2020.176
1882
54. Frieman, M., Basu, D., Matthews, K., Taylor, J., Jones, G., Pickles, R., Baric, R., Engel,
D.A.: Yeast based small molecule screen for inhibitors of SARS-CoV. PLoS ONE 6(12), 1–9
(2011). https://doi.org/10.1371/journal.pone.0028479
55. Galasiti, A.C., Kim, Y., Damalanka, V.C., Rathnayake, A.D., Fehr, A.R., Mehzabeen, N.,
Battaile, K.P., Lovell, S., Lushington, G.H., Perlman, S., Chang, K.O., Groutas, W.C.:
Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL
protease that utilize a piperidine moiety as a novel design element. Eur. J. Med. Chem. 150,
334–346 (2018). https://doi.org/10.1016/j.ejmech.2018.03.004
56. Ghosh, A.K., Xi, K., Grum-Tokars, V., Xu, X., Ratia, K., Fu, W., Houser, K.V., Baker, S.C.,
Johnson, M.E., Mesecar, A.D.: Structure-based design, synthesis, and biological evaluation of
peptidomimetic SARS-CoV 3CLpro inhibitors. Bioorg. Med. Chem. Lett. 17(21), 5876–5880
(2007). https://doi.org/10.1016/j.bmcl.2007.08.031
57. Gil, C., Ginex, T., Maestro, I., Nozal, V., Barrado-Gil, L., Cuesta-Geijo, M.Á., Urquiza, J.,
Ramírez, D., Alonso, C., Campillo, N.E., Martinez, A.: COVID-19: drug targets and potential
treatments. J. Med. Chem. (2020). https://doi.org/10.1021/acs.jmedchem.0c00606
58. Giovanetti, M., Benvenuto, D., Angeletti, S., Ciccozzi, M.: The first two cases of 2019-nCoV
in Italy: where they come from? J. Med. Virol. 92(5), 518–521 (2020). https://doi.org/10.
1002/jmv.25699
59. Graham, R.L., Sims, A.C., Baric, R.S., Denison, M.R.: The nsp2 proteins of mouse hepatitis
virus and SARS coronavirus are dispensable for viral replication. Adv. Exp. Med. Biol. 581,
67–72 (2006). https://doi.org/10.1007/978-0-387-33012-9_10
60. Grum-Tokars, V., Ratia, K., Begaye, A., Baker, S.C., Mesecar, A.D.: Evaluating the 3C-like
protease activity of SARS-coronavirus: recommendations for standardized assays for drug
discovery. Virus Res. 133(1), 63–73 (2008). https://doi.org/10.1016/j.virusres.2007.02.015
61. Gupta, M.K., Vemula, S., Donde, R., Gouda, G., Behera, L., Vadde, R.: In-silico approaches
to detect inhibitors of the human severe acute respiratory syndrome coronavirus envelope
protein ion channel. J. Biomol. Struct. Dyn. 1–11 (2020). https://doi.org/10.1080/07391102.
2020.1751300
62. Gurung, A.B.: In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and
repurposing of FDA approved antiviral drugs as dual inhibitors. Gene Rep. 21, 100860 (2020).
https://doi.org/10.1016/j.genrep.2020.100860
63. Gyebi, G.A., Ogunro, O.B., Adegunloye, A.P., Ogunyemi, O.M., Afolabi, S.O.: Potential
inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): an in silico screening of
alkaloids and terpenoids from African medicinal plants. J. Biomol. Struct. Dyn. 1–13 (2020).
https://doi.org/10.1080/07391102.2020.1764868
64. Hagemeijer, M.C., Monastyrska, I., Griffith, J., van der Sluijs, P., Voortman, J., van Bergen en
Henegouwen, P.M., Vonk, A.M., Rottier, P.J.M., Reggiori, F., De Haan, C.A.M.: Membrane
rearrangements mediated by coronavirus nonstructural proteins 3 and 4. Virology 458–459(1),
65. Hagemeijer, M.C., Ulasli, M., Vonk, A.M., Reggiori, F., Rottier, P.J.M., de Haan, C.A.M.:
Mobility and interactions of coronavirus nonstructural protein 4. J. Virol. 85(9), 4572–4577
(2011). https://doi.org/10.1128/jvi.00042-11
66. Han, Y.S., Chang, G.G., Juo, C.G., Lee, H.J., Yen, S.H., Hsu, J.T.A., Chen, X.: Papain-
like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV):
expression, purification, characterization, and inhibition. Biochemistry 44(30), 10349–10359
(2005). https://doi.org/10.1021/bi0504761
67. He, J., Hu, L., Huang, X., Wang, C., Zhang, Z., Wang, Y., Zhang, D., Ye, W.: Potential of
coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs:
insights from structures of protease and inhibitors. Int. J. Antimicrob. Agents 56(2), 106055
(2020). https://doi.org/10.1016/j.ijantimicag.2020.106055
68. Heald-Sargent, T., Gallagher, T.: Ready, set, fuse! the coronavirus spike protein and acquisition
of fusion competence. Viruses 4(4), 557–580 (2012). https://doi.org/10.3390/v4040557
69. Hegyi, A., Ziebuhr, J.: Conservation of substrate specificities among coronavirus main
proteases. J. Gen. Virol. 83(3), 595–599 (2002). https://doi.org/10.1099/0022-1317-83-3-595
70. Holshue, M.L., DeBolt, C., Lindquist, S., Lofy, K.H., Wiesman, J., Bruce, H., Spitters, C.,
Ericson, K., Wilkerson, S., Tural, A., Diaz, G., Cohn, A., Fox, L.A., Patel, A., Gerber, S.I.,
Kim, L., Tong, S., Lu, X., Lindstrom, S., Pallansch, M.A., Weldon, W.C., Biggs, H.M., Uyeki,
T.M., Pillai, S.K.: First case of 2019 novel coronavirus in the United States. N. Engl. J. Med.
382(10), 929–936 (2020). https://doi.org/10.1056/NEJMoa2001191
71. Hsu, M.F., Kuo, C.J., Chang, K.T., Chang, H.C., Chou, C.C., Ko, T.P., Shr, H.L., Chang,
G.G., Wang, A.H.J., Liang, P.H.: Mechanism of the maturation process of SARS-CoV 3CL
protease. J. Biol. Chem. 280(35), 31257–31266 (2005). https://doi.org/10.1074/jbc.M50257
7200
72. Hu, Y., Wen, J., Tang, L., Zhang, H., Zhang, X., Li, Y., Wang, J., Han, Y., Li, G., Shi,
J., Tian, X., Jiang, F., Zhao, X., Wang, J., Liu, S., Zeng, C., Wang, J., Yang, H.: The M
protein of SARS-CoV: basic structural and immunological properties. Genomics, Proteomics
Bioinforma/Beijing Genomics Inst. 1(2), 118–130 (2003). https://doi.org/10.1016/S1672-022
9(03)01016-7
73. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X.,
Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H.,
Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., Cao, B.: Clinical features of
patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223), 497–506
(2020). https://doi.org/10.1016/S0140-6736(20)30183-5
74. Huang, Y., Yang, C., Xu-feng, X., Xu, W., Liu, S.: Structural and functional properties
of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta
Pharmacol. Sin. 41(9), 1141–1149(2020b). https://doi.org/10.1038/s41401-020-0485-4
75. Hulswit, R.J.G., de Haan, C.A.M., Bosch, B.J.: Coronavirus Spike Protein and Tropism
Changes, 1st edn. Elsevier Inc. (2016)
76. Imbert, I., Snijder, E.J., Dimitrova, M., Guillemot, J.C., Lécine, P., Canard, B.: The SARS-
Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein. Virus
Res. 133(2), 136–148 (2008). https://doi.org/10.1016/j.virusres.2007.11.017
77. Inhibitors, M.P., Hung, H., Ke, Y., Huang, Y., Huang, P., Kung, Y., Chang, T., Yen, K.: crossm
64(9), 1–9 (2020)
78. Its, E., Acid, N., Affinity, B.: crossm 92(17), 1–15 (2018)
79. Ivanov, K.A., Ziebuhr, J.: Human coronavirus 229E nonstructural protein 13: characterization
of duplex-unwinding, nucleoside triphosphatase, and RNA 5 -triphosphatase activities. J.
Virol. 78(14), 7833–7838 (2004). https://doi.org/10.1128/jvi.78.14.7833-7838.2004
80. Alsaadi, E.A.J., Jones, I.M.: Membrane binding proteins of coronaviruses. Future Virol. 14(4),
275–286 (2019). https://doi.org/10.2217/fvl-2018-0144
81. Jain, R.P., Pettersson, H.I., Zhang, J., Aull, K.D., Fortin, P.D., Huitema, C., Eltis, L.D., Parrish,
J.C., James, M.N.G., Wishart, D.S., Vederas, J.C.: Synthesis and evaluation of keto-glutamine
analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro. J. Med. Chem.
47(25), 6113–6116 (2004). https://doi.org/10.1021/jm0494873
82. Jaiswal, G., Kumar, V.: In-silico design of a potential inhibitor of SARS-CoV-2 S protein.
PLoS One 15(10 October), 1–15 (2020). https://doi.org/10.1371/journal.pone.0240004
83. Janabi, A.H.D.: Effective anti-sars-cov-2 rna dependent RNA polymerase drugs based on
docking methods: the case of milbemycin, ivermectin, and baloxavir marboxil. Avicenna J.
Med. Biotechnol. 12(4), 246–250 (2020)
84. Jiang, Y., Yin, W., Xu, H.E.: RNA-dependent RNA polymerase: structure, mechanism, and
drug discovery for COVID-19. Biochem. Biophys. Res. Commun. (2020). https://doi.org/10.
1016/j.bbrc.2020.08.116
85. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C.,
Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X.,
Bai, F., Liu, H., Liu, X., Guddat, L.W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao,
Z., Yang, H.: Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature
582(7811), 289–293 (2020). https://doi.org/10.1038/s41586-020-2223-y
86. Jo, S., Kim, S., Shin, D.H., Kim, M.S.: Inhibition of SARS-CoV 3CL protease by flavonoids. J.
Enzyme Inhib. Med. Chem. 35(1), 145–151 (2020). https://doi.org/10.1080/14756366.2019.
1690480
87. Joseph, J.S., Saikatendu, K.S., Subramanian, V., Neuman, B.W., Brooun, A., Griffith, M., Moy,
K., Yadav, M.K., Velasquez, J., Buchmeier, M.J., Stevens, R.C., Kuhn, P.: Crystal structure
of nonstructural protein 10 from the severe acute respiratory syndrome coronavirus reveals a
novel fold with two zinc-binding motifs. J. Virol. 80(16), 7894–7901 (2006). https://doi.org/
10.1128/jvi.00467-06
88. Kamitani, W., Huang, C., Narayanan, K., Lokugamage, K.G., Makino, S.: A two-pronged
strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein. Nat. Struct.
Mol. Biol. 16(11), 1134–1140 (2009). https://doi.org/10.1038/nsmb.1680
89. Kamitani, W., Narayanan, K., Huang, C., Lokugamage, K., Ikegami, T., Ito, N., Kubo, H.,
Makino, S.: Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host
gene expression by promoting host mRNA degradation. Proc. Natl. Acad. Sci. USA 103(34),
12885–12890 (2006). https://doi.org/10.1073/pnas.0603144103
90. Kang, S., Yang, M., Hong, Z., Zhang, L., Huang, Z., Chen, X., He, S., Zhou, Z., Zhou, Z., Chen,
Q., Yan, Y., Zhang, C., Shan, H., Chen, S.: Crystal structure of SARS-CoV-2 nucleocapsid
protein RNA binding domain reveals potential unique drug targeting sites. Acta Pharm. Sin.
B 10(7), 1228–1238 (2020). https://doi.org/10.1016/j.apsb.2020.04.009
91. Karypidou, K., Ribone, S.R., Quevedo, M.A., Persoons, L., Pannecouque, C., Helsen, C.,
Claessens, F., Dehaen, W.: Synthesis, biological evaluation and molecular modeling of a
novel series of fused 1,2,3-triazoles as potential anti-coronavirus agents. Bioorg. Med. Chem.
Lett. 28(21), 3472–3476 (2018). https://doi.org/10.1016/j.bmcl.2018.09.019
92. Ke, M., Chen, Y., Wu, A., Sun, Y., Su, C., Wu, H., Jin, X., Tao, J., Wang, Y., Ma, X., Pan,
J.A., Guo, D.: Short peptides derived from the interaction domain of SARS coronavirus
nonstructural protein nsp10 can suppress the 2 -O-methyltransferase activity of nsp10/nsp16
complex. Virus Res. 167(2), 322–328 (2012). https://doi.org/10.1016/j.virusres.2012.05.017
93. Keun, J., Curtis-long, M.J., Ho, K., Wook, D., Won, H., Joo, H., Hun, K.: Since January
2020 Elsevier has created a COVID-19 resource centre with free information in English and
Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on
Elsevier Connect, the company’s public news and information (2020)
94. Kirchdoerfer, R.N., Ward, A.B.: Structure of the SARS-CoV nsp12 polymerase bound to nsp7
and nsp8 co-factors. Nat. Commun. 10(1), 1–9 (2019). https://doi.org/10.1038/s41467-019-
10280-3
95. Konno, H., Onuma, T., Nitanai, I., Wakabayashi, M., Yano, S., Teruya, K., Akaji, K.: Synthesis
and evaluation of phenylisoserine derivatives for the SARS-CoV 3CL protease inhibitor.
Bioorg. Med. Chem. Lett. 27(12), 2746–2751 (2017). https://doi.org/10.1016/j.bmcl.2017.
04.056
96. Konno, H., Wakabayashi, M., Takanuma, D., Saito, Y., Akaji, K.: Design and synthesis of
a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL
protease. Bioorg. Med. Chem. 24(6), 1241–1254 (2016). https://doi.org/10.1016/j.bmc.2016.
01.052
97. Kumar, N., Kanchan, T., Unnikrishnan, B., Thapar, R., Mithra, P., Kulkarni, V., Holla, R.,
Bhagwan, D., Radhakrishnan, Y.: Characterization of Rubia cordifolia L. root extract and its
evaluation of cardioprotective effect in Wistar rat model. Indian J. Pharmacol. 49(5), 344–347
(2018). https://doi.org/10.4103/ijp.IJP
98. Kumar, P., Gunalan, V., Liu, B., Chow, V.T.K., Druce, J., Birch, C., Catton, M., Fielding, B.C.,
Tan, Y.J., Lal, S.K.: The nonstructural protein 8 (nsp8) of the SARS coronavirus interacts with
its ORF6 accessory protein. Virology 366(2), 293–303 (2007). https://doi.org/10.1016/j.virol.
2007.04.029
99. Kumar, V., Tan, K., Wang, Y., Lin, S., Liang, P.: Identification, synthesis and evaluation
of SARS-CoV and MERS-CoV 3C-like protease inhibitors. Bioorg. Med. Chem. 24(13),
3035–3042 (2016). https://doi.org/10.1016/j.bmc.2016.05.013
100. Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L.,
Wang, X.: Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2
receptor. Nature 581(7807), 215–220 (2020). https://doi.org/10.1038/s41586-020-2180-5
101. Lei, J., Kusov, Y., Hilgenfeld, R.: Nsp3 of coronaviruses: structures and functions of a large
multi-domain protein. Antiviral Res. 149, 58–74 (2018). https://doi.org/10.1016/j.antiviral.
2017.11.001
102. Li, F.: Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3,
237–261 (2016). https://doi.org/10.1146/annurev-virology-110615-042301
103. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K.S.M., Lau, E.H.Y.,
Wong, J.Y., Xing, X., Xiang, N., Wu, Y., Li, C., Chen, Q., Li, D., Liu, T., Zhao, J., Liu,
M., Tu, W., Chen, C., Jin, L., Yang, R., Wang, Q., Zhou, S., Wang, R., Liu, H., Luo, Y.,
Liu, Y., Shao, G., Li, H., Tao, Z., Yang, Y., Deng, Z., Liu, B., Ma, Z., Zhang, Y., Shi, G.,
Lam, T.T.Y., Wu, J.T., Gao, G.F., Cowling, B.J., Yang, B., Leung, G.M., Feng, Z.: Early
transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl.
J. Med. 382(13), 1199–1207 (2020). https://doi.org/10.1056/NEJMoa2001316
104. Littler, D.R., Gully, B.S., Colson, R.N., Rossjohn, J.: Crystal structure of the SARS-CoV-
2 non-structural protein 9, Nsp9. iScience 23(7), 0–5 (2020). https://doi.org/10.1016/j.isci.
2020.101258
105. Liu, W., Zhu, H., Niu, G., Shi, E., Chen, J., Sun, B., Chen, W., Zhou, H.G., Yang, C.:
Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV
3C-like protease inhibitors. Bioorg. Med. Chem. 22(1), 292–302 (2014). https://doi.org/10.
1016/j.bmc.2013.11.028
106. Ma, Y., Wu, L., Shaw, N., Gao, Y., Wang, J., Sun, Y., Lou, Z., Yan, L., Zhang, R., Rao, Z.:
Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proc.
107. Maiti, B.K.: Can papain-like protease inhibitors halt SARS-CoV-2 replication? ACS Phar-
macol. Transl. Sci. 3(5), 1017–1019 (2020). https://doi.org/10.1021/acsptsci.0c00093
108. Manuscript, A.: 2013 Jacobs Discovery synthesis and structure-based optimization of a series
of...inhibitors of SARS-CoV 3CLpro. JMC 56(2), 534–546 (2014). https://doi.org/10.1021/
jm301580n.Discovery
109. McBride, R., van Zyl, M., Fielding, B.C.: The coronavirus nucleocapsid is a multifunctional
protein. Viruses 6(8), 2991–3018 (2014). https://doi.org/10.3390/v6082991
110. McClenaghan, C., Hanson, A., Lee, S.J., Nichols, C.G.: Coronavirus proteins as ion channels:
current and potential research. Front. Immunol. 11(October), 1–11 (2020). https://doi.org/10.
3389/fimmu.2020.573339
111. Menachery, V.D., Debbink, K., Baric, R.S.: Coronavirus non-structural protein 16: evasion,
attenuation, and possible treatments. Virus Res. 194, 191–199 (2014). https://doi.org/10.1016/
j.virusres.2014.09.009
112. Miknis, Z.J., Donaldson, E.F., Umland, T.C., Rimmer, R.A., Baric, R.S., Schultz, L.W.:
Severe acute respiratory syndrome coronavirus nsp9 dimerization is essential for efficient
viral growth. J. Virol. 83(7), 3007–3018 (2009). https://doi.org/10.1128/jvi.01505-08
113. Min, Y.Q., Mo, Q., Wang, J., Deng, F., Wang, H., Ning, Y.J.: SARS-CoV-2 nsp1: bioinfor-
matics, potential structural and functional features, and implications for drug/vaccine designs.
Front. Microbiol. 11(September), 1–12 (2020). https://doi.org/10.3389/fmicb.2020.587317
114. Mirza, M.U., Froeyen, M.: Structural elucidation of SARS-CoV-2 vital proteins: computa-
tional methods reveal potential drug candidates against main protease, Nsp12 polymerase and
Nsp13 helicase. J. Pharm. Anal. 10(4), 320–328 (2020). https://doi.org/10.1016/j.jpha.2020.
04.008
115. Mu, J., Fang, Y., Yang, Q., Shu, T., Wang, A., Huang, M., Jin, L., Deng, F., Qiu, Y., Zhou, X.:
SARS-CoV-2 N protein antagonizes type I interferon signaling by suppressing phosphoryla-
tion and nuclear translocation of STAT1 and STAT2. Cell Discov. 6(1), 10–13 (2020). https://
doi.org/10.1038/s41421-020-00208-3
116. Narayanan, K., Huang, C., Lokugamage, K., Kamitani, W., Ikegami, T., Tseng, C.-T.K.,
Makino, S.: Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expres-
sion, including that of type I interferon, Infected cells. J. Virol. 82(9), 4471–4479 (2008).
https://doi.org/10.1128/jvi.02472-07
117. Narkhede, R.R., Pise, A.V., Cheke, R.S., Shinde, S.D.: Recognition of natural products as
potential inhibitors of COVID-19 main protease (Mpro): in-silico evidences. Nat. Prod.
Bioprospect. 10(5), 297–306 (2020). https://doi.org/10.1007/s13659-020-00253-1
118. Neuman, B.W., Kiss, G., Kunding, A.H., Bhella, D., Baksh, M.F., Connelly, S., Droese, B.,
Klaus, J.P., Makino, S., Sawicki, S.G., Siddell, S.G., Stamou, D.G., Wilson, I.A., Kuhn, P.,
Buchmeier, M.J.: A structural analysis of M protein in coronavirus assembly and morphology.
J. Struct. Biol. 174(1), 11–22 (2011). https://doi.org/10.1016/j.jsb.2010.11.021
119. Nguyen, T.T.H., Woo, H.J., Kang, H.K., Nguyen, V.D., Kim, Y.M., Kim, D.W., Ahn, S.A., Xia,
Y., Kim, D.: Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed
in Pichia pastoris. Biotechnol. Lett. 34(5), 831–838 (2012). https://doi.org/10.1007/s10529-
011-0845-8
120. Ogando, N.S., Ferron, F., Decroly, E., Canard, B., Posthuma, C.C., Snijder, E.J.: The curious
case of the nidovirus exoribonuclease: its role in RNA synthesis and replication fidelity. Front.
Microbiol. 10(August), 1–17 (2019). https://doi.org/10.3389/fmicb.2019.01813
121. Ohnishi, K., Hattori, Y., Kobayashi, K., Akaji, K.: Evaluation of a non-prime site substituent
and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease
inhibitor. Bioorg. Med. Chem. 27(2), 425–435 (2019). https://doi.org/10.1016/j.bmc.2018.
12.019
122. Oostra, M., te Lintelo, E.G., Deijs, M., Verheije, M.H., Rottier, P.J.M., de Haan, C.A.M.:
Localization and membrane topology of coronavirus nonstructural protein 4: involvement of
the early secretory pathway in replication. J. Virol. 81(22), 12323–12336 (2007). https://doi.
org/10.1128/jvi.01506-07
123. Ortega, J.T., Serrano, M.L., Pujol, F.H., Rangel, H.R., Biology, S.: Original article: role of
changes in Sars-Cov-2 spike protein in the interaction with the human Ace2 receptor. Excli.
J. (19):410–417 (2020)
124. Pandey, P., Rane, J.S., Chatterjee, A., Kumar, A., Khan, R., Prakash, A., Ray, S.: Targeting
SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in
silico study for drug development. J. Biomol. Struct. Dyn. 1–11 (2020). https://doi.org/10.
1080/07391102.2020.1796811
125. Park, J., Hoon, J., Min, Y., Jae, H., Wook, D., Hun, K., Kwon, H., Park, S., Song, W., Bae,
Y.: Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases.
Bioorg. Med. Chem. 20(19), 5928–5935 (2012a). https://doi.org/10.1016/j.bmc.2012.07.038
126. Park, J.Y., Jeong, H.J., Kim, J.H., Kim, Y.M., Park, S.J., Kim, D., Park, K.H., Lee, W.S.,
Ryu, Y.B.: Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute
respiratory syndrome coronavirus. Biol. Pharm. Bull. 35(11), 2036–2042 (2012b). https://doi.
org/10.1248/bpb.b12-00623
127. Park, J.Y., Ko, J.A., Kim, D.W., Kim, Y.M., Kwon, H.J., Jeong, H.J., Kim, C.Y., Park, K.H.,
Lee, W.S., Ryu, Y.B.: Chalcones isolated from Angelica keiskei inhibit cysteine proteases of
SARS-CoV. J. Enzyme Inhib. Med. Chem. 31(1), 23–30 (2016). https://doi.org/10.3109/147
56366.2014.1003215
128. Pawełczyk, A., Zaprutko, L.: Anti-COVID drugs: repurposing existing drugs or search for
new complex entities, strategies and perspectives. Future Med. Chem. 12(19), 1743–1757
(2020). https://doi.org/10.4155/fmc-2020-0204
129. Peng, Q., Peng, R., Yuan, B., Zhao, J., Wang, M., Wang, X., Wang, Q., Sun, Y., Fan, Z., Qi, J.,
Gao, G.F., Shi, Y.: Structural and biochemical characterization of the nsp12-nsp7-nsp8 core
polymerase complex from SARS-CoV-2. Cell Rep. 31(11), 107774 (2020). https://doi.org/
10.1016/j.celrep.2020.107774
130. Perrier, A., Bonnin, A., Desmarets, L., Danneels, A., Goffard, A., Rouillé, Y., Dubuisson, J.,
Belouzard, S.: The C-terminal domain of the MERS coronavirus Mprotein contains a trans-
Golgi network localization signal. J. Biol. Chem. 294(39), 14406–14421 (2019). https://doi.
org/10.1074/jbc.RA119.008964
131. Peti, W., Johnson, M.A., Herrmann, T., Neuman, B.W., Buchmeier, M.J., Nelson, M., Joseph,
J., Page, R., Stevens, R.C., Kuhn, P., Wüthrich, K.: Structural genomics of the severe acute
respiratory syndrome coronavirus: nuclear magnetic resonance structure of the protein nsP7.
J. Virol. 79(20), 12905–12913 (2005). https://doi.org/10.1128/jvi.79.20.12905-12913.2005
132. Phan, L.T., Nguyen, T.V., Luong, Q.C., Nguyen, T.V., Nguyen, H.T., Le, H.Q., Nguyen, T.T.,
Cao, T.M., Pham, Q.D.: Importation and human-to-human transmission of a novel coronavirus
in Vietnam. N. Engl. J. Med. 382(9), 872–874 (2020). https://doi.org/10.1056/nejmc2001272
133. Pillaiyar, T., Manickam, M., Namasivayam, V., Hayashi, Y., Jung, S.H.: An overview
of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors:
peptidomimetics and small molecule chemotherapy. J. Med. Chem. 59(14), 6595–6628
(2016). https://doi.org/10.1021/acs.jmedchem.5b01461
134. Pokhrel, R., Chapagain, P., Siltberg-Liberles, J.: Potential RNA-dependent RNA polymerase
inhibitors as prospective therapeutics against SARS-CoV-2. J. Med. Microbiol. 69(6), 864–
873 (2020). https://doi.org/10.1099/jmm.0.001203
135. Ramajayam, R., Tan, K.P., Liu, H.G., Liang, P.H.: Synthesis and evaluation of pyrazolone
compounds as SARS-coronavirus 3C-like protease inhibitors. Bioorg. Med. Chem. 18(22),
7849–7854 (2010). https://doi.org/10.1016/j.bmc.2010.09.050
136. Ratia, K., Pegan, S., Takayama, J., Sleeman, K., Coughlin, M., Baliji, S., Chaudhuri, R., Fu,
W., Prabhakar, B.S., Johnson, M.E., Baker, S.C., Ghosh, A.K., Mesecar, A.D.: A noncovalent
class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc.
0105
137. Roomi, M., Mahmood, M., Khan, Y.: Identifying Therapeutic Compounds Targeting RNA-
Dependent-RNA-Polymerase of Sars-Cov-2 (2020). https://doi.org/10.26434/chemrxiv.124
77761
138. Rowaiye, A., Onuh, O., Asala, T., Ogu, A., Bur, D., Nwankwo, E., Orji, U., Ibrahim, Z., Hamza,
J., Ugorji, A.: In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2
Helicase (2020). https://doi.org/10.26434/chemrxiv.12570551
139. Ruch, T.R., Machamer, C.E.: The coronavirus E protein: assembly and beyond. Viruses 4(3),
363–382 (2012). https://doi.org/10.3390/v4030363
140. Ryu, Y.B., Jeong, H.J., Kim, J.H., Kim, Y.M., Park, J.Y., Kim, D., Naguyen, T.T.H., Park, S.J.,
Chang, J.S., Park, K.H., Rho, M.C., Lee, W.S.: Biflavonoids from Torreya nucifera displaying
SARS-CoV 3CLpro inhibition. Bioorg. Med. Chem. 18(22), 7940–7947 (2010). https://doi.
org/10.1016/j.bmc.2010.09.035
141. Ryu, Y.B., Park, S.J., Kim, Y.M., Lee, J.Y., Seo, W.D., Chang, J.S., Park, K.H., Rho, M.C., Lee,
W.S.: SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Triptery-
gium regelii. Bioorg. Med. Chem. Lett. 20(6), 1873–1876 (2010). https://doi.org/10.1016/j.
bmcl.2010.01.152
142. Sakai, Y., Kawachi, K., Terada, Y., Omori, H., Matsuura, Y., Kamitani, W.: Two-amino acids
change in the nsp4 of SARS coronavirus abolishes viral replication. Virology 510(June),
143. Saxena, A.: Drug targets for COVID-19 therapeutics: ongoing global efforts. J. Biosci. 45(1)
(2020). https://doi.org/10.1007/s12038-020-00067-w
144. Schoeman, D., Fielding, B.C.: Coronavirus envelope protein: current knowledge. Virol. J.
16(1), 1–22 (2019). https://doi.org/10.1186/s12985-019-1182-0
145. Schoeman, D., Fielding, B.C.: Is there a link between the pathogenic human coronavirus
envelope protein and immunopathology? A review of the literature. Front. Microbiol.
11(September), 1–11 (2020). https://doi.org/10.3389/fmicb.2020.02086
146. Senanayake, S.L.: Overcoming nonstructural protein 15-nidoviral uridylate-specific endori-
bonuclease (nsp15/NendoU) activity of SARS-CoV-2. Future Drug Discov. 2: FDD42 (2020).
https://doi.org/10.4155/fdd-2020-0012
147. Shao, Y.M., Bin, Y.W., Kuo, T.H., Tsai, K.C., Lin, C.H., Yang, A.S., Liang, P.H., Wong, C.H.:
Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL
protease. Bioorg. Med. Chem. 16(8), 4652–4660 (2008). https://doi.org/10.1016/j.bmc.2008.
02.040
148. Shereen, M.A., Khan, S., Kazmi, A., Bashir, N., Siddique, R.: COVID-19 infection: origin,
transmission, and characteristics of human coronaviruses. J. Adv. Res. 24, 91–98 (2020).
https://doi.org/10.1016/j.jare.2020.03.005
149. Shie, J.J., Fang, J.M., Kuo, T.H., Kuo, C.J., Liang, P.H., Huang, H.J., Wu, Y.T., Jan, J.T.,
Cheng, Y.S.E., Wong, C.H.: Inhibition of the severe acute respiratory syndrome 3CL protease
by peptidomimetic α, β-unsaturated esters. Bioorg. Med. Chem. 13(17), 5240–5252 (2005).
https://doi.org/10.1016/j.bmc.2005.05.065
150. Shimamoto, Y., Hattori, Y., Kobayashi, K., Teruya, K., Sanjoh, A.: Fused-ring structure of
decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors. Bioorg. Med.
Chem. 23(4), 876–890 (2015). https://doi.org/10.1016/j.bmc.2014.12.028
151. Shu, T., Huang, M., Wu, D., Ren, Y., Zhang, X., Han, Y., Mu, J., Wang, R., Qiu, Y., Zhang,
D.Y., Zhou, X.: SARS-coronavirus-2 Nsp13 possesses NTPase and RNA helicase activities
that can be inhibited by bismuth salts. Virol. Sin. 35(3), 321–329 (2020). https://doi.org/10.
1007/s12250-020-00242-1
152. Shyr, Z.A., Gorshkov, K., Chen, C.Z., Zheng, W.: Drug discovery strategies for sars-cov-2. J.
Pharmacol. Exp. Ther. 375(1), 127–138 (2020). https://doi.org/10.1124/JPET.120.000123
153. Singh Tomar, P.P., Arkin, I.T.: SARS-CoV-2 E protein is a potential ion channel that can be
inhibited by Gliclazide and Memantine. Biochem. Biophys. Res. Commun. 530(1), 10–14
(2020). https://doi.org/10.1016/j.bbrc.2020.05.206
154. Siu, Y.L., Teoh, K.T., Lo, J., Chan, C.M., Kien, F., Escriou, N., Tsao, S.W., Nicholls, J.M.,
Altmeyer, R., Peiris, J.S.M., Bruzzone, R., Nal, B.: The M, E, and N structural proteins of the
severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking,
and release of virus-like particles. J. Virol. 82(22), 11318–11330 (2008). https://doi.org/10.
1128/jvi.01052-08
155. Smith, E.C., Case, J.B., Blanc, H., Isakov, O., Shomron, N., Vignuzzi, M., Denison, M.R.:
Mutations in coronavirus nonstructural protein 10 decrease virus replication fidelity. J. Virol.
89(12), 6418–6426 (2015). https://doi.org/10.1128/jvi.00110-15
156. Su, D., Lou, Z., Sun, F., Zhai, Y., Yang, H., Zhang, R., Joachimiak, A., Zhang, X.C.,
Bartlam, M., Rao, Z.: Dodecamer structure of severe acute respiratory syndrome coronavirus
nonstructural protein nsp10. J. Virol. 80(16), 7902–7908 (2006). https://doi.org/10.1128/jvi.
00483-06
157. Subissi, L., Posthuma, C.C., Collet, A., Zevenhoven-Dobbe, J.C., Gorbalenya, A.E., Decroly,
E., Snijder, E.J., Canard, B., Imbert, I.: One severe acute respiratory syndrome coronavirus
protein complex integrates processive RNA polymerase and exonuclease activities. Proc. Natl.
Acad. Sci. USA 111(37), E3900–E3909 (2014). https://doi.org/10.1073/pnas.1323705111
158. Sutton, G., Fry, E., Carter, L., Sainsbury, S., Walter, T., Nettleship, J., Berrow, N., Owens,
R., Gilbert, R., Davidson, A., Siddell, S., Poon, L.L.M., Diprose, J., Alderton, D., Walsh,
M., Grimes, J.M., Stuart, D.I.: The nsp9 replicase protein of SARS-coronavirus structure
and functional insights. Structure 12(2), 341–353 (2004). https://doi.org/10.1016/j.str.2004.
01.016
159. Swargiary, A.: Ivermectin as a Promising RNA-Dependent RNA Polymerase Inhibitor and a
Therapeutic Drug Against SARS-CoV-2: Evidence from in Silico Studies
160. Tahir ul Qamar, M., Alqahtani, S.M., Alamri, M.A., Chen, L.L.: Structural basis of SARS-
CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J. Pharm. Anal.
10(4), 313–319 (2020). https://doi.org/10.1016/j.jpha.2020.03.009
161. Tanaka, T., Kamitani, W., DeDiego, M.L., Enjuanes, L., Matsuura, Y.: Severe acute respira-
tory syndrome coronavirus nsp1 facilitates efficient propagation in cells through a specific
translational shutoff of host mRNA. J. Virol. 86(20), 11128–11137 (2012). https://doi.org/10.
1128/jvi.01700-12
162. Tatar, G., Tok, T.T.: Structures and functions of coronavirus proteins: molecular modeling of
viral nucleoprotein. Int. J. Virol. Infect. Dis. 1(June), 001–001 (2017)
163. te Velthuis, A.J.W., Arnold, J.J., Cameron, C.E., van den Worm, S.H.E., Snijder, E.J.: The
RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids
Res. 38(1), 203–214 (2009). https://doi.org/10.1093/nar/gkp904
164. Te Velthuis, A.J.W., Van Den Worm, S.H.E., Snijder, E.J.: The SARS-coronavirus nsp7+nsp8
complex is a unique multimeric RNA polymerase capable of both de novo initiation and
primer extension. Nucleic Acids Res. 40(4), 1737–1747 (2012). https://doi.org/10.1093/nar/
gkr893
165. Thanigaimalai, P., Konno, S., Yamamoto, T., Koiwai, Y., Taguchi, A., Takayama, K., Yakushiji,
F., Akaji, K., Kiso, Y., Kawasaki, Y., Chen, S.E., Naser-Tavakolian, A., Schön, A., Freire, E.,
Hayashi, Y.: Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV
3CL protease inhibitors: structure-activity relationship study. Eur. J. Med. Chem. 65, 436–447
(2013). https://doi.org/10.1016/j.ejmech.2013.05.005
166. Thoms, M., Buschauer, R., Ameismeier, M., Koepke, L., Denk, T., Hirschenberger, M.,
Kratzat, H., Hayn, M., MacKens-Kiani, T., Cheng, J., Straub, J.H., Stürzel, C.M., Fröhlich.
T., Berninghausen, O., Becker, T., Kirchhoff, F., Sparrer, K.M.J., Beckmann, R.: Structural
basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2.
Science (80) 369(6508), 1249–1256 (2020). https://doi.org/10.1126/SCIENCE.ABC8665
167. Tohya, Y., Narayanan, K., Kamitani, W., Huang, C., Lokugamage, K., Makino, S.: Suppression
of host gene expression by nsp1 proteins of group 2 bat coronaviruses. J. Virol. 83(10),
5282–5288 (2009). https://doi.org/10.1128/jvi.02485-08
168. Totura, A.L., Bavari, S.: Broad-spectrum coronavirus antiviral drug discovery. Expert Opin.
Drug Discov. 14(4), 397–412 (2019). https://doi.org/10.1080/17460441.2019.1581171
169. Tvarogava, J., Ramakanth, M., Ganesh, B., Lyndsey, F.J., Nadja, K., John, Z.: Identification
and characterization of a human coronavirus. crossm (March), 1–21 (2019)
170. Unni, S., Aouti, S., Thiyagarajan, S., Padmanabhan, B.: Identification of a repurposed drug as
an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods.
J. Biosci. 45(1) (2020). https://doi.org/10.1007/s12038-020-00102-w
171. Venkatagopalan, P., Daskalova, S.M., Lopez, L.A., Dolezal, K.A., Hogue, B.G.: Coronavirus
envelope (E) protein remains at the site of assembly. Virology 478, 75–85 (2015). https://doi.
org/10.1016/j.virol.2015.02.005
172. Von Grotthuss, M., Wyrwicz, L.S., Rychlewski, L.: mRNA Cap-1 methyltransferase in the
SARS genome. Cell 113(6), 701–702 (2003). https://doi.org/10.1016/S0092-8674(03)004
24-0
173. Walls, A.C., Park, Y.J., Tortorici, M.A., Wall, A., McGuire, A.T., Veesler, D.: Structure,
function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181(2), 281-292.e6
(2020). https://doi.org/10.1016/j.cell.2020.02.058
174. Wang, L., Bao, B., Song, G., Chen, C., Zhang, X., Lu, W., Wang, Z., Cai, Y., Li, S., Fu, S.,
Song, F.H., Yang, H., Wang, J.G.: Discovery of unsymmetrical aromatic disulfides as novel
inhibitors of SARS-CoV main protease: chemical synthesis, biological evaluation, molecular
docking and 3D-QSAR study. Eur. J. Med. Chem. 137, 450–461 (2017). https://doi.org/10.
1016/j.ejmech.2017.05.045
175. Wang, Y., Anirudhan, V., Du, R., Cui, Q., Rong, L.: RNA-dependent RNA polymerase of
SARS-CoV-2 as a therapeutic target. J. Med. Virol. (June), 1–11 (2020b). https://doi.org/10.
1002/jmv.26264
176. Wang, Y., Sun, Y., Wu, A., Xu, S., Pan, R., Zeng, C., Jin, X., Ge, X., Shi, Z., Ahola, T., Chen,
Y., Guo, D.: Coronavirus nsp10/nsp16 methyltransferase can be targeted by nsp10-derived
peptide in vitro and in vivo to reduce replication and pathogenesis. J. Virol. 89(16), 8416–8427
(2015). https://doi.org/10.1128/jvi.00948-15
177. Wu, C., Liu, Y., Yang, Y., Zhang, P., Zhong, W., Wang, Y., Wang, Q., Xu, Y., Li, M., Li, X.,
Zheng, M., Chen, L., Li, H.: Analysis of therapeutic targets for SARS-CoV-2 and discovery
of potential drugs by computational methods. Acta Pharm. Sin. B 10(5), 766–788 (2020).
https://doi.org/10.1016/j.apsb.2020.02.008
178. Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei,
Y.Y., Yuan, M.L., Zhang, Y.L., Dai, F.H., Liu, Y., Wang, Q.M., Zheng, J.J., Xu, L., Holmes,
E.C., Zhang, Y.Z.: A new coronavirus associated with human respiratory disease in China.
Nature 579(7798), 265–269 (2020). https://doi.org/10.1038/s41586-020-2008-3
179. Xiu, S., Dick, A., Ju, H., Mirzaie, S., Abdi, F., Cocklin, S., Zhan, P., Liu, X.: Inhibitors of
SARS-CoV-2 entry: current and future opportunities. J. Med. Chem. (2020). https://doi.org/
10.1021/acs.jmedchem.0c00502
180. Xu, Y., Lou, Z., Liu, Y., Pang, H., Tien, P., Gao, G.F., Rao, Z.: Crystal structure of severe
acute respiratory syndrome coronavirus spike protein fusion core. J. Biol. Chem. 279(47),
49414–49419 (2004). https://doi.org/10.1074/jbc.M408782200
181. Xue, X., Yu, H., Yang, H., Xue, F., Wu, Z., Shen, W., Li, J., Zhou, Z., Ding, Y., Zhao, Q.,
Zhang, X.C., Liao, M., Bartlam, M., Rao, Z.: Structures of two coronavirus main proteases:
implications for substrate binding and antiviral drug design. J. Virol. 82(5), 2515–2527 (2008).
https://doi.org/10.1128/jvi.02114-07
182. Yang, H., Yang, M., Ding, Y., Liu, Y., Lou, Z., Zhou, Z., Sun, L., Mo, L., Ye, S., Pang, H.,
Gao, G.F., Anand, K., Bartlam, M., Hilgenfeld, R., Rao, Z.: The crystal structures of severe
acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc. Natl.
Acad. Sci. USA 100(23), 13190–13195 (2003). https://doi.org/10.1073/pnas.1835675100
183. Yang, Q., Chen, L., He, X., Gao, Z., Shen, X., Bai, D.: ChemInform abstract: design and
synthesis of cinanserin analogues as severe acute respiratory syndrome coronavirus 3CL
protease inhibitors. ChemInform 40(13), 1400–1405 (2009). https://doi.org/10.1002/chin.200
913079
184. Yang, S., Chen, S.J., Hsu, M.F., Wu, J.D., Tseng, C.T.K., Liu, Y.F., Chen, H.C., Kuo, C.W.,
Wu, C.S., Chang, L.W., Chen, W.C., Liao, S.Y., Chang, T.Y., Hung, H.H., Shr, H.L., Liu, C.Y.,
Huang, Y.A., Chang, L.Y., Hsu, J.C., Peters, C.J., Wang, A.H.J., Hsu, M.C.: Synthesis, crystal
structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus
3CL protease inhibitor. J. Med. Chem. 49(16), 4971–4980 (2006). https://doi.org/10.1021/
jm0603926
185. Yoshimoto, F.K.: The proteins of severe acute respiratory syndrome coronavirus-2 (SARS
CoV-2 or n-COV19), the cause of COVID-19. Protein J. 39(3), 198–216 (2020). https://doi.
org/10.1007/s10930-020-09901-4
186. Yuen, C.K., Lam, J.Y., Wong, W.M., Mak, L.F., Wang, X., Chu, H., Cai, J.P., Jin, D.Y., To,
K.K.W., Chan, J.F.W., Yuen, K.Y., Kok, K.H.: SARS-CoV-2 nsp13, nsp14, nsp15 and orf6
function as potent interferon antagonists. Emerg. Microbes Infect. 9(1), 1418–1428 (2020).
https://doi.org/10.1080/22221751.2020.1780953
187. Zhai, Y., Sun, F., Li, X., Pang, H., Xu, X., Bartlam, M., Rao, Z.: Insights into SARS-CoV
transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nat. Struct.
Mol. Biol. 12(11), 980–986 (2005). https://doi.org/10.1038/nsmb999
188. Zhang, H., Zhang, H., Kemnitzer, W., Tseng, B., Cinatl, J., Michaelis, M., Doerr, H.W., Cai,
S.X.: Brief Articles 7, 1198–1201 (2006)
189. Zhang, L., Lin, D., Kusov, Y., Nian, Y., Ma, Q., Wang, J., Von Brunn, A., Leyssen, P., Lanko, K.,
Neyts, J., De Wilde, A., Snijder, E.J., Liu, H., Hilgenfeld, R.: α-Ketoamides as broad-spectrum
inhibitors of coronavirus and enterovirus replication: structure-based design, synthesis, and
activity assessment. J. Med. Chem. 63(9), 4562–4578 (2020). https://doi.org/10.1021/acs.jme
dchem.9b01828
190. Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K.,
Hilgenfeld, R.: Crystal structure of SARS-CoV-2 main protease provides a basis for design
of improved a-ketoamide inhibitors. Science (80) 368(6489), 409–412 (2020b). https://doi.
org/10.1126/science.abb3405
191. Zhang, M., Li, X., Deng, Z., Chen, Z., Liu, Y., Gao, Y., Wu, W., Chen, Z.: Structural biology
of the arterivirus nsp11 endoribonucleases. J. Virol. 91(1), 1–14 (2017). https://doi.org/10.
1128/jvi.01309-16
192. Zhang, R., Li, Y., Cowley, T.J., Steinbrenner, A.D., Phillips, J.M., Yount, B.L., Baric, R.S.,
Weiss, S.R.: The nsp1, nsp13, and M proteins contribute to the hepatotropism of murine
coronavirus JHM.WU. J. Virol. 89(7), 3598–3609 (2015). https://doi.org/10.1128/jvi.035
35-14
193. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R.,
Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G.F., Tan, W.: A novel coronavirus
from patients with pneumonia in China, 2019. N. Engl. J. Med. 382(8), 727–733 (2020a).
https://doi.org/10.1056/NEJMoa2001017
194. Zhu, W., Chen, C.Z., Gorshkov, K., Xu, M., Lo, D.C., Zheng, W.: RNA-dependent RNA
polymerase as a target for COVID-19 drug discovery. SLAS Discov. (2020). https://doi.org/
10.1177/2472555220942123
195. Zhu, W., Xu, M., Chen, C.Z., Guo, H., Shen, M., Hu, X., Shinn, P., Klumpp, C., Michael, S.G.,
Zheng, W.: Identification of SARS-CoV-2 3CL protease inhibitors by a quantitative high-
throughput screening. bioRxiv: the preprint server for biology, 2020.07.17.207019 (2020).
https://doi.org/10.1101/2020.07.17.207019
196. Zumla, A., Chan, J.F.W., Azhar, E.I., Hui, D.S.C., Yuen, K.Y.: Coronaviruses-drug discovery
and therapeutic options. Nat. Rev. Drug Discov. 15(5), 327–347 (2016). https://doi.org/10.
1038/nrd.2015.37
COVID-19 Modeling Under Uncertainty:
Statistical Data Analysis for Unveiling
True Spreading Dynamics and Guiding
Correct Epidemiological Management
Anamaria Sanchez-Daza, David Medina-Ortiz, Alvaro Olivera-Nappa,

and Sebastian Contreras
Abstract In this chapter, we aim to provide a biological, statistical, and mathemat-

ical framework to understand and formulate sensible models to study the spreading
dynamics of COVID-19. First, we discuss the epidemiological and clinical features
that make COVID-19 challenging-to-control in different scales and ways. We then
describe the different error sources present in raw COVID-19 epidemiological data
and the logistic limitations associated with non-pharmaceutical interventions (NPIs),
like test-trace-and-isolate (TTI). By studying compartmental SIR and SIR-like math-
ematical models and their underlying hypotheses, we demonstrate the derivation of
significant parameters for evaluating this pandemic’s progression, as the reproduction
number Rt . Then, we provide the statistical basis for the correction of delay-induced
errors in raw data through the “nowcasting” of infections and describe the Machine-
Learning-based approaches to tackle significant challenges in modeling COVID-19.
We end our chapter with several case studies, where we describe the modeling aspects
as carefully as their results, providing the reader with fresh multi-disciplinary insights
to inspire their own models.
Keywords COVID-19 · Mathematical modelling · SARS-CoV-2 · Infectious

diseases · Uncertainty
A. Sanchez-Daza
Institute for Cell Dynamics and Biotechnology (ICDB), Centre for Biotechnology and
Bioengineering—CeBiB, University of Chile, Santiago, Chile
e-mail: ana.sanchez@ing.uchile.cl
D. Medina-Ortiz · A. Olivera-Nappa (B)
Centre for Biotechnology and Bioengineering—CeBiB, University of Chile, Santiago, Chile
e-mail: aolivera@ing.uchile.cl
D. Medina-Ortiz
e-mail: david.medina@cebib.cl
S. Contreras (B)
Max Planck Institute for Dynamics and Self-Organization, Göttingen, Lower Saxony, Germany
e-mail: sebastian.contreras@ds.mpg.de
246 A. Sanchez-Daza et al.
1 Introduction
COVID-19, the broad-encompassing syndrome caused by SARS-CoV-2, a novel

beta-coronavirus [53], has spread during the last year from initial cases in Wuhan,
China, to all regions in the world. Associated symptoms range from asymptomatic
infection to severe viral pneumonia with fatal outcomes, with markedly biased effects
by age and pre-existing chronic diseases. Contagion spread has been characterized by
a very high infectivity rate, delay in symptom onset, asymptomatic but still contagious
cases [98], and unresolved mechanisms, leading to symptom worsening and fatalities.
Since WHO’s official declaration of COVID-19 as a pandemic on March 11,
2020 [127], much effort has been devoted by the scientific community to study-
ing the disease, the viral causative agent, mechanism of human body response, and
epidemiologic features. Many scientists have turned from their respective fields to
studying COVID-19 and SARS-CoV-2 to guide public health policies to control dis-
ease effects and attenuate the toll on national health and social systems and economy.
In the absence of an effective vaccine, much energy has been committed to strength-
ening public health measures and understanding when and how non-pharmaceutical
public health interventions (NPIs) should be applied in each different country and
region to control disease evolution and its associated death toll. The unique charac-
teristics of this ongoing pandemics, such as its high infectivity rate, the unknown
long-term immunity [18] and effects generated in infected individuals, and the high
mortality rate in specific population groups, have prompted new developments in
mathematical modeling to understand relevant factors that could ensure epidemio-
logical control around the globe. Moreover, the high percentage of immunized pop-
ulation required to prevent uncontrolled spread (estimated around 67% of the total
population) [106] anticipates varying wave dynamics when strict social distancing
measures are relaxed, which is currently the case in several parts of the world where
the pandemics started earlier, such as European countries. Thus, ensuing second and
third waves are expected in regions where the pandemics arrived later, such as the
Americas. Very importantly, these dynamics are expected to prevail even when effec-
tive vaccines are available due to a general reticence to vaccination encouraged by
anti-vaccine opinion groups.
In this work, we first examine physiological and epidemiological aspects of
COVID-19, including the disease’s biological basis, its spreading dynamics, and
the infection timeline, with an analysis of each disease period’s relevance and the
accuracy and principles underlying current diagnostic testing for COVID-19. We
subsequently discuss problems implied by delayed data generation for public epi-
demiological reports and associated test-trace-and-isolate (TTI) logistics in COVID-
19, including latency periods, collision biases in testing, true asymptomatic ratio,
health-system capacity, and governmental actions [33].
We will subsequently present an overview of recent developments in mathemati-
cal modeling strategies to assist public health decisions to rationally control disease
spread without seriously compromising affected countries’ economy, especially rely-
ing on compartmental mathematical models for COVID-19 modeling and correct
COVID-19 Modeling Under Uncertainty: Statistical Data Analysis … 247
forecast [36]. We also discuss the applicability of different regression models for
forecasting the spread of COVID-19 [85] and strategies for parameter inference in
COVID-19 epidemiological models under temporal and testing uncertainty [35–37,
85]. Finally, we review different case studies to apply predictive mathematical models
to specific countries, especially focused on COVID-19 spreading dynamics in Chile,
scenarios considering the efficacy of vaccination, partial and complete immuniza-
tion, and application of machine learning tools for diagnostic models for COVID-19
using chest X-ray images.
We aim to build a multi-disciplinary framework for modeling COVID-19 under
uncertainty and thereby support policymakers in understanding this pandemic’s local
and global properties. We further provide the reader with an up-to-date overview of
the open challenges in COVID-19 epidemiological modeling. In this way, our goal is
to generate a deep understanding that could be reflected in optimal epidemiological
management of the current pandemic and prepare humanity to cope with future
similar threats.
2 Related Work
From a modeling point of view, our work builds on our earlier research on spreading
dynamics in heterogeneous populations [36], on the real-time calculation of the repro-
duction number of COVID-19 [37] and forecasts on its evolution on a country-wise
level [85]. We further analyse the effect of delays in reported data on the calculation
of Rt , both using our methodology [33] and those used by German health authorities
[108]. We discuss different compartmental models, the inclusion of vaccination and
Test-Trace-and-Isolate strategies [34]. As we aim to provide the reader with clear
ideas of the factors that should be considered and included in the models, we present
other related works in context and when needed.
3 Physiological and Epidemiological Aspects of COVID-19
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identi-

fied in Wuhan, Hubei Province, China, at the end of December 2019. SARS-CoV-2
was recognized as the etiological agent of a cluster of abnormal pneumonia cases,
subsequently named COVID-19. Since then, the incredibly fast global spread of
COVID-19, declared a pandemic by the World Health Organization on 11 March
2020, has resulted in 213 countries affected to date [128]. In this section we will pro-
vide an overview of the different biological, virological, and epidemiological aspects
that have influenced and explain the rapid spread of SARS-CoV-2.
3.1 Biological Aspects of SARS-CoV-2
SARS-CoV-2 is the seventh reported coronavirus that can infect humans [24, 129].
Coronaviruses (CoVs) belong to the Coronaviridae family, collective of large,
spherical and enveloped viruses with single-stranded positive-sense RNA genomes
(+ssRNA). There are four genera, into the subfamily Orthocoronavirinae: α, β, γ ,
and δ-CoVs. SARS-CoV-2 is a β coronavirus [53].
Up to September 2020, more than 124,000 SARS-CoV-2 complete genomes have
been worldwide collected thanks to the Global Initiative on Sharing All Influenza
Data (GISAID). According to the phylogenetic categorization, the geographic and
genomic distribution of the mutations have been analyzed, resulting in six clades
(i.e., clade: composed of a common ancestor and all its lineal descendants). The
original clade L emerged in China in December 2019 is the most common and the
reference genome. The first mutated virus, clade S, appeared at the beginning of
2020, followed by the simultaneous apparition of the clade V and the clade G in
January 2020 in Europe, and the G-derives clades (GH and GR) arrived in North
America and Asia in March 2020. The G, GH, and GR are the most common clades,
counting for 23, 22, and 29%, respectively, of the analyzed genomes. GR is the most
frequent clade in Europe and South America, GH in North America, G in Africa, in
Oceania the clades are balanced, and the G, GH, and GR clades prevalence are rising
in Asia [88].
Structurally, SARS-CoV-2 has a large RNA genome of approximately 30 kb,
i.e. approximately 30,000 nucleotides (A, G, C, U), enveloped by a lipidic bi-layer
[88]. Four structural proteins are considered essential for the virus-cell assembling,
leading to infection: protein S (spike protein), protein E (envelope), protein M (mem-
brane), and protein N (nucleocapsid) (Fig. 1) [129]. Protein S mediates host-receptor
interaction and membrane fusion, being critical for the virus infection capacity and
tropism. The protein S host-receptor is angiotensin-converting enzyme 2 (ACE2)
[79]. SARS-CoV-2 proteins E, M, and N need to be further characterized, even though
their functions can be approximated from previous CoVs studies. Protein E plays a
role in the virion assembly and the viral egress, the stress response in the host, and has
ion channel activity [109]. Protein M interacts with the protein N to encapsidate the
RNA genome and promote membrane curvature [93, 115]. Protein N stabilizes the
viral RNA by binding directly, forming the ribonucleoprotein. Moreover, N protein
can repress RNAi activity and interfere with the cell cycle’s progression by inhibiting
the S phase [129, 137].
3.2 Diagnostic Testing for SARS-CoV-2
Several efforts have been made to develop tests to diagnose SARS-CoV-2 infected
patients. The Foundation for Innovative New Diagnostics (FIND) holds a search-
able database showing the current status of SARS-CoV-2 tests in development and
Fig. 1 Graphical representation of the Human Coronavirus structure. SARS-CoV-2 is an ≈100 nm

diameter +ssRNA enveloped virus, four essential structural proteins are shown. Apadted from
“Human Coronavirus Structure” by BioRender.com (2020)
commercialized [49], at the time of writing, 713 commercially available tests are
reported, including direct and indirect test target. Direct tests are designated to detect
virus elements like RNA nucleic acid or viral antigens. Nucleic acid amplification
tests (NAAT) such as RT-PCR are recommended due to their high sensitivity and
specificity. On the other hand, antigen tests have an advantage over their rapidity,
straightforward interpretation, and less equipment and infrastructure requirements.
Nevertheless, sensitivity, specificity, and false-negative rates need to be improved
[71, 111].
Unlike direct tests, indirect tests do not target a viral element. Instead, antibod-
ies (Ab) developed as an immune response for infection are detected (serologi-
cal diagnosis), helping to determine whether the individual tested was previously
infected, even being asymptomatic [22]. Antibody test development requires anti-
genic viral-proteins identification, which triggers specific antibodies as acquired
immune response; antibody-test specificity relies on avoiding cross-reactivity with
similar viruses [71, 111]. Comparing to RT-PCR, indirect testing is advantageous
because it is less workload and less time-consuming. Nevertheless, the presence of
antibodies depends on the clinical host response, which is not yet fully understood.
The dynamics of antibodies against SARS-CoV-2 has been studied, showing that the
most sensitive and first detectable serological marker is total antibodies, which have
been found positive as early as six days post symptom onset (dpso), increasing at the
second week, with a median of 9 days, followed by IgM and IgG seroconversion with
a median of 10 and 12 days, according to [78], and 11, 12, and 14 days, respectively,
according to [140].
Currently, the SARS-CoV-2 confirmatory laboratory diagnosis relies on NAAT.
Serological testing is a supporting diagnosis tool when NAAT assays are negatives,
and there is a strong epidemiological link to COVID-19 infection [125]. In the study
of [140], 173 patients were enrolled, and the dynamics of Ab with the disease pro-
gression were analyzed. In the first seven days of illness, RT-PCR has the highest
sensitivity (66.7%), while the Ab test presents a lower positive rate (38.3%). Then,
in the middle phase (8–14 dpso), the sensitivity of Ab (over 90% across 12 dpso) sur-
passes the RT-PCR test (54%). In the later phase (15-39 dpso), viral RNA was only
detectable in 45.5% of samples, in contrast to the sensitivity of Ab, IgM, and IgG,
which were 100, 94.3, and 79.8% [140]. These findings suggest that both, direct and
indirect tests, have a role in diagnosis, and combined could improve the diagnostic
sensitivity and clinical management for COVID-19 patients according to the phase
of the illness to enhance the monitoring and response to SARS-CoV-2 spreading [71]
(Fig. 2).
An indirect diagnosis is an essential tool to follow the immune response progres-
sion in COVID-19 patients and identify the seroconverted individuals to determine
the proportion of a population previously infected with SARS-CoV-2. By studying
demographic and geographic patterns of seroconversion can help determine which
communities may have experienced a higher infection rate [22]. Nevertheless, sero-
logic tests should not be used to determine if an individual is immune, the WHO
scientific brief of April 24, 2020 [124], states
No study has evaluated whether the presence of antibodies to SARS-CoV-2 confers immunity
to subsequent infection by this virus in humans, at this point in the pandemic, there is not
enough evidence about the effectiveness of antibody-mediated immunity to guarantee the
accuracy of an “immunity passport” or “risk-free certificate”
The duration of the antibody response to SARS-CoV-2 is still unknown. How-

ever, it is known that antibodies to previous coronaviruses as SARS-CoV-1 (the
virus that caused SARS) wane over time, concentrations of IgG remained high for
approximately 4–5 months before subsequently declining slowly during the next 2–3
years, and reinfections have been shown [63, 131]. For SARS-CoV-2, IgM and IgG
antibody levels may remain over seven weeks (Fig. 2) [134].
The immune response to COVID-19 is not fully understood yet. Sero-
epidemiological studies that follow infected individuals immunity over a prolonged
period are required, in order to establish whether recovery from COVID-19 confers
a long-lasting or a temporary immunity against reinfection [65]. An overview of the
published sero-epidemiological findings in EU/EEA Member States was updated on
June 30, 2020, showing that the general population has still low levels of seropositiv-
ity [45]. For example, in a study conducted in Spain a 5.47 and 38.5% IgG prevalence
in asymptomatic (n = 311) and symptomatic (n = 634) individuals,respectively, was
found [18].
3.3 Clinical Characteristics of COVID-19 and Their

Progression
Infected individuals that develop symptoms of COVID-19, typically show them

within 5 days after being infected [16, 73, 74]. The first symptoms to appear are
Fig. 2 Clinical, epidemiological, and detection COVID-19 timeline. The onset of symptoms is rep-
resented as the starting point (day 0). The previous stage is considered as the asymptomatic period,
which includes the Latency and Incubation periods. The viral load could be detected with higher
sensitivity, while clinical manifestations are present. Antibodies-detection sensitivity increase since
the second week, surpassing the RT-PCR sensitivity. Antibody’s prevalence duration is not fully
unraveled yet
usually related to upper airways infection such as congestion or runny nose, nonpro-
ductive cough, sore throat accompanied with fever or chills, fatigue, muscle or body
aches, headache, loss of taste or smell, nausea or vomiting, and diarrhea [132].
Of those individuals whose symptoms would require medical aid, the first visit
to the clinic happened in a median of 3 days since the apparition of the symptoms
[27]. Some patients develop difficulty breathing, pneumonia with or without symp-
toms, mostly dyspnea. The median time from onset of symptoms to shortness of
breath is 8.0 days [60]. Patients with complications such as acute respiratory distress
syndrome (ARDS), would require intensive care (ICU) and mechanical ventilation
within 10.5 days from the onset of symptoms [60], while more severe cases would
require intubation within 14.5 days [142]. The next stage is decisive. Patients could
be healed, or sadly, are defeated by the disease. Death occurs in a median of 18.5 days
after symptoms onset [142]. A recovered patient is discharged in a median of 22 days
post symptom onset (Fig. 2). For survivors, the median duration of viral detection
is 20 days from illness onset. The shortest observed period of viral shedding among
survivors is eight days, whereas the longest is 37 days [83, 142].
As revised above, knowledge about SARS-CoV-2 and COVID-19 has grown
impressively fast, and so has the amount of data produced. Nevertheless, raw data
is not enough to deal with the pandemic; thus, mathematical, statistical, and com-
putational tools are required to process and cast forecasts of the ongoing pandemic
progression. In the following sections, we study relevant statistical and mathematical
models to better understand the disease progression under uncertainty.
3.4 Epidemiological and Temporal Parameters of COVID-19

Progression
Knowing the disease’s temporal progression is fundamental to policy-makers and

decision-taking actors, both for pharmaceutical and non-pharmaceutical interven-
tions (NPIs). Although six other coronaviruses-caused colds have been described,
COVID-19 is a novel disease, and the timeline information can not be directly inferred
from other coronavirus infections. Efforts have focused on accurately estimating the
temporal parameters associated with COVID-19 infection, as early as data was avail-
able. Some relevant epidemiological and clinical parameters are:
• Incubation period is defined as the time between infection and appearance of the
first symptoms [105].
• Latent period is the time between exposure and become infective [9].
• Infectious period is the time for which an individual is infective, able to spread
the virus to someone else. It can start before, during, or after the symptoms onset,
and it might finish before or after the manifestation of the symptoms [9].
• Serial interval is defined as the duration between symptom onset of an infector
(e.g., a primary case) and that of an infectee (e.g., a secondary case) in a transmis-
sion chain [80].
• Basic Reproduction Number R0 represents the number of persons a single
infected individual might infect before either recovering or dying, in a naïve pop-
ulation [100]. This number remains constant and gives a scale of the infectivity of
the disease/pathogen.
• Effective Reproduction Number Rt represents the number of persons a single
infected individual might infect before either recovering or dying, in a population
that is aware of the disease and some intervention measurements might be in place
[100]. This number evolves over time, with a characteristic timescale related to
behavioral changes of the population under study.
3.4.1 Incubation Period
The incubation period varies from person to person. Still, a characteristic range can
be determined for a disease. For COVID-19, this range is roughly estimated as five
days, with some variations depending on the dataset, and the analysis used [76].
One of the first studies was conducted by Li et al. [74], establishing a mean of 5.2
days (95% confidence interval [CI], 4.1–7.0, with 95% of the distribution at 12.5
days). Lauer et al. [73] estimated the length of the incubation period, in a pooled
analysis of 181 COVID-19 cases reported between 4 January and 24 February 2020,
obtaining a median of 5.1 days (95% CI, 4.5–5.8 days), and 97.5% of those who
develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection.
Then, based on 183 cases with a well defined period of exposure and symptom onset,
Bi et al. [16] estimated the median incubation period to be 4.8 days (95% CI 4.2–5.4)
and calculated that 95% of those who develop symptoms will do so within 14 days
(95% CI 12.2–15.9).
3.4.2 Latent Period
To identify the exact time accurately at infection occurs is challenging, and so is

to establish the end of the latent period and the beginning of the infectious period
because infectiousness can not be assured solely by laboratory confirmation trough
an RT-PCR. The presence of viral RNA in an individual does not indicate that viral
load can infect cells or whether the individual is infectious or not, and can not account
when an infection began. A positive result indicates that a person was in contact with
the virus in the past. Besides, viral nucleic acids can still be present weeks after viral
clearance and clinical discharge [62]. SARS-CoV-2 RNA can be detected by RT-PCR
1-3 days before symptom onset, with the highest viral load around the onset day [126]
He et al. [57, 58], based in 77 transmission pairs obtained from publicly available
sources, had statistically inferred that the infectious period starts from 12.3 days
(95% CI, [5.9–17.0 days]) before symptom onset and peaked at the onset (95%CI, [–
0.9–0.9 days]) and only 9% of the transmission would occur before three days before
symptom onset. Therefore the estimated presymptomatic infection was 44 (95% CI,
[30–57%]). Besides, infectiousness was estimated to decline quickly within seven
days. In a different study, a median estimate of 3.69 and 3.47 days for the latency and
infectious period was inferred [75]. In addition, Ma et al. [80] estimated the upper
limit of latent period as 2.52 days (mean 95% CI, median 1 day) (Fig. 2).
3.4.3 Viral Infectivity and Serial Interval
To assess viral infectivity, cell-culture assays are required. By infecting Vero cells
–cell line isolated from kidney epithelial cells extracted from an African green
monkey– and observing the cytopathic effect, it is possible to evaluate whether the
virus can replicate and infect cells at which rate [59]. Despite this is the golden stan-
dard to predict infectivity, this is not recommended as a WHO’s routine diagnostic
tool because of their implementation requirements (Biosafety level III) [125]. Never-
theless, several studies have been conducted to relate SARS-CoV-2, RT-PCR results,
and infectiousness [62] (see, e.g., andreferencesthereinforasyntheticreviewofthem).
Most relevant studies use respiratory samples (nasopharyngeal, oropharyngeal, and
sputum samples) because they are the primary specimen to be collected, as recom-
mended by the WHO. For example, in the study of [19], positive viral culture was
only observed up to 8 days after symptoms onset. Viral shedding occurs when a virus
is released from an infected host; it may or may not be contagious. The minimum
duration of RNA shedding (i.e., viral RNA release from an infected host) detected
by PCR was seven days, while the maximum was 35 days after symptom onset [62].
Infectiousness profile, viral shedding kinetics, and viral culturability were correlated,
suggesting that 68.4% (n = 1251, 95% CI, [67–69.7%]) of the infections, instead of
the 44% predicted by [57, 58], occur before symptoms onset [104].
The serial interval is estimated by identifying infector-infectee pairs, that is, the
time between two consecutive infection. For COVID-19, its mean ranges between
5.1 and 7.5 days (5.1 days, 95% CI [1.3–11.6] [138]; 5.8 days, 95% CI [4.8–6.8]
[58]; 6.3 days, 95% CI [5.2–7.6] [16]; 6.7 days, 95% CI [6.31–7.1] [80]; 7.5 days,
95%, CI [5.3–19] [74]).
3.4.4 Basic Reproduction Number R0
Basic reproduction number R0 is one of the most used epidemiological parameters,

for COVID-19 it has been estimated in different periods of infection and in different
geographical regions. Data for the first 435 confirmed cases in Wuhan were analyzed,
estimating R0 to be 2.2 (95% CI, [1.4-3.9]) [74] agree with studies in the similar
period of time (R0 2.38 (95% CI, [2.03-2.77]) [75]; R0 2.68 (95 % CI, [2.47–2.86])
[130]). A meta-analysis and systematic review of 23 studies with 29 records that
estimated the R0 of COVID-19 were analyzed, according to the results of the random-
effects model, the pooled R0 for COVID-19 was estimated as 3.32 (95 % CI, [2.81-
3.82]) [3].
3.4.5 Effective Reproduction Number Rt
The effective reproduction number is a widely used parameter representing the per
capita number of offspring infections characteristic of a certain disease. This num-
ber is linked with the system’s stability. As when greater than one would evolve
to an uncontrolled outbreak, while when lower than one, the outbreak size would
decay exponentially. Its calculation, however, is not straightforward. Unlike R0 , the
effective reproduction number Rt does not assume a naïve population. It will vary
depending on the viral characteristics, isolation measures, physical distancing, and
immune population state, among others. If Rt > 1 the disease will propagate into the
population. In a pandemic outbreak, vaccination could bring Rt below 1. The herd
immunity threshold (HIT) is the proportion of a population that needs to be immune
to become stable for an infectious disease.
Herd immunity confers indirect protection to susceptible individuals when is a
large proportion of immune individuals in a population. In the simplest models, the
herd immunity threshold depends on the basic reproduction number R0 and can be
defined as 1 − 1/R0 [4]. Consequently, the main goal of vaccination is to keep Rt <
1. For this purpose, the population should exceed the herd immunity threshold with
immunity. For SARS-CoV-2, given an R0 ∼ 3, HIT is around 67 %, which means that
67 % of the population must acquire immunity for infection starting to decline[106].
3.5 Post-infection Immunity
As mentioned previously, whether a complete or partial post-infection immunity is

kept after SARS-CoV-2 infection remains uncertain. Nevertheless, several vaccine
prospects have been developed, 40 of them are currently in clinical evaluation. More-
over, Ri11 of these are in phase 3 [123]. A brief compilation of them is presented in
Table 1.
4 Data Generation and Test-Trace-and-Isolate Logistics in

COVID-19
Even though data is reported in a daily basis, the reported infections are likely to
underestimate the extents of the pandemic; new cases would only be spotted through
testing, and most of the reported cases acquired the virus from an carrier with-
out symptoms [75]. Moreover, delays in case-reports and discrepancies in clinical
discharge criteria worldwide induce errors that might propagate to models-derived
parameters [33].
It has been reported that a great part of contagions occur in the presymptomatic
period of the infected individual [7], accounting for 44 % (95 % CI, 30–57 %) of the
total infections [57, 58]. Moreover, a fraction of individuals, the so-called asymp-
tomatic carriers, would never develop symptoms through the timeline of the infection,
thus challenging any control strategy [98]. In addition, they seem to have similar viral
load as symptomatic cases, thus being detectable by RT-PCR [8]. The asymptomatic
ratio ξ relies on the homogeneity of the population under study, as great variability
has been reported to date in different populations and contexts. As subjects carrying
symptoms or having contact with infected individuals are more likely to be tested
[55], researchers have pointed a collidor bias as the reason for such variability in ξ
[20, 25]. Using unbiased studies and meta-analysis techniques for correcting bias in
the case of suspecting it, the RT-PCR-derived asymptomatic ratio ξ has been esti-
mated to be 15 % (95% CI: 12–18%) overall [20]. Nevertheless, Pollán et al. [103]
reported that around a third of the seropositive patients considered in their study were
asymptomatic, suggesting that ξ varies slightly when different tests are considered.
Even though in normal conditions asymptomatic individuals would be more likely
to have close contact with other individuals, not having symptoms would decrease
considerably their contagion potential, as fewer aerosols/droplets would be produced
[56]. Besides, some symptomatic individuals would avoid at any cost contact with
authorities, and therefore, any SARS-CoV-2 testing facility, setting an intricate trade-
off between public-health matters and individual freedom [84]. Individuals refusing
to be tested have been modeled, in mean field, as if they virtually behave as hidden
asymptomatic infections [34].
In principle, it would be possible to test randomly selected individuals to estimate
the true disease prevalence in a population. However, if the disease prevalence is
Table 1 Vaccine candidates in Phase 3 Clinical Trial

Vaccine developer/ Type of candidate Number Route of Clinical trial
manufacturer vaccine of doses administra-
tion
University of Non-replicating 2 Intramuscular ISRCTN89951424
OxfordAstraZeneca Viral vector NCT04516746
ChAdOx1-S NCT04540393
CTRI/2020/08/027170
CanSino Biological Non-replicating 1 Intramuscular NCT04526990
Inc.Beijing Institute Viral vector NCT04540419
of Biotechnology Adenovirus Type 5
vector
Gamaleya Research Non-replicating 2 Intramuscular NCT04530396
Institute Viral vector NCT04564716
Adeno-based
(rAd26-S+rAd5-S)
Sinovac Inactivated 2 Intramuscular NCT04456595
669UN6.KEPEC2020
NCT04582344
NCT04617483
Wuhan Institute of Inactivated 2 Intramuscular ChiCTR2000034780
Biological Prod- ChiCTR2000039000
uctsSinopharm NCT04612972
Beijing Institute of Inactivated 2 Intramuscular ChiCTR2000034780
Biological Prod- NCT04560881
uctsSinopharm
ModernaNIAID RNA 2 Intramuscular NCT04470427
LNP-encapsulated
mRNA
BioNTechFosun RNA 3 2 Intramuscular NCT04368728
PharmaPfizer LNP-mRNAs
Janssen Pharmaceu- Non-replicating 12 Intramuscular NCT04505722
tical Companies Viral vector NCT04614948
Ad26COVS1
Novavax Full length recom- 2 Intramuscular 2020-004123-16
binant NCT04611802
SARS CoV-2
glycoprotein
nanoparticle
vaccine adjuvanted
with matrix M
low, very little information is garnered from each individual test [13], and intensive
random testing would lead to a greater number of false-positives than true-positives
[65]. Even using highly specific and sensitive tests, false-positive and false-negatives
would accumulate in the case of mass-testing, thus misleading political interventions
[54]. For the evaluation of indirect test performance, we need to consider the preva-
lence proportion in the population, namely, the probability of selecting an individual
with either the infection or antibodies to it. Prevalence changes as more people are
infected and develop protective antibodies. The number of false positives and wrong
positive tests depends on the prevalence proportion. For example, for a test with
70% sensitivity and 98% specificity, the proportion of positive tests that are wrong is
35% at 5% population seroprevalence (19 false positives/1000 tested), 13% at 20%
seroprevalence (16 false positives/1000 tested) and 3% at 50% seroprevalence [71].
Even when using a high sensitivity and specificity test, a high false positives rate
could result when the population prevalence is low [70].
It has been reported that an intensive random testing in a population where the
virus prevalence is low would produce a greater number of false positive than true
positives [65, 71]. Therefore, localized random sampling is suggested only when
suspecting a secondary outbreak, which might arise in certain susceptible pockets
within the population, even when the overall reproduction number is lower than one.
Given that, as discussed above, 44 % of the total infections occur in the absence
of symptoms, and that the basic reproduction number R0 of COVID-19 is around
3.32 (95%CI of [2.81–3.82]) [3], testing and isolating policies alone are likely to
be not enough for controlling an outbreak, also requiring the implementation of
contact tracing strategies [50]. Consequently, the evaluation of effective tracing of
contacts in the absence of intense political interventions or cost-effective random
testing strategies, is imperative. As many infections can occur without symptoms
[48], isolation of symptomatic cases and contact tracing alone are unlikely to contain
an outbreak unless a high proportion of cases are isolated and contacts successfully
traced and quarantined [52, 66, 67]. Moderate physical distancing measures and self-
isolation would be more likely to achieve control when combined with testing and
contact tracing [47, 66]. Nevertheless, it would be extremely difficult to decouple the
effectiveness of sets of several measures applied together (for instance, lockdowns,
social distancing, use of face masks), to determine at which time to modify them,
and whether a subset of them would have had a similar impact [2, 41, 48].
Different combinations of Test-Trace-Isolate (TTI) strategies have been used to
reduce/control the spread of COVID-19, according to the local current status of the
outbreak and the legal framework [30]. Strong RT-PCR based TTI can be used when
the incidence of the virus is sufficiently low, or when the suppression strategies have
reached a partial control of a major spreading event [39]. Similarly/Accordingly,
[116] proposed compartmental model with compartments for diagnosed and undiag-
nosed individuals, which was subsequently used to model the health and economic
impacts of population-wide TTI Strategies in the UK [32, 97].
5 Compartmental Mathematical Models for COVID-19
Compartmental epidemiological models have been widely used for modelling

COVID-19, with different levels of success worldwide [1, 36, 82, 96, 116, 136]
(see, e.g., andreferencesthereinforabriefreviewofthem). To understand the reasons
why these models have succeeded (or failed) to catch the main trends on the evolu-
tion of this pandemic, we must explore the limitations set in the underlying hypothe-
ses they rely. Despite their particularities, most of them are modifications of the
well-known Susceptible-Infected-Removed SIR model, proposed by Kermack and
McKendrick [64]:
dS βSI
=− , (1)
dt N
dI βSI
= − γ I, (2)
dt N
dR
= γ I. (3)
dt
In the SIR and other compartmental models, the whole population is compart-
mentalized and divided according to their role in the spread of the disease. The
susceptible S individuals are all those that can be infected, should they have signif-
icant interaction with infected individuals. The exposed E compartment accounts
for those individuals that were infected, but are not yet infectious. After the latency
period of the infection, individuals from E would migrate to the I (infected) com-
partment, where they remain until their infection results either in recovery or death
(compartments R and D, respectively). Some diseases, as COVID-19, can be spread
by asymptomatic carriers A, which might not present evident symptoms but remain
infectious. More complex models also involve compartments for fractions of the
populations with remarkable behavioural differences, as age groups, social groups,
territorial and hierarchical models, geographical isolation of communities [36, 51],
etc. The core assumptions are rather the same for all of them:
1. The population is large enough, so that the sizes of each compartment can be
considered as continuous variables.
2. Births and -natural- deaths occur at the same rate, or in a timescale much larger
than the one of the infection.
3. Main-field interactions: All susceptible individuals have the same probability of
getting infected, or in other words, all individuals are simultaneously interacting.
4. The different compartments are assumed to be homogeneous, so that the individ-
uals within share common epidemiological parameters, as infectiousness, typical
contacts, susceptibility, recovery/death rates, among others.
Restricting our search to those epidemiological models recently proposed, tailored

for representing the COVID-19 spreading dynamics, we find SIR [17, 28, 113], SIRD
[10, 21, 46], SEIR [99, 135, 136], and other remarkable contributions that aimed to
evaluate the effectiveness of public-health measures [1, 68, 96].
5.1 SEIR Models
SEIR compartmental models include a compartment for those individuals that have
been exposed to the virus, but whose viral load has not yet reached the transmission
threshold. The exposed compartment E acts as a delay between the acquisition of the
virus and infecting other susceptible individuals. The parameter ε = t1c is the rate at
which exposed individuals become infectious, which happen after the latency period
tc . The differential equations governing the dynamics are similar to those for the SIR
model:
dS βSI
=− , (4)
dt N
dE βSI
= − εE, (5)
dt N
dI
= εE − γ I, (6)
dt
dR
= γ I. (7)
dt
From the modelling perspective, SEIR models can be easily modified to include
as many compartments as required. In the Case Study of Sect. 8.2, we present a
SEIRDM model with compartments for deaths (D) and vaccinated (M) individuals,
providing modelling guidelines and qualitatively evaluating different scenarios.
5.2 Estimation of the Effective Reproduction Number Rt

from Compartmental Models
As discussed previously, the reproduction numbers (effective, basic) are critical

parameters for understanding an infectious disease’s spreading dynamics. Differ-
ent challenges arise from their estimation and correct interpretation. For instance,
if we understand the reproduction number as the number of offspring infections an
infected individual generates -on average-, it would be a behavioral-driven parame-
ter, driving the contagion dynamics. Nevertheless, Contreras et al. [34] showed that
even when knowing the ground-truth Rt , addressed as the hidden reproduction num-
ber by the authors, the data-driven observed values of it would differ considerably. In
this section, we will further discuss the methodologies presented in [37], and one of
the Robert Koch Institute, a major health advisory institution of the German govern-
ment [108]. We will also conciliate both approaches from a modeling perspective,
to consequently apply them in the Case Study of Sect. 8.1.
5.2.1 Data-Driven Rt Derived from a Time Dependant SIR Model
As the timescale where public actions would become noticeable from data is longer
than the resolution of the data, we can assume that, in short time-frames, epidemio-
logical parameters are likely to remain constant. In such configuration, the spreading
dynamics could be well-described by a simple SIR model, represented by Eqs. 1–3,
but with time varying parameters β = β(t), γ = γ (t). Assuming that in a given
time-frame I , which can coincide with the temporal resolution of the data, the epi-
demiological parameters remain constant β = βi and γ = γi , we can derive an easy
βi
expression for Rt ≈ as follows. If we assume the infected individuals could be
γi
expressed as a function of the susceptible population, it would make sense to compute
its derivative:
dI dI dS
= , (8)
dt dS dt
where we applied the chain rule, and every variable is evaluated accordingly. After
replacing Eqs. 2 and 1 in 8, we obtain:
dI 1 N
= −1 + , (9)
dS Rt S
Following the formalism of [37], after using the hypothesis NS ≈ 1, we write the
discrete version of the equation in the time-frame discussed above:
I 1
= −1 + . (10)
S Rt
By definition, summing all the compartments X i would retrieve the total population.
Therefore, summing all the variations in a given time-frame should add up zero:

X i = N =⇒ S = − X. (11)
i X = S
Even though its equation was not included explicitly, deaths due to COVID-19 are
often reported among the other variables, so we may write Eq. 11 as
S = −I − D − R. (12)
Then, after replacing this expression in Eq. 10, we obtain

I
Rt = + 1, (13)
R + D
where I , R, and D, represent the new reported infections, recoveries and deaths
in the estimation time-frame. Understandably, errors in the data would drastically
impact the reported values for Rt , as will be discussed further in the case study 1.
To emphasize its importance, we can get an approximate analytical solution to the
number of infections in terms of Rt . In the so-called exponential phase of the outbreak,
we can safely assume that most of the population is susceptible to contagion, and
therefore NS ≈ 1. Under this assumption, Eq. 2 becomes a first-order linear ODE:

βS
I =I − γ ≈ γ I (Rt − 1) , (14)
N
which has a unstable bifurcation when Rt = 1, exhibiting an exponential growth or

decay depending whether Rt is, respectively, greater or lower than 1, as its solution
is
I = I0 exp (γ (Rt − 1) t) . (15)
5.2.2 Use of the Serial Interval to Infer Rt
Another approach to the time-dependant evolution of Rt is reached by the use of

the serial interval tSI , namely, the time-frame between a successful infection and the
secondary onset of infectivity [94]. Note that this value is coupled with the local
behavioral characteristics of the spreading dynamics, as the time between the start
of infectiousness (end of latent period) and the first successful contagion depends
on the contact pattern and the contagion probability. Therefore, assuming a constant
value for tSI also constitutes an approximation. This approach has also been referred
as “model-free”, as they underlying hypotheses are rather invariant to the choice of
a model [40].
By its definition, if we compare the number of new infections at a given time
T (t) with the ones registered one serial interval behind (T (t − tSI )), we would
assess the effective number of offspring cases which come from one infection
T (t)
R̂t = (16)
T (t − tSI )
To minimize the impact of day-to-day variability and temporal misclassification,

several smoothing procedures can be applied.
If we assume that spreading dynamics are well represented by a given epidemi-
ological model, for instance an SIR model, we can compute each epidemiological
variable in terms of the involved parameters, as the solution of the set of differential
Eqs. 2–3. From them, we infer that the new daily cases are the positive term in Eq. 2:
S
T (t) = β I. (17)
N
Under the hypothesis for which Eq. 14 was derived and after solving it for an
arbitrary initial condition, we can rewrite Eq. 16:
exp (γ (Rt − 1) t)
R̂t ≈ = exp (γ (Rt − 1) tSI ) . (18)
exp (γ (Rt − 1) (t − tSI ))
From Eq. 18 we may extract two main results:

• Variations in the definition of the serial interval would distort the understanding
of the dynamics. In the context of tSI , an R̂t value of 1 would say that the new
infections at time t match the expectation from time t − tSI ; the disease spreading
is critically controlled, as every infection generates only one within the time only
one was expected. Any other value of R̂t would account for an accelerated spread
(if greater than one), or a controlled outbreak (if lesser than one).
• Estimations of R̂t do not necessarily match in value the ground-truth reproduction
number of the disease Rt , as reported by Contreras et al. [34]. Yet, they expose
the same tipping point of the dynamics when they reach the value 1, for any
tSI > 0. This is the typically addressed tipping point which separates exponential
growth from exponential extinction at the first stages of an outbreak. Nevertheless,
as will be shown in the next section, others can arise from non-pharmaceutical
interventions (NPIs), as the test-trace-and-isolate strategies.
5.3 On the Conditional Stability of the System: Nations

Relying on TTI for Controlling the Dynamics
Testing, contact tracing, and isolation of infections (TTI) have proven to curb the
spread of infectious diseases. The fundamentals behind it are based in the infection
timeline: from contagion to the onset of symptoms and subsequent testing/isolation,
several contacts occurred. Those contacts might or not cause an infection, represented
as purple dots in Fig. 3. After testing, the health authorities would try to capture all
the different contacts in the estimated timeline, catching a fraction of those that were
positive, depending on how efficient and timely they were (yellow contour line in
Fig. 3).
Depending on the clinical progression in symptomatic individuals, and the infec-
tiousness timeline, different combinations of them might be required [50]. The moti-
vation for TTI and other non-pharmaceutical interventions (NPIs) is the same: to
reduce the effective reproduction number Rt of the disease. As contact-distancing
and strong public policies inflect considerable collateral damage—which is still to be
addressed for the ongoing pandemic—, the aim is to have Rt as large as possible, as
long as the outbreak is controlled. Even though testing capabilities are, in principle,
adaptable to match the required levels, contact-tracing is intrinsically challenged by
Infection Symptoms
Latency Isolation
Days
Contacts
Fig. 3 Throughout the infection timeline, as schematized here for the case of symptomatic infection,
indicates the evolution of the viral load, the number of contacts (dots) and successful infections
(purple dots). After being diagnosed, health authorities would trace previous contacts, catching a
fraction of them (covered by the yellow curve). Understandably, some of the infections produced
may be lost, thus remaining hidden
logistics and an intricate legal framework. The above translates to a tracing delay and
a limited case-handling capacity, above which contacts would not be timely traced
before producing offspring infections [34].
In that way, a second non-trivial tipping-point in the spreading dynamics, namely,
the transition between controlled and uncontrolled outbreak, arises from a TTI-
conditioned system. Assuming that testing and social distancing alone cannot curb
the spread of COVID-19, the sufficient condition would be granted by the contact-
tracing efforts—which, as discussed above, are limited—. In this configuration, major
outbreaks would be prevented by the timely identification of contact-chains and the
pre-symptomatic (and asymptomatic) infections within. If the health authorities’
tracing capacity were overwhelmed at a given moment, those cases would remain
unidentified—or hidden, in the words of [34]—thus continuing their chain of infec-
tions, resulting in a self-accelerating increase in case numbers. Given the previously
discussed particularities in the spreading dynamics of SARS-CoV-2, an uncertain
post-infection immunity, lack of immunization drugs, or effective vaccines, signifi-
cant behavioral changes must be kept on time to prevent secondary outbreaks, even
when the case numbers are relatively low.
6 “Nowcasting” of Infections: Statistical-Driven Curation

of COVID-19 Data
A non-trivial-to-solve problem regarding data-treatment arises from the different

delays associated with the infectiousness and overall infection timeline, as presented
in Fig. 2. From effective contagion to recovery, different periods are distinguishable
and relevant for different features of the spread. Namely, the incubation period tc
of SARS-CoV-2, which is the time between the effective contagion and the onset
Temporal
Reporting delay
reclassification
daily new cases reporting delay
s
om
si
io
tin
no
ag
s
pt
te
ag
nt
m
co
di
sy
day of effective day of
contagion report
Fig. 4 Schematic representation of the temporal reclassification methodology presented in [33]. In

our framework, we assume that cases are reported with significant delays from the day of effective
contagion. These delays can be due to the incubation periods (in the case of symptomatic infections),
delays in the contact-tracing scheme (especially for asymptomatic infections), or delays between
testing and diagnosis. Modeling these contributions through sensible random variables can help us
identify the most probable day of contagion so that the cases can be “reassigned” to the most likely
day of effective contagion
of symptoms, impacts severely the efficacy of contact-tracing schemes, especially

because individuals may get infectious before the onset of symptoms, making the
contention of the disease even more challenging. Moreover, other delays might occur
between the onset of symptoms, testing, diagnosis, report, and practical isolation. In
this section, we aim to model them when the objective is to retrieve the epidemio-
logical curve at the moment of effective contagion (also known as “nowcasting”), as
presented in [33] and schematized in Fig. 4.
To model the total delay between infection and case-report, we start with the
incubation period tc . We use tc with log-normal distribution, as reported in [73] and
suggested in [94]:
tc ∼ log N μ, σ 2 . (19)
We will sum up secondary delays, such as the symptom-to-testing and testing-to-

diagnosis time gaps, into a random variable td , which, for the sake of simplicity, will
be assumed to follow a uniform distribution between tmin and tmax :
td ∼ U ([tmin , tmax ]) . (20)
Further knowledge on the nature of factors affecting td could lead to a different

distribution, which is likely to vary between different countries and stages of the
pandemic. Let Z = tc + td be the random variable for the total delay, which distri-
bution function—obtained by the method of the convolution, assuming that tc and td
are independent—is given by
⎧
⎪ 0, ⎞⎤ if z < tmin
⎪
⎪ ⎡ ⎛
⎪
⎪ z − tmin
⎪
⎪ ln
⎪
⎪ 1 ⎢ ⎜ tc ⎟⎥
⎪
⎪ ⎢1 + erf ⎜ √ ⎟⎥ , if tmin ≤ z ≤ tmax
⎪
⎪ ⎣ ⎝ ⎠⎦
⎪
⎨
2 (tmax − tmin ) σ 2
f Z (z) =
⎪
⎪ ⎞ ⎞⎤
⎪
⎪ ⎡ ⎛ ⎛
⎪
⎪ z − tmin z − tmax
⎪
⎪ ln ln
⎪
⎪ 1 ⎢ ⎜ tc ⎟ ⎜ tc ⎟⎥
⎪
⎪ ⎢erf ⎜ √ ⎟ − erf ⎜ √ ⎟⎥ , if z > tmax .
⎪ ⎣ ⎝ ⎠ ⎝ ⎠⎦
⎩ 2 (tmax − tmin )
⎪ σ 2 σ 2
(21)
As data would be discretely-reported day by day, we estimate the probability mass

of a delay of exactly k days using the continuous approach:
k
pk = f Z (z)dz. (22)
k−1
To restrict its support, namely, the delay possibilities, we truncate and re-normalize
the distribution to a certain level U < 1:
P (Z ≤ n 1 ) ≥ U, (23)
Therefore, the statistical correction for the “now cast” of infections is given by
equation n 1
pk T (t + k)
Tcorr (t) = k=0
n 1 . (24)
pk
k=0
Note that the last equation can be rewritten as a convolution for enhancing compu-
tational performance.
7 Machine Learning-Based Models for COVID-19:

Applications to Forecast and Diagnosis
Machine Learning (ML) and Artificial Intelligence (AI) techniques have been widely
used to the study, prevention, and modelling of COVID-19 [72]. The principle behind
these approaches is using existing knowledge about a particular problem to predict its
evolution or a desirable response [90]. The learning type behind the model-training
algorithm depends on the required task: supervised learning for predictive models,
and unsupervised for clustering/pattern recognition. Current approaches also con-
template the use of self-learning, meta-learning, and reinforced learning [61]. In this
section, we present a comprehensive overview of current ML approaches aiming to
evaluate, curb, or forecast the evolution of the ongoing pandemic.
7.1 Prediction of COVID-19 Outbreaks and Case Numbers
One of the most relevant applications of ML-based models has been focused on
predicting COVID-19 outbreaks, providing an alternative to the extensively used
mathematical models. Ardabili et al. [6] propose a method based on multi-layer
perceptron and adaptive-network fuzzy inference system, contemplating variations
in the data sets represented by the number of infections at different points tn to predict
the value at point tn+1 , applied to countries such as Italy, China, Germany, Iran, and
the USA, achieving a correlation coefficient with their predictions above 0.9. Despite
its success, this method seems not to consider proper time series representations, as
the influence of timescales larger than the previous step is neglected [72]. Other
approaches combine logistic growth with Machine Learning techniques to predict
the number of infections, the rate of recovered, and the number of deaths [15, 26,
42, 120]. Time-series modeling and ARIMA autoregression models have also been
satisfactorily implemented to predict case-numbers and number of deaths in countries
such as France, Italy, Spain, and Brazil, among others [14, 23, 107, 114]. However,
as other data-driven approaches, these methods do not explicitly include relevant
parameters characteristic of COVID-19.
ML-based models also find applications in the prediction of relevant epidemi-
ological parameters, such as the reproduction number Rt . Approaches have been
proposed to predict this value from various data sources, using different modelling
strategies, algorithms, and performance metrics [29, 92, 117]. Medina-Ortiz et al.
[85] presents forecast models of Rt for different countries world-wide, following the
methodology proposed by Contreras et al. [37], combining ARIMA, logistic growth,
and supervised learning models. However, it requires a daily update to improve per-
formance metrics and estimate parameters efficiently for each associated country.
Recent methods have focused on developing hybrid prediction strategies, com-
bining Machine Learning and compartmental models [91, 136]. Pinter et al. [101]
proposes prediction methods to estimate the rate of infections and deaths based on SIR
models and machine learning methods in an adaptive network-based fuzzy inference
system (ANFIS), and multi-layered perceptron-imperialist competitive algorithm
(MLP-ICA). The validation was performed for nine days with promising results for
Hungary. Poirier et al. [102] proposes the use of mechanistic models in combination
with supervised learning algorithms, producing stable and accurate forecasts two
days ahead of the current time and outperforming a collection of baseline models
in 27 out of 32 Chinese provinces. Approaches applying cloud computing strate-
gies [118], internet search [77], and AI-Drive [81, 110] have also been successfully
implemented. However, its global applications require all countries to engage with
the same rigorously in data curation, validation, and resources to carry it out.
Despite the different methodologies applied and the great diversity of proposed
predictive models including Machine Learning, predictions remain inaccurate in
broader forecast windows. This affirmation straightforward to explain by the data-
dependency of all these methods.
7.2 ML Models in COVID-19 Diagnosis
Machine Learning and data mining methods have played a fundamental role as
COVID-19 diagnostic tools, especially by their application to chest x-ray images [5,
112, 133]. Elaziz et al. [44] proposes a Machine Learning method based on Fractional
Multichannel Exponent Moments (FrMEMs) for feature extraction, achieving 96%
accuracy in diagnosis. Similarly, Nour et al. [95] offers a predictive model based
on the SVM classifier achieving an accuracy of 98.97%, a sensitivity of 89.39%, a
specificity of 99.75%, and an F-score 96.72%.
As an information extraction strategy, methods based on the Convolutional Neural
Network are used, whilst Bayesian inference is preferred for parameter fitting tasks.
Wang et al. [121] proposes a novel method using Deep Learning to classify Computed
Tomography (CT) images for supporting positive diagnosis cases, achieving a total
accuracy of 82.9% with a specificity of 80.5% and sensitivity of 84%. Another
approach with similar datasets was proposed by Wang et al. [122] applying Bayesian
Optimization Convolutional Neural Network methods to classify the patients into
high-risk and low-risk groups, reporting a performance of AUC = 0.87. Despite the
performance being lower compared to other similar approaches, this method was
trained with the largest dataset, thus providing a major generalization of the patterns
related to risk level on diagnosis COVID-19. Finally, one of the most relevant methods
has been proposed by Mei et al. [87], who argues that the information obtained by
CT images may be deficient, which is why complementary clinical procedures are
required to corroborate the diagnosis. They used Machine Learning in combination
with chest CT findings, clinical symptoms, exposure history, and laboratory testing
to diagnose patients who are positive for COVID-19, validating their results with the
RT-PCR diagnosis of 905 patients (419 positive for SARS-CoV-2), achieving an area
under the curve of 0.92 and sensitivity similar to a senior thoracic radiologist. The
AI system also improved detecting patients who were positive for COVID-19 via
RT–PCR who presented with standard CT scans. Besides, Mei et al. [87] suggested
that when CT scans and associated clinical history are available, their AI system can
rapidly diagnose COVID-19 patients.
7.3 ML Applied to Drug Discovery
One of the most relevant applications of Machine Learning methods in biotechnol-

ogy and protein engineering is related to identifying drugs or candidate targets for
drug design. Different computational strategies have been implemented to identify or
design a compound with a clinical effect on SARS-CoV-2 [69, 119]. Batra et al. [11]
combined machine learning (ML)-based models and ensemble docking studies to
enable rapid screening of possible therapeutic ligands. This method was used target-
ing the binding affinity of molecules for either the isolated SARS-CoV-2 S-protein at
its host-receptor region, or the S-protein-human ACE2 interface complex. Screening
datasets of drug and biomolecules that might disrupt the host-virus interactions they
found 75 ligands approved by the Food and Drug Administration, further validating
them by all-atom docking studies. Other relevant approach was proposed by Zha-
voronkov et al. [141]. The authors used a proprietary pipeline to find inhibitors for
the 3C-like protease. Their models use three types of input: First, the protein’s crystal
structure, second, the co-crystallized ligands, and finally, the homology model of the
protein. For each input type, the authors fit 28 different models, including Generative
Autoencoders and Generative Adversarial Networks, exploring potential candidates
using a reinforcement learning approach with a reward function that incorporates
measures of drug-likeness, novelty, and diversity. Besides, they confirm that the
identified candidate molecules are dissimilar to existing compounds, suggesting that
they have indeed found novel candidate drugs.
In general, computational methods for drug discovery rely on candidate recog-
nition based on phylogenetic, thermodynamic, or structural properties, which are
evaluated by applying ML-based predictive models. Finally, the selected candidates
are validated, employing structural simulation techniques or molecular dynamics for
assessing if the protein-ligand interaction is feasible in terms of energy. Despite the
usefulness of these methods, the particularities of each molecule of interest, their
interactions at a structural level, the post-translational behaviors of the proteins, and
the wide variety of possibilities to be evaluated, require extraordinary computing
capabilities. Therefore, this type of study is extraordinarily challenging without hav-
ing further –and typically pre-existing– information [43, 139].
8 Discussion
Throughout this chapter, we have presented the epidemiological, biological, and

virological basis of the COVID-19 pandemic, aiming to formulate sensible models.
We discuss the results of this paper with direct applications, presented below as a Case
Study. In the first case study, COVID-19 spreading dynamics in Chile, we apply both
the statistical correction presented in Sect. 6 and the different methodologies for the
calculation of Rt presented in Sect. 5.2, discussing their similarities and differences.
In the second case study, Scenarios considering effective vaccination, partial and
complete immunity, using the virological particularities of SARS-CoV-2, we modify
an SEIR model for discussing the effects of vaccination and the -eventually- vanishing
post-infection immunity. Lastly, in Developing diagnostic models for COVID-19
using chest X-ray images we implement and discuss the suitability of different ML
approaches to the diagnosis of COVID-19.
A B 6
Raw data Raw data
6k
reproduction number
Stat. correction Stat. correction
Observed effective
Stat. correction
Daily new cases
(smooth)
(smooth) 4
4k
2
2k
0 0
ril y ne ly g pt ril y ne ly g pt
Ap Ma Ju Ju Au Se Ap Ma Ju Ju Au Se
2020 2020
Fig. 5 COVID-19 spreading dynamics in Chile. a statistical “nowcasting” of new cases to correct
the effect of delays on reported data. b Estimation of the effective reproduction number Rt with
Eq. 13, using raw data (dotted) and the now-cast data (solid). A mobile average of ±3 days was
selected as smoothing procedure to both trends
8.1 COVID-19 Spreading Dynamics in Chile
In this case study, we evaluate the early spreading dynamics of COVID-19 through the
“nowcasting” of infections to obtain robust estimators for Rt , applying the method-
ologies presented in the previous sections and based in the work of Contreras et al.
[33]. We use ARIMA auto-regression models for casting predictions on the trends
of T performing the temporal reclassification of cases. Figure 5A presents the cur-
rent and forecast trends. Estimating R from literature (as the recovery rates are
known), and using the daily deaths data D, we proceed to calculate the variation
on the active cases I using Eq. 11.
Following the governmental agenda on non-pharmaceutical interventions applied
in Chile in the early stages of the pandemic, an abrupt growth in Rt was evidenced
around April 22nd, consistently with the relaxation of restrictive measures that were
applied in Santiago –the capital and most populated city in the country (Fig. 5b). In
particular, the apogee of the governmental plan for a safe return to work occurred
in a temporal window where raw-data-driven Rt values were at a minimum. Still,
the the corrected contagion rates anticipated a steep growing trend for the following
days.
We also compare the results obtained for the reproduction number Rt following
the different methodologies presented in the previous sections. Figure 6 shows the
four different curves, which represent respectively the inferred reproduction number
using Eq. 13 on raw data (dotted), on the statistical temporal reclassification of cases
(solid), or Eq. 16 on the temporally reclassified cases, with tSI = 14 and tSI = 7
(dashed, light and dark respectively). Even though the serial interval of COVID-19,
as discussed previously, is much shorter than that, an interesting match arises between
R̂t (tSI = 14) and the raw data. The temporal reclassification of cases displaces the
curve to the left but keeping intact its shape. What at the beginning seems surprising
is nothing but a result of data-handling.
Fig. 6 Comparison of 6 Raw data

different estimators for the
Stat. correction
reproduction number. In
reproduction number
Stat. correction
Observed effective
solid we see the nowcast
estimation of Rt (Eq. 13), 4 Stat. correction
whilst all others represent
estimations of the observed
reproduction number R̂t
(Eq. 16), using unrealistic 2
values of the serial interval
tSI
0
ril y ne ly g pt
Ap Ma Ju Ju Au Se
2020
As reported by the Chilean health authorities, infected individuals are declared as

recovered if symptoms have vanished by day 14 from testing positive. Note that this
definition would include those cases that had a fatal outcome. Therefore, we could
estimate (R(t) + D(t)) ≈ T (t − 14). Therefore, Eqs. 13 and 16 would match:
I (t) T (t) − (R(t) + D(t))

Rt = +1= +1 (25)
R(t) + T (t) R(t) + D(t)
T (t)
≈ = R̂t (t S I = 14) (26)
T (t − 14)
Despite the strong similarities between the curve for raw data and the estimated
reproduction number R̂t (with tSI ), there are strong theoretical discrepancies that
make that match unfeasible. First, the serial interval for COVID-19 has been esti-
mated to be much shorter than tSI = 14 days. Consequently, calculations of R̂t would
return higher values, as more offspring infections would be recorded in a wider time-
frame. For instance, when evaluating its value with tSI = 7, which is also an over
estimation of it, values are much smaller, but still shape-consistent. Nevertheless,
they are still reliable on whether the system is stable or not, as –by construction of
the different estimators– R = 1 will always be the tipping point between exponential
growth or decay.
8.2 Scenarios Considering Effective Vaccination, Partial and

Complete Immunity
In this case study, we only aim to provide a modelling overview; we will not discuss
further the values selected for certain parameters. Rather, we invite the readers to
adapt them to the particular situation they would like to model.
To study the effects of vaccination and vanishing post-infection immunity, we

propose a modified SEIR model. As the recovered compartment R would naturally
account for those individuals having post-infection immunity, we introduce a term
accounting for immunity loss. We further add compartments for deaths (D) and
individuals having permanent immunity because of the vaccine (M). We will address
this modified model as SEIRDM. Besides the typical underlying hypotheses for SEIR
epidemiologic models, we assume the following:
• There exists a vaccine which is 100% protective against SARS-CoV-2, granting
long term immunity to healthy susceptible individuals. We assume that, due to
logistics and availability, the government can provide a rate of p vaccines per day,
which are to be applied to the susceptible population. Subsequently, the sink term
in the differential equation should be proportional to NS .
• Post-infection immunity is not long-term lasting, thus having a timescale relevant
for the dynamics. Assuming that the characteristic time an individual is protected
against reinfection is given by τl , its reciprocal would indicate the rate at which
they leave this compartment to become susceptible again.
S S 1
S = −β I − p + R, (27)
N N τl
S 1
E = β I − E, (28)
N te
1
I = E − (γ + θ ) I, (29)
te
1
R = γ I − R. (30)
τl
D = θ I. (31)
S
M =p . (32)
N
The different parameters involved are defined and reported in Table 2. We analyze
three different scenarios for the vaccination logistics, where, respectively, 5000,
15,000, and 25,000 vaccines can be provided per day. For all the above mentioned
scenarios we considered that post-infection immunity lasts, on average, 6 months.
The existence of an effective vaccine against SARS-CoV-2 managed to curb its spread
radically, preventing also second waves due to immunity-loss in two of them. Some
factors that could refine the modelling at this level would be the incorporation of:
(1) individuals unwilling to be vaccinated, (2) partial immunity, (3) mutations of the
virus that might generate drug-resistance.
On the other hand, when evaluating the loss of post-infection immunity, different
dynamics arise. Figure 7b shows the effect of different immunity periods at a given
vaccination rate. As the underlying dynamics are of a SIR-like type, the behavior
change point (namely, exponential growth or decay) occurs when the susceptible
Table 2 SEIRDM model parameters

Parameter Meaning Values Units
N Population size 10 Million people
β Infection rate 0.25 day−1
γ Recovery rate 0.10 day−1
θ COVID-19-induced 0.02 day−1
death rate
τl Post-infection {1 2 3 6 12} Months
immunity period
p Vaccination rate {5000 15,000 25,000} Vaccines day−1
te Latent period 4 Days
A B
1.5 m
Active cases
1.0 m
0.5 m
0
k r ar ar k r ar ar
rea ea ye ye rea ea ye ye
tb ty d tb ty
ou 1s 2n 3rd ou 1s 2n
d 3rd
Vaccination rate Post infection immunity

5000 vaccines/ day 1 month
6 months
15000 vaccines/ day 2 months
12 months
25000 vaccines/ day 3 months
Fig. 7 Effect of an effective vaccine and waning post-infection immunity on the spreading dynamics
of COVID-19. Subfigure a illustrates the effects of an effective vaccine, which grants complete
immunity. Subfigure b qualitative shows different epidemiologic scenarios, assuming that recovered
individuals would lose their post-infection immunity at different rates
population is partially depleted, not because of any behavioral change. We see that,
even in the case of a long period post-infection immunity, new outbreaks could
re-appear if the behavioral factors remain the same. The above is not a doomsday
prognosis, but a reminder that the solution has always been in our hands. Considering
more recent evidence, if not enough individuals accept the vaccine when offered and
the overall population uptake remains low, we will face further COVID-19 waves
[12, 38, 89].
8.3 Developing Diagnostic Models for COVID-19 Using

Chest X-ray Images
In this case study, we illustrate the use of Deep Convolutional Neural Network (CNN)
to design and implement diagnostic models of COVID-19 using chest X-ray images.
The dataset used for the development of predictive models was obtained from the
repository of Cohen et al. [31]. First, pre-treatment and statistical analysis of the
dataset was performed using the DMAKit-Lib python library [86]. There are 941
records in the initial set, which are divided into 584 images related to COVID-19, 286
to viral-type pneumonia, and 71 to bacterial-type pneumonia. Overall, 371 positive
cases, 348 negatives, and 222 unclear are reported. Finally, the average age range for
men is 52.92 and 54.76 for women.
Under the light of the reported data, two types of classification models for chest
X-ray images were implemented. The first was based on the classification of the kind
of Pneumonia, while the second was used for the clinical diagnosis of COVID-19.
The images classified as unclear are not considered within the training of the models.
Deep Convolutional Neural Network were implemented using the TensorFlow
python library. The configuration parameters of the network architecture were
28 × 28 initial layer of dimensionality reduction, 128 nodes in the inner layer, 2
or 3 output layers depending on the number of classes. Besides, Adam optimizer is
used, and the Relu activation function. As a strategy to prevent overfitting, a division
of the data sets in training and validation of 80:20 was used, additionally apply-
ing cross-validation k-fold with k = 10. The pneumonia type classification model
achieved 90.32% accuracy, while the diagnostic model achieved 96.5%. Both the
confusion matrices and the sensitivity and specificity analyzes are shown in Fig. 8.
A Pneumonia diagnosis B COVID-19 diagnosis
1
1
Real
density
2
3
1 2 3 1 2
100
Percentage
75
Sensitivity
50 Specificity
25
0
Bacterial COVID-19 Viral Negative Positive
Prediction
Fig. 8 Deep learning diagnosis models using chest X-ray images and convolutional neural network
(CNN)
It is appreciated that the models perform an excellent classification for the classes
related to COVID-19. Furthermore, the results obtained are comparable with previ-
ously reported methods, achieving similar performance.
9 Conclusions
Throughout this chapter, we have built a multi-disciplinary basis to support model-

ing COVID-19 under uncertainty. We briefly described the biological, physiological,
and epidemiological features of SARS-CoV-2, how they influence the propagation
dynamics of COVID-19, the sensitivity-specificity of the available tests, and the time-
line of infectiousness. The above aims to provide the reader with a fresh and up-to-
date overview of the open challenges in COVID-19 modeling and drug discovery. We
described and highlighted sources of uncertainty and limitations associated with data
generation and curation, and the logistic challenges different non-pharmaceutical
interventions (NPIs) have to overcome to be effective. By doing that, we considered
modeling aspects of the different kinds of tests that can be applied, and practical
considerations about contact tracing (NPIs) and data processing. Then, we presented
the already well-known compartmental SIR and SEIR models for epidemiology,
highlighting their limitations and underlying hypotheses, the real-world meaning of
every parameter involved in their equations, and how to incorporate more compart-
ments should they be required for the pursued modeling purpose. Then we illus-
trated the derivation of parameters with epidemiological meaning, as the reproduc-
tion number Rt , using compartmental models, and a statistically-driven methodology
to “nowcast” possibly delayed epidemiologic curves. We completed our theoretical
analysis with a comprehensive overview of Machine Learning-based approaches to
COVID-19 modeling and drug discovery, highlighting the uses different algorithms
have found in the ongoing pandemic. Finally, we applied all the methods developed
throughout the chapter in three original case studies. In the first one, we analyzed
the spreading dynamics of COVID-19 in Chile by nowcasting the contagion trends
and using different estimators for the reproduction number, demonstrating that they
might differ in value but not in meaning. The second simulated a vaccine’s effect
and a vanishing post-infection immunity using a modified SEIR model; without a
substantial behavioral change, our fate is to repeat what we have already experienced.
We finished our case studies with an application of ML models as a diagnostic tool,
using experimental data such as chest X-ray images to train predictors. We gen-
uinely believe this chapter presents a fresh and insightful approach to modeling, as
the only way to generate high-quality models is from a deep understanding. In that
way, modeling is much more than equations, numbers, and parameters; it is about
understanding them.
Acknowledgements The authors gratefully acknowledge support from the Chilean National
Agency for Research and development (ANID) through the Centre for Biotechnology and Bioengi-
neering - CeBiB (PIA project FB0001, Conicyt, Chile). DM-O gratefully acknowledges Conicyt,
Chile, for PhD fellowship 21181435. AS-D thanks PAI Programme (I7818010006). SC received
support from the Max-Planck-Society.
References
1. Aguilar, J.B., Faust, J.S., Westafer, L.M., Gutierrez, J.B.: Investigating the impact of asymp-
tomatic carriers on COVID-19 transmission (2020)
2. Alamo, T., Reina, D., and Millán, P.: Data-driven methods to monitor, model, forecast and
control COVID-19 pandemic: leveraging data science, epidemiology and control theory.
arXiv:2006.01731 (2020)
3. Alimohamadi, Y., Taghdir, M., Sepandi, M., Wirawan, I.M.A., Januraga, P.P., Kim, H.-J.,
Hwang, H.-S., Choi, Y.-H., Song, H.-Y., Park, J.-S., et al.: Estimate of the basic reproduction
number for covid-19: a systematic review and meta-analysis. J Prev Med Public Health 53(3),
151–157 (2020)
4. Anderson, R. M. and May, R. M. (1985). Vaccination and herd immunity to infectious diseases.
Nature, 318(6044), 323–329
5. Apostolopoulos, I.D., Mpesiana, T.A.: Covid-19: automatic detection from X-ray images
utilizing transfer learning with convolutional neural networks. Phys. Eng. Sci. Med. 1 (2020)
6. Ardabili, S.F., Mosavi, A., Ghamisi, P., Ferdinand, F., Varkonyi-Koczy, A.R., Reuter, U.,
Rabczuk, T., Atkinson, P.M.: (2020). COVID-19 outbreak prediction with machine learning.
Available at SSRN 3580188
7. Arons, M.M., Hatfield, K.M., Reddy, S.C., Kimball, A., James, A., Jacobs, J.R., Taylor, J.,
Spicer, K., Bardossy, A.C., Oakley, L.P., et al.: Presymptomatic SARS-CoV-2 infections and
transmission in a skilled nursing facility. New England J. Med. (2020)
8. Bai, Y., Yao, L., Wei, T., Tian, F., Jin, D.-Y., Chen, L., and Wang, M.: Presumed asymptomatic
carrier transmission of COVID-19. JAMA (2020)
9. Bar-On, Y.M., Flamholz, A., Phillips, R., Milo, R.: Science forum: SARS-CoV-2 (COVID-19)
by the numbers. Elife 9 (2020)
10. Bastos, S.B., Cajueiro, D.O.: Modeling and forecasting the COVID-19 pandemic in brazil.
arXiv:2003.14288 (2020)
11. Batra, R., Chan, H., Kamath, G., Ramprasad, R., Cherukara, M.J., Sankaranarayanan, S.K.:
Screening of therapeutic agents for COVID-19 using machine learning and ensemble docking
studies. J. Phys. Chem. Lett. 7058–7065 (2020)
12. Bauer, S., Contreras, S., Dehning, J., Linden, M., Iftekhar, E., Mohr, S.B., Olivera-Nappa, A.,
Priesemann, V.: Relaxing restrictions at the pace of vaccination increases freedom and guards
against further COVID-19 waves. arXiv preprint arXiv:2103.06228 (2021)
13. Baunez, C., Degoulet, M., Luchini, S., Pintus, P., Teschl, M.: Sub-national allocation of
COVID-19 tests: an efficiency criterion with an application to Italian regions. Available at
SSRN 3576161 (2020)
14. Benvenuto, D., Giovanetti, M., Vassallo, L., Angeletti, S., Ciccozzi, M.: Application of the
ARIMA model on the COVID-2019 epidemic dataset. Data Brief 105340 (2020)
15. Bhandari, S., Shaktawat, A.S., Tak, A., Patel, B., Shukla, J., Singhal, S., Gupta, K., Gupta,
J., Kakkar, S., Dube, A., et al.: Logistic regression analysis to predict mortality risk in covid-
19 patients from routine hematologic parameters. Ibnosina J. Med. Biomed. Sci. 12(2), 123
(2020)
16. Bi, Q., Wu, Y., Mei, S., Ye, C., Zou, X., Zhang, Z., Liu, X., Wei, L., Truelove, S.A., Zhang,
T., et al.: Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close
contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect. Diseases (2020)
17. Biswas, K., Khaleque, A., Sen, P.: COVID-19 spread: reproduction of data and prediction
using a sir model on Euclidean network. arXiv:2003.07063 (2020)
18. Brotons, C., Serrano, J., Fernandez, D., Garcia-Ramos, C., Ichazo, B., Lemaire, J., Montene-
gro, P., Moral, I., Perez-Wienese, R., Pitarch, M., et al.: Seroprevalence against COVID-19
and follow-up of suspected cases in primary health care in Spain (2020)
19. Bullard, J., Dust, K., Funk, D., Strong, J.E., Alexander, D., Garnett, L., Boodman, C., Bello,
A., Hedley, A., Schiffman, Z., et al.: Predicting infectious SARS-CoV-2 from diagnostic
samples. Clin. Infect. Diseases (2020)
20. Byambasuren, O., Cardona, M., Bell, K., Clark, J., McLaws, M.-L., Glasziou, P. Estimating
the extent of true asymptomatic COVID-19 and its potential for community transmission:
systematic review and meta-analysis. Available at SSRN 3586675 (2020)
21. Calafiore, G. C., Novara, C., Possieri, C.: A modified sir model for the COVID-19 contagion
in Italy. arXiv:2003.14391 (2020)
22. Centers for Disease Control and Prevention: Interim guidelines for COVID-19 antibody testing
(2020) Updated 1 Aug
23. Ceylan, Z.: Estimation of COVID-19 prevalence in Italy, Spain, and France. Sci. Total Environ.
138817 (2020)
24. Chan, J.F.-W., Kok, K.-H., Zhu, Z., Chu, H., To, K.K.-W., Yuan, S., Yuen, K.-Y.: Genomic
characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient
with atypical pneumonia after visiting wuhan. Emerging Microbes & Infections 9(1), 221–
236 (2020). PMID: 31987001
25. Chau, N.V.V., Thanh Lam, V., Thanh Dung, N., Yen, L.M., Minh, N.N.Q., Hung, L.M., Ngoc,
N.M., Dung, N.T., Man, D.N.H., Nguyet, L.A., et al.: The natural history and transmission
potential of asymptomatic SARS-CoV-2 infection. Clin. Inf. Diseases (2020)
26. Chen, C., Yan, J., Zhou, N., Zhao, J., Wang, D.: Analysis of myocardial injury in patients
with covid-19 and association between concomitant cardiovascular diseases and severity of
covid-19. Zhonghua xin xue guan bing za zhi 48, E008–E008 (2020a)
27. Chen, J., Ye, J., Li, H., Xia, Z., Yan, H.: Changes in the clinical characteristics of 62 patients
who died from coronavirus disease 2019. BioMed Res. Int. (2020b)
28. Chen, Y.-C., Lu, P.-E., Chang, C.-S.: A time-dependent sir model for COVID-19.
arXiv:2003.00122 (2020c)
29. Chimmula, V.K.R., Zhang, L.: Time series forecasting of COVID-19 transmission in Canada
using LSTM networks. Chaos Solit. Fract. 109864 (2020)
30. Chung, S.-C., Marlow, S., Tobias, N., Alogna, I., Alogna, A., You, S.-L.: A rapid systematic
review and case study on test, contact tracing, testing, and isolation policies for COVID-19
prevention and control (2020)
31. Cohen, J.P., Morrison, P., Dao, L., Roth, K., Duong, T.Q., Ghassemi, M.: COVID-19 image
data collection: prospective predictions are the future. 2006.11988 (2020)
32. Colbourn, T., Waites, W., Panovska-Griffiths, J., Manheim, D., Sturniolo, S., Colbourn, G.,
Bowie, C., Godfrey, K.M., Peto, J., Burgess, R.A., et al.: Modelling the health and economic
impacts of population-wide testing, contact tracing and isolation (PTTI) strategies for COVID-
19 in the UK. Available at SSRN 3627273 (2020)
33. Contreras, S., Biron-Lattes, J.P., Villavicencio, H.A., Medina-Ortiz, D., Llanovarced-Kawles,
N., Olivera-Nappa, Á.: Statistically-based methodology for revealing real contagion trends
and correcting delay-induced errors in the assessment of COVID-19 pandemic. Chaos Solit.
Fract. 139 (2020a)
34. Contreras, S., Dehning, J., Loidolt, M., Spitzner, F. P., Urrea-Quintero, J.H., Mohr, S.B.,
Wilczek, M., Zierenberg, J., Wibral, M., Priesemann, V.: The challenges of containing SARS-
CoV-2 via test-trace-and-isolate. arXiv:2009.05732 (2020b)
35. Contreras, S., Medina-Ortiz, D., Conca, C., Olivera-Nappa, Á.: A novel synthetic model of the
glucose-insulin system for patient-wise inference of physiological parameters from small-size
ogtt data. Frontiers in bioengineering and biotechnology 8, 195 (2020c)
36. Contreras, S., Villavicencio, H.A., Medina-Ortiz, D., Biron-Lattes, J.P., Álvaro Olivera-
Nappa: A multi-group SEIRA model for the spread of COVID-19 among heterogeneous
populations. Chaos, Solit. Fract. 136 (2020d)
37. Contreras, S., Villavicencio, H.A., Medina-Ortiz, D., Saavedra, C.P., Olivera-Nappa, A.: Real-
time estimation of Rt for supporting public-health policies against COVID-19. Front. Pub.
Health 8 (2020e)
38. Contreras, S., Priesemann, V.: Risking further COVID-19 waves despite vaccination. Lancet
Infect. Dis. 21(6), 745–746 (2021)
39. de Walque, D., Friedman, J., Gatti, R., Mattoo, A.: How two tests can help contain COVID-19
and revive the economy (2020)
40. Dehning, J., Spitzner, F.P., Linden, M.C., Mohr, S.B., Neto, J.P., Zierenberg, J., Wibral, M.,
Wilczek, M., Priesemann, V. Model-based and model-free characterization of epidemic out-
breaks (2020a)
41. Dehning, J., Zierenberg, J., Spitzner, F.P., Wibral, M., Neto, J.P., Wilczek, M., Priesemann, V.:
Inferring change points in the spread of COVID-19 reveals the effectiveness of interventions.
Science (2020b)
42. Du, R.-H., Liang, L.-R., Yang, C.-Q., Wang, W., Cao, T.-Z., Li, M., Guo, G.-Y., Du, J., Zheng,
C.-L., Zhu, Q., et al.: Predictors of mortality for patients with COVID-19 pneumonia caused
by SARS-CoV-2: a prospective cohort study. Eur. Respiratory J. 55(5) (2020)
43. Duarte, Y., Márquez-Miranda, V., Miossec, M.J., González-Nilo, F.: Integration of target
discovery, drug discovery and drug delivery: a review on computational strategies. Wiley
Interdiscip. Revi.: Nanomed. Nanobiotechnol. 11(4) (2019)
44. Elaziz, M.A., Hosny, K.M., Salah, A., Darwish, M.M., Lu, S., Sahlol, A.T.: New machine
learning method for image-based diagnosis of COVID-19. PloS ONE 15(6) (2020)
45. European Centre for Disease Prevention and Control: Immune responses and immunity to
SARS-CoV-2 (2020). Updated 30 June 2020
46. Fanelli, D., Piazza, F.: Analysis and forecast of COVID-19 spreading in china, Italy and
France. Chaos Solit. Fract. 134 (2020)
47. Firth, J.A., Hellewell, J., Klepac, P., Kissler, S.M., Kucharski, A.J., Spurgin, L.G., Working
Group, C. C.-., et al.: Combining fine-scale social contact data with epidemic modelling
reveals interactions between contact tracing, quarantine, testing and physical distancing for
controlling COVID-19 (2020)
48. Flaxman, S., Mishra, S., Gandy, A., Unwin, H.J.T., Mellan, T.A., Coupland, H., Whittaker,
C., Zhu, H., Berah, T., Eaton, J.W., et al.: Estimating the effects of non-pharmaceutical inter-
ventions on COVID-19 in Europe. Nature 1–8 (2020)
49. Foundation for Innovative New Diagnostics: COVID-19, diagnostics & testings. https://www.
finddx.org/covid-19/. Accessed: 29 Sept 2020 (2020)
50. Fraser, C., Riley, S., Anderson, R.M., Ferguson, N.M.: Factors that make an infectious disease
outbreak controllable. Proc. Natl. Acad. Sci. 101(16), 6146–6151 (2004)
51. Freire-Flores, D., Llanovarced-Kawles, N., Sanchez-Daza, A., Olivera-Nappa, A.: On the
heterogeneous spread of COVID-19 in Chile. Chaos Solitons & Fractals. https://doi.org/10.
1016/j.chaos.2021.111156 (2021)
52. Giordano, G., Blanchini, F., Bruno, R., Colaneri, P., Di Filippo, A., Di Matteo, A., Colaneri,
M.: Modelling the COVID-19 epidemic and implementation of population-wide interventions
in Italy. Nat. Med. 1–6 (2020)
53. Gorbalenya, A.E., Baker, S.C., Baric, R.S., de Groot, R.J., Drosten, C., Gulyaeva, A.A.,
Haagmans, B.L., Lauber, C., Leontovich, A.M., Neuman, B.W., Penzar, D., Perlman, S.,
Poon, L.L.M., Samborskiy, D.V., Sidorov, I.A., Sola, I., Ziebuhr, J., Viruses, C. S. G. o. t.
I. C. o. T..: The species severe acute respiratory syndrome-related coronavirus: classifying
2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5(4), 536–544 (2020)
54. Gray, N., Calleja, D., Wimbush, A., Miralles-Dolz, E., Gray, A., De-Angelis, M., Derrer-
Merk, E., Oparaji, B.U., Stepanov, V., Clearkin, L., et al.: “No test is better than a bad test":
impact of diagnostic uncertainty in mass testing on the spread of COVID-19 (2020)
55. Griffith, G., Morris, T.T., Tudball, M., Herbert, A., Mancano, G., Pike, L., Sharp, G.C., Palmer,
T.M., Smith, G.D., Tilling, K., et al.: Collider bias undermines our understanding of COVID-
19 disease risk and severity (2020)
56. He, D., Zhao, S., Lin, Q., Zhuang, Z., Cao, P., Wang, M.H., Yang, L.: The relative transmis-
sibility of asymptomatic cases among close contacts. In. J. Infect. Diseases (2020a)
57. He, X., Lau, E.H., Wu, P., Deng, X., Wang, J., Hao, X., Lau, Y.C., Wong, J.Y., Guan, Y.,
Tan, X., et al.: Author correction: Temporal dynamics in viral shedding and transmissibility
of covid-19. Nature Medicine 26, 1491–1493 (2020b)
58. He, X., Lau, E.H., Wu, P., Deng, X., Wang, J., Hao, X., Lau, Y.C., Wong, J.Y., Guan, Y., Tan,
X., et al.: Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat. Med.
1–4 (2020c)
59. Hematian, A., Sadeghifard, N., Mohebi, R., Taherikalani, M., Nasrolahi, A., Amraei, M.,
Ghafourian, S.: Traditional and modern cell culture in virus diagnosis. Osong public health
and research perspectives 7(2), 77–82 (2016)
60. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X.,
et al.: Clinical features of patients infected with 2019 novel coronavirus in wuhan, china. The
lancet 395(10223), 497–506 (2020)
61. Jakhar, D., Kaur, I.: Artificial intelligence, machine learning and deep learning: definitions
and differences. Clinical and experimental dermatology 45(1), 131–132 (2020)
62. Jefferson, T., Spencer, E., Brassey, J., Heneghan, C.: Viral cultures for COVID-19 infectivity
assessment. systematic review (2020)
63. Kellam, P., Barclay, W.: The dynamics of humoral immune responses following SARS-CoV-2
infection and the potential for reinfection. J. Gen. Virol. jgv001439 (2020)
Proceed. R. Soc. Lond. Ser. A Contain. Pap. Math. Phys. Char. 115(772), 700–721 (1927)
65. Kirkcaldy, R.D., King, B.A., Brooks, J.T.: Covid-19 and postinfection immunity: Limited
evidence, many remaining questions. Jama 323(22), 2245–2246 (2020)
66. Kretzschmar, M., Rozhnova, G., and van Boven, M. (2020). Effectiveness of isolation and
contact tracing for containment and slowing down a covid-19 epidemic: a modelling study.
67. Kucharski, A.J., Klepac, P., Conlan, A., Kissler, S.M., Tang, M., Fry, H., Gog, J., Edmunds,
J., Group, C.C.-W., et al.: Effectiveness of isolation, testing, contact tracing and physical
distancing on reducing transmission of SARS-CoV-2 in different settings (2020a)
F., Jit, M., Munday, J.D., et al.: Early dynamics of transmission and control of COVID-19: a
mathematical modelling study. Lancet Infect. Diseases (2020b)
69. Kumar, A., Gupta, P.K., Srivastava, A.: A review of modern technologies for tackling covid-19
pandemic. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14(4), 569–573
(2020)
70. Kumleben, N., Bhopal, R., Czypionka, T., Gruer, L., Kock, R., Stebbing, J., Stigler, F.L.: Test,
test, test for COVID-19 antibodies: the importance of sensitivity, specificity and predictive
powers. Public Health (2020)
71. La Marca, A., Capuzzo, M., Paglia, T., Roli, L., Trenti, T., Nelson, S.M.: Testing for SARS-
CoV-2 (COVID-19): a systematic review and clinical guide to molecular and serological
in-vitro diagnostic assays. Reprod. Biomed. Online (2020)
72. Lalmuanawma, S., Hussain, J., Chhakchhuak, L.: Applications of machine learning and arti-
ficial intelligence for COVID-19 (SARS-CoV-2) pandemic: a review. Chaos Solit. Fract.
110059 (2020)
73. Lauer, S.A., Grantz, K.H., Bi, Q., Jones, F.K., Zheng, Q., Meredith, H.R., Azman, A.S., Reich,
N.G., Lessler, J.: The incubation period of coronavirus disease 2019 (covid-19) from publicly
reported confirmed cases: estimation and application. Annals of internal medicine 172(9),
577–582 (2020)
74. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K.S., Lau, E.H.,
Wong, J.Y., et al.: Early transmission dynamics in Wuhan, china, of novel coronavirus-infected
pneumonia. New England J. Med.(2020a)
75. Li, R., Pei, S., Chen, B., Song, Y., Zhang, T., Yang, W., Shaman, J.: Substantial undocu-
mented infection facilitates the rapid dissemination of novel coronavirus (sars-cov-2). Science
368(6490), 489–493 (2020b)
76. Linton, N.M., Kobayashi, T., Yang, Y., Hayashi, K., Akhmetzhanov, A.R., Jung, S.-M., Yuan,
B., Kinoshita, R., Nishiura, H.: Incubation period and other epidemiological characteristics
of 2019 novel coronavirus infections with right truncation: a statistical analysis of publicly
available case data. Journal of clinical medicine 9(2), 538 (2020)
77. Liu, D., Clemente, L., Poirier, C., Ding, X., Chinazzi, M., Davis, J.T., Vespignani, A., San-
tillana, M.: A machine learning methodology for real-time forecasting of the 2019-2020
COVID-19 outbreak using internet searches, news alerts, and estimates from mechanistic
models. arXiv:2004.04019 (2020)
78. Lou, B., Li, T.-D., Zheng, S.-F., Su, Y.-Y., Li, Z.-Y., Liu, W., Yu, F., Ge, S.-X., Zou, Q.-D., Yuan,
Q., Lin, S., Hong, C.-M., Yao, X.-Y., Zhang, X.-J., Wu, D.-H., Zhou, G.-L., Hou, W.-H., Li, T.-
T., Zhang, Y.-L., Zhang, S.-Y., Fan, J., Zhang, J., Xia, N.-S., Chen, Y.: Serology characteristics
of SARS-CoV-2 infection since exposure and post symptom onset. Eur. Respiratory J. (2020)
79. Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi,
Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., Chen, J., Meng,
Y., Wang, J., Lin, Y., Yuan, J., Xie, Z., Ma, J., Liu, W.J., Wang, D., Xu, W., Holmes, E.C.,
Gao, G.F., Wu, G., Chen, W., Shi, W., Tan, W.: Genomic characterisation and epidemiology
of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet
395(10224), 565–574 (2020)
80. Ma, S., Zhang, J., Zeng, M., Yun, Q., Guo, W., Zheng, Y., Zhao, S., Wang, M.H., Yang,
Z.: Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly
reported individual data of 1155 cases from seven countries (2020)
81. Malki, Z., Atlam, E.-S., Hassanien, A.E., Dagnew, G., Elhosseini, M.A., Gad, I.: Association
between weather data and COVID-19 pandemic predicting mortality rate: machine learning
approaches. Chaos Solit. Fract. 138 (2020)
82. Mandal, M., Jana, S., Nandi, S.K., Khatua, A., Adak, S., Kar, T.: A model based study on the
dynamics of COVID-19: prediction and control. Chaos Solit. Fract. 109889 (2020)
83. Matricardi, P.M., Dal Negro, R.W., Nisini, R.: The first, holistic immunological model
of COVID-19: implications for prevention, diagnosis, and public health measures. Pediat.
Allergy Immunol. (2020)
84. McDermott, J.H., Newman, W.G.: Refusal of viral testing during the SARS-CoV-2 pandemic.
Clini. Med. (2020)
85. Medina-Ortiz, D., Contreras, S., Barrera-Saavedra, Y., Cabas-Mora, G., Olivera-Nappa, Á.:
Country-wise forecast model for the effective reproduction number RT of coronavirus disease.
Front. Phys. 8, 304 (2020a)
86. Medina-Ortiz, D., Contreras, S., Quiroz, C., Asenjo, J.A., Olivera-Nappa, Á. Dmakit: a user-
friendly web platform for bringing state-of-the-art data analysis techniques to non-specific
users. Inf. Syst. 101557 (2020b)
87. Mei, X., Lee, H.-C., Diao, K.-Y., Huang, M., Lin, B., Liu, C., Xie, Z., Ma, Y., Robson, P.M.,
Chung, M., et al.: Artificial intelligence-enabled rapid diagnosis of patients with COVID-19.
Nat. Med. 1–5 (2020)
88. Mercatelli, D., Giorgi, F.M.: Geographic and genomic distribution of SARS-CoV-2 mutations.
Front. Microbiol. 11, 1800 (2020)
89. Moore, S., Hill, E.M., Tildesley, M.J., Dyson, L., Keeling, M.J.: Vaccination and non-
pharmaceutical interventions for COVID-19: a mathematical modelling study. Lancet Infect.
Dis. https://doi.org/10.1016/S1473-3099(21)00143-2 (2021)
90. Murdoch, W.J., Singh, C., Kumbier, K., Abbasi-Asl, R., Yu, B.: Definitions, methods, and
applications in interpretable machine learning. Proceedings of the National Academy of Sci-
ences 116(44), 22071–22080 (2019)
91. Ndiaye, B.M., Tendeng, L., Seck, D.: Analysis of the COVID-19 pandemic by SIR model
and machine learning technics for forecasting. arXiv:2004.01574 (2020a)
92. Ndiaye, B.M., Tendeng, L., Seck, D.: Comparative prediction of confirmed cases with COVID-
19 pandemic by machine learning, deterministic and stochastic sir models. arXiv:2004.13489
(2020b)
93. Neuman, B.W., Kiss, G., Kunding, A.H., Bhella, D., Baksh, M.F., Connelly, S., Droese, B.,
Klaus, J.P., Makino, S., Sawicki, S.G., et al.: A structural analysis of m protein in coronavirus
assembly and morphology. Journal of structural biology 174(1), 11–22 (2011)
94. Nishiura, H.: Early efforts in modeling the incubation period of infectious diseases with an
acute course of illness. Emerging themes in epidemiology 4(1), 2 (2007)
95. Nour, M., Cömert, Z., Polat, K.: A novel medical diagnosis model for COVID-19 infection
detection based on deep features and Bayesian optimization. Appl. Soft Comput. 106580
(2020)
96. Pang, W.: Public health policy: COVID-19 epidemic and SEIR model with asymptomatic
viral carriers. arXiv:2004.06311 (2020)
97. Panovska-Griffiths, J., Kerr, C., Stuart, R.M., Mistry, D., Klein, D., Viner, R.M., Bonell, C.:
Determining the optimal strategy for reopening schools, work and society in the UK: balancing
earlier opening and the impact of test and trace strategies with the risk of occurrence of a
secondary COVID-19 pandemic wave (2020)
98. Peirlinck, M., Linka, K., Costabal, F.S., Bendavid, E., Bhattacharya, J., Ioannidis, J., Kuhl, E.:
Visualizing the invisible: the effect of asymptomatic transmission on the outbreak dynamics
of COVID-19 (2019)
99. Peng, L., Yang, W., Zhang, D., Zhuge, C., Hong, L.: Epidemic analysis of COVID-19 in china
by dynamical modeling. arXiv:2002.06563 (2020)
100. Perasso, A.: An introduction to the basic reproduction number in mathematical epidemiology.
ESAIM: Proc. Surv. 62, 123–138 (2018)
101. Pinter, G., Felde, I., Mosavi, A., Ghamisi, P., Gloaguen, R.: Covid-19 pandemic prediction
for hungary; a hybrid machine learning approach. Mathematics 8(6), 890 (2020)
102. Poirier, C., Liu, D., Clemente, L., Ding, X., Chinazzi, M., Davis, J., Vespignani, A., Santillana,
M.: Real-time forecasting of the COVID-19 outbreak in Chinese provinces: machine learning
approach using novel digital data and estimates from mechanistic models. J. Med. Internet
Res. 22(8) (2020)
103. Pollán, M., Pérez-Gómez, B., Pastor-Barriuso, R., Oteo, J., Hernán, M.A., Pérez-Olmeda, M.,
Sanmartín, J.L., Fernández-García, A., Cruz, I., de Larrea, N.F., et al.: Prevalence of SARS-
CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study.
Lancet (2020)
104. Prakash, M.K.: Quantitative COVID-19 infectiousness estimate correlating with viral shed-
ding and culturability suggests 68% pre-symptomatic transmissions (2020)
105. Qin, J., You, C., Lin, Q., Hu, T., Yu, S., Zhou, X.-H.: Estimation of incubation period distri-
bution of COVID-19 using disease onset forward time: a novel cross-sectional and forward
follow-up study (2020)
106. Randolph, H.E., Barreiro, L.B.: Herd immunity: Understanding covid-19. Immunity 52(5),
737–741 (2020)
107. Ribeiro, M.H.D.M., da Silva, R.G., Mariani, V.C., dos Santos Coelho, L. Short-term fore-
casting COVID-19 cumulative confirmed cases: perspectives for brazil. Chaos Solit. Fract.
109853 (2020)
108. Robert-Koch-Institut: Epidemiologisches Bulletin 32/33 2020. https://www.rki.de/DE/
Content/Infekt/EpidBull/Archiv/2020/Ausgaben/32-33_20.pdf. Accessed 27 Aug 2020
(2020)
109. Ruch, T.R., Machamer, C.E.: The coronavirus e protein: Assembly and beyond. Viruses 4(3),
363–382 (2012)
110. Santosh, K.: Ai-driven tools for coronavirus outbreak: need of active learning and cross-
population train/test models on multitudinal/multimodal data. Journal of medical systems
44(5), 1–5 (2020)
111. Sethuraman, N., Jeremiah, S.S., Ryo, A.: Interpreting Diagnostic Tests for SARS-CoV-2.
JAMA 323(22), 2249–2251 (2020)
112. Shi, F., Wang, J., Shi, J., Wu, Z., Wang, Q., Tang, Z., He, K., Shi, Y., Shen, D.: Review of
artificial intelligence techniques in imaging data acquisition, segmentation and diagnosis for
COVID-19. IEEE Rev. Biomed. Eng. (2020)
113. Simha, A., Prasad, R.V., Narayana, S.: A simple stochastic sir model for COVID 19 infection
dynamics for Karnataka: Learning from Europe. arXiv:2003.11920 (2020)
114. Singh, R.K., Rani, M., Bhagavathula, A.S., Sah, R., Rodriguez-Morales, A.J., Kalita, H.,
Nanda, C., Sharma, S., Sharma, Y.D., Rabaan, A.A., et al.: Prediction of the COVID-19
pandemic for the top 15 affected countries: advanced autoregressive integrated moving average
(ARIMA) model. JMIR Public Health Surveil. 6(2) (2020)
115. Siu, Y.L., Teoh, K.T., Lo, J., Chan, C.M., Kien, F., Escriou, N., Tsao, S.W., Nicholls, J.M.,
Altmeyer, R., Peiris, J.S.M., Bruzzone, R., Nal, B.: The m, e, and n structural proteins of the
severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking,
and release of virus-like particles. Journal of Virology 82(22), 11318–11330 (2008)
116. Sturniolo, S., Waites, W., Colbourn, T., Manheim, D., Panovska-Griffiths, J.:. Testing, tracing
and isolation in compartmental models (2020)
117. Sujath, R., Chatterjee, J.M., Hassanien, A.E.: A machine learning forecasting model for
COVID-19 pandemic in India. Stoch. Environ. Res. Risk Assess. 1 (2020)
118. Tuli, S., Tuli, S., Tuli, R., Gill, S.S.: Predicting the growth and trend of COVID-19 pandemic
using machine learning and cloud computing. Internet of Things 100222 (2020)
119. Vaishya, R., Javaid, M., Khan, I.H., Haleem, A.: Artificial intelligence (ai) applications for
covid-19 pandemic. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14(4),
337–339 (2020)
120. Wang, P., Zheng, X., Li, J., Zhu, B.: Prediction of epidemic trends in COVID-19 with logistic
model and machine learning technics. Chaos Solitons Fract. 110058 (2020a)
121. Wang, S., Kang, B., Ma, J., Zeng, X., Xiao, M., Guo, J., Cai, M., Yang, J., Li, Y., Meng, X.,
et al.: A deep learning algorithm using ct images to screen for corona virus disease (COVID-
19) (2020b)
122. Wang, S., Zha, Y., Li, W., Wu, Q., Li, X., Niu, M., Wang, M., Qiu, X., Li, H., Yu, H., et al.:
A fully automatic deep learning system for COVID-19 diagnostic and prognostic analysis.
Euro. Respir. J. (2020c)
123. World Health Organization: Draft landscape of COVID-19 candidate vaccines—12 November
2020. WHO (2020a)
124. World Health Organization: "immunity passports" in the context of COVID-19: scientific
brief, 24 April 2020. Technical Report. World Health Organization (2020b)
125. World Health Organization: Laboratory testing for coronavirus disease (COVID-19) in sus-
pected human cases: interim guidance, 19 March 2020. Technical Report. World Health Orga-
nization (2020c)
126. World Health Organization: Transmission of SARS-CoV-2: implications for infection preven-
tion precautions: scientific brief, 09 July 2020. Technical Report. World Health Organization
(2020d)
127. World Health Organization: Rolling updates on coronavirus disease (COVID-19), updated
31 July 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-
as-they-happen. Accessed 08 July 2020 (2020e)
128. Worldometers.info: COVID-19 coronavirus pandemic, reported cases and deaths by country,
territory, or conveyance. https://www.worldometers.info/coronavirus/#countries. Accessed
08 July 2020 (2020)
129. Wu, J., Yuan, X., Wang, B., Gu, R., Li, W., Xiang, X., Tang, L., Sun, H.: Severe acute
respiratory syndrome coronavirus 2: From gene structure to pathogenic mechanisms and
potential therapy. Frontiers in Microbiology 11, 1576 (2020a)
international spread of the 2019-ncov outbreak originating in wuhan, china: a modelling study.
The Lancet 395(10225), 689–697 (2020b)
131. Wu, L.-P., Wang, N.-C., Chang, Y.-H., Tian, X.-Y., Na, D.-Y., Zhang, L.-Y., Zheng, L., Lan,
T., Wang, L.-F., Liang, G.-D.: Duration of antibody responses after severe acute respiratory
syndrome. Emerging infectious diseases 13(10), 1562 (2007)
132. Wu, Z., McGoogan, J.M.: Characteristics of and important lessons from the coronavirus
disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the
chinese center for disease control and prevention. Jama 323(13), 1239–1242 (2020)
133. Wynants, L., Van Calster, B., Bonten, M.M., Collins, G.S., Debray, T.P., De Vos, M., Haller,
M.C., Heinze, G., Moons, K.G., Riley, R.D., et al. Prediction models for diagnosis and prog-
nosis of COVID-19 infection: systematic review and critical appraisal. BMJ 369 (2020)
134. Xiao, A.T., Gao, C., Zhang, S.: Profile of specific antibodies to SARS-CoV-2: the first report.
J. Infect. (2020)
135. Yang, C., Wang, J.: A mathematical model for the novel coronavirus epidemic in wuhan,
china. Mathematical Biosciences and Engineering 17(3), 2708–2724 (2020)
136. Yang, Z., Zeng, Z., Wang, K., Wong, S.-S., Liang, W., Zanin, M., Liu, P., Cao, X., Gao, Z.,
Mai, Z., et al.: Modified seir and ai prediction of the epidemics trend of covid-19 in china
under public health interventions. Journal of Thoracic Disease 12(3), 165 (2020)
137. Yoshimoto, F.K.: The proteins of severe acute respiratory syndrome coronavirus-2 (sars cov-2
or n-cov19), the cause of covid-19. The Protein Journal 39(3), 198–216 (2020)
138. Zhang, F., Abudayyeh, O.O., Gootenberg, J.S.: A protocol for detection of COVID-19 using
CRISPR diagnostics. A protocol for detection of COVID-19 using CRISPR diagnostics. 8
(2020)
139. Zhao, C., Rakesh, K., Ravidar, L., Fang, W.-Y., Qin, H.-L.: Pharmaceutical and medicinal
significance of sulfur (svi)-containing motifs for drug discovery: A critical review. European
journal of medicinal chemistry 162, 679–734 (2019)
140. Zhao, J., Yuan, Q., Wang, H., Liu, W., Liao, X., Su, Y., Wang, X., Yuan, J., Li, T., Li, J., Qian,
S., Hong, C., Wang, F., Liu, Y., Wang, Z., He, Q., Li, Z., He, B., Zhang, T., Fu, Y., Ge, S., Liu,
L., Zhang, J., Xia, N., Zhang, Z.: Antibody responses to SARS-CoV-2 in patients of novel
coronavirus disease 2019. Clin. Infect. Diseases. ciaa344 (2020)
141. Zhavoronkov, A., Zagribelnyy, B., Zhebrak, A., Aladinskiy, V., Terentiev, V., Vanhaelen, Q.,
Bezrukov, D.S., Polykovskiy, D., Shayakhmetov, R., Filimonov, A., et al.: Potential non-
covalent SARS-CoV-2 3c-like protease inhibitors designed using generative deep learning
approaches and reviewed by human medicinal chemist in virtual reality (2020)
142. Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., et al.:
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan,
China: a retrospective cohort study. Lancet (2020)
Application of Mathematical Modelling
Approach in COVID-19 Transmission
and Interventions Strategies
Joseph Bamidele Awotunde , Roseline Oluwaseun Ogundokun ,

Abidemi Emmanuel Adeniyi , Kazeem Moses Abiodun ,
and Gbemisola Janet Ajamu
Abstract The coronavirus (COVID-19) outbreak has been a global tragedy,

which emerged in Wuhan, China December 2019 and has posed critical concerns on
prediction, diagnosis, control, and mitigation globally. Subsequently, there have been
unprecedented measures to curtail the outbreak worldwide, which include closures
of businesses, schools, and country bounders among others. The COVID-19 seems
to have a greater impact on the global economy when compared to severe acute
respiratory syndrome (SARS) that occurs in 2013. The hypothetical epidemiology
has provided remarkable conceptual and technical development, this area of research
not only aims to analyze and anticipate the spread of different diseases but also help in
controlling the diseases effectively. Mathematical modeling has been at the forefront
since the COVID-19 pandemic started in late December 2019 to form decisions
concerning various non-pharmaceutical approaches to curtail its’ spread globally,
but this has been studies in Nigeria contents. Therefore, this chapter discusses the
use of a mathematical model in fighting COVID-19 spread, assessing the impact
of the mitigation strategies and control put in place worldwide. The chapter was
concluded by using Nigeria as a case study to incorporate features appropriate to
COVID-19 spread dynamics and control in Nigeria. The significant contributions of
this chapter are (a) Proposed a mathematical model for finding COVID-19 pandemics
J. B. Awotunde (B)
Department of Computer Science, University of Ilorin, Ilorin, Nigeria
e-mail: awotunde.jb@unilorin.edu.ng
R. O. Ogundokun · A. E. Adeniyi · K. M. Abiodun
Department of Computer Science, Landmark University, Omu Aran, Nigeria
e-mail: ogundokun.roseline@lmu.edu.ng
A. E. Adeniyi
e-mail: adeniyi.eemanuel@lmu.edu.ng
K. M. Abiodun
e-mail: moses.abiodun@lmu.edu.ng
G. J. Ajamu
Department of Agricultural Extension and Rural Development, Landmark University, Omu Aran,
Nigeria
e-mail: ajamu.gbemisola@lmu.edu.ng
284 J. B. Awotunde et al.
dynamics and control strategies in Nigeria (b) study prior mathematical models
developed to research COVID-19 disease outbreak dynamics behavior and contain-
ment globally and (c) lastly, investigation the importance of mathematical model in
COVID-19 pandemic. The results show that mathematical modeling can be used as
a powerful tool to understand the transmission and exploring different containment
scenarios of the COVID-19 outbreak. Dynamic interventions were expected to reduce
the percentage of the population infected in a shorter period and could reduce the
number of infected cases in ICU below current estimates of Nigeria’s ICU strength.
Keywords Coronavirus · Mathematical model · Transmission dynamics ·

COIVD-19 pandemic · Epidemiology · Intervention strategies
1 Introduction
Coronavirus (COVID-19) has been an epidemic worldwide that currently ravaging

the world [1]. Globally as of 8:38 a.m. CEST, 30 June 2020, COVID-19 has spread
to over 218 countries and regions, with 10,117,687 confirmed cases, 502,278 deaths,
5,692,120 recovered, 96,286 new cases and Americas leads with 5,136,705 confirmed
cases (https://covid19.who.int/). The related severe and death cases are within the
aged persons (65 and older) and individuals with serious health problems [2, 3]. The
approaches for containment, monitoring, and alleviating the liability of the epidemic
since the lack of a safe and active vaccine or antivirals are non-pharmaceutical inter-
ventions like quarantine, isolation, nose mask in open places, social-distancing, and
contact-tracing are the focus of the world.
For instance, China on April 8, 2020, lifted strict lockdown for 76-day and this was
achieved during the first relaxing periods of 9 February 2020. Communication-tracing
is another effective public health technique to stop the outbreak. This involves iden-
tifying or investigating persons with whom the recorded case is associated directly
within that period of time, particularly between two days of the start of the case [4],
thereby testing and isolate or hospitalize them if they have the symptoms or have
the disease [5–7]. The popular practice was the use of surgical masks in public by
community members to restrict or slow the transmission of related infections, tracing
back to the 1918 H1N1 pandemic of influenza [8–11]. This has also remained helpful
in combating the spread of the SARS disease in Asia of 2002/2003 especially in
Taiwan, Hong Kong, China, and Singapore, and proved useful in the containment of
COVID-19 in many countries of the world.
With all the about measures, it is undeniable that after a while, due to the pres-
sure from the populace and pressure of economic operation and the need to go back
to normal life, many countries will take new control strategies and leave primary
responses of COVID-19 prevention. Estimating the effectiveness of the control poli-
cies and the understanding of early transmission dynamics of epidemic diseases play
foreseeable roles in the prevention of the diseases. Hence, identifying the various
factors affecting the spread rate of the COVID-19 will intensely help to control
Application of Mathematical Modelling Approach … 285
the outbreak. Also, some fundamental questions need to be answered accurately

and quickly, questions like what measures or strategies should the government take
to prevent the economy from collapse and to prevent the pandemic? Can people
relieve themselves from self-production after changing the emergency response?
When people will get back to their normal lives?
A major obstacle for both research institutions and public health workers is the
identification and practical evaluation of community health action methods to battle
COVID-19 in real-time. Many experiments have been used to simulate different
dynamics of the diseases for decades, such diseases are Malaria [12, 13], Tubercu-
losis, Human Immunodeficiency Virus (HIV) Influenza, and Ebola virus. The use of
the mathematical model in diseases enables both short-term and long-term prediction
of disease incidence, thus, provide an insightful understanding of disease control and
prevention [14].
Mathematical modeling is an important method of understanding how an infection
mutates within a community, however, the essence of this resides in writing a series of
numerical formulas that represent reality, and are used to analyze those input factors
within the equations. The knowledge already understands about the transmission
of the disease like obtainable data on the number of infectious diseases identified,
several hospitalizations, or the confirmed number of deaths that can be used to refine
the solutions of a mathematical model. This model refinement can be achieved on
several occasions till the numerical methods solutions comply with what COVID-19
knows about spreading. This helps the optimized model being used to learn more
about the potential actions of the infection spread.
Mathematical modeling can be used as a powerful tool to understand the transmis-
sion and exploring different scenarios of COVID-19 [15]. Since one model cannot
answer it all and the pandemic outbreak needs the jigsaw to hold together several
models that can address supplementary sub-questions and stop COVID-19 spread,
instead of focusing on which model is correct [15]. The number of asymptomatic or
slightly symptomatic people following the outbreak was very low in earlier disease
outbreaks such as SARS, thereby making it simpler to track and identify the affected
persons through touch monitoring. There is insufficient knowledge of whether this
would be the same for COVID-19. So, the use of a mathematical model will answer
this question.
Mathematical modeling has been at the forefront Since the COVID-19 spread
began at the end of January to influence the direction of various non-pharmaceutical
approaches to minimize their spread throughout the world. The conceptual model
by Neil Ferguson’s group at Imperial College London [84] is frequently cited as
the guiding factor behind the social-distancing initiatives adopted worldwide and
especially in the UK to stop COVID-19 spread.
Therefore, this chapter will discuss the use of a mathematical model in fighting
COVID-19 spread, assessment of the effect at the population level of the above-
mentioned mitigation strategies, and control put in place worldwide. The chapter
will study various mathematical models developed to research COVID-19 disease
outbreak dynamic behavior and containment worldwide. The chapter will be
concluded by using Nigeria as a case study to includes dynamics and control func-
tions related to COVID-19 transmissions put in place in the country like isolation,
quarantine, contact-tracing, and the use of face-masks in public places. The chapter
will be concluded by taking the strict model review to show that the disease-free
balance is regionally-asymptotically stable is there a certain epidemiological limit
below unity.
This chapter is prearranged into 8 sections. Section 2 discusses the problem formu-
lation and mathematical model of infectious diseases. Section 3, discussed prior and
related work in the mathematical model. Section 4 presents the proposed method
using the SIR model. Section 5, discusses experimental results and discussion.
Finally, the main findings and conclusions are presented in Sect. 6.
1.1 The State and Responses to COVID-19 Pandemic

in Nigeria
The COVID-19 epidemic has been a serious public health threat worldwide with
nations around the globe taking aggressive infection control measures steps to imme-
diately curb the COVID-19 deadly virus. Public awareness, attitudes, and actions
regarding COVID-19 are crucial to understanding the virus’s epidemiological trends
and the efficacy, enforcement, and performance of steps undertaken in a community.
Previous studies have shown that the source of the infection is linked to a
seafood restaurant in Wuhan, however, no confirmation has been given for specific
breed associations. Symptoms reported involving fever, cough, tiredness, pneu-
monia, headaches, diarrhea, hemoptysis, and dyspnea. As a means of minimizing
spread, reasonable precautions like wearing masks, washing hands hygiene proce-
dures, avoiding public interaction, case identification, touch monitoring, and quaran-
tines were addressed. There is currently no available antiviral medication or vaccine
which has proved effective; therefore, people who are infected rely mainly on cura-
tive relief and supportive care. COVID-19s rapid spread poses an unprecedented
health problem the planet is dealing with. As well as the human effects, there are
also major economic, industrial, and financial impacts that are experienced globally.
The influences will keep spreading as viruses know no boundaries.
Leading up to COVID-19 being declared a global threat to public health and
epidemic by the WHO, many Nigerians treated the virus as a remote white man’s sick-
ness that can never propagate to local homes [16]. Without subscribing to professional
advice and guidance, Nigerians and their leadership have undermined the outbreak of
COVID-19 in their country, waiting too long to implement preliminary safety precau-
tions that would save resources while shielding people from unnecessary exposure
to the virus. With the detection of the COVID-19 cases index in Lagos, Nigeria on
20 February 2020, other areas of the country along with the north-central region
continued their usual routines and leisure gatherings without complying with the
shady precautionary action previously described by the Nigerian Center for Disease
Control [16, 17]. The popular sentiment in central Nigeria has been that COVID-19
is a “big man infection” (i.e., widely respected individual infection).
With the lower levels of education within this area of Nigeria [18], their imminent
assumption was predicted and misconceptions on those fragile to the diseases. As the
volume of COVID-19 instances increases gradually among the Nigerian population,
mainly urban centers like Abuja, central Nigeria’s Federal Capital Territory (FCT),
unfounded uncertainty, palpable apprehension among misconceptions about COVID-
19 described the condition of the nation’s populace. Nigeria announced its first case
of COVID-19 on 27th February 2020 and since then; there has been an increase in
cases daily. When compare the outbreak with other countries in Africa, the speed
of daily cases is used as an indicator of how quickly the virus is spreading or being
contained, Nigeria has overtaken many countries in Africa. Nigeria is number three
while South Africa leads and Egypt is second in Africa. This will, of course, depend
on how accurate and timely the Nigerian government makes its daily announcements.
Initially, most Nigerian cases have come from international travelers arriving in Lagos
and Abuja.
The novel coronavirus case was first reported in Nigeria on 27th February 2020
and the number of cases has continued to rise ever since. As of 3 June 2020, Nigeria
recorded 11,166 confirmed cases spread across 35 states and the Federal Capital
Territory (FCT), Abuja [17]. In the absence of a cure or a vaccine and to manage
the spread of the virus and the infection, Nigeria has relied on a combination of
non-pharmaceutical interventions that include testing, contact tracing, isolation, and
treatment [19], as well as a range of containment measures such as strict enforcement
of hygiene practices like hand-washing, observation of social distancing, and travel
restrictions.
The Nigerian government also imposed full lockdowns in areas deemed to have
the highest propensities for transmission. On 30 March 2020, the federal government
of Nigeria announced the full lockdown of Lagos and the Ogun States, and the FCT
for 14 days in the first instance. The lockdown was further extended following the
expiration of the initial lockdown and the increasing number of cases across many
states. Some State governments have also implemented partial lockdown involving
banning of, public gatherings, closure of open markets, and restriction of inter-state
movements. Thus, businesses are being forced to shut down without alternative plans,
rendering vulnerable informal sector workers who work daily to earn a living and
are now stranded at home, unable to sustain themselves and their families.
There is a need to engender an indigenous (Afro-centred) approach to the contain-
ment of the COVID-19 pandemic. COVID-19 protocols such as “lockdown” and
“social distancing” are products of “copy and paste” by African leaders, without
critically thinking about their peculiar social and economic circumstances domi-
nated by the poor, unemployed and informal sector workers (which constituted 90%
of Africa’s workforce compared to 18% in developed countries), most of whom live
by daily bread/earnings and handouts to survive [20, 21].
African leaders did not carefully consider the feasibility, affordability, and coping
abilities of the borrowed Western-style lockdown and social distancing policies
among the majority of their poor and socially excluded citizens. This has merely
reduced most of the so-called rapid response strategies to a mere conventional “trial
and error” (template of the Western nations), as these strategies are not working in
Africa. Public perceptions consider these measures as elitist and not in the interest of
the people, who are “forced” to suffer the twin debacle of the COVID-19 pandemic
and excruciating hunger. For example, a rise in community criminality, looting, and
terror perpetrated by the “one-million-boys” gang, aged between 14 and 18 years,
was reported with some 200 bandits arrested in Lagos, Nigeria (where half of the
city’s 21 million people survive on daily earnings) [20].
Moreover, the prevalence of urban slums, densely populated, insufficient access
to drinking water, weak medical systems, distribution of sanitary facilities with a
high level of physical interaction among the residents of central Nigeria would make
it difficult to enforce hygiene initiatives and other public health policies required
to curtail coronavirus [22]. Also, the dissemination of misconceptions and stories
about COVID-19 and the advancement of non-scientific traditional care in central
Nigeria compromised safety precautions [23, 24]. Government failure to manage the
policies of social distancing and prohibit large-scale gatherings, including religious
and cultural events, funerals, weddings, and sports, can inevitably generate esca-
lated COVID-19 amazingly-spreading situations [25]. To effectively monitor and
mitigate COVID-19 in this area, action-oriented and prompt epidemiological infor-
mation gathered from the population can allow health professionals to implement
comprehensive strategies and policies appropriate and understandable to the citizens
of this area.
1.2 The COVID-19 Economic Impact and Pandemic

Planning in Nigeria
The global epidemic COVID-19 is described by increased morbidity and mortality

rates [26] in addition to other illnesses. The shutdown of community interactions
worldwide to prevent the spread of the disease outbreak has resulted in a global
lockout, triggering a slowdown and decline in economic activity due to a breakdown
in the global market [27]. The situation in Nigeria may be worse than estimated
because most nations were completely unprepared for the spread of diseases due
to weak prevention strategies and monitoring systems, as well as insufficient and
excessive healthcare infrastructure and equipment.
The implications will keep spreading, as diseases recognize no limits. In reality,
94% of the world’s Fortune 1000 and Nigerian firms were affected and are already
witnessing COVID-19 disruptions [28]. We anticipate the COVID-19 hazard to grad-
ually vanish, as has been the case in recent years with Ebola, Zika, and Extreme Acute
Respiratory Syndrome (SARS) viruses [28]. The socio-economic effect will however
still be felt long after the infection disappears [29, 30]. Nigeria is confronting turbu-
lent times, as are all the countries of the world. This is a double disruption for
Nigeria as an oil-driven business: COVID-19 external and national pandemic shock,

and crude prices shock.
The vulnerability of Nigeria to the effects of these market volatility could be
attributed to increased reliance on global markets for national income, foreign
currency inflows; budget deficit financing, and foreign investment needed to sustain
the country’s economic operations. The world continues to combat the COVID-19
outbreak with 3,175,207 coronavirus infections and 224,172 deaths worldwide. Even
before the epidemic, the impact on the global economy and particularly in developing
countries such as Nigeria was weak, with global GDP growth projected at just 2.5%
in 2020. Though comparatively fewer cases are reported in many developed nations,
Nigeria currently has 56,478 cases reported and 1088 deaths as of writing [17].
These countries’ poor ability is likely to worsen the outbreak and its effect on their
economies, and elsewhere in the world.
Nigeria is in a dangerous situation, already faced with the likelihood of lower-for-
longer oil prices. A global economic shutdown is particularly harmful to a country
reliant on external capital and imported raw materials [28]. Meanwhile, increasing
cases of COVID-19 within the country foreshadows a partial shutdown of the local
economy. This combination of global recession and local pandemic will only expose
the structural defects in the Nigerian economy, some of which are the result of flawed
policy-making. Notwithstanding the worrying health prospects as COVID-19 spreads
within the country, it is clear that the economic impact of the virus will be long and
severe for Nigeria. Consumer demand will dry up during a local economic shutdown,
rendering businesses unable to pay salaries or meet their debt obligations. Left alone,
many will not survive the next 12 months. Unfortunately, the policy response so far
is not aggressive enough to provide the cushion the economy needs.
The COVID-19 disease outbreak’s micro-economic costs apply to those incurred
by individuals/households, businesses, and other institutions such as schools, hospi-
tals, clinics, health centers, health services, health personnel, and government. This
involves morbidity and mortality strain. With the COVID-19 epidemic, households
could bear diagnostic and therapeutic expenses where, for instance, government or
health coverage plans don’t cover them. Although where these charges are covered,
individuals could still face copayments, transportation costs, and other associated
costs, like associated care spending. In several Nigeria, out-of-pocket healthcare
expenditure continues to increase and maybe as high as >70% of existing healthcare
spending [21].
The COVID-19 outbreak may intensify the pressure of individuals’ out-of-pocket
healthcare spending and lessen financial health security. Any reduction or elimination
of the opportunity to work and make a living, particularly for working people who
are overwhelmingly female and responsible for about 89% of all jobs in sub-Saharan
Africa, would cause a burden on households [31]. The uncertain nature of the working
population, as demonstrated by the lack of an agreement or income security, implies
that the COVID-19 outbreak can have a major impact on their sources of revenue,
particularly when communities are locked up. South Africa, for instance, is among the
lowest shares of working people, responsible for around one-third of all employees
[32], and its contribution is projected at ~10% of gross domestic product (GDP) in
the world [33]. Although casual labor may not have a complete impact, 10% of South
Africa’s GDP is greater than the share of the overall medical statistics age category.
The effect on certain African nations, where the informal sector is reasonably
large, would be greater. Facilities have been supported by several private estab-
lishments, such as the contribution of grants to aid the country in resolving the
COVID-19 outbreak. To prevent the potential spread of disease, many companies and
organizations suffer economic losses from every shutdown of enterprises and from
allowing workers permission to stay home. They can also face costs associated with
disinfecting their workplaces. Educational institutions are close, supermarkets, like
casual grocery stores, restaurants, and hotels, and demand is facing a major decline.
Agricultural and manufacturing operations in Nigeria are adversely affected.
The deferral or interruption of several practices like soccer games, conventions,
workshops, and seminars significantly impacted conference coordinating corpora-
tions and people that have pre-booked flights and accommodation. Flight companies,
particularly airlines, have fewer clients, terminate flights, and/or face an elevated
production revenue required to disinfect the atmosphere. Restaurants and other hotels
and travel companies have dramatically reduced the number of customers. Unfortu-
nately, it is difficult to precisely measure the related ‘basic economic’ expenses in
Nigeria at this time as the COVID-19 epidemic gathers momentum and expenses
will affect the extent of the unpredictability/fear and real/assumed instances and
casualties.
Conversely, production losses linked with industrial action suggest possible
impacts. For instance, but that is restricted, the 2014 platinum mining walkout in
South Africa contributed to a decrease of 0.72–0.78% in the region’s real National
income [34]. The estimated cost of every shutdown or worker leaves allowed by
companies and other private organizations are unavoidable to outweigh that recorded
for the platinum mining walkout, developing countries like Nigeria, which is domi-
nated by the informal sector. In Nigeria, government expenditure on health care is
extremely small, the overall budget for the health industry is quite small compared to
other developed countries [21]. The COVID-19 epidemic is accompanied by signif-
icantly increased costs for governments. A decrease in business growth can have
a severe impact on the financial growth of the nation, particularly on government
revenue (both internal and external income tax). It is also projected that global
health costs will increase throughout this time to maintain and monitor health care
consumers and to control the transmission of the infection.
Moreover, governments ought to bear the burden of quarantining migrants and
other situations. Charges associated with the design, equipment, and maintenance
of facilities to handle, treat, and control the COVID-19 epidemic would typically
be borne by governments. Governments could also be grappling with the need to
assist families hit by temporary workplace closures with financial compensation and
assistance. The extent of government funds would depend, inter alia, on the projected
disease prevalence, the seriousness of diseases, and the capacity of Nigeria’s order
to limit numbers of new infections. Many health-related expenses of resources are
derived from the essential focus that countries put on addressing the COVID-19
disease outbreak.
For instance, a ‘crowding-out’ trend may emerge also with minimal govern-
ment funds, as additional government health investment to resolve the COVID-19
pandemic can decrease financing for other important public health priorities, such
as communicable, dietary, and contagious diseases. This may lead to reduced expo-
sure to some medical care, which could intensify the risk of illness. Self-isolation
and shutdown may also have a major effect on general wellbeing because loneliness
(physically and mentally) is negatively linked to wellbeing. [35]. Families closed-
down in unpleasant residential conditions (e.g. overpopulated with poorly ventilated),
which constitute many villages and irregular urbanized areas and ghettos in Nigeria,
may experience negative health outcomes.
2 Problem Formulation and Mathematical Model

of Infectious Diseases
Mathematical simulations of the mechanisms of transmission of infectious diseases

are today omnipresent. The aforementioned replicas execute a significant function
in assisting to measure potential approaches for managing and preventing infec-
tious diseases [26–38]. There are several models for communicable illnesses; as for
compartment models, from the actual traditional SIR model to extra multifaceted
concepts [39]. Owing to thousands of established outbreaks, followed by thou-
sands of demises worldwide, the COVID-19 contagion is regarded as the greatest
environmental hazard worldwide.
The global epidemic issue has drawn the attention of researchers from various
fields, bestowing increment to a range of applications to study and forecast the
pandemic’s development [40]. As applied to every compartment model, this new class
implies a range of analyzes on disease-free equilibrium points [38]. It is important
to understand the dissemination mechanisms of a virus in the initial phases of the
novel communicable sickness epidemic. An assessment of propagation shifts over
epoch could offer intuitions into the epidemiological circumstances [41] and assess
if disease prevention steps have a tangible impact [42, 43]. Such analyzes can inform
forecasts of possible future development [44], help quantifies risks for other countries
[45], and direct alternate intervention designs [46].
These analyzes do, however, face many challenges, particularly in real-time. The
symptom presentation can be delayed as a result of the incubation cycle and the
identification of cases arising from the diagnosis and monitoring capability can be
delayed [47]. By deliberately integrating uncertainties arising from the normal part
events of contagion and notification procedures, modeling methods may compen-
sate for these uncertainties and confusion [48]. To a greater extent, distinctive data
antecedents could be skewed, unreliable, or record solitary some facets of the nature
of the epidemic. Synthesis of proof methods that match several databases some-
what than a solitary dataset will allow an extra reliable estimate of the fundamental
dynamics of noisy data conveyance [49, 50].
Humans and other societies have long regarded infectious diseases as a significant
cause of mortality [51]. The propagation of a transmittable illness includes not barely
features linked to the disease such as a transmittable mediator, method of conveyance,
concealed time, communicable time, as well as socio-economic, demographic, and
environmental features [52]. Epidemiology is an analysis of the spread and deter-
mining factor of the occurrence of diseases in individuals and faunae. Experiments
may be performed in many sciences to collect knowledge, check theory, prepare and
enforce control systems. Experiments on the propagation of infectious disease in
human societies, however, are frequently unlikely or immoral.
Mathematical models are also helpful in determining the general trajectory of a
contagion. An epidemiological model seeks to explain the macroscopic nature of the
illness transmitted via residents to deduce forecasts, analyze management systems,
and propose preventive strategies.
Theoretically, ideal vaccine methods can be identified by using simulation. For
example, an outbreak model was used to decide how many individuals would be
vaccinated within a city to avoid measles transmission. Modeling methodology was
also used to assess which age ranges in an influenza outbreak will be vaccinated first
to reduce the risk of death. In epidemiology, a widespread sickness is a huge outburst
of sickness in a brief period, that is, the number of people that become affected first
increases to a limit then falls to zero. Such a brief epidemic does not indicate any
population impact. Historically, these serious yet short-term epidemics have also
occurred, like non A and B hepatitis in Tug Wajale, Somalia, 1986, and measles in
Dallas, Texas, 1970, in which the overview of a trivial figure of invectives into an
inhabitant has caused a quick rise in illness occurrence accompanied by the gradual
absence of illness, including healthful members of the residents. The syndrome, with
the absence of contagion when possible, makes patients go on healthful, and this was
originally described using the following model by [53]:
S (t) = β S(t) I (t),

I (t) = β S(t) I (t) − 1 τ I (t)
R (t) = 1 τ I (t) (1)
where populace I(t) was classified into t3 subcategories: S(t) symbolizes the number
of persons vulnerable to the illness; I (t) signifies the sum of persons infected with
the virus; and R(t) signifies the sum of persons excluded from the risk of conta-
gion by seclusion, vaccination, or improvement from complete immunity and re-
contamination. The first model is built on the 3 elementary expectations which
follow:
1. There is no birth, no demises apart from sickness-connected to demises, and no
relocation. Then, [S(t) + I (t) + R(t)] = 0 or the entire residents’ magnitude
S(t) + I (t) + R(t) is a constant K.
2. There is a ban on social intervention to spread the disease since the population
is mixed homogeneously. The incidence of the disease’s new invasion is propor-
tionate to both the figure of vulnerability and the sum of invectives. The total
number of sufficient contacts per communicable daily is the everyday touch
rate. An appropriate touch of an infected individual is an interaction that, if the
individual is vulnerable, leads to contamination of the other person. Besides the
entire sum of susceptible contaminated with the contagious type is β S(t)I (t)
per day.
3. Those healed are excluded from the contagious community at a degree that is
equal to the number of invectives for the rate of improvement to be excluded
1/τ . The latent time is zero. R(t) describes numbers of deaths incurred from
the diseases and such deadly diseases include plague and cholera and the model
is represented by the foremost and subsequent equations. The proportion of
contagious people at the time t0 that are already contagious at the time t0 + 1 is
e− t t and the total infectious duration is τ (Hethcote et al. 1981).
1
Model (1) is a S–I–R construct such that participants switch from the vulnerable
class S to the contagious class I and transfer to the class R withdrawn afterward.
Models S–I–R are suitable for illnesses spread by pathological mediators for instance
bacterial Ebola, SARs, measles, hepatitis, and uniformly deadly animal diseases
such as rabies and humanoid sicknesses such as plague and cholera. Model (1) is
a temporary form that solitary integrates epidemiological results. By interchanging
R(t) = K − S(T ) − I (t), Model (1) can be extracted and the two-dimensional
structure obtained:
S (t) = −β S(t)I (t),

1
I (t) = β S(t)I (t) − I (t) (2)
t
which is termed the Kermack–McKendrick model.

Model (2) has the result: if βτ S(0) ≤ 1, the answer I (t) declines to zero as
t → ∞ βτ S(0) > 1, at that time I (t) first, intensify to a limit IM and at that
moment diminish to zero as t [2]. In mathematical epidemiology, the presence of a
threshold condition is one of the most essential and universal concepts. There is a
velocity magnitude R0 , sometimes known as the simple reproductive number or touch
number, whose principles decide the distribution of a disease’s qualitative actions.
The simple number of reproductive reflects the number of secondary infections per
infected person. In model (1.1), R0 = βτ K (S(0) = K − ≈ K , ε <; 0 small). If
R0 is less than 1, then the virus will die out in most epidemiological simulations,
while if R0 is more than 1, there will be an outbreak [53] (Brauer 1990a), or an unpre-
dictable germ-free symmetry (Brauer 1990b; Thieme and Castillo-Chavez 1989). The
Kermack–McKendrick model, with transformations from S to I to R, is an example
of a compartment model. The S–I–S is another form of compartment model:
1
S (t) = β S(t)I (t) + I (t)
t
1
I (t) = β S(t)I (t) − I (t) (3)
t
In the S–I–S model, constituents of the vulnerable class S can become contam-
inated and transferred to infectious class I, and hence recuperate from re-infection
outside protection, returning to vulnerable class S. Numerous illnesses such as rubella
and gonorrhea are indications for which S–I–S models are ideal.
In the equation, the acceptance is that the overall populace magnitude is contin-
uous (S(t) + I (t) = K ), the degree of contagion is β S(t)I (t) and the degree of
regeneration is 1/τ I (t).
The simple reproductive R0 = βτ K . If R0 in model (3). If R0 is lesser than 1 the
virus deceases out and if R0 is larger than 1, the equilibrium is asymptotically steady
and I have an optimistic worth for that. Population implications for the long-term
projections were deliberated on. Hethcote [56] suggested an S–I–R model by the
application of births and deaths;
S (t) = −β S(t)I (t) + μ (K − S(t)),

1
I (t) = β S(t)I (t) − I (t) μI (t),
t
1
R (t) = I (t) − μR(t), (4)
t
that depicts a sickness from which members recuperate with complete protection in
a populace of continuous overall magnitude K with the acceptance that all deliveries
are in the vulnerable class S and the delivery and demise degree are equivalent to
the dimensions of each class. For this model, the simple procreative figure is R0 =
βτ K 1 + μτ and if R0 > 1 there is a stable widespread symmetry. Model (4) is
not ideal for a terminal illness due to the normal death in the class R(t) excluded.
Thus, a model of this kind, can’t sustain a stable overall population size for a lethal
illness. Nonlinear population models provide the modeling of certain diseases one
reference. Another path Anderson and May well-thought-out is longitudinal delivery
proportion and disease-limited populations. While in Hethcote’s model, the model
can also assume constant birth and death rates to permit entire residents’ magnitude
to either expand exponentially or reach zero, the preferred solution would be to
integrate nonlinear thickness-dependent populace dynamics into the model [54, 55,
57]. Since delivery and demise extent rely on scale, S–I–R models have to be divided
into 2 categories models: S–I–R(r ecover y) models and S–I–R(death) models. In
an S–I–R(r ecover y) model, Class R is made up of restored members that add to the
childbearing degree and in an S–I–R(r emoval) model, R is made up of members
excluded by demise. To make the proposed models more practical and viable for more
diseases, particularly after integrating nonlinear populace dynamics into sickness
models, the proposed model needs to take on an extra universal procedure for novel
infection rates. For instance, inference refers to sexually conveyed illnesses [58] as
well as a virally conveyed sickness.
3 Prior and Related Work
Mathematical models are effective instruments for understanding current COVID-

19 patterns. Frameworks are required to make a meditative choice when beyond the
surge potential or without ready access to laboratory tests [59, 60]. The models are
critical for policymakers to procure medical equipment, assign technical services
and hospital beds, and guarantee health system continuity during the epidemic’s
height and duration [59, 60]. After its spread, scientists and experts have conducted
several COVID-19 mathematical modeling and statistical method [60]. We review
similar suggested strategies in the following section and introduce the updated results
with an emphasis on the following topics: death rate, susceptibility to disease, basic
reproductive statistics, asymptomatic infection, herd immunity, and the impact of
intervention measures [60].
SEIR refers accordingly to the Prone, Uncovered, Contagious, and Removed or
Recovered. It is centered mostly on the SIR model but incorporates the Exposed
container with a variable. Exposed are people that are currently contaminated but are
asymptomatic, contagious are people that display symptoms of the disease and can
spread the virus, eliminated or healed are people that are previously infected but are
no longer susceptible and already resistant to the virus. Vulnerable describes people
who would contract the virus and could become carriers if exposed [61]. Modeling
can be achieved through a variety of techniques once the components of SIR or SEIR
prototypes are established. In [62], a Conditional Autoregressive (CAR) was used to
address outbreaks with a cognitive or transportation-related matrix and formulated
with Markov chain Monte Carlo (MCMC). In [61], demographic effects such as birth
and death rates were added to the SEIR to model equilibria with vital dynamics.
3.1 Death Case Rate
Prevalence is one of the most troubling factors in a disease occurrence. The casualty
ratio is a vital indicator of how serious transmittable disease could be [60]. Predicting
the rate of fatality as it shifts over time is a daunting challenge, and could be calculated
in several various variations during an outbreak. The Death Case Ratio (DFR) is a
conventional measurement that predicts the percentage of fatalities from illness to
the overall amount of disease-diagnosed cases. A popular DFR component is the
deferred DFR which itself is described as follows [60, 63].
D(t)
D F Rd (t, Ttr es ) =
N (t − Tr es )
where D(t) represents the number of deaths at time t; N(t − T_res) specifies the
number of diagnosed cases in the period (t − T_res); and t_res denotes a corre-
sponding time lag indicating the duration from the day when the first symptoms
occurred to the day of outcome (recovery or death).
On 11 February 2020, Wu and McGoogan forecast that COVID-19s DFR-d (t, 0)
in China reaches 2.3%, which means that t-res reaches zero and therefore underplays
the real CFR [64]. Wu et al. determine that the total symptomatic CFR (the chance of
mortality after experiencing symptoms) of COVID-19 in Wuhan is 1.4% (0.9–2.1%)
with the aid of further public knowledge [65], which would be slightly lower than
both the misguided CFR (2169/48,557 = 4.5%) and the mortality rate (2169/(2169
+ 17,572) = 11%).
Böttcher et al. [63] both person- and population-based CFR are compared. The
prior is the likelihood that a person who was affected for a time died by time t; the
latter is the measure of the volume of fatalities over the numbers of result instances
(death/recovery) [63]. They found out that the population-based CFR became obso-
lete to infectious diseases at the population level and correlates with individual-based
CFR only when the recovery rate and fatality rate are stable [63]. In particular, the
population-based CFR may not be as valuable as the individual-based CFR because:
(i) the time estimates of disease which are relevant at the interpersonal basis may not
meet those who are at the population level; and (ii) the death proportions at the popu-
lation level appear to be time-dependent and only constant as soon as the epidemic
stops.
Dorigatti et al. [66] COVID-19 CFR projection, both person and populace-based.
First, they determine the periods during the onset of symptoms and results. Here,
we refer to F-oD(.) as the feature of probability density (PDF) synonymous with the
period from symptoms to death, which represents a distribution of gamma. Therefore,
the PDF that mortality is detected at period td with suspected occurrence τ days
earlier.
3.2 Susceptible-Infected-Removed (SIR) Model
To fully understand the main factors affecting the dissemination of COVID-19 [60],
the goal of disease management is to develop a predictive model. The SIR model is
one of the essential epidemiological models that describe the complexity of an infec-
tious outbreak provided that a huge population has indeed been prone, contaminated,
and healed. Given that the infection is normally only transmitted once, an infected
person either dies or survives. The prone people are likely to get contaminated as the
infection spreads, and the people infected have to be withdrawn (whether in death
or survival) [60]. It assumes that a fixed number of N is the maximum number of the
Fig. 1 Susceptible-Infected-Removed (SIR) model
populace and finally the overall contaminated community goes into the eliminated
group.
The method defines a homogeneous and separated populace into the following
three types:
Susceptible (S). This one has not got the disease but may be contaminated as
a consequence of communication with an infected person. As illustrated in Fig. 1,
the S originally displays a gradual decline, and gradually it fades out and becomes
empty.
Infected (I). They had got the virus already. It is defined in Fig. 3, the I display
a slow rise at first. As time progresses, it transitions into a rapid increase after the
optimal height.
Removed (R). The infection progresses to one of two different directions: whether
one individual survives or dies, both are handled uniformly in this framework. As
shown in Fig. 1, The R, therefore, indicates a depletion as often as the maximum
value seems to have been exceeded.
A time-dependent SIR framework is designed to determine the amount of COVID-
19 reported cases [67]. Utilizing hedge regression to monitor two-time series, they
transform the Model developed into a discrete-time system; respectively, the trans-
mission rate and the recovery rate at time t. The proposed framework complies with
different steps for disease prevention, most prominently the shutdown of communi-
ties. The approach describes that the regular prediction errors for the cases reported
in China are lower than 3% besides the day since there was a radical shift in the cases
reported, it seemed more accurate than the specific estimate of the number of cases
reported.
Biswas et al. [68] adapt the accumulated data of COVID-19 to an experimental

SIR model coupled with a Euclidean framework. Assessing the number of reported
cases against the geographic proximity to the epicenter for both China and Italy, an
extremely robust spatial dependence was found in the COVID-19 epidemic, demon-
strating an estimated difference in a normal distribution with an exponential of 1.85.
The SIR model, integrated with the Euclidean system, has also been shown to improve
data-based quality in China.
The initial sequence number R0 is an important requisite in epidemiology to reflect
how an infectious disease progresses an epidemic. R0 reflects the average number of
associated diseases spread by a particular infected person who is positioned into a
completely susceptible population underneath the SIR model [69]. The highest values
of another-generation matrix G are described in computational express R0 , where
the ij component is the expected number of category I cases due to people infected
with category j. More precisely, if R0 is greater than one, the infection progresses
exponentially. If R0 is below one, on the other hand, the disease spreads steadily and
fades away before anyone becomes infected.
Wu et al. devised a modified SIR model to forecast the scale of the Wuhan infection
by integrating local transportation data [65]. The datasets utilized here is focused on
regular bookings of flights and human mobility around China’s more than 300 cities.
Based on the statistics in Wuhan, the estimate of R0 is around 2.68 (2.47–2.86, 95%
CI). One drawback is that their claim is built on the concept that COVID-19 does
not alter travel behavior, and signs do eventually be observed by all people infected.
Riou and Althaus [70] estimate R0 using adverse-binomial offspring distributions
with mean R0 and absorption variable k from a simulator, where k evaluates hetero-
geneity in the variety of various cases. A gamma distribution is assumed to obey the
time complexity interval D. The model uses different parameter combinations, which
predicts that R0 is 2.2 (1.4–3.8, 90% CI), considering that the number of targeted
cases grew from 1000 to 9700 by 18 January 2020. One of the approach’s constraints
is that it is centered on a relatively limited number of observations. Nevertheless, by
running further experiments, a large range of parameters can be applied.
Liu et al. measure R0 to match the response time by introducing a subsequent
Gamma spread, suggesting that the instances may be at an exponential growth rate
[71]. To calculate the exponential growth rate, they use Poisson regression and calcu-
late the time-varying simultaneous reproduction quantity R0 (t), which means the R0
at time t if factors remain unchanged after time t [71]. Related to R0 , the Rt is predicted
but utilizes the previous ten-day moving timeframe. The national Chinese estimate
of R0 (t) is 4.5 (4.4–4.6, 95% CI). Rt rises around 6.9 (5.5–8.4, 95% CI) to peak 8.8
(8.3–9.4, 95% CI) by 16 January 2020, then declines steadily by 6 February 2020 to
1.59 (1.57–1.61, 95% CI). The downside of this analysis is that a generalized linear
model forecasts the occurrence date, which might lead to misclassifying bias.
Read, et al. modulate the model with the air traveler in mind, assuming that
the Poisson distribution reflects the regular growth of reported cases [72]. Confirmed
cases reported between 1 January 2020 and 22 January 2020 will be selected to match
the model. For parameter assessment, maximum likelihood estimation (MLE) is used.
It is estimated that the value of R0 is 3.11 (2.39–4.13, 95% CI). The key drawback of
a model is that it contains just the spatial portion of the airline model, which does not
include other transit, like rail and road transport. As a consequence, local connectivity
and Wuhan’s connections to many other regions are possibly underestimated.
Hong and Li [73] expand the traditional SIR model. By adding time-independent
parameters to study the dynamics of distribution and elimination rates, to predict an
imminent essential reproduction number R-0 (t), which provides real-time estima-
tion of R-0 in the outbreak, the literature uses a Poisson model with a polynomial
approach. The model is also validated by analyzing data from multiple critically
affected regions, which indicates that the dynamics of the epidemic can be predicted.
While this time-dependent R0 (t) is useful in assessing the effectiveness of preventive
measures in real-time, the key limitation is that the model doesn’t take into account
the influence of asymptomatic infections, which may minimize the R0 (t).
3.3 Asymptomatic Transmission
For infectious diseases, Ferretti et al. [74] defines four types: symptomatic, asymp-
tomatic, pre-symptomatic, and environmental transmission. R0 is the aggregate of
the four types of basic reproduction number. The estimate of R0 is at about 2.0
(1.7–2.5, 95% CI) using Bayesian methods and Maximum Likelihood Estimation
(MLE), with a proportion of the 4 groups: pre-symptomatic 0.47 (0.11–0.58 CI),
symptomatic 0.38 (0.09–0.49 CI), environmental 0.1 (0.02–0.56 CI), and asymp-
tomatic 0.06 (0–0.57 CI). A substantial number of pre-symptomatic interactions are
indicated by the findings. It is also notable that, relative to other findings, the estimate
of R0 in this literature is significantly smaller, e.g. Refs. [16–19]. This is based on
the fact that shorter generation cycles are given by COVID-19. A smaller amount of
pathogens may also be prevented by containment (R0 < 1). This doesn’t imply that it
is easier to accomplish repression. The transmissions, on the other hand, grow faster
and a greater portion gets infected after the manifestations.
The SEIR model is updated to classify untraceable cases that take into consid-
eration movement in 375 Chinese cities [75]. To analyze propagation mechanisms
during the initial stage of the epidemic, a mathematical method was implemented
by modeling findings between 10 January 2020 and 23 January 2020. Parameters
of the model are assumed from the use of the Kalman filter (IF-EAKF) applica-
tion framework modification iterative process filter ensemble (IF-EAKF) [76]. The
prediction of R0 at the onset of the outbreak is 2.38 (2.04–2.77, 95% CI). Also, only
14% (10–18, 95% CI) of overall illnesses in China were expected to be registered.
The COVID-19 R0 level was around 1.4 and 4.6, which is greater than the Middle
East Respiratory Syndrome (MERS) R0 (R0 : 0.3–0.8) and near to Extreme Acute
Respiratory Syndrome (SARS) (R0 : 2–5) (R0 : 2–5) [77].
Jenny et al. [78] expand the SIR model with untraceable cases, which could be
translated into observed cases by screening. From 22 January 2020 to 12 March
2020, the model features are computed using verified cases of COVID-19 beyond
China. The findings demonstrate that the successful prevention technique is rapid-
testing and follow-up isolation of reported [78]. By collecting more accurate data
and taking into account various age groups and latency times, the model could be
further enhanced.
Yuan et al. [79] created a standardized method to predict a turning time during
an outbreak of disease. As model input, they expand the typical SEIR method to
a specific SEIR and use experienced regular cases in Wuhan. The evolution of the
disease dynamics in the coming days can be predicted, which indicates that the model
can also be used to predict the turnaround period, i.e. one week after 14 February
2020, for the Wuhan outbreaks. This forecast is accepted as quick and accurate. This
model, nevertheless, is still deterministic and can be strengthened by using stochastic
models, such as the Markov chain.
3.4 Herd Immunity
In infection philosophy, herd immunity is a basic idea about the population-level

impact of human resistance to avoid the spread of infections [80]. If a reasonably
large percentage of the population possesses immunity to the outbreak, a population is
known to have antibiotic resistance for an outbreak, then the risk of active interaction
between contaminated and prone individuals is reduced [81]. Many factors, like
infection patterns and forms of propagation, affect herd immunity, alongside people
in a population who gain antibodies [82].
Mathematically, if the community is homogeneously mixed, if a sufficiently large,
evenly distributed populace is resistant, antibiotic resistance can be accomplished
[80]. A significant number of individuals should be immune to ensure that the vulner-
able proportion is sufficiently small to prevent the spread of an infectious virus, which
ensures that the total number of infections is less than one. This can exist in multiple
ways: (i) natural immunity; many individuals catch the disease in time and develop
an immune reaction, and (ii) vaccination; a large proportion of the population is
vaccinated against the infection. Herd immunity could go into the essence for so
many diseases when 40% of people in a community become immune to the virus. In
certain cases, however, 80–95% of the population ought to be resistant to prevent its
propagation [81].
Lourenco et al. [83] developed the SIR models to examine the vulnerability of the
particular percentage of the population at risk of serious illness and disability. Under
the principle that such losses are well-reported and happen only in a fragile portion of
the population, they adjust the models using the total deaths reported of COVID-19
in the UK and Italy. Based on previous estimates of critical epidemiological variables
like R-0, CFR, highly contagious duration, and the time from illness to death, different
models are used, and so forth. Problems are designed independently with R0 = 2.25
and R0 = 2.75. It is projected that about 36% of the UK population could have been
susceptible to COVID-19 by 19 March 2020 if R-0 = 2.25 and 40% if R0 = 2.75 [83].
An equivalent test is carried assuming that R0 is 2.25 and that the percentage of the
population vulnerable to extreme infection is 0.1%. The tentative outcome indicates

that by 19 March 2020, 68% of the UK population may have been contaminated.
Sir Patrick Vallance, Chief Scientific Advisor to the UK Government, argues that
to attain herb resistance for COVID-19, approximately 60% of the population is
needed. If the modeling is true, the outcome may indicate that antibiotic resistance
may have already been established by the UK. Conversely, this analysis is based on an
initial-stage dataset conceptual model, which allows the model reasonably resilient
to a multitude of simplistic assumptions. It suggests, for instance, that the populace
is well-mixed, which means that the model will exaggerate the rate of transmission
and thus the affected percentage. The contaminated ratio is significantly decreased
to 36% and 40% if it implies that the percentage of the population at risk is 1%.
3.5 Effect of Intervention Measures
Preventive measures are necessary for a disease outbreak where a vaccine isn’t avail-
able, intending to lower community transmission rates and thereby reduce infectious
disease. There are two broad types of mitigation and control methodologies: I ther-
apeutic approaches, including antivirals and vaccines; and (ii) non-pharmaceutical
interventions (NPIs), including case isolation, home quarantine, market shutdown,
college closure or office closure, travel bans, respectively [84]. To lower the trans-
mission of the infection, some authorities introduce a set of strict NPIs, whereas
other regions pledge to enforce more extreme preventive measures if needed in the
future. Mathematical models are efficient methods to analyze the dynamic situation
of intervention strategies and to quantify the possible benefits and costs of various
strategies. Series of experiments were carried out to encourage the selection of various
approaches by policymakers.
Tian et al. [85] employ linear regression to analyze the propagation control
measures in China. Relevant data from China, involving case reports, human behav-
iors, and intervention measures, are used to evaluate the preventive measures of
COVID-19. The interventions are proved to be extremely likely to delay the occur-
rence of an infection and contribute to a decrease in the number of reported cases
over the 50 days of China’s lockdown duration. The closure of Wuhan City has
also been shown to have postponed outbreaks in other towns by at least 2.91 days
(2.54–3.29: 95% CI). In comparison to the communities that began to regulate later
(20.6; 14.5–26.8), communities that introduced control measures officially display
fewer cases during the first week of their outbreaks (13.0; 7.1–18.8). This research
is focused on data from 31 December 2019 to 19 February 2020 in China. This is
still an early outcome and does not typically have a full effect on all areas of NPIs
in a wide field.
For control measures previously initiated, the data collection, comprising reported
cases and travel history, is used by Kraemer et al. [86] to determine the effect of
control laws. Three models are developed, namely Poisson Generalized Linear Model
(GLM), negative binomial GLM, and log-linear regression with four factors, i.e. the
number of events, an indication of real-time quantitative polymerase chain reaction

availability test an indication of the date before or after 26 January 2020 (RT-q
PCR), approximate mobility [86]. To forecast regularly reported cases, they conduct
classification techniques and find that models integrating the versatility data into
linear regression can forecast the number of cases with more accurate results. It
is suggested that the traveling restrictions imposed in China greatly reduced the
COVID-19 outbreaks.
To research how changes in population levels impact the progression of the
epidemic in Wuhan [87]. Prem and Cook use regional contact information from
different age brackets in Wuhan. They use SEIR for 16 age ranges to predict the
outbreaks in Wuhan and improve the model with location-based distancing steps such
as school closures. The findings indicate that the volatility of R0 has a major influ-
ence on the prime times of the infection and the overall magnitude of the measures
of disease and social distance is most successful when individuals return to work.
The influence of each NPI due to a lack of data cannot be definitively established by
this analysis.
Ferguson et al. [84] are evaluating the possible effects of public health policies
on the level of virus transmission for new approaches that may be successful in
the future. Two basic types of techniques are considered: (i) prevention based on
slowing the propagation of the disease and (ii) suppression aimed at slowing disease
development. By simulating two models of UK and US data [84], they evaluate the
damage of continuous transmissions. They use a stochastic, individual-based model,
spatially organized, recommended [84].
The process is characterized by the populace in a geographic area that can be
modeled with variables guided by population size determined by Poisson. It also
suggests that there are three channels of transmission: families, schools and busi-
nesses, and culture. The propagation of the Population relies strictly on length, i.e.
the likelihood of individuals i infecting individual k is calculated by a kernel function
f(d(i, k)), where d(i, k) is the interval between persons i and k. A vulnerable person
i have a likelihood for any time step T. 1 − exp (−λ i ?? T) of infections, where λ i
is the immediate risk of contamination for a person [88]. To discover the subsequent
distributions of parameter values including latent duration, contagiousness over time,
and propagation coefficients, Markov chain Monte Carlo (MCMC) and Maximum
Likelihood Estimate (MLE) are implemented.
In the 3 sources of propagation, they evaluate five NPIs and suggest that the overall
efficiency of a single intervention is sometimes minimal, in need of reinforcing a
series of action steps to have a meaningful effect on transmission. The peak demand
for healthcare can be decreased by two-thirds, and deaths can be reduced significantly
as a product of prevention policies that include self-isolation, self-quarantine, and
social distancing. It is also established that in both the UK and the US, repression
also includes a combination of social distance, home isolation, and quarantine.
4 Proposed Method
4.1 Data Sources
To approximately calculate the dynamics of communication of COVID-19 in

Nigeria, the dataset from https://covid19.ncdc.gov.ng/gis/ and https://nairametrics.
com/covid-19-update-in-nigeria/ dataset are publicly available on cases from Nigeria
from the first case index on February 27, 2020. The data used cover February 27 to
June 20, 2020, contains the confirmed, recovered, and death cases. The total cases
were cropped for the model. The total cases as of June 20, 2020, are 19,808 confirmed,
6718 recovered and 506 death cases have been reported in the country and exist in
at least 20 states and union territories.
4.2 Model Formation
The model has two major assumptions: firstly, since there is no cure or immunity for
COVID-19, the model will be lethal, the infected can die at a certain rate. Secondly,
unlike the SIR method where the healed sets attain resistance from ailment after
they have been contaminated, the Recovered group, in this case, will not to the
confirmed cases. Also, around δ percent of the people, COVID-19 infects always
kills about, the stayers (100 − δ) percent become the recovered cases. There is no
immunity for Individuals that recover from the virus. There are no births or unrelated
deaths from the susceptible, thus, the population involved stays constant. Therefore,
the model divided each human sub-population into four classes: susceptible =
S(t), con f ir med = C(t), r ecover ed = R(t) and Death = D(t).
There will be depletion of the population when susceptible come in contact with
the confirmed then the susceptible (S) turn out to be contaminated at proportion
“α”. The population change will be equal to −αS I and the recovered group become
susceptible again at γ , giving γ R. Thus, the equation will be:
S(t) = − αS I − γ R (5)
From the susceptible population, confirmed group add to what was just removed,
αS I and the reduction are in two ways: people recovered or killed by the virus. Hence,
susceptible recovered at a degree “β” and slew at “δ” degree, hence the equation will
be:
I(t) = − αS I − β I − δ I (6)
Those that recovered from the virus increased the recovered cases, thus decreased
by the numeral of individuals that unite the vulnerable cases at a degree “γ ”, and
articulated as:
R(t) = β I − γ R (7)
And lastly, the figure of individuals slain by the disease at degree “δ” are the death
cases and the final group can be expressed as:
D(t) = δ I (8)
The adapted method, therefore, contains the succeeding structure of discrepancy

equations:
⎧
⎪
⎪ S(t) = − αS I − γ R
⎨
I (t) = αS I − β I − δ I
(9)
⎪
⎪ R(t) = β I − γ R
⎩
D(t) = δ I
where α = rate o f in f ection, γ = rate o f susceptibilit y, β =

rate o f r ecover y and δ = rate o f death.
ds(t) ds(t) ds(t) ds(t)

S(t) = , I(t) = , R(t) = , D(t) = (10)
dt dt dt dt
Note that S, I, R, and D sum individuals in every assembly as a function of period
and not by a portion of the populace. Hence, the mass action communication is the
transmission procedure employed for the model, and the communication process for
the nonlinear αS I is given as:
S
αN × × I = αS I (11)
N
where N is the overall sum of Residents, α N is the sum of the confirmed case by
contacts for each element period necessary to communicate the ailment and NS is the
proportion of these links with the vulnerable.
4.3 The Model with Quarantine
The model of the effects of partial quarantine of the confirmed individual is imperative
to comprise the outburst. The quarantined patients are removed from the population
to not contaminate novel persons despite the fact they continue to be restricted.
Hence, the improved method contains:
Only the confirmed population are quarantined at a rate ω.
The confirmed individuals after treatment could possess time-based salvage and
proceed to the healthier assembly at proportion β.
The confirmed individuals’ abortive to retort to healing could pass away and be
enthused to the demise collection at proportion δ.
Hence, the method equivalences are:
⎧
⎪
⎪ S (t) = − αS I − γ R
⎪
⎪
⎪
⎨ I (t) = αS I − ωI

Q (t) = ωI − β Q − δ Q (12)
⎪
⎪
⎪
⎪ R (t) = β Q − γ R
⎪
⎩ D (t) = δ Q
where α = rate o f in f ection, γ = rate o f susceptibilit y, β =

rate o f r ecover y, ω = rate o f r ecover y and δ = rate o f death.
ds(t) ds(t) ds(t) ds(t)

S (t) = , I (t) = , Q (t) = , D (t) = (13)
dt dt dt dt
4.4 Dynamics of Both SIR Model and Quarantine Model
From models (9) and (12) an aligned forth, calculation illustrates that the methods are
unremitting and Lipschizian in R3+ . Both models’ positive initial conditions exist and
unique from the solution. Thus, the primary discrepancy equivalence in both methods
has a resolution and likewise exceptional, that is F(t, s) = − αS I − γ R with
positive initial conditions. Therefore, S (t) = −αS I − γ R and its partial derivative
∂
∂s
F(t, s) = − δ I are defined and continuous at all points (t, s). This resolution
is exclusive in few probably lesser interludes positioned at t0 and the proposition
assures a resolution to the ODE occurs in few exposed interludes positioned at t0 .
This’s likewise correct for the residual equivalences for both methods.
The steadiness of the Disease-Free Equilibrium (DFE) and Existence of the
Methods.
4.5 The SIR Model
The ODEs satisfy at the equilibrium,S + I + R + D = 0 since S + I + R +

D = N and N is constant, this implied that the outburst possessed a petite period,
thus disregard natal and contextual demise proportions, therefore bir th rate =
death rate = 0. Model (9) can then be set to zero and have
⎧
⎪
⎪ − αS I − γ R = 0
⎨
αS I − β I − δ I = 0
(14)
⎪
⎪ βI − γ R = 0
⎩
δI = 0
The model with Quarantine.

The ODEs satisfy at the equilibrium,S + I + R + D = 0 since S + I + R + D =
N and N is constant, model (12) can then be set to zero and have
⎧
⎪
⎪ −αS I − γ R = 0
⎪
⎪
⎪
⎨ αS I − ωI = 0
ωI − β Q − δ Q = 0 (15)
⎪
⎪
⎪
⎪ β Q − γ R = 0
⎪
⎩ δQ = 0
The DFE model can be unstable, thus there is a propensity for the ailment to be
activated.
5 Experimental Results and Discussion
In this study, differential equations and linearized equilibrium were merged into a
deterministic model for the COVID-19 model of transmission dynamics to research
the effect of relapse and regulation on the transmission of viruses. Matlab software
with Euler’s rule was used with received data to estimate and simulate solutions
to the ODE’s. The simulation was performed to discover the consequence of such
parameters on the nature of the contagion’s transmission. The criteria used are as
follows:
α = rate o f in f ection: α = k/N ,
where N is overall populace magnitude and k is the usual sum of passable links
created by a contaminated individual each period, δ = rate o f death: this was
approximated to be the regular fatality proportion of the ailment since 2019 before
the present outburst and β = rate o f r ecover y (1 − δ).
5.1 Experiment I
Once there is a huge proportion of communicable interactions amid contaminated

and vulnerable: α = 3.15 × 10−5 ; β = 0.30; γ = 0.7.
The simulated result shows an unexpected reduction of the vulnerable assembly

and the contamination begin to increase unfluctuating to the best opinion where some
of the numbers of the populace are contaminated within limited times and thereafter
deteriorates. The preceding prey moreover passes on or joins the salvage collection,
the recovery group hits its peak but well along starts to reach nothing similar to the
contaminated assembly. Hence, more than 50% of the population was infected with
the virus a very high percentage. This portends a high epidemic situation more so
that COVID-19 disease conveys over interactions and polluted equipment and an
aerial ailment, will increase the aforementioned capability to convey the disease and
this possibly will spell doom if measures are not taking immediately.
5.2 Experiment II

and vulnerable: α = 2.36 × 10−5 ; β = 0.3; γ = 0.2 and δ = 0.73
This illustrates comparatively comparable results but with petite enhancement
over the first experiment because of the comparative deterioration in the figure of
interactions made by the contaminated collection. Hence, an abridged ultimate of
the contaminated (around 31% of the populace) and a steady reduction of the vulner-
able collection. The topmost of the recovered group is not having high experiment
1, also the death group is slightly lower show a mark of improvement. The suscep-
tibility increased higher as the infected and recovery approached zero at the same
stage. This may be a result of preventive measures put in place such as lockdown
in affected regions, washing of hands, using a face mask, and closure of the border,
but the demise level is comparatively tranquil huge. Therefore, an improved choice
will additionally decrease the interaction of contaminated by isolating, also with
homeopathic sustenance.
5.3 Experiment III (COVID-19 Control Model)

and vulnerable: α = 8.7 × 10−6 ; β = 0.3; γ = 0.2, ω = 0.75, and δ = 0.73.
The result of experiment III shows a more remarkable result than in what we
have in experiment I and experiment II. Currently, the confirmed group at its peak
is quite low and the susceptible group is reducing very gradually, about 3.27% of
the population. The infected population is a little higher than the quarantined group.
The quarantined and infected groups are higher than the recovered group and all
approach the zero mark together. As compared to experiment I and experiment II
about the same time, the death case is relatively low. Therefore, the mortality rate is
very low, meaning that a better proportion of the populace is animated, though still
susceptible.
5.4 Discussion
The COVID-19 model (9) experiment as a function of time reveals with the deficiency
of action that both overall and combined numbers of novel incidence of COVID-19-
infected individuals are increasing with the numbers of confirmed, recovered, re-
infected persons, and deaths. Reinfection of the recovered individuals would result
in more infectious cases compared with decreasing infections if the rate of reinfec-
tion is higher than the rate of degradation and vice versa. The Ebola model (15)
expands models of SIR transmission by introducing an infected population quar-
antine system, reinfection of recovered persons, and incorporation of infected and
recovered groups. Consequently, the models tested the impact of the models using
numerical simulations of stable parameter values using the Nigerian outbreak data
COVID-19 2020.
Coronavirus is fatal and by nature very infectious since there is no immunity or
cure as of present, and global solutions are in search of the outbreak. In this study,
we combined the Modified SIR model and linearized stability techniques into a
deterministic model for the conveyance dynamics of the COVID-19 model to study
the impact of relapse and control on the virus transmission. It was observed from
the numerical experiments carried out with a huge degree of contagious contact
amid contaminated and vulnerable, and the outcome was disastrous. The infected
incidence was very huge here, reported by more than 50% of the population. This
may be somewhat different from the present truth, but the unquestionable fact is that
owing to some unchecked epidemic of the COVID-19 virus, the amount of infected
will still be alarming. It was also discovered from the tests that there is a situation
from the previous high touch in which the touch was marginally decreased to assess
the results of the change in the contagious interaction level and the outcome was
comparable to the preceding one with a small decrease in the demise level.
The model further exhibits in the presence of disease reinfection, the ultimate
of the improved cluster does not have huge like experiment 1, also the death group
is slightly lower show a mark of improvement, where the steady disease-free equi-
librium co-exists with a steady widespread equilibrium when the connected replica
sum is fewer than unity. This in effect showed that the rate of confirmed cases is
directly proportional to the recovered rate and the death case effortlessly reduced
when compared with the figure of established and recovered incidence. The experi-
ments also revealed that the most way to limit the fatal effects and the conveyance of
the COVID-19 disease is the introduction of the quarantine system that greatly limited
transmittable interactions amid contaminated and vulnerable. Also, the introduction
of lockdown and closure of national borders with other countries greatly helps in
containing the spread of the deadly virus. Although all these measured occasionally
difficult to practice, due to some fundamental factors such as economic, political, or
social problems, it is still the greatest choice to be well-thought-out in handling the
huge demise degree of coronavirus outburst at least when there are no medications
or vaccine circumstances.
Well-documented weaknesses in testing ability in Nigeria at the time of writing,

and a lack of knowledge on ICU occupancy by COVID-19 patients, made it difficult
to know where we are positioned on the epidemic curve. A poor metric of under-
lying disease behavior accounts for the difficulties in both the spectrum of research
and the speed of testing. Acquisition of ICU occupancy data from the province
has proven difficult, while investigative reports have recently rendered accessible
the required metrics. Importantly, in this version of our model, we do not have
details of the hospital transmission periods. Transmission in health care environments
can reduce the capacity of ICUs quickly and significantly, by eliminating qualified
nurses, doctors, and respiratory therapists from active duty and by rapidly filling
new patients with ICUs (health care staff and patients admitted with nosocomial
COVID-19 infection for other reasons).
6 Conclusion
The 2019 coronavirus outbreaks at Wuhan, China was estimated to have caused over
31,664,104 confirmed and 972,221 mortalities cases around the globe according
to WHO as of 24 September 2020. Since the Wuhan COVID-19 outbreak in China,
Nigeria the most populated country in Africa announced the initially established case
of the coronavirus contagion in the national of Kerala, and the pretentious case had a
travel past event from Wuhan, China. In this investigation, the modified SIR method
was developed for the dynamic transmission and control of the coronavirus outbreak.
However mathematical models in other infectious and vector-borne illnesses were
well recognized, the impractical acceptance of constant populace magnitude or the
pseudo equilibrium theory were frequently made. Therefore, the investigation devel-
oped a modified SIR-type model where consideration was tending to the dynamic’s
transmission of the populace and control measures put in place to fight the outbreak.
The COVID-19 outbreak can be an actual hazard to a nonviolent reality as estab-
lished globally, especially in Nigeria. As established by the mathematical models,
it is perceived that unrestrained contagious contact between the susceptible and the
infected can result in a huge demise degree since no drugs or protection is present. The
current outbreak shows a shred of evidence which has majorly affected almost all the
countries of the world that had a travel history from Wuhan, China or even contact it
from other neighboring countries and most documented the bad-case scenario with a
maximum decreased degree much further than the overall demise since the recovery
of the disease in December 2019. Therefore, an improved administration choice by
the model revealed a forceful isolation scheme with therapeutic backing that even-
tually lessen the contagious links of the outbreak and greatly reduce the mortality
rate of the affected population. In managing and understanding the outbreak of this
kind of infectious disease, mathematical modeling is very crucial. Future work can
consider a constant flow of novel members into the entire populace per unit time
with susceptible or infective fraction, thus N susceptibility becomes functions of
time. The mathematical model was used for its short-term and long-term predic-
tion of disease incidence and the power to provide an insightful understanding of
disease avoidance and control. There are several limitations of the proposed model
with the source of uncertainty, nevertheless, the relatively long intervention durations
required to bend the COVID-19 outbreak curve, the qualitative insights around the
role of strategies controls, and the prospective use of repeated interventions can be
used by policy-makers and decision-makers, to consider the best strategies for infec-
tion management over the coming months, along with emerging scientific data from
other countries. It was important to note that the calculated parameters could have
some errors when predicted the epidemic trend of COVID-19 without any control
steps, due to the limited amount of data reported, and the predicted outcomes could
reflect an over-prediction.
References
1. World Health Organization: Population-based age-stratified seroepidemiological investiga-

tion protocol for coronavirus 2019 (COVID-19) infection, 26 May 2020 (No. WHO/2019-
nCoV/Seroepidemiology/2020.2). World Health Organization (2020)
2. Onder, G., Rezza, G., Brusaferro, S.: Case-fatality rate and characteristics of patients dying in
relation to COVID-19 in Italy. JAMA 323(18), 1775–1776 (2020)
3. Nikolich-Zugich, J., Knox, K.S., Rios, C.T., Natt, B., Bhattacharya, D., Fain, M.J.: SARS-
CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune
responses, and outcomes. Geroscience, 1–10 (2020)
4. Bi, Q., Wu, Y., Mei, S., Ye, C., Zou, X., Zhang, Z., Liu, X., Wei, L., Truelove, S.A., Zhang,
T. Gao, W.: Epidemiology and transmission of COVID-19 in Shenzhen China: analysis of 391
cases and 1286 of their close contacts. MedRxiv (2020)
5. Lippi, G., Plebani, M.: The critical role of laboratory medicine during coronavirus disease 2019
(COVID-19) and other viral outbreaks. Clin. Chem. Lab. Med. (CCLM), 1(ahead-of-print)
(2020)
6. Ogundokun, R.O., Lukman, A.F., Kibria, G.B., Awotunde, J.B., Aladeitan, B.B.: Predictive
modeling of COVID-19 confirmed cases in Nigeria. Infect. Dis. Modell. 2020(5), 543–548
(2020)
7. Ngonghala, C.N., Iboi, E., Eikenberry, S., Scotch, M., MacIntyre, C.R., Bonds, M.H., Gumel,
A.B.: Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing
the 2019 novel Coronavirus. Math. Biosci. 108364 (2020)
8. Bootsma, M.C., Ferguson, N.M.: The effect of public health measures on the 1918 influenza
pandemic in US cities. Proc. Natl. Acad. Sci. 104(18), 7588–7593 (2007)
9. Morens, D.M., Taubenberger, J.K., Folkers, G.K., Fauci, A.S.: A historical antecedent of
modern guidelines for community pandemic influenza mitigation. Public Health Rep. 124(1),
22–25 (2009)
10. Tognotti, E.: Influenza pandemics: a historical retrospect. J. Infect. Dev. Countries 3(05), 331–
334 (2009)
11. Short, K.R., Kedzierska, K., van de Sandt, C.E.: Back to the future: lessons learned from the
1918 influenza pandemic. Front. Cell. Infect. Microbiol. 8, 343 (2018)
12. Ayo, F.E., Ogundokun, R.O., Awotunde, J.B., Adebiyi, M.O., Adeniyi, A.E.: Severe acne skin
disease: a fuzzy-based method for diagnosis. Lecture Notes in Computer Science (including
subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2020,
vol. 12254, LNCS, pp. 320–334 (2020)
13. Oladele, T.O., Ogundokun, R.O., Awotunde, J.B., Adebiyi, M.O., Adeniyi, J.K.: Diagmal:
A malaria coactive neuro-fuzzy expert system. Lecture Notes in Computer Science
(including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinfor-
matics), 2020, vol. 12254, LNCS, pp. 428–441 (2020)
14. Ayo, F.E., Awotunde, J.B., Ogundokun, R.O., Folorunso, S.O., Adekunle, A.O.: A decision
support system for multi-target disease diagnosis: a bioinformatics approach. Heliyon, 6(3),
e03657 (2020)
15. Panovska-Griffiths, J.: Can mathematical modeling solve the current COVID-19 crisis? (2020)
16. Reuben, R.C., Danladi, M.M., Saleh, D.A., Ejembi, P.E.: Knowledge, attitudes, and practices
towards COVID-19: an epidemiological survey in North-Central Nigeria. J. Community Health,
1–14 (2020)
17. NCDC: An update of the COVID-19 outbreak in Nigeria. 01 August 2020 (2020).
Retrieved from https://ncdc.gov.ng/diseases/sitreps/?cat=14&name=An%20update%20of%
20COVID19%20outbreak%20in%20Nigeria
18. Ige, A.M.: The poverty of primary education in Nigeria: the way forward. Education 3–13,
42(6), 637–647 (2014)
19. Van Zandvoort, K., Jarvis, C.I., Pearson, C., Davies, N.G., Russell, T.W., Kucharski, A.J., Jit,
M., Flasche, S., Eggo, R.M., Checchi, F., CMMID COVID-19 working group: Response strate-
gies for COVID-19 epidemics in African settings: a mathematical modeling study. MedRxiv
(2020)
20. Iwuoha, V.C., Aniche, E.T.: COVID-19 lockdown and physical distancing policies are elitist:
towards an indigenous (Afro-centred) approach to containing the pandemic in sub-urban slums
in Nigeria. Local Environ. 1–10 (2020)
21. World Health Organization: Emergencies preparedness, response. Pneumonia of unknown
origin–China. Dis. Outbreak News, 5 (2020)
22. Winter, S., Dzombo, M.N., Barchi, F.: Exploring the complex relationship between women’s
sanitation practices and household diarrhea in the slums of Nairobi: a cross-sectional study.
BMC Infect. Dis. 19(1), 242 (2019)
23. Ioannidis, J.P.: Coronavirus disease 2019: the harms of exaggerated information and non-
evidence-based measures. Eur. J. Clin. Invest. 50(4), e13222 (2020)
24. Vigdor, N.: Man fatally poisons himself while self-medicating for coronavirus, doctor says.
New York Times 24 (2020)
25. Wong, G., Liu, W., Liu, Y., Zhou, B., Bi, Y., Gao, G.F.: MERS, SARS, and Ebola: the role of
super-spreaders in infectious disease. Cell Host Microbe 18(4), 398–401 (2015)
26. Roy, D., Tripathy, S., Kar, S.K., Sharma, N., Verma, S.K., Kaushal, V.: Study of knowledge,
attitude, anxiety & perceived mental healthcare need in the Indian population during COVID-19
pandemic. Asian J. Psychiatry, 102083 (2020)
27. Ebrahim, S.H., Ahmed, Q.A., Gozzer, E., Schlagenhauf, P., Memish, Z.A.: COVID-19 and
community mitigation strategies in a pandemic (2020)
28. Akpoveta, O.A., Joy, O., Joy, O.: COVID-19 pandemic: Nigeria’s economic and business
disruptions. Int. Scholar J. Arts Soc. Sci. Res. 2(4), 14–31 (2020)
29. Maital, S., Barzani, E.: The global economic impact of COVID-19: a summary of research.
Samuel Neaman Institute for National Policy Research (2020)
30. Ashraf, B.N.: The economic impact of government interventions during the COVID-19
pandemic: international evidence from financial markets. J. Behav. Exp. Finan. 100371 (2020)
31. Bonnet, F., Vanek, J., Chen, M.: Women and Men in the Informal Economy: A Statistical
Picture. Women in Informal Employment: Globalizing and Organizing (WIEGO) (2019)
32. Budlender, D.: Statistics on Informal Employment in South Africa. Women in Informal
Employment: Globalizing and Organizing (WIEGO) (2011)
33. Davies, R., Thurlow, J.: Formal-informal economy linkages and unemployment in South Africa.
Pretoria: Human Sciences Research Council (HSRC); 2009. 22. Global Health Expenditure
Database [online database]. Geneva: World Health Organization (2019). https://apps.who.int/
nha/databuse/ViewData/Indicators/en. Accessed 27 Mar 2020.
34. Bohlmann, H.R., Van Heerden, J.H., Dixon, P., Rimmer, M.: The impact of the 2014 platinum
mining strike in South Africa: an economy wide analysis. J. Econ. Model. 51, 403–411 (2015)
35. Leigh-Hunt, N., Bagguley, D., Bash, K., Turner, V., Turnbull, S., Valtorta, N., et al.: An overview
of systematic reviews on the public health consequences of social isolation and loneliness.
Public Health 152, 157–171 (2017)
36. Djordjevic, J., Silva, C.J., Torres, D.F.: A stochastic SICA epidemic model for HIV
transmission. Appl. Math. Lett. 84, 168–175 (2018)
37. Rachah, A., Torres, D.F.: Dynamics and optimal control of Ebola transmission. Math. Comput.
Sci. 10(3), 331–342 (2016)
38. Ndairou, F., Area, I., Nieto, J.J., Torres, D.F.: Mathematical modeling of COVID-19
transmission dynamics with a case study of Wuhan. Chaos, Solitons & Fractals, 109846 (2020)
39. Brauer, F., Castillo-Chavez, C., Feng, Z.: Mathematical Models in Epidemiology. Springer,
New York (2019)
40. Chen, T.M., Rui, J., Wang, Q.P., Zhao, Z.Y., Cui, J.A., Yin, L.: A mathematical model for
simulating the phase-based transmissibility of a novel coronavirus. Infect. Dis. Poverty 9(1),
1–8 (2020)
41. Camacho, A., Kucharski, A., Aki-Sawyerr, Y., White, M.A., Flasche, S., Beguelin, M.,
Pollington, T., Carney, J.R., Glover, R., Smout, E., Tiffany, A.: Temporal changes in Ebola
transmission in Sierra Leone and implications for control requirements: a real-time modeling
study. PLoS Currents, 7 (2015)
42. Funk, S., Ciglenecki, I., Tiffany, A., Gignoux, E., Camacho, A., Eggo, R.M., Kucharski, A.J.,
Edmunds, W.J., Bolongei, J., Azuma, P., Clement, P.: The impact of control strategies and
behavioural changes on the elimination of Ebola from Lofa County, Liberia. Philos. Trans.
Royal Soc. B: Biol. Sci. 372(1721), 20160302 (2017)
43. Riley, S., Fraser, C., Donnelly, C.A., Ghani, A.C., Abu-Raddad, L.J., Hedley, A.J., Leung, G.M.,
Ho, L.M., Lam, T.H., Thach, T.Q., Chau, P.: Transmission dynamics of the etiological agent
of SARS in Hong Kong: impact of public health interventions. Science 300(5627), 1961–1966
(2003)
44. Viboud, C., Sun, K., Gaffey, R., Ajelli, M., Fumanelli, L., Merler, S., Zhang, Q., Chowell,
G., Simonsen, L., Vespignani, A.: The RAPIDD Ebola forecasting challenge: synthesis and
lessons learned. Epidemics 22, 13–21 (2018)
45. Cooper, B.S., Pitman, R.J., Edmunds, W.J., Gay, N.J.: Delaying the international spread of
pandemic influenza. PLoS Med. 3(6), e212 (2006)
46. Kucharski, A.J., Camacho, A., Checchi, F., Waldman, R., Grais, R.F., Cabrol, J.C., Briand,
S., Baguelin, M., Flasche, S., Funk, S., Edmunds, W.J.: Evaluation of the benefits and risks of
introducing Ebola community care centers, Sierra Leone. Emerg. Infect. Dis. 21(3), 393 (2015)
47. WHO Ebola Response Team: Ebola virus disease in West Africa—the first 9 months of the
epidemic and forward projections. N. Engl. J. Med. 371(16), 1481–1495 (2014)
48. Nishiura, H., Klinkenberg, D., Roberts, M., Heesterbeek, J.A.: Early epidemiological assess-
ment of the virulence of emerging infectious diseases: a case study of an influenza pandemic.
PLoS One 4(8), e6852 (2009)
49. Birrell, P.J., De Angelis, D., Presanis, A.M.: Evidence synthesis for stochastic epidemic models.
Stat. Sci. Rev. J. Inst. Math. Stat. 33(1), 34 (2018)
50. Baguelin, M., Flasche, S., Camacho, A., Demiris, N., Miller, E., Edmunds, W.J.: Assessing
optimal target populations for influenza vaccination programmes: an evidence synthesis and
modeling study. PLoS Med. 10(10), e1001527 (2013)
51. Bahi-Jaber, N., Pontier, D.: Modeling transmission of directly transmitted infectious diseases
using colored stochastic Petri nets. Math. Biosci. 185(1), 1–13 (2003)
52. Li, L.X., Xu, L.D.: An integrated information system for the intervention and prevention of
AIDS. Int. J. Biomed. Comput. 29(3–4), 191–206 (1991)
Proc. Royal Soc. London. Ser. A, Containing Papers Math. Phys Charact. 115(772), 700–721
(1927)
54. Brauer, F.: Models for the spread of universally fatal diseases. J. Math. Biol. 28(4), 451–462
(1990)
55. Brauer, F.: Models for the spread of universally fatal diseases II. Differential Equations Models
in Biology, Epidemiology, and Ecology (pp. 57–69). Springer, Berlin, Heidelberg (1991)
56. Hethcote, H.W.: Asymptotic behavior and stability in epidemic models. Mathematical Problems
in Biology (pp. 83–92). Springer, Berlin, Heidelberg (1974)
57. Pugliese, A.: Population models for diseases with no recovery. J. Math. Biol. 28(1), 65–82
(1990)
58. Castillo-Chavez, C., Cooke, K., Huang, W., Levin, S.A.: On the role of long incubation periods
in the dynamics of acquired immunodeficiency syndrome (AIDS). J. Math. Biol. 27(4), 373–398
(1989)
59. Wu, J.T., Leung, K., Bushman, M., Kishore, N., Niehus, R., de Salazar, P. M., Cowling, B.J.,
Lipsitch, M., Leung, G.M.: Estimating the clinical severity of COVID-19 from the transmission
dynamics in Wuhan, China. Nat. Med. 26(4), 506–510 (2020)
60. Wang, N., Fu, Y., Zhang, H., Shi, H.: Evaluation of mathematical models for the outbreak of
COVID-19. Precis. Clin. Med. (2020)
61. Rachah, A., Torres, D.F.: Analysis, simulation, and optimal control of an SEIR model for the
Ebola virus with demographic effects. arXiv preprint arXiv:1705.01079 (2017)
62. Porter, A.T.: A path-specific approach to SEIR modeling (2012)
63. Böttcher, L., Xia, M., Chou, T.: Why estimating population-based case fatality rates during
epidemics may be misleading. medRxiv (2020)
64. Wu, Z., McGoogan, J.M.: Characteristics of and important lessons from the coronavirus disease
2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese
Center for Disease Control and Prevention. JAMA 323(13), 1239–1242 (2020)
international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modeling
study. The Lancet 395(10225), 689–697 (2020)
66. Dorigatti, I., Okell, L., Cori, A., Imai, N., Baguelin, M., Bhatia, S., Boonyasiri, A., Cucunubá,
Z., Cuomo-Dannenburg, G., FitzJohn, R., Fu, H.: Report 4: Severity of 2019-Novel Coronavirus
(nCoV). Imperial College London, London (2020)
67. Chen, Y.C., Lu, P.E., Chang, C.S.: A time-dependent SIR model for COVID-19. arXiv preprint
arXiv:2003.00122 (2020)
68. Biswas, K., Khaleque, A., Sen, P.: COVID-19 spread: reproduction of data and prediction using
a SIR model on the Euclidean network. arXiv preprint arXiv:2003.07063 (2020)
69. Sahoo, B.: Disease control through the provision of alternative food to predator: a model-based
study. Int. J. Dyn. Control 4(3), 239–253 (2016)
70. Riou, J., Althaus, C.L.: Pattern of early human-to-human transmission of Wuhan 2019 novel
coronavirus (2019-nCoV), December 2019 to January 2020. Eurosurveillance 25(4), 2000058
(2020)
71. Liu, T., Hu, J., Xiao, J., He, G., Kang, M., Rong, Z., Lin, L., Zhong, H., Huang, Q., Deng, A.,
Zeng, W.: Time-varying transmission dynamics of Novel Coronavirus Pneumonia in China.
BioRxiv (2020)
72. Read, J.M., Bridgen, J.R., Cummings, D.A., Ho, A., Jewell, C.P.: Novel coronavirus 2019-
nCoV: early estimation of epidemiological parameters and epidemic predictions. MedRxiv
(2020)
73. Hong, H.G., Li, Y.: Estimation of time-varying transmission and removal rates underlying
epidemiological processes: a new statistical tool for the COVID-19 pandemic. arXiv preprint
arXiv:2004.05730 (2020)
74. Ferretti, L., Wymant, C., Kendall, M., Zhao, L., Nurtay, A., Abeler-Dörner, L., Parker, M.,
Bonsall, D., Fraser, C.: Quantifying SARS-CoV-2 transmission suggests epidemic control with
digital contact tracing. Science 368(6491) (2020)
75. Li, R., Pei, S., Chen, B., Song, Y., Zhang, T., Yang, W., Shaman, J.: Substantial undoc-
umented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2).
Science 368(6490), 489–493 (2020)
76. Ravela, S., Sandu, A. (Eds.): Dynamic Data-Driven Environmental Systems Science: First Inter-
national Conference, DyDESS 2014, Cambridge, MA, USA, November 5–7, 2014, Revised
Selected Papers (vol. 8964). Springer (2015)
77. Daley, D.J., Gani, J.: Epidemic Modeling: An Introduction (vol. 15). Cambridge University
Press (2001)
78. Jenny, P., Jenny, D.F., Gorji, H., Arnoldini, M., Hardt, W.D.: Dynamic Modeling to Identify
Mitigation Strategies for COVID-19 Pandemic. medRxiv (2020)
79. Yuan, G.X., Di, L., Gu, Y., Qian, G., Qian, X.: The Framework for the Prediction of the Critical
Turning Period for Outbreak of COVID-19 Spread in China Based on the iSEIR Model (2020).
80. Fine, P.E.: Herd immunity: history, theory, practice. Epidemiol. Rev. 15(2), 265–302 (1993)
81. Fine, P., Eames, K., Heymann, D.L.: “Herd immunity”: a rough guide. Clin. Infect. Dis. 52(7),
911–916 (2011)
82. Smith, D.R.: Herd immunity. Vet. Clin. Food Anim. Pract. 35(3), 593–604 (2019)
83. Lourenco, J., Paton, R., Ghafari, M., Kraemer, M., Thompson, C., Simmonds, P., Klenerman,
P., Gupta, S.: Fundamental principles of epidemic spread highlight the immediate need for
large-scale serological surveys to assess the stage of the SARS-CoV-2 epidemic. MedRxiv
(2020)
84. Ferguson, N., Laydon, D., Nedjati Gilani, G., Imai, N., Ainslie, K., Baguelin, M., Bhatia,
S., Boonyasiri, A., Cucunuba Perez, Z.U.L.M.A., Cuomo-Dannenburg, G., Dighe, A.: Report
9: Impact of Non-pharmaceutical Interventions (NPIs) to Reduce COVID19 Mortality and
Healthcare Demand (2020)
85. Tian, S., Hu, W., Niu, L., Liu, H., Xu, H., Xiao, S.Y.: Pulmonary pathology of early phase 2019
novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J. Thor. Oncol.
(2020)
86. Kraemer, M.U., Yang, C.H., Gutierrez, B., Wu, C.H., Klein, B., Pigott, D.M., Du Plessis, L.,
Faria, N.R., Li, R., Hanage, W.P., Brownstein, J.S.: The effect of human mobility and control
measures on the COVID-19 epidemic in China. Science 368(6490), 493–497 (2020)
87. Prem, K., Cook, A.R., Jit, M.: Projecting social contact matrices in 152 countries using contact
surveys and demographic data. PLoS Comput. Biol. 13(9), e1005697 (2017)
88. Ferguson, N.M., Cummings, D.A., Fraser, C., Cajka, J.C., Cooley, P.C., Burke, D.S.: Strategies
for mitigating an influenza pandemic. Nature 442(7101), 448–452 (2006)
Robust Statistical Modeling of COVID-19
Prevalence in African Epicentres’
Adewale F. Lukman, Aladeitan Benedicta, Joseph Bamidele Awotunde,

Charle E. Okon, Olajumoke Oludoun, Abiodun Oluwakemi,
Opeyemi E. Ayinde, Olusegun O. Alabi, and Abidemi Emmanuel Adeniyi
Abstract The world at large has been confronted with several disease outbreaks
which have posed and still posing a serious menace to public health globally.
Recently, COVID-19 a new kind of coronavirus emerge from Wuhan city in China
and was declared a pandemic by the World Health Organization. There has been
reported case of about 10,021,401 with global death of 499,913 as of 15.15 GMT,
June 29 2020. There are 382,190 and 9664 positive cases and deaths in Africa, respec-
tively as of June 29 at 7:00 GMT. South-Africa, Egypt, Nigeria, Ghana, Algeria and
Cameroon are the most affected African countries with this outbreak. The chapter
referred to them in this study as Africa epicenters’. Thus, there is a need to monitor
and predict COVID-19 prevalence in this region for effective control and manage-
ment. Different statistical tools and time series model such as the linear regression
model and auto-regressive integrated moving average (ARIMA) models have been
applied for disease prevalence/incidence prediction in different diseases outbreak.
This book chapter adopted the linear regression model and the ARIMA models to
forecast the trend of COVID-19 prevalence in the aforementioned African coun-
tries. The datasets examined in this analysis spanned from February 21, 2020, to
October 4, 2020, and was extracted from the European Centre for Disease Preven-
tion and Control website. The cumulative confirmed cases of COVID-19 cases were
subjected to different curve estimation statistical models in simple, quadratic, cubic,
and quartic forms. In the chapter, we identified the best model in each country and
A. F. Lukman (B) · A. Benedicta · O. Oludoun · A. Oluwakemi

Department of Mathematics, Landmark University, Kwara State, Omu-Aran, Nigeria
e-mail: adewale.folaranmi@lmu.edu.ng
J. B. Awotunde
Department of Computer Science, University of Ilorin, Ilorin, Nigeria
C. E. Okon · O. O. Alabi
Department of Statistics, Federal University of Technology, Akure, Nigeria
O. E. Ayinde
Department of Agric-Economics and Farm Management, University of Ilorin, Ilorin, Nigeria
A. E. Adeniyi
Department of Computer Science, Landmark University, Kwara State, Omu-Aran, Nigeria
316 A. F. Lukman et al.
use the same for prediction and forecasting purposes. In conclusion, we obtained the
future trend of this virus across Africa epicenters’ and this, in turn, will assist the
government and health authorities to plan and take precautions that will help to curb
this pandemic in Africa.
Keywords Coronavirus · Linear regression model · Time series model · Curve

estimation · COIVD-19 pandemic · Prevalence · Incidence
1 Introduction
The new coronavirus (SARS-CoV-2) spread widely in China, and a large number
of people became infected from the outbreak in December 2019. The World Health
Organization (WHO) declared the outbreak is a public health emergency of interna-
tional concern on 30 January 2020 [1, 2]. In February, WHO announced a name for
the new coronavirus disease as the COVID-19 3, and on 11 March, the COVID 19
outbreak as pandemic [3, 4]. The new COVID-19 outbreak has a great threat to the
health and safety of people all over the world due to its amazing spreading power and
potential harms [5, 6]. COVID-19 has spread to all continents, as of 30 September
2020, there have been 33,441,919 confirmed cases of COVID-19 with 1,003,497
deaths (3.0% case-fatality ratio) [7].
COVID-19 pandemic is the greatest global health crisis we have faced for a long
time. The pandemic has also created an unprecedented socio-economic crisis besides
a health crisis. It has the potential to create devastating social, economic, and political
effects that will leave deep and long-standing scars on every one of the countries it
spreads [8]. Faced with this unprecedented situation, governments all around the
world have been focusing on taking the pandemic under control and reviving their
economies again after the lockdown period.
The crucial question which the researchers (actually all people) have been seeking
the answer since the beginning of the pandemic that is how many people will be
possibly infected and die of COVID-19 until the end of the pandemic. We still
have limited knowledge about the epidemic for example whether the virus has a
seasonal effect and a second wave will come. A way to answer these questions is the
interpretation of the behaviors of the pandemic through modeling of the COVID-19
data. There are numerous mathematical models and methods in the literature. We
should keep in mind that these models aren’t a magic wand to find out everything’s
about the pandemic. Another important point to be taken into account is the lack
of correct data. This is caused by the misreporting of the cases for many reasons.
The studies are so important for decision-makers and government leaders to allocate
resources to health care facilities and to take precautions against the spreading of the
virus.
COVID-19 is extremely infectious and can spread complications before and after
the onset. Monitoring and lockdown have to encompass anyone with symptoms and
properly isolate persons who have been infected from those who are not, to allow
Robust Statistical Modeling of COVID-19 Prevalence … 317
good containment. Patients carrying the virus could either be minor symptomless
(like fever, sore throat, and sneezing) or have serious clinical signs (such as pneu-
monia, respiratory failure, and eventually death) [9]. The transmittable SARS-CoV-2
condition is called “coronavirus disease” (COVID-19) [10]. Gratitude to the recent
developments in analytical techniques and information and communication tech-
nologies (ICTs), Machine Learning (ML) and big data will aid manage the immense,
unparalleled volume of data generated from patient monitoring, real-time tracking
of disease outbreaks, now-casting/predicting patterns, daily situation briefings and
public updates [11].
By this time, the pandemic appears to be under control in most countries, although
there is still criticism of the utilization of what others have called “draconian” steps
to stifle its circulation. The globe is presently trying to monitor the exceptional
virus circulation that involves the greatest sum of indispositions plus deaths. As
there is no such thing as definite medical care for coronaviruses and attempts to
control the circulation have yet remained unsuccessful [12, 13], there’s a crucial
necessity for worldwide investigation of persons with intense COVID-19 contagion.
A unified inclusion of automated sickness management scheme could be key to
managing this virus. Scientists in physical science and engineering are trying to
resolve these glitches, formulate new ideas, clarify innovative research difficulties,
construct user-centered clarifications, and establish themselves including the civilian
overall.
In times of crisis, governments, leaders and policymakers have 2 major respon-
sibilities: to address the immediate issue and prevent it from occurring again [14,
15]. An African Coronavirus Preparedness and Response Task Force (AFTCOR)
has been set up, focusing on 6 work streams: laboratory diagnosis and subtyping;
surveillance, including entry point and cross-border screening; infection prevention
and control in health care facilities; clinical treatment of people with extreme COVID-
19; risk communication; and supply chain management Most countries would not
be able to afford large-scale diagnostics should COVID-19 spread rapidly in Africa,
while AFTCOR could expand this ability to more than 40 African countries. There-
fore, triage based on clinical case description or presumptive diagnosis should be
prioritized in the absence of research.
Many local transmission-related cases of COVID-19 have been reported in coun-
tries located in the northern hemisphere that are in the “flu” winter season. Similarly,
the global epidemic of SARS-CoV in February 2003 did not have a significant impact
on Africa or South America, meaning that respiratory viruses spread more efficiently
in the winter, and that the southern hemisphere would therefore be affected later in
the year, if at all. Climate-specific cultural differences (living more outdoors than
indoors), the effect of UV light on surface survival of the virus, population immune
differences (innate immunity), coronavirus pre-exposure or higher temperatures may
all have contributed to this. To date, all cases of COVID-19 in Africa found have
arisen in Europe and not in China.
The number of patients needing ventilatory assistance outnumbered the available
intensive care unit (ICU) beds at the height of the Chinese COVID-19 outbreak
[16]. General beds were quickly converted to ICU beds and general hospitals were
converted to critical care hospitals; additional doctors and nurses trained in critical
care medicine were moved to the most affected area. In Africa, as measured in the
Republic of Gambia, ICU beds and personnel trained in critical care are restricted to
tertiary hospitals; thus, COVID-19-related mortality is likely to surpass the recorded
case fatality rate of 2.3% [17]. In addition, it is debatable if low- and middle-income
countries (LMICs) can fund the increased cost of critical care units from their limit.
Classification can also be defined as the procedure of categorizing a report. An
instance of classification is to scrutinize whether it is raining or not and the response
can either be yes or no. Hence, there is a precise number of selections. Although
occasionally there could be more than two groups to categorize and this is called
multiclass classification [18, 19]. An instance in real life is a bank requiring to
consider whether granting a mortgage to a specific customer is uncertain or not. In
this instance, a replica is created to discover the uncompromising label.
The goal of the data classification task is to build a machine learning model that
will accurately and effectively classify or group a set of inputs (features) into their
respective classes. The classification problem could be binary i.e. with two different
classes as “0” or “1” [20, 21], Yes or No or True or False. It could be a multiple
class problem where there are three (3) or more classes as “COVID-19+”, “COVID-
19−” and “Healthy lungs” [22]. A classification problem could also be multiple label
problem where a class could have two or more labels [23].
Prediction is the process of learning from historical data to make estimates about
the future or unknown event. For health care, predictive analytics will enable the
best decisions to be made, allowing for care to be personalized to each individual.
When the prediction is done right in healthcare will help the medical scientist to see
an increase in patient access, lower cost, increased revenue, increased asset utiliza-
tion, and also improved patient experience. Predictive analytics tried to apply what
doctors have been doing on a larger scale. The most changes brought to healthcare by
predictive analytics are the ability to make sense of previously non-existent behav-
ioral, to better measure, quantitative, psychosocial, and biometric data, so the wheel
is not reinvented [24–26]. It allows individual treatment to be personalized to each
person and allows the best health care decisions to be made. The medium goal of
healthcare predictive analytics is to reliably predict the unpredictable. Confidence
in predictions affects the type of question posed with a high certainty of response.
For example, it can be answered with a high degree of certainty to ask a historical
question like “what did I eat today.”
Applying predictive analytics in healthcare through data analytics helps improve
the operational efficiency, planning, and execution of key care delivery systems,
use of resources, staff schedules, and admission and discharge of patients. All of this
leads to increased patient access to good health care delivery and income, lower costs,
increased use of assets, and improved patient experience. New data sources are used
for predictive analytics, including those directly from patients. The simultaneous use
of two or more forms of statistical analysis is called a predictive model and is a subset
of concurrent analytics. Predictive modeling’s main objective is to forecast action,
outcome, or occurrence using a multivariate array of predictors [27]. Therefore, this
chapter will adopt the linear regression model to forecast the trend of COVID-19
prevalence in the aforementioned African countries. The datasets examined in this

analysis spanned from February 21, 2020, to June 30, 2020, and will be extracted
from the European Centre for Disease Prevention and Control website.
2 The Covid-19 Pandemic in Africa Nations
African nations with dysfunctional healthcare services and travel ties with Wuhan,
Italy, Spain and other higher COVID-19 infected nations have largely remained unaf-
fected, that are the most susceptible. World Health Organization, the Africa Centers
for Disease Control and Prevention (CDC), government bodies, and community
health officials has devoted two months optimizing prevention measures to combat
the transmission of the COVID-19 disease outbreak across Africa in expectation of
the importation of cases to Africa [1, 28, 29]. This contribution is crucial in allowing
national leaders to adopt guidelines from the global health Regulatory Emergency
Committee.
Previously, the WHO African Region had seen huge rise in cases. As at the forth
month of the year 21,388 of novel coronavirus cases were recorded and registered
from 33 countries with 875 deaths (4.0% case death) [29]. Amongst these reported
cases, the male-to-female ratio is 1.4, and the average age is 41.5 years (interquartile
range, 31–54 years), which may decrease the overall number of fatalities relative
to the world average. South Africa, Algeria, Cameroon and Ghana recorded highest
number of cases in April, 2020 with 4793, 3517, 1621 and 1550 cases respectively
as shown in Fig. 1 [29]. Mostly in African continent, several of the cases include
intermittent imported from the European Union or the United States, and, oddly, no
one is from China, as predicted [30]. The history of traveling to France, the United
Kingdom, Italy, Switzerland, Spain, Germany, the United States, the United Arab
Emirates, India, Iran, Japan or New Zealand has been registered in all early disease
index cases documented in the WHO African Region [31].
Because of the high volume of air traffic and trade between China and Africa,
Nkengasong [32], Africa seems to be at a elevated danger of the emergence and
dissemination of the latest 2019 coronavirus outbreak (COVID-19); while the first
occurrence from a non-national has been identified by only Egypt [33]. The biggest
concern for health professionals would be whether, as has now been seen in many
nations, COVID-19 is becoming a global epidemic, with prolonged year-round
infection close to influenza [34].
What will happen to Africa where, if a disease outbreak happens, several nations
have poor medical systems, including insufficient surveillance and diagnostic capa-
bility, shortage of resources in public health, and restricted economic resources?
The impact could be disastrous with neither medication nor vaccinations, without
any previously existing resistance, due to the numerous medical problems the nation
currently encounters: growing populations and increased mobility of individuals;
Present infectious illnesses, like human immunodeficiency virus, tuberculosis and
Fig. 1 Coronavirus disease-2019 status in Africa, as of 28 April 2020 [31]
malaria, and the growing occurrence of non-communicable diseases, including Ebola

virus, Lassa haemorrhagic fever among others.
On Feb 14, 2020, Africa reported the first occurrence in Egypt. China is Africa’s
largest business associate, so there are significant amounts of movement by which
the region can be penetrated by extreme acute respiratory syndrome coronavirus
2. So many steps are already introduced to avoid and monitor potential imports of
cases from China [35]; nevertheless, the power to regulate and control local post-
importation spread depends on the implementation and compliance of rigorous iden-
tification, prevention strategies. These steps involve improved monitoring and rapid
detection of doubtful cases, followed by relocation and isolation of patients, rapid
diagnosis, tracking and monitoring of possible contacts. The application of such a
large technological and operational number of approaches rests on the health policy
and laboratory setup services and facilities of each nation.
There have been no remarkably successful therapies for COVID-19 infection till
present. Therapeutic approaches combating the SARS-CoV-2 illness and its destruc-
tive immune system in the respiratory organ, that induces severe lower lung tract
disease and is a leading source of death, are undergoing testing in multiple trials [32].
Phase III research conducted remdesivir (GS-5734), a nucleoside analog inhibitor
previously being developed for Ebola which has demonstrated in vitro effectiveness
against SARS-CoV-2 and avoids severe in vivo pulmonary complications, began in

March and are expected to complete in May 2020 [36].
A randomized controlled trial conducted in China of lopinavir/ritonavir, an HIV
therapy commonly used in Africa, showed no changes in infection duration, epidemi-
ologic cracking, or 28-day fatalities [32]. A small (n = 36), in a non-randomized
medical trial examining the use of hydroxyl-chloroquine/azithromycin, these were
confirmed that hydroxyl-chloroquine was successful in resolving SARS-CoV-2 viral
nasopharyngeal carriage in French COVID-19 patients in just 3–6 days. Neverthe-
less, given the limited sample size, shortage of clinical data, and shortage of random
sampling, the quality of scrutiny was poor, and thus the findings of the analysis are not
definitive [37]. There are an imminent necessity sufficiently strong, clinical studies
to validate the efficiency of hydroxychloroquine in the cure of novel coronavirus.
3 Review of the COVID-19 Prevalence in African

Epicentres’
African leaders were keenly aware that failure to control COVID-19 would endanger
health, stability and protection, building on experience from the 2014 Ebola virus
disease crisis in West Africa [38]. Member States of the African Union (AU) were
swift to concentrate on preventing the importation of COVID-19 and containing
forward transmission within countries. Ivory Coast [39, 40], soon followed by other
African countries, began to introduce enhanced airport surveillance as early as 2
January 2020, screening all passengers with a recent travel history to China. In
exchange, direct flights to and from China were suspended by most African airlines
[34].
Initially, this strategy seemed to pay off: the first case of COVID-19 on the conti-
nent, recorded by Egypt on 14 February 2020, involved the touch of a person with
a history of traveling to China. Nine African countries (Algeria, Cameroon, Egypt,
Morocco, Nigeria, Senegal, South Africa, Togo and Tunisia) had registered over 40
cases by the end of the first week of March. The majority of index cases emerged
in Europe [41], where by 13 March the epicenter had moved [29, 31], leading to an
early spread of the pandemic on the African continent.
3.1 Algeria as An Epicentre in Africa
Algeria is a country in the North Africa suburb of Maghreb. Algiers, which has the
highest population in the country is also the country’s capital. The name Algeria
was derived from the Algiers which is in turn derived from the word al-jaza’ir [42].
Algeria gained its independence from France in May 1945 [43]. On January 12th,
2020 the WHO (http://www.who.int) confirmed that a novel corona virus was the
cause of a respiratory illness in a cluster of people in Wuhan City, Hubei Province,

China. This had initially came to the attention of World Health Organization on the
31st of December, 2019 [44]. The Corona Virus Pandemic in Algeria is part of the
World wide pandemics of corona virus disease 2019 (COVID-19) caused by severe
acute respiratory syndrome corona virus 2 (SARS-CoV-2).
The virus was confirmed to have spread to Algeria in February, 2020 (Algeria
health minister). On 25th of February, 2020, Algeria laboratory confirmed its first
case of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). An Italian
who arrived on 17th of February, 2020 brought the virus into Algeria [45]. Although
the man was deported back to Italy via a special flight from Hassi Messaoud Airport
where he was subjected to quarantine [45]. According to the health ministry of the
country on the 2nd of March, 2020 Algeria confirmed two (2) new cases of SARS-
CoV-2, a woman and her daughter [45]. From then, occurrence of the disease has
been in increase up till today Schools were closed due to the corona virus spread in
Algeria on the 12th of March, 2020. On 22nd of March, 2020, the Algerian Minister
of health, Abderrahmane Benbouzid announced that Algeria entered the third phase
of the corona virus epidemic and that the country should get prepared for the worst
[46]. Shortly after his declaration, on 24th of March corona virus spread to thirty-six
provinces in Algeria. With Blida province as an epicenter of COVID-19 in Algeria
with record of one eighty confirmed cases as of then.
As a result of this incidence of Covid-19 Algeria government decided to take the
following control measures:
1. Total Lockdown.
2. Ban on public gatherings of more than two people with exception of people
working on curbing the spread of Covid-19 through may19.
3. Suspension of all public transport services including all ride-sharing services.
4. Social distancing rules requiring individuals to remain 1 m (3 ft) apart when
interacting.
5. Close of private & public schools.
6. Suspension of land, air & see passenger connection until further notice, freight
transport remains unaffected.
7. Basic health precautions. Especially frequent hand washing with soap and water
or alcohol based hand sanitizers, practice good coughing and sneezing etiquette.
But with all these control measures, COVID-19 is still a serious problem in the
country.
Blida and Algiers provinces are still competing for Province epicenter in Algeria,
up to date the 28th of September 2020, the Corona virus confirmed cases, recovery
cases and deaths cases distribution record in Algeria were given for ten provinces in
ascending order in Table 1.
In all, we have fifty one thousands and sixty one confirmed cases, thirty five
thousands eight hundred and sixty recovered cases and one thousands seven hundred
and fourteen recoded deaths cases in Algeria up to date.
Hamidouche [47] estimated the case number growth in the early stages of COVID
19 outbreak, they introduced the Alg-COVID-19 model to help decision-makers
Table 1 The distribution of

Province No. of No. of No. of deaths
the most infected nine (9)
confirmed cases recovered cases
provinces with COVID-19 in
Algeria Algiers 5695 261 145
Oran 3939 234 22
Blida 4123 133 131
Oran 3939 234 22
Setif 3227 2 61
Batna 1854 0 17
Bejaia 1821 1 28
Constantine 1651 0 25
Batna 1854 0 17
forecast the incidence and reproduction number R0 in the coming months. The Alg-
COVID-19 model is crucial as the model is only true if the majority of the population
is susceptible to the infection. However, the COVID-19 infection can be modified to
match the new values of the parameters.
Lounis [48] explains the current situation of COVID-19 in Algeria, the steps taken
to prevent and manage the disease and, ultimately, the contribution of the Algerian
Scientific Community.
A compartmental epidemic model based on the algorithm of genetic fitting was
proposed by Rouabah et al. [49]. This generic enhanced SEIR model enables the
estimation of approximate now cast and forecast of epidemic evolution, including
key epidemic parameters and non-measurable asymptomatic infected portion of
the susceptible population, and a cross-validation method to solve the over-fitting
problem. The model is used to study the dynamics of COVID-19 outbreaks between
February 25 and May 24 in Algeria.
3.2 Nigeria as An Epicentre in Africa
The corona virus is a class of virus that affects majorly the respiratory organs and
affects mostly animals and humans. The outbreak of coronavirus was first reported in
2019, in Wuhan, China. The virus was named Severe Acute Respiratory Syndrome
Coronavirus-2 (SARS-Cov-2) due to its similarities with the SARS-Cov. The virus
can be transmitted from one infected person (symptomatic or asymptomatic) to
another. It can also be transmitted by coming in contact with infected surfaces
and objects. Symptoms of COVID-19 include fever, cough, whizzy breathing, and
shortness of breath among others.
The COVID-19 was declared a pandemic by the world health organization (WHO)
and has since then become a global concern [50]. Nigeria along with 12 other African
countries were declared by WHO as having high risk for the spread of the virus. The
first confirmed case was an Italian who worked in Nigeria and had just returned from
Italy. He arrived in Nigeria on the 25th of February 2020. He was tested and confirmed
positive by the virology lab of LUTH (Lagos University Teaching Hospital). He was
also found stable with no serious signs and symptoms of the virus.
Leading up to COVID-19 being declared a global threat to public health and
epidemic by the WHO, many Nigerians treated the virus as a remote white man’s
sickness that can never propagate to local homes [51]. Without subscribing to profes-
sional advice and guidance, Nigerians and their leadership have undermined the
outbreak of COVID-19 in their country, waiting too long to implement preliminary
safety precautions that would save resources while shielding people from unnec-
essary exposure to the virus. With the detection of the COVID-19 cases index in
Lagos, Nigeria on 27 February 2020, other areas of the country along with the
north-central region continued their usual routines and leisure gatherings without
complying with the shady precautionary action previously described by the Nigerian
Center for Disease Control [51]. The popular sentiment in central Nigeria has been
that COVID-19 is a “big man infection” (i.e., widely respected individual infection).
With the lower levels of education within this area of Nigeria [52], their immi-
nent assumption was predicted and misconceptions on those fragile to the diseases.
As the volume of COVID-19 instances increases gradually among the Nigerian
population, mainly urban centers like Abuja, central Nigeria’s Federal Capital Terri-
tory (FCT), unfounded uncertainty, and palpable apprehension among misconcep-
tions about COVID-19 described the condition of the nation’s populace. Nigeria
announced its first case of Covid-19 on 27th February 2020 and since then; there
has been an increase in cases daily. When compare the outbreak with other countries
in Africa, the speed of daily cases is used as an indicator of how quickly the virus
is spreading or being contained, Nigeria has overtaken many countries in Africa.
Nigeria is number three while South Africa leads and Egypt is second in Africa. This
will, of course, depend on how accurate and timely the Nigerian government makes
its daily announcements. Initially, most Nigerian cases have come from international
travelers arriving in Lagos and Abuja.
A second case of the virus was confirmed on the 9th of March as a citizen who
had close contact with the first case. On the 23rd of March, a death case due to the
corona virus was confirmed as a Nigerian who had newly returned from the United
Kingdom and had an underlying heath condition. A month after the first confirmed
case, the total number of infected individual had risen to 81 with one death and one
recovered case. As at that time, Lagos state had the highest number of cases in the
country. The number of confirmed cases kept increasing despite the safety measures
that had been put in place. Lockdown measures were enforced in some states with
high number of cases such as Lagos state, Ogun state, FCT. Some other states also
adopted the lockdown as a measure to combat the virus. A ban was also placed on
both local and international flights.
With the lower levels of education within this area of Nigeria [52], their immi-
nent assumption was predicted and misconceptions on those fragile to the diseases.
As the volume of COVID-19 instances increases gradually among the Nigerian
population, mainly urban centers like Abuja, central Nigeria’s Federal Capital Terri-
tory (FCT), unfounded uncertainty, and palpable apprehension among misconcep-
tions about COVID-19 described the condition of the nation’s populace. Nigeria
announced its first case of Covid-19 on 27th February 2020 and since then; there
has been an increase in cases daily. When compare the outbreak with other countries
in Africa, the speed of daily cases is used as an indicator of how quickly the virus
is spreading or being contained, Nigeria has overtaken many countries in Africa.
Nigeria is number three while South Africa leads and Egypt is second in Africa. This
will, of course, depend on how accurate and timely the Nigerian government makes
its daily announcements. Initially, most Nigerian cases have come from international
travelers arriving in Lagos and Abuja.
As of 30 September 2020, Nigeria recorded 58,848 confirmed cases, 50,358 recov-
ered cases and 1112 death cases, spread across 35 states and the Federal Capital
Territory (FCT), Abuja [53]. In the absence of a cure or a vaccine and to manage
the spread of the virus and the infection, Nigeria has relied on a combination of
non-pharmaceutical interventions that include testing, contact tracing, isolation, and
treatment [54], as well as a range of containment measures such as strict enforcement
of hygiene practices like hand-washing, observation of social distancing, and travel
restrictions.
The Nigerian government also imposed full lockdowns in areas deemed to have
the highest propensities for transmission. On 30 March 2020, the federal government
of Nigeria announced the full lockdown of Lagos and the Ogun States, and the FCT
for 14 days in the first instance. The lockdown was further extended following the
expiration of the initial lockdown and the increasing number of cases across many
states. Some State governments have also implemented partial lockdown involving
the banning of, public gatherings, closure of open markets, and restriction of inter-
state movements. Thus, businesses are being forced to shut down without alternative
plans, rendering vulnerable informal sector workers who work daily to earn a living
and are now stranded at home, unable to sustain themselves and their families.
There is a need to engender an indigenous (Afro-centred) approach to the contain-
ment of the COVID-19 pandemic. COVID-19 protocols such as “lockdown” and
“social distancing” are products of “copy and paste” by African leaders, without
critically thinking about their peculiar social and economic circumstances domi-
nated by the poor, unemployed and informal sector workers (which constituted 90%
of Africa’s workforce compared to 18% in developed countries), most of whom live
by daily bread/earnings and handouts to survive [55, 56].
African leaders did not carefully consider the feasibility, affordability, and coping
abilities of the borrowed Western-style lockdown and social distancing policies
among the majority of their poor and socially excluded citizens. This has merely
reduced most of the so-called rapid response strategies to a mere conventional “trial
and error” (template of the Western nations), as these strategies are not working in
Africa. Public perceptions consider these measures as elitist and not in the interest of
the people, who are “forced” to suffer the twin debacle of the COVID-19 pandemic
and excruciating hunger. For example, a rise in community criminality, looting, and
terror perpetrated by the “one-million-boys” gang, aged between 14 and 18 years,
was reported with some 200 bandits arrested in Lagos, Nigeria (where half of the
city’s 21 million people survive on daily earnings) [55].
Moreover, the prevalence of urban slums, densely populated, insufficient access
to drinking water, weak medical systems, and distribution of sanitary facilities with a
high level of physical interaction among the residents of central Nigeria would make
it difficult to enforce hygiene initiatives and other public health policies required to
curtail coronavirus [57]. Also, the dissemination of misconceptions and stories about
COVID-19 and the advancement of non-scientific traditional care in central Nigeria
compromised safety precautions [58]. Government failure to manage the policies of
social distancing and prohibit large-scale gatherings, including religious and cultural
events, funerals, weddings, and sports, can inevitably generate escalated COVID-19
amazingly-spreading situations [59]. To effectively monitor and mitigate COVID-19
in this area, action-oriented and prompt epidemiological information gathered from
the population can allow health professionals to implement comprehensive strategies
and policies appropriate and understandable to the citizens of this area.
Various models have been proposed in order to monitor trend and predict the
spread of the virus as it becomes threat to the economy and the citizens of the
country.
Ayinde et al. [60] carried out a comparative analysis of models and estimators by
subjecting daily reported cases of COVID-19 confirmed cases, discharged cases and
death cases to nine different curve estimation statistical models such as the simple,
quadratic, cubic, and quartic forms. The best of the models were identified and used
for further prediction and forecasting. From their findings, the forecasted results were
rather high so recommendations were made to the government to review activities
and method of intervention so as to be able to curb the spread of the disease.
Ayinde et al. [61] analyzed a mathematical model in Lagos for the COVID-19
population. They formulated a model to examine the effect of control measures on the
dynamics of the Lagos population through simulation, effect of the control measures
was being measured and also forecasts were made for the different levels of the
measures. It was observed that if measures put in place such as social distancing,
use of face mask and increase in testing rate are enforced, then there will be a great
decrease in the number of cases recorded.
Regression models were used in modeling COVID-19 Cases in Nigeria [62]. The
Poisson Regression (PR), Negative Binomial Regression (NBR) and Generalized
Poisson Regression (GPR) model were used to fit the most appropriate regression
model to the number of confirmed cases, active cases and critical cases of COVID-
19 in the country after 130 days. Results show that the number of critical cases and
active cases has positive significant effect on the number deaths due to COVID-19
in the country.
Iboi et al. [63] also developed a mathematical model which enhanced the under-
standing of the transmission and control dynamics of COVID-19 in Nigeria. It was
observed that if the control measures had been ignored, then there would have been
a great repercussion as the number of cases and mortality rate recorded would have
been so high. This indicates that the use of social distancing as a remedial measure
can be effective in the control of the virus. On the contrary, use of face mask cannot be
solely effective in combating the virus. Emphasis was laid on the maintenance of the
lockdown measures in order to ensure that the country does not encounter a second
wave. The role of mathematical models in curbing COVID-19 was considered by
Madubueze et al. [64]. While the control measures were considered, a community-
based transmission model for COVID-19 was formed. From the study, the country
will be able to bring the spread of the disease to a stop if there is an increase in testing
rate and the control measures are observed moderately. Due to this, the government
is advised to enforce the safety measures put in place and also increase the rate of
testing per day.
Balah and Djeddou [65] used the autoregressive fractionally integrated moving
average (ARFIMA) model to model and forecast what the new cases would have
been after the lockdown. The ARFIMA model was compared with the ARIMA (1,
0, 0), and ARIMA (1, 0, 1) and was found to be better using the AIC and the BIC
criteria. The results show that there would have been a significant decrease in the rate
of spread of COVID-19 if the lockdown had been continued. Government is advised
to further enforce safety measures if life must return to normal.
Nonlinear Forces of Infection was modelled against the transmission of Covid-
19 in Nigeria. A SEIQCRW mathematical model was proposed by Corman et al.
[66] where the SEIR model was adopted to examine the outbreak of COVID-19 in
Nigeria. The transmission outlets were defined and the effect of the environment on
rate of transmission. With a detailed simulation study, the number of confirmed cases
is estimated to reach about 55,000 people by December 25, 2020.
3.3 South Africa as An Epicentre in Africa
On Tuesday 14 July 2020, South Africa (SA) registered more than 10,000 new
cases of Covid-19, causing the nation’s cases to be 298,292 and overtaking the UK.
The ever first case of COVID-19 was conveyed by the World Health Organization
(WHO) on 31 December 2019 in Wuhan City, China [67, 68]. ‘Severe Acute Coron-
avirus Syndrome 2’ (SARS-CoV-2) was established as the cause of the novel disease
COVID-19 [69]. The disease has meanwhile transmitted to more than one hundred
nations, including South Africa.
COVID-19 has traveled rapidly across the world and entered all continents.
Although Africa was amid the latter provinces affected by the novel disease, having
the first incident established in Egypt on February 14, 2020, as of conclusion of
April, BBC Coronavirus in Africa reported more than 34,000 confirmed cases [70,
71]. South Africa announced its initial COVID-19 occurrence on 5 March 2020 and
is reportedly one of the continents’s top incidences [72]. As of 30 September 2020,
there were 674,339 confirmed cases, 608,112 recovered with 16,734 deaths.
The advent of COVID-19 in South Africa has introduced structural deficien-
cies in the standard of service delivery in numerous communities across the region,
including water and hygiene systems, health management, health care and capital
equipment. The initiative to control the transmission of the disease has also exposed
the shortage of core capacities, such as the manufacture of face masks, gloves with
laboratory devices, plus the willingness to combat of the country’s critical resources
for a global epidemiology epidemic, including COVID-19. The infection has likewise
demonstrated the efficacy (or absence of) and sensitivity of economic mechanisms
for instance joblessness indemnification programs and recognition lifetime indemni-
fication plans, and elevated concerns concerning the general stability and sturdiness
of the economic structure in South Africa in managing the effects and outcome of
such a multi-layered and speedily changing occurrences. The information acquired
will also be sufficiently known and utilized to establish frameworks and lasting emer-
gency feedback systems for the potential occurrence of such a contagion. Capabilities
that are considered to be missing should be clearly targeted and tackled, not just in
order to boost preparation but also in order to build jobs that are already dreadfully
missing in South Africa.
On 5 March 2020, the nation declared its first COVID-19 event, the sum of cases
had raised to sixty-one, as of March 15, 2020. President Cyril Ramaphosa at that
moment affirmed a state of nationwide adversity and presented a few of procedures to
avert the disease from spreading. These initiatives, first was constantly monitored by
the régime with the aim of reacting to the rapidly evolving pandemic as effectively as
possible. Second for example, the number of people permitted to meet in one place has
been limited from 100 to 50, since the steps were first revealed. Numerous governance
buildings were rapidly set up to take care of the transmission of the infection, for
instance COVID-19 Inter-Ministerial Committee, a Development Surgical Procedure
Center, plus a governing National Command Council. Even, the sum of infections
has risen to 402 as of 23 March 2020.
The president publicized a 21-day nationwide restriction beginning on March 26,
2020 in partnership with the National Command Council to aid curtail the trans-
mission of the infection as well as reduce its effects on South African residents.
On April 26th, 2020, 2506 reported illnesses, 34 demises including 410 discharges
cases were documented in South Africa. Thirdly, limiting residents’ journey, main-
taining public seclusion and tracing everyone who had come in communication with
infected individual (many of these are achieved to differing extent worldwide) tend
to be successful means of managing the transmission of the virus. Various COVID-
19 help desk were as well developed for instantaneous police, medical care, and
urgent feedback to corruption, fire department, and extra community duty delivery
requirement. The COVID-19 outbreak has numerous effects and influences on South
African civilization, this comprises of financial, cultural, medical, ecological, and
technical domains.
The government-mandated shutdown limited the mobility of individuals, except
for individuals working in critical organizations for instance police, safety, defense,
army, hospitals, superstores and transport and, further lately, casual food trade. The
public is expected to remain at home and for the occasional times they have request
to receive therapeutic attention, purchase grocery food or prescription drugs. In fact,
these outlets are often expected to ensure that at any given time there are no more
than 50 employees at their premises. The policy of social isolation led to the cessation
of all spiritual assemblies, education and socio-cultural activities. Destitute persons
were moved to well-spaced temporary housing. However, the lockdown and the
social distancing policies present strong challenges.
Gender-based violence (GBV) and violence against children pose a significant
threat to South Africa [73]. From 26 March 2020, when the lockout ended, 8700
cases of GBV were registered until 3 April 2020. Fourthly, other problem associ-
ating to liquor, selling and use of alcohol have been restricted to reduce alcoholism
and the subsequent public exacerbations and disputes between individuals wedged
collectively throughout the lockout, particularly in broken families and incomprehen-
sible or criminal populations. Nevertheless, given the social distress this has created
(especially when it associates to liquor and further obsessions), the police supervising
minister stated that other forms of crime in South Africa have been minimized by
the lockdowns and prohibitions on alcohol selling and use.
Another problem is countryside, peri-urban or familiar residences where strictly
placed shacks and the nonappearance of accessible facilities make social isolation
difficult. For those staying in overcrowded shacks it seems safer to live outdoors than
indoors. Therefore, there are lots of areas with cramped and informal homes outdoor,
solitary to find law enforcement agency and military perambulations that impose
restriction instructions. As a result, pressures among humanity and the militaries
are growing, which is named to reinforce the law enforcement agency attempts
to maintain the lockout. For instance, some social network videocassettes showed
noncombatants discovering that security personnel were forcing the lockdown order
through military-style drills.
3.3.1 Financial Impacts
Restriction instruction that signify no financial action and revenue-acquiring

prospects, particularly for the entrepreneurial and relaxed subdivision (which
comprises typically of minor and medium-sized innovativeness), have worsened the
previously high levels of poverty in South Africa. Yet society is now in the process of
agitating to relieve the lockout practice. Originally, busses and mini-busses, known
locally as the “combi,” were permitted to embark on solitary an insignificant sum
of travelers to meet public distance necessities, and function solitary to hold vital
staff for a specific number of hours. This however made the transportation occu-
pation fruitless. The ensuing problems for both workers and travelers lead to new
legislation now allowing mini-busses to entrain about 70% of their capability while
forcing everybody to wear masks as well. Prior to the lockout, SA recession was still
officially in a downturn.
The structured competitive division is currently under enormous further diffi-
culty from initiatives to respond to coronavirus. For instance, the investment needed
to minimize the transmission of the epidemic which includes monitoring devices
and enforcing prevention mechanisms, repositioning and assisting for the vulner-
able, carrying out contact mark out and examining the sick would put an additional
problem on the nationwide funds, which has previously been heavily limited by
recurrent bailouts of unsatisfactory operating region-possessed innovativeness. The
holding back Financial Institution of South Africa replied to the disaster by lowering
prime interest rates by 100 basis points. This, in effect, would result in a decline
in short-term interest rates to make paying current obligation further attractive to
mortgagors, whether individuals or companies, financial institutions plus further
monetary establishments.
Institutions in the Africa System offer three-month mortgage and credit card
payment holidays to permit families and businesses to adapt all through and imme-
diately lockdown is over. Further monetary organizations suggest that customers
should document entitlements with their credit life assurance strategies to wrap-up
mortgages that they could not then pay. Nevertheless, till today there has been no
extended termination of such financial obligations such as rent payments. Further
aggravating the economic condition and prospects, Moody’s lately demoted SA’s
independent recognition assessment to distressed status (Ba1 with a gloomy outlook),
whose effectiveness was perceived by many in SA to be insensitive.
This reduction has resulted in the withdrawal of South Africa from the Global
Bond Index which would raise the funding rates for South Africa on international
capital markets. As an outcome, the South African Rand (SAR) has dramatically
belittled contrary to key coinages, e.g. from R15 to USD$1 to R18.59 to the dollar.
8 The willingness of South Africa to rebound available forbidding post-COVID-19
economic condition would be a big encounter resolve to relying on how much the
worldwide financial institute as entirely is improving.
3.3.2 Health and the Climate
Increased pressure remained imposed on medical care amenities when further conta-
gions develop if the lockout continues and present extenuation efforts fail to control
the transmission of the disease. Medical hospitals with laboratories are seeing a
spike, plus seclusion places were built to assist separate the ill. Increasing mandate
for several beds including ventilators is expected to rise as additional patients get
sick. Regular hand wash, staying hydrated, remaining at home, preventing hand-
shakes and interaction with the body and maintaining proper individual cleanliness
were prescribed as effective steps to prevent the transmission of the virus. South
Africans are doing all of these as best they can. There are, however, bigger safety
and environmental problems beyond human influence.
First is some communities have poor water and sanitation facilities. South Africa
is a water-scarce region, losing access to clean water in some communities. Addition-
ally, sanitation services in many townships are in a deplorable condition, with many
families sometimes needing to share very inadequate services. Additionally, littering
produces unhygienic conditions in certain areas, along with inadequate waste pick-
up operation. Such bad standards of sanitation usually promote the transmission of
diseases. All these factors together make proper sanitation, daily hand washing and
hydration a big trial for those South Africans who only have contact to polluted or
if not bad water.
3.3.3 Technology Dimensions
Technology has always played a double-edged role in the spread and containment of
this pandemic. In the other side, social media has many contradictory opinions on
how this illness originated, as well as other fake news and rumors on whether it can
be healed. Self-styled medical “experts” post all manner of home-made treatments
that can possibly eliminate or treat the infection. This has clouded social media’s
official use for disseminating truthful and valuable information to the general public.
On the other hand, technology has developed a contact-tracing approach, which is
an important aid in curbing disease spread. Using the location recording of mobile
phones helps authorities to correctly determine where an infectious person was and
which cell phone numbers were nearby.
You can then contact the holders of these cell phone numbers for testing to deter-
mine whether they contracted the disease through close proximity to the primary
infected person. This breakthrough has solved the problem of touch tracing in a
secure and science way, as the use of mobile phones in South Africa is prevalent and
almost everybody brings their cell phones everywhere, they go. Digital information
technology has now allowed individuals to live their programs and creations from
home, churches and musicians, and schools to teach remotely and also to award
college diplomas. Such activities helped discourage people from coming together
and therefore improved the transmission of the virus.
3.4 Egypt as An Epicentre in Africa
The world is presently experiencing a serious prevalent of a Novel 2019 coronavirus

infection (COVID-19) which started as an epidemic of pneumonia of unidentified
causes in December 2019 in China’s Wuhan City [2, 6] and On 12 March 2020, the
World Health Organization recognized it as a pandemic, as a result, the Egyptian
Government issued different decisions to confront such a pandemic. Global attempts
have been made to intercept the spread of the disease in accordance with personal
activities that depend on Knowledge for the public by political resolution [8].
As of 24th September 2020, 32,110,901 individuals were infected with COVID-
19, 982,196 deaths and 23,692,015 recovered globally with 215 countries affected,
while as of 23rd September 2020 world Health Organization reported 31,425,029
total confirmed cases with 967,164 death cases and 24,155 new cases reported
[29, 31, 56]; and 2,285,565 total cases with 59,191 deaths and 1,976,610 recov-
ered/discharged case reported from the Eastern Mediterranean region with 22 coun-
tries affected, [31]. In Africa, Egypt announced the first case of COVID-19 on 14
February 2020 [35, 56]. As of 24th September, 2020, 1,436,433 total cases have
been confirmed out of the 133,088,750 total tested case, 34,587 death cases with
1,180,677 recovered/discharged cases (out of which 102,375 confirmed cases, 5822
total deaths, 91,843 recovered cases with 5.7% case fatality rate (CFR) cases were
from Egypt) [29, 31, 56].
In Egypt, a 60-year-old German man who went to tourist hotspots during a Nile
cruise trip was the first person to die of COVID-19. He began to have a fever while
moving from the historic city of Luxor to the Red Sea resort town of Hurghada. On
March 6th, he went to a local hospital where he was checked and reported to be
positive for COVID-19 and developed respiratory failure traceable to acute pneu-
monia within days. His case was one of many in Upper Egypt related to Nile cruises.
Subsequently, the Egyptian authorities screened hundreds of people on board cruise
ships operating in the region and reported 45 positive coronavirus cases, including
12 members of staff. Reportedly, none of them had displayed a manifestation of
the deadly pathogen. Even at the beginning of March, weeks before the Egyptian
authorities began to wake up to the severity of the epidemic, public health officials
as far as the US, Taiwan and Canada were putting together a serious, but unreported,
outbreak deep in the heartland of Egypt.
Ahmed et al. [74] examined the awareness, expectations and attitudes of the Egyp-
tian public towards the disease of COVID-19 and conducted a cross-sectional survey
distributed among adult Egyptians on these points. Zhao et al. [13] analyzed the initial
period of the COVID-19 epidemic in Africa between 1 March and 13 April 2020,
using the simple exponential growth model and modeling the COVID19 generation
interval (GI) distribution as Gamma distributions with an average of 4.7 days and a
standard deviation of 2.9 days, following the Poison data fitting and parameter esti-
mation probability process. Ali Hasab [75] analyzed the impact of mitigation efforts
to reduce the overall attack rate of COVID-19 and to flatten the COVID-19 curve
in Egypt. In the situation reports of the WHO, Worldometer and Egyptian MoHP
reports on the COVID-19 epidemic in Egypt, secondary data were analyzed until
24 April 2020. A comparison of day-level prediction models on COVID-19 affected
cases using time series models and mathematical formulation was proposed by El
Desouky [76].
Ali Hasab [77] proposed approaches focused on statistical and artificial intelli-
gence to model the prevalence of COVID-19 in Egypt and forecast it. They used
autoregressive integrated moving average (ARIMA) and nonlinear autoregressive
artificial neural networks (NARANN) methods. It was estimated the time of the
potential peak and simulated the changes that could occur during Ramadan (the
holy month) by Egyptians’ social actions. He used compartmental models of SIR
and SEIR to estimate the peak time. Hasab et al. [78] performed a research to
demonstrate the epidemiological distribution and modeling in Egypt of the novel
Coronavirus (COVID-19) epidemic. Joshua Kiddy et al. [79] proposed a model
for prone, exposed, asymptomatic, quarantined, asymptomatic, seriously contam-
inated, hospitalized, healed, deceased and partially quarantined susceptible indi-
viduals (SEAQIsHRRADSp) to explain COVID-19 dynamics. To estimate model
parameters, they adapt the model to real data from Ghana and Egypt.
Shinde et al. [80] suggested an online forecasting system that streams information
from the Nigeria Center for Disease Control to update the parameters of an ensemble
model, which in turn offers modified COVID-19 forecasts every 24 h. In accor-
dance with Generalized Autoregressive Conditional Heteroscedasticity (GARCH),
their community includes an Auto Regressive Integrated Moving Average (ARIMA)
model, a Facebook-developed Prophet additive regression model, and a Holt

Winters Exponential Smoothing model. Joshua Kiddy et al. [79] used statistical anal-
ysis and optimal control theory to analyze the human-environment-human. In the time
period between 12 March 2020 and 7 May 2020, they analyzed the global stability of
the proposed model and adapted the model to real Ghanaian results. The outcomes
and challenges of SIR, SEIR, SEIRU, SIRD, SLIAR, ARIMA, SIDARTHE, etc.
models used in the prediction of spread, peak and reduction of Covid19 cases were
established by Anirudh [81] with spatial mapping of the reported incidents. The top
15 nations were classified by Singh et al. [82]. A comparison was made between
the mentioned top 15 countries for confirmed incidents, deaths, and recoveries, and
an advanced autoregressive integrated moving average (ARIMA) model was used
to forecast COVID19 disease spread trajectories for the next 2 months. Two types
of datasets were addressed in 2020 by Guo et al. [83] big data accessed from World
Health Organization/National databases and social media contact data. Guo et al. [83]
summarized the latest research progress on COVID-19 epidemiology, pathogenesis,
and clinical features, and addressed current treatment and scientific developments in
the battle against the new outbreak coronavirus.
3.5 Cameroon as An Epicentre in Africa
The first case of corona virus can be traced back to the 17th of November 2019 in
Wuhan, China. The virus caused by SARS-CoV-2 is also known as COVID-19 and
was declared as an epidemic in December 2019 [84]. This viral infection is known to
have symptoms such as fever, cough, tiredness, shortness of breath, sore throat and
many others. Egypt was the first country on the African continent to record the first
case of the corona virus disease which was announced on the 14th of February, 2020
[85]. The disease then rapidly spreads to many other parts of the African continent
and the world at large. The disease was therefore declared a pandemic by the World
health organization on the 11th of March 2020.
The first case of COVID-19 in Cameroon was confirmed on the 6th of March
from a French citizen who got into the country on the 24th February. Days later,
a second case was also confirmed as a Cameroonian who was closely related with
the first case. Number of infected people increased daily and by the 30th of March,
there were 142 cases with 6 deaths. State of emergency was declared on the 17th
of March by the government as drastic measures were put in place. Cameroon was
being badly hit with the pandemic as the number of death due to COVID-19 was one
of the highest in the Sub-Saharan region [86].
Since the inception of the virus, there has been a total of 20,593 cases, 416 deaths
and a total of 19,124 recovered cases as at the 22nd of September 2020 (Ministry
of health, Cameroun, 2020). The effect of the measures taken into consideration
by the government led to the cancellation and (or) postponement of some events
earlier scheduled to hold in the year. This also led to the compulsory use of a face
mask and other hygiene measures such as washing of hands, social distancing and
use of hand sanitizers. Although safety measures were put in place, there was still
a consistent increase in the number of infected persons. Since there has been no
approved treatment for the corona virus, treatments are only being given for the
relief of symptoms [85]. Treatments used for SARS and MERs have been suggested
as good alternative for the treatment of COVID-19 [87].
There has also been an adverse effect of the pandemic on activities of companies
where small and medium-sized Enterprises and service companies are mostly hit. As
it is evident that pandemic will continue to spread, several studies and mathematical
tools can be used to know the best control measures to adopt to combat the pandemic.
Luc Magloire Mbarga Atangana who is the minister for trade said in one of his
addresses that the production of locally made goods will be boosted in Cameroun as
precautionary measures to handle the effect of the economic hardship which resulted
from the COVID-19 crisis. Goods are encouraged to be produced in the country so as
to give rise to the food sector. Local manufacturing of products are also encouraged
such that goods and products are used by the citizens of the country.
Several models have been proposed in order to understand and control COVID-19
[88, 89]. Nkwayep et al. [90] developed the Enkf model which is used for the estima-
tion of unmeasurable state variables and unknown parameter using Cameroon as a
case study. The proposed model took into consideration the possibility of having
susceptible individuals contract the disease through indirect contact such as the
environment which was not included in most of the other studies.
Djaoue et al. [91] in their work used the biological features of the corona virus
disease and control strategies to formulate a general model of COVID-19 model
transmission. The control strategies were based on isolation of the exposed people,
lockdown of the entire population, wearing of face mask, massive testing in risk areas
and personal hygiene rules. It was observed that those without symptoms might play
a major role in the transmission of the virus. The model was also used to investigate
ways to combat the virus. When about 80% of the exposed population are isolated,
the disease disappears. In about 100 days. It was also observed that when there is a
total confinement of about 10% of the partially confined population then the spread
of the disease stops in about 150 days. The model was also able to identify that when
there is identification and isolation of more than 95% of moderate and symptomatic
infected people, the disease can be controlled after 90 days.
Chan et al. [85] in their study analyzed the evolution of the coronavirus disease
and the efficiency of the models adopted in Cameroon. It was observed that by
increasing the public health interventions in a simulation, a more flattened curve was
observed for the epidemic. This shows the importance of effective campaign and
compliance by the government and the population respectively till a permanent cure
is found. Recently, Djaoue et al. [92] developed a mathematical model which was used
describe the rate of transmission of the corona virus. The model helps to understand
the dynamics of the susceptible and infected individuals’ class if barrier measures
are applied in public and private places. Barrier measures such as containment of
suspected cases, isolation of confirmed cases, social distancing and the use of face-
masks in public were all considered. It was observed that the peak of the disease
is low in magnitude and retracts where there is no contribution of the contained

individual to the infection class.
Adela et al. [93] also carried out a cross sectional study on the knowledge, attitude
and practices (KAP) towards COVID-19 preventive measures and symptoms when
there was an exponential rise in the number of outbreaks Cameroun. An overall
high score of 84.19% was observed for knowledge, 69% for attitude and 60.8% for
practices of preventive measures and symptoms of COVID-19. Emphasis were place
on the need for further investigation on how effective the measures put in place to
curb the spread of the virus are as there was still a continuous increase in the number
of cases despite having good scores for the KAP.
The world has been greatly affected by the corona virus pandemic. Economies
of the world have also been affected especially developing countries. Bin et al. [94]
examined the impact of the pandemic on household welfare in Cameroun. The linear
regression model and the Heckman sample correction bias were used for the analysis.
Results showed that there was a reduction in household welfare of the Cameroonians
due to COVID-19. Means of reducing the impact of the virus such as new sources
of income and engagement in agricultural activities were suggested. The role of the
government was spelt out as strategic allocation of grants and also the adoption of
the triple helix approach so as to be able to develop vaccine for the virus in order to
regain economic balance.
3.6 Ghana as An Epicentre in Africa
Mathematical models of infectious diseases allow us to understand from information

available the state and progress of a disease outbreak. COVID-19 is an infectious
disease that has recently been found to be caused by a new coronavirus. This novel
virus appears to have emanated from Wuhan, China late 2019. Egypt was the first
African country to announce a reported coronavirus disease on 14 February 2020.
The first two cases of Coronavirus disease 2019 (COVID-19) in Ghana were found
on 12 March 2020 [29, 31]. These two people that were positive to the novel disease
returned from trips abroad; one from Norway, and the other one from Turkey, since
then, the number has increased.
The global statistics as of 23rd of September, 2020 is 31,808,253 confirmed
cases, 975,810 deaths cases and 23,415,581 recovered cases. Ghana recorded 46,062
confirmed cases, 45,258 recovered cases and 297 death cases (World meters). As a
first rejoinder, the Ghanaian president banned all public meetings on 15 March,
closed all schools and universities, and closed all the borders of the country on 23
March. On 30 March, in the interests of public well-being, a partial curfew in areas
with strongly reported cases was imposed. Ghana was ranked as the seventh-highest
COVID-19 nation in Africa in September 2020, with 12,929 cases (Fig. 2).
A great number of people who contacted this disease experience mild to moderate
respiratory illness and recover. The aged and people with underlying health issues
Fig. 2 COVID-19 cumulative confirmed cases in Ghana between 15/2/2020 and 18/09/2020
are more vulnerable and experience extreme complications. Different measures have
been taken by the government of Ghana to curtail the disease.
Wiah et al. [95], considered among other things, quarantining and testing of immi-
grants, contact tracing and isolation in the form of quarantining or hospitalization,
as control measures in mitigating the spread of the pandemic. They incorporated the
various intervention strategies into their model and ascertain their impact on COVID-
19. The model validated the current preventative measures, such as isolation, contact
tracing and treatment are, indeed, critical components in the control of COVID-19
until appropriate cure or vaccine is found.
Joshua Kiddy et al. [79] used mathematical modeling analysis and optimization
control theory to study the relationship between the human-environment-human.
The stability of the model proposed was evaluated using the Lyapunov function.
They adapted the model with primary data from Ghana from12th March 2020 to 7th
May 2020 using the least-squares process. Without controls, the basic reproduction
number was approximated averagely as 2.688. Based on the sensitivity analysis, an
optimal control was formulated. Asamoah et al. [96] proposed a model to describe
the dynamical analysis of COVID-19 for Ghana and Egypt. They adapted the model
with primary data from Ghana and Egypt to estimate model parameters and presented
relatively detail projections for the disease control in Ghana and Egypt. The sensi-
tivity analysis carried out on their model can help to minimize the basic reproduction
number to less than unity. They also found that the selection of an infection force
impacts the control’s reproduction number.
Adekunle et al. [97] studied the implications of temperature, humidity, precipita-

tion, wind speed and the particular government policy interference of partial lock-
down. For model fitting, a time series generalized linear model was used that permits
regression on previous observations of the response variable and covariates. Their
findings showed that maximum temperature, relative humidity and precipitation had
major effects on the estimation of new cases arising from the disease.
In order to predict the true spread of coronavirus disease, Binta et al. [98] suggested
a deterministic model that takes into account age structures, urbanization and comor-
bidities (HIV, tuberculosis, anaemia). Effective policies for containment may result
in reduced rates of serious cross infection. While most cases will be moderate, they
also predict that between 0.78 and 1.03%, 0.61 and 1.22%, and 0.60 and 0.84% of
individuals in Ghana, Kenya and Senegal, respectively, may develop serious symp-
toms at the time of the height of the outbreak, in the absence of policies that further
involve the spread.
Gilbert et al. [35] assessed African countries’ preparedness and vulnerability
against their risk of importing COVID-19. To estimate the risk of imports per country
to Africa, they used data on the amount of air traffic from airports in China’s polluted
provinces. Countries were crowded according to Chinese regions, contributing the
most to their risk. Countries with the highest import risk have a moderate to high
capacity to respond to outbreaks while moderate risk countries have variable potential
and high vulnerability.
4 Methodology
In this study, we applied the linear regression model and the Auto-Regressive Inte-
grated Moving Average (ARIMA) model to predict the prevalence of COVID-19 in
the selected countries. Following [60], we employed the following linear regression
model:
Linear regression model of order 1:
yt = β0 + β1 t + et (1)
yt = β0 + β1 t + β2 t 2 + et (2)
yt = β0 + β1 t + β2 t 2 + β3 t 3 + et (3)

yt = β0 + β1 t + β2 t 2 + β3 t 3 + β4 t 4 + et (4)
where yt is the cumulative confirmed cases of COVID-19

in each of the countries
and et is the error term such that et ∼ N 0, σ 2 . The most appropriate model was
selected using the following criterion: Akaike Information Criterion (AIC), Schwarz
Information Criterion (SIC), Hana-Quinn Criterion (HQC), the coefficient of deter-
mination (R2) and the adjusted coefficient of determination (adj R2). Model with
the lowest AIC, SIC, HQC are considered best. Also, model with the highest R2
and adj R2 are generally preferred. The parameters in model (1–4) are estimated
using the Ordinary Least Squares Estimator (OLSE). The models are diagnosed to
ascertain that they satisfy the assumptions in the classical linear regression model.
The assumptions include: normality of error term, independence of error terms and
constant variance. According to Lukman et al. [99, 100], the performance of the
OLSE drops when any of these assumptions is violated. According to Ayinde et al.
[101], the least absolute deviation is preferred to the OLSE when the error term
is non-normal. Also, the Cochrane-Orcutt estimator is adopted as an alternative to
the OLSE when the error terms are related [60, 102] while the Heteroscedasticity
corrected estimator in the Gretl software is used when the error term variance is not
constant.
Following Cao et al. [37], the ARIMA models have made significant progress
in the different fields of study especially in the medical sciences for an efficient
epidemic forecast. This model is employed in this study. The ARMA(p,q) is defined
as follows:
yt = η + ϕ1 yt−1 + ϕ2 yt−2 + · · · + ϕ p yt− p + εt − ϑ1 εt−1 − ϑ2 εt−2 − · · · − ϑq εt−q .

(5)
where yt is the observed value at time t, η is a constant, ϕ and ϑ are the autoregressive
(AR) and moving average (MA) parameters, respectively. εt is the residual at time t
such that εt ∼ N 0, σ 2 .
The following procedures are needful in ARIMA modelling: model identification
and model selection, parameter estimation, diagnostic checking, and forecasting. It is
important to test if the variable of interest is stationary or not. The Augmented Dickey-
Fuller test was employed to assess the stationarity state of the variable. We adopted
the autocorrelation function (ACF) and the partial autocorrelation function (PACF)
functions of the dependent variable (yt ) for model identification and selection. The
parameters in model (5) are estimated using the maximum likelihood estimator. The
model is diagnosed to be certain that the residual satisfies the conditions of normality.
5 Result and Discussion
From Table 2, the linear regression model of order 4 (model 4) was generally preferred
for all the countries. The model is preferred because of the high values of the R2 and
Table 2 Model adequacy for COVID-19 confirmed cases

COVID-19 Statistic OLS estimator
MODEL 1 MODEL 2 MODEL 3 MODEL 4
Algeria R2 0.9104 0.9861 0.9880 0.9951
Adj. R2 0.9100 0.9860 0.9878 0.9950
AIC 4443.563 4031.331 4002.043 3804.438
HQC 4446.310 4035.452 4007.538 3811.307
SBIC 4450.368 4041.539 4015.653 3821.452
Egypt R2 0.9124 0.9100 0.9830 0.9850
Adj. R2 0.9120 0.9192 0.9828 0.9848
AIC 5065.1120 5046.2530 4686.6470 4659.1340
HQC 5067.8950 5050.4280 4692.2130 4666.0920
SBIC 5072.0140 5056.6060 4700.4510 4676.3890
Ghana R2 0.9389 0.9571 0.9942 0.9950
Adj. R2 0.9386 0.9566 0.9941 0.9949
AIC 4049.759 3978.967 3570.208 3541.233
HQC 4052.451 3983.005 3575.591 3547.963
SBIC 4056.415 3988.950 3583.519 3557.873
Nigeria R2 0.9366 0.9674 0.9951 0.9984
Adj. R2 0.9363 0.9671 0.9950 0.9983
AIC 4424.788 4280.614 3866.212 3625.590
HQC 4427.529 4284.725 3871.694 3632.442
SBIC 4431.576 4290.795 3879.787 3642.448
South R2 0.8663 0.9398 0.9689 0.9909
Africa Adj. R2 0.8656 0.9393 0.9685 0.9908
AIC 5506.180 5338.149 5199.139 4938.893
HQC 5508.897 5342.225 5204.573 4945.685
SBIC 5512.903 5348.233 5212.584 4955.700
Cameroun R2 0.9579 0.9579 0.9930 0.9940
Adj. R2 0.9577 0.9575 0.9929 0.9939
AIC 3737.545 3739.364 3360.533 3330.306
HQC 3740.258 3743.434 3365.960 3337.090
SBIC 3744.258 3749.434 3373.960 3347.089
the adjusted R2. The AIC, HQC and SBIC were also found to have the lowest values.
Consequently, we fit a linear regression model of order 4 to the dataset for each of
the countries. The result is presented in Table 2. The ordinary least square estimator
is employed to estimates the parameters of each of the model. We diagnosed the
model and observed that there are certain violations of the classical linear regression
model. The result of the parameter estimation and the diagnostic tests for each of
the countries is available in Table 3. The Durbin-Watson test shows that there is
problem of autocorrelation in all the estimated models. The p-value for each of the
Durbin-Watson statistic is less than the level of significance (α = 0.05). Also, the
white test revealed that all the models have the problem of heteroscedasticity, that
is, non-constant variance. For the following countries, the error terms in the model
is not normally distributed: Algeria, Egypt and Cameroun (Jarque Bera-test < 0.05).
It is obvious from the diagnostic test results in Table 2, that the performance of
the OLS estimator in forecasting will drop. We adopted the Cochrane estimator, the
heteroscedasticity corrected estimator and the least absolute deviation estimator as
alternative to the OLS estimator. Due to the complexity of handling two or three
problems simultaneously, we decided to solve each problem at a time.
The adequacy of the alternative estimators is examined in Table 3. It is important
to adopt one of these estimators as the best to estimate the parameters of each model.
It is possible it will vary from country to country. The result in Table 4 show that the
HC estimator and the CORC estimator seems to fit well to the data set.
In this session, we presented the results of the ARIMA modelling. The time plot
was obtained for all the series. Figure 3a–f shows that there is an increasing trend of
COVID-19 in all the countries.
Figure 3a–f shows that the number of confirmed cases of COVID-19 in all the
countries exhibit the same pattern. There was an increasing trend from the beginning
of the outbreak in each of the countries. However, after some time there was a
slow movement in the number of cases recorded daily. The Augmented Dickey-
Fuller (ADF) test was employed to assess the stationarity status of each of the series
(cumulative confirmed cases of COVID-19 in the African epicenters’). The ADF
result is provided in Table 5. The dataset for all the countries are not stationary
at the original level and the first difference but became stationary at the second
difference since the p-values are less than 0.05. Consequently, the series is subjected
to the Box-Jenken ARIMA modelling technique. We determined the parameters of
the ARIMA models according to the autocorrelation function (ACF) and the partial
autocorrelation function (PACF) plots (see Fig. 4a–f). The plots in Fig. 2a–f assist in
identifying the potential models combination for each of the countries. The order of
the model was determined according to ACF and PACF after applying the individual
difference of the country’s prevalence series. The result of the different possible
models is presented in Table 6.
5.1 ACF and PACF Plots
From Table 6, the ARIMA models with minimum AIC, SBIC or HQC are selected as
the best models. Accordingly, the ARIMA (1,2,2), ARIMA (3,2,2), ARIMA (1,2,1),
ARIMA (1,2,1), ARIMA (3,2,1) and ARIMA (2,2,3) models were chosen as the
best models for Algeria, Egypt, Ghana, Nigeria, South Africa and Cameroun respec-
tively. The best models were observed based on the minimum AIC, HQC and SBIC
Table 3 Parameter estimation using OLSE and its diagnostic test
Countries Variable Coefficient S.E t-stat Diagnostic test
Algeria β0 −2635.82 434.352 −6.068 R2 0.9951 Durbin-Watson test 0.006
(0.000) (0.000)
β1 272.548 26.860 10.15 F-test 11,016.31 White test 91.487
(0.000) (0.0000) (0.000)
β2 −5.764 0.488 −11.81 Jarque Bera-test 12.496
(0.000) (0.002)
β3 0.054 0.003 16.53
(0.000)
β4 −0.0001 0.000 −17.78
(0.000)
Egypt β0 7245.560 1769.550 4.095 R2 0.985 Durbin-Watson test 0.006
(0.000) (0.000)
β1 −580.055 104.308 −5.561 F-test 3755.320 White test 85.366
(0.000) (0.000) (0.000)
Robust Statistical Modeling of COVID-19 Prevalence …
β2 7.011 1.807 3.879 Jarque Bera-test 19.682

(0.000) (0.000)
β3 0.019 0.012 1.644
(0.102)
β4 −0.000 0.000 −5.549
(0.000)
Ghana β0 2461.38 333.287 7.3852 R2 0.9950 Durbin-Watson test 0.0319 (0.000)
(0.000)
(continued)
341
Table 3 (continued)
342

β1 −189.201 11.0515 −17.1199 F-test 9941.54 White test 133.241 (0.0000)
(0.000)
β2 3.24503 0.0788748 41.1416 Jarque Bera-test 42.63(0.1187)
(0.000)
β3 −8.20525e−010 3.04071e−011 −26.9847
(0.000)
β4 0 0 5.7108
(0.000)
Nigeria β0 1166.57 314.176 3.713 R2 0.9984 Durbin-Watson test 0.018
(0.000) (0.00)
β1 −85.609 19.603 −4.367 F-test 32,873.99 White test 115.564
(0.000) (0.000) (0.00)
(0.987) (0.1226)
β3 0.032 0.002 13.12
(0.000)
β4 −0.0001 5.482 −20.80
(0.000)
South β0 −23,735.7 9139.28 −2.597 R2 0.9909 Durbin-Watson test 0.012
Africa (0.010) (0.000)
β1 4009.53 588.817 6.809 F-test 5686.902 White test 98.88
(0.000) (0.000) (0.000)
(continued)
A. F. Lukman et al.
Table 3 (continued)
(0.000) (0.018)
β3 1.4914 0.0782 19.07
(0.000)
β4 −0.0041 0.0002 −22.46
(0.000)
Cameroun β0 1453.62 217.810 6.674 R2 0.9940 Durbin-Watson test 0.078
(0.000) (0.000)
β1 −165.820 14.098 −11.76 F-test 8590.84 White test 50.791
(0.000) (0.000) (0.000)
β2 4.101 0.268 15.29 Jarque Bera-test 9.088
(0.000) (0.011)
β3 −0.019 0.002 −10.11
(0.000)
Robust Statistical Modeling of COVID-19 Prevalence …
β4 0.000 0.000 5.830

(0.000)
343
Table 4 Selection of most preferred estimators

COVID-19 Statistic Estimators
OLS HC LAD CORC
Algeria F 11,016.31 40,039.06 871.777
(0.0000) (0.000) (0.000)
R2s 0.9951 0.9987 0.9999
Adj. R2 0.9950 0.9986 0.9999
Standard error of 1259.517 1.2715 82.011
regression
AIC 3804.44 741.59 3826.28
HQC 3811.31 748.47 3833.15
SBIC 3821.45 758.61 3843.29
Egypt F 3755.320 5500.665 220.009
(0.0000)
R2 0.9850 0.9897 0.999
Adj. R2 0.9848 0.9869 0.999
regression
AIC 4659.134 789.9250 4695.896
HQC 4666.092 796.8830 4702.854
SBIC 4676.389 807.1802 4713.151
Ghana F 9941.54 44,868.26 245.0053
(0.000) (0.000) (0.000)
R2 0.9389 0.9989 0.9998
Adj. R2 0.9386 0.9989 0.9998
regression
AIC 3541.233 706.4890
HQC 3547.963 713.2185
SBIC 3557.873 723.1284
SW-test
D-W test 0.0319 0.0276 2.038433
(0.000)
Nigeria F 32,873.99 59,825.11 723.888
(0.000) (0.000) (0.000)
R2 0.9984 0.9991 0.9999
Adj. R2 0.9983 0.9991 0.9999
Standard error of 906.695 1.377 22,228.72
regression
AIC 3625.590 769.901
(continued)
Table 4 (continued)
OLS HC LAD CORC
HQC 3632.442 776.754
SBIC 3642.448 786.869
South Africa F 5686.902 6753.889 158.67
(0.000) (0.000) (0.000)
R2 0.9909 0.9924 0.9999
Adj. R2 0.9908 0.9922 0.9999
Standard error of 25,928.82 1.3955 2288.96
regression
AIC 4938.893 751.37 4956.96
HQC 4945.685 758.16 4963.76
SBIC 4955.700 768.17 4973.77
Cameroun F 8590.842 12,958.49 276.422
(0.000)
R2 0.994 0.996 0.999
Adj. R2 0.994 0.996 0.999
regression
AIC 3330.306 779.019 3355.300
HQC 3337.090 785.802 3362.084
SBIC 3347.089 3372.083
respectively. The parameter estimation result for the selected model is presented in
Table 7.
Consequently, there is a need to conclude on the most efficient model and the
estimation methods to efficient forecast. Hence, we obtained the predicted values
using the maximum likelihood estimator (MLE) for the ARIMA model, the CORC
estimator and the HC estimator for the linear regression model of order 4. We obtained
the in-forecast for all the countries using the earlier mentioned estimators from 27
June 2020 to October 4 2020 and compute the mean squared error. The result is
presented in Table 4. We observed that the ARIMA model fit in well to all the series
with minimum mean squared error except for Cameroonian data. This agree with
the study of Cao et al. 37. According to them, the ARIMA models have made great
progress in the medical sciences and other fields for an efficient epidemic forecast
(Table 8).
The forecast for the different countries is presented in Fig. 4a–f. We observed that
for all the countries the increase of the cumulative number of cases for COVID-19
is not sporadic. It appears the pandemic will be under control in the coming months
except in Cameroon that shows an exponential increase (Fig. 5).
60000
120000
50000
CONFIRMED_CASES
100000
CONFIRMED_CASES
40000 80000
30000 60000
20000 40000
10000 20000
0 0
Mar Apr May Jun Jul Aug Sep Oct Mar Apr May Jun Jul Aug Sep Oct
a b
60000
50000
45000
50000
CONFIRMED_CASES
CONFIRMED_CASES
40000
35000 40000
30000
25000 30000
20000
15000 20000
10000
10000
5000
0 0
Apr May Jun Jul Aug Sep Oct Mar Apr May Jun Jul Aug Sep Oct
c d
700000
120000
600000
CONFIRMED_CASES
100000
CONFIRMED_CASES
500000
80000
400000
60000
300000
200000 40000
100000 20000
0 0
Mar Apr May Jun Jul Aug Sep Oct Mar Apr May Jun Jul Aug Sep Oct
e f
Fig. 3 Confirmed cases of COVID-19 in African Epicentres’, a Confirmed cases of COVID-19

in Algeria b Confirmed cases of COVID-19 in Egypt, c Confirmed cases of COVID-19 in Ghana,
d Confirmed cases of COVID-19 in Nigeria, e Confirmed cases of COVID-19 in South Africa,
fConfirmed cases of COVID-19 in C
6 Conclusion
In this study, we conducted a robust modelling of the novel COVID-19 in African

epicenters’. We applied the linear regression model and the autoregressive integrated
moving average (ARIMA) models to the cumulative confirmed COVID-19 cases to
Table 5 Unit root test for the cumulative confirmed cases of Covid-19
Country Transformation Augmented Dickey-Fuller test
Test without Test with constant Test with constant
constant and trend
Algeria Level 0.1972 −0.2328 −2.118
(0.7436) (0.932) (0.5351)
Difference 1 −1.0466 −2.0840 −1.8855
(0.2669) (0.2513) (0.662)
Difference 2 −20.8612 −20.8329 −21.0619
(0.0000) (0.0000) (0.0000)
Egypt Level −0.1461 −1.2596 −3.2973
(0.6334) (0.6505) (0.06664)
Difference 1 −1.3185 −1.8927 −1.7744
(0.1736) (0.3361) (0.7174)
Difference 2 −17.9827 −17.9439 (0.0000) −17.9758
(0.0000) (0.0000)
Ghana Level −0.5154 −1.3518 (0.6074) −2.6560
(0.4936) (0.2553)
Difference 1 −0.9132 −1.5368 (0.515) −1.2481
(0.3209) (0.8996)
Difference 2 −4.3907 −4.3789 (0.0003) −4.5498
(0. 005) (0.0012)
Nigeria Level −1.1735 −1.9174 (0.3245) −3.33932
(0.2204) (0.0599)
Difference 1 −0.57582 −1.4566 (0.5558) −0.722944
(0.4681) (0.9706)
Difference 2 −3.5706 −3.57713 (0.0062) −3.9669
(0.0004) (0.0097)
South Africa Level 1.1503 0.2431 −2.2674
(0.936) (0.9753) (0.4514)
Difference 1 −1.8120 −2.6757 −2.8379
(0.0666) (0.0783) (0.1835)
Difference 2 −15.0567 −15.0218 −15.0073
(0.0000) (0.0000) (0.0000)
Cameroun Level −0.0653 −1.2894 −1.6768
(0.6611) (0.6368) (0.7617)
Difference 1 −1.0410 −1.9588 −1.9035
(0.2691) (0.3054) (0.6526)
Difference 2 −6.45999 −6.4432 −6.5636
(0.0000) (0.0000) (0.0000)
*The p-value is in the parenthesis
ACF for d_d_CONFIRMED_C

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag
PACF for d_d_CONFIRMED_C

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag
a
0.3
+- 1.96/T^0.5
0.2
0.1
0
-0.1
-0.2
-0.3
0 5 10 15 20
lag

0.3
+- 1.96/T^0.5
0.2
0.1
0
-0.1
-0.2
-0.3
0 5 10 15 20
lag
b
Fig. 4 ACF and PACF for African Epicentres’ a ACF and PACF for Algeria, b ACF and PACF for
Egypt, c ACF and PACF for Ghana, d ACF and PACF for Nigeria, e ACF and PACF for Cameroon,
f ACF and PACF for South Africa

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag
c
+- 1.96/T^0.5
0.4
0.2
0
-0.2
-0.4
0 5 10 15 20
lag

+- 1.96/T^0.5
0.4
0.2
0
-0.2
-0.4
0 5 10 15 20
lag
d
Fig. 4 (continued)

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag
e
1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag

1
+- 1.96/T^0.5
0.5
-0.5
-1
0 5 10 15 20
lag
f
Fig. 4 (continued)
African epicenters’. We determined the best order for the linear regression model and
the ARIMA models that spans from the outset of the outbreak in each of the countries.
The parameters in the linear regression model were estimated using the ordinary least
squares estimator, the Cochrane-Orcutt estimator (CORC), the heteroscedasticity
corrected estimator (HCE) and the least absolute deviation estimator. The parameters
in the ARIMA models were estimated using the maximum likelihood estimator
Table 6 Comparison of tested ARIMA models

Country Candidate models Selection criterion Best model
AIC HQC SBIC
Algeria ARIMA(2,2,2) 2054.799 2063.022 2075.161 ARIMA(1,2,2)
ARIMA(2,2,1) 2054.670 2061.523 2071.638
ARIMA(1,2,2) 2053.724 2060.576 2070.692
ARIMA(1,2,1) 2062.177 2067.659 2075.752
Egypt ARIMA (4,2,7) 2772.991 2791.040 2817.742 ARIMA (3,2,2)
ARIMA (4,2,6) 2776.329 2792.990 2817.638
ARIMA (4,2,5) 2773.098 2788.371 2810.964
ARIMA (3,2,2) 2774.338 2784.058 2798.435
ARIMA (3,2,4) 2788.646 2801.142 2819.628
ARIMA (3,2,3) 2785.333 2796.441 2812.873
ARIMA (2,2,2) 2785.373 2793.704 2806.028
ARIMA (2,2,1) 2783.362 2790.305 2800.575
Ghana ARIMA(2,2,1) 2791.273 2797.984 2807.863 ARIMA(1,2,1)
ARIMA(2,2,2) 2793.271 2801.324 2813.180
ARIMA(2,2,3) 2795.296 2804.692 2818.523
ARIMA(1,2,3) 2792.883 2800.936 2812.791
ARIMA(1,2,2) 2791.373 2798.084 2807.963
ARIMA(1,2,1) 2789.896 2795.265 2803.168
Nigeria ARIMA(2,2,1) 2538.060 2544.895 2554.982 ARIMA(1,2,1)
ARIMA(2,2,2) 2536.687 2544.890 2556.994
ARIMA(2,2,3) 2534.997 2544.567 2558.689
ARIMA(1,2,1) 2536.112 2541.580 2549.650
ARIMA(1,2,2) 2538.108 2544.943 2555.030
ARIMA(1,2,3) 2536.748 2544.951 2557.055
South-Africa ARIMA(8,2,10) 3391.051 3416.794 3454.736 ARIMA(3,2,1)
ARIMA(3,2,1) 3391.697 3405.246 3425.246
ARIMA(4,2,3) 3392.568 3407.472 3429.438
ARIMA(3,2,2) 3391.105 3404.654 3424.624
ARIMA(3,2,1) 3391.745 3403.939 3421.912
Cameroun ARIMA(3,2.2) 2768.157 2777.629 2791.587 ARIMA(2,2,3)
ARIMA(3,2,3) 2769.429 2780.254 2796.206
ARIMA (2,2,1) 2772.721 2779.486 2789.456
ARIMA(2,2,2) 2773.388 2781.506 2793.470
ARIMA(2,2,3) 2766.144 2775.615 2789.573
ARIMA(1,2,1) 2771.041 2776.454 2784.43
ARIMA(1,2,2) 2772.057 2778.822 2788.792
ARIMA(1,2,3) 2773.198 2781.317 2793.281
Table 7 Parameters of the best ARIMA models

Country Best model Coefficients SE
Algeria ARIMA(1,2,2) ar1 0.9442 0.0364
ma1 −1.2992 0.0705
ma2 0.3970 0.0595
Egypt ARIMA(3,2,1) ar1 0.0363 0.5365
ar2 −0.0769 0.2156
ar3 0.1147 0.1551
ma1 −0.2420 0.5369
ma2 −0.1309 0.1838
Ghana ARIMA(1,2,1) ar1 −0.2505 0.0776
ma1 −0.7743 0.0494
Nigeria ARIMA(1,2,1) ar1 −0.0116 0.0967
ma1 −0.6475 0.0752
South Africa ARIMA(3,2,1) ar1 0.3761 0.0982
ar2 −0.1651 0.0711
ar3 −0.1929 0.0717
ma1 −0.5277 0.0771
Cameroun ARIMA(2,2,3) ar1 −0.3611 0.0471
ar2 −0.8843 0.0355
ma1 −0.5891 0.0313
ma2 0.6848 0.0337
ma3 −0.9286 0.0366
Table 8 Comparison of the best estimators

Model Countries
MSE Algeria Egypt Ghana Nigeria South Africa Cameroon
HC 2,779,113.3 53,679,781.9 2,511,960.7 2,322,233.5 1,255,772,847 159,578.9
CORC 7675.031 41,389.09 75,912.86 8178.939 7,912,202.98 34,230.5
MLE 484.1 7642.11 74,284.71 7123.90 1,744,012 36,554.48
(MLE). We observed that the HCE, the CORC and the MLE performs best. However,
there is a need to adopt a single method of forecasting. We compared the three
estimators (HCE, CORC, MLE) using the mean squared error and found that the
fitting the ARIMA models using the MLE is generally preferred for forecasting in
all the countries of interest except for Cameroon where the linear regression model
is used. The results show that there will be no sporadic increase in the cumulative
confirmed cases in all the countries except in Cameroon. The forecast in Cameroon
shows an exponential progression. However, the government have to put measures
140000 99 percent interval

CONFIRMED CONFIRMED
forecast forecast
120000
200000
100000
150000
80000
60000 100000
40000
50000
20000
0 0
2020.5 2020.6 2020.7 2020.8 2020.9 2021 2020.5 2020.6 2020.7 2020.8 2020.9 2021
a b
120000 130000 99 percent interval

99 percent interval
Confirmed CONFIRMED
forecast 120000 forecast
100000 110000
100000
80000
90000
60000 80000
70000
40000
60000
50000
20000
40000
0 30000
20000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
-20000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
d
c
1.6e+006 99 percent interval

confirmed
forecast cummulative_cas
1.4e+006 55000 forecast
50000
1.2e+006
45000
1e+006
40000
800000 35000
30000
600000
25000
400000
20000
200000 15000
10000
0 2020.5 2020.6 2020.7 2020.8 2020.9 2021
2020.5 2020.6 2020.7 2020.8 2020.9 2021
e f
Fig. 5 Forecast of the cumulative confirmed cases in African Epicentres’ using the ARIMA model,
a Forecast of the cumulative confirmed cases in Algeria using the ARIMA model b Forecast of
the cumulative confirmed cases in Egypt using the ARIMA model, c Forecast of the cumulative
confirmed cases in Ghana using the ARIMA model, d Forecast of the cumulative confirmed cases
in Nigeria using the ARIMA model, e Forecast of the cumulative confirmed cases in South Africa
using the ARIMA model, f Forecast of the cumulative confirmed cases in Cameroon using the
ARIMA model
in place to curb the increase in this pandemic. Also, government and other health
authorities should continue to plan and supply resources for effective management
of this pandemic in the days to come.
References
1. World Health Organization: COVID 19 Public Health Emergency of International Concern

(PHEIC). Global research and innovation forum: towards a research roadmap (2020)
modelling of COVID-19 confirmed cases in Nigeria. Inf. Dis. Modell. 5, 543–548 (2020)
3. Rodrigues-Pinto, R., Sousa, R., Oliveira, A.: Preparing to perform trauma and orthopaedic
surgery on patients with COVID-19. J. Bone Joint Surg. American Volume (2020)
4. Ebrahim, S.H., Ahmed, Q.A., Gozzer, E., Schlagenhauf, P., Memish, Z.A.: Covid-19 and
community mitigation strategies in a pandemic (2020)
5. Li, L., Yang, Z., Dang, Z., Meng, C., Huang, J., Meng, H., Huang, J., Meng, H., Wang, D.,
Chen, G., Zhang, J., Peng, H., Shao, Y.: Propagation analysis and prediction of the COVID-
19. Inf. Dis. Modell. 5, 282–292 (2020)
6. Adeniyi, E.A., Awotunde, J.B., Ogundokun, R.O., Kolawole, P.O., Abiodun, M.K., Adeniyi,
A.A.: Mobile health application and COVID-19: opportunities and challenges. J. Crit. Rev.
7(15), 3481–3488 (2020)
7. WHO: Coronavirus Disease (COVID-19) Dashboard (2020). Accessed 24 Sept 2020. 291–
292. Available https://covid19.who.int/
8. Arthi, V., Parman, J.: Disease, downturns, and wellbeing: Economic history and the long-run
impacts of COVID-19 (No. w27805). National Bureau of Economic Research (2020)
9. Perrella, A., Carannante, N., Berretta, M., Rinaldi, M., Maturo, N., Rinaldi, L.: Editorial–
novel coronavirus 2019 (Sars-CoV2): a global emergency that needs new approaches. Eur.
Rev. Med. Pharmacol. 24, 2162–2164 (2020)
10. Kannan, S., Ali, P.S.S., Sheeza, A., Hemalatha, K.: COVID-19 (Novel Coronavirus 2019)-
recent trends. Eur. Rev. Med. Pharmacol. Sci 24(4), 2006–2011 (2020)
11. Wong, Z.S., Zhou, J., Zhang, Q.: Artificial intelligence for infectious disease big data analytics.
Inf. Dis. Health 24(1), 44–48 (2019)
12. Pullano, G., Pinotti, F., Valdano, E., Boëlle, P.Y., Poletto, C., Colizza, V.: Novel coronavirus
(2019-nCoV) early-stage importation risk to Europe, January 2020. Eurosurveillance 25(4),
2000057 (2020)
13. Zhao, S., Lin, Q., Ran, J., Musa, S. S., Yang, G., Wang, W., Lou, Y., Gao, D., Yang, L., He, D.,
Wang, M.H.: Preliminary estimation of the basic reproduction number of novel coronavirus
(2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the
outbreak. Int. J. Inf. Dis. 92, 214–217 (2020)
14. Gates, B.: Responding to Covid-19—a once-in-a-century pandemic? N. Engl. J. Med. 382(18),
1677–1679 (2020)
15. Ogundokun, R.O., Awotunde, J.B.: Machine learning prediction for COVID-19 pandemic in
India. medRxiv (2020)
16. Xie, J., Tong, Z., Guan, X., Du, B., Qiu, H., Slutsky, A.S.: Critical care crisis and some
recommendations during the COVID-19 epidemic in China. Intensive Care Med. 1–4 (2020)
17. Touray, S., Sanyang, B., Zandrow, G., Dibba, F., Fadera, K., Kanteh, E., Danso, M., Sanyang,
L.N., Njie, M., Johnson, G., Sanyang, A.: An assessment of critical care capacity in the
Gambia. J. Crit. Care 47, 245–253 (2018)
18. Radha, P., Srinivasan, B.: Predicting diabetes by cosequencing various data mining classifi-
cation techniques. Int. J. Innovative Sci. Eng. Technol. 1(6), 334–339 (2014)
19. Roiger, R.J.: Data mining: a tutorial-based primer. Chapman and Hall/CRC (2017)
20. Fitkov-Norris, E., Folorunso, S.O.: Impact of sampling on neural network classification perfor-
mance in the context of repeat movie viewing. In: International Conference on Engineering
Applications of Neural Networks, pp. 213–222. Springer, Berlin, Heidelberg (2013)
21. Awotunde, J.B., Matiluko, O.E., Fatai, O.W.: Medical diagnosis system using fuzzy logic.
Afr. J. Comput. ICT 7(2), 99–106 (2014)
22. Pereira, R.M., Bertolini, D., Teixeira, L.O., Silla Jr., C.N., Costa, Y.M.: COVID-19 identifi-
cation in chest X-ray images on flat and hierarchical classification scenarios. Comput. Meth.
Programs Biomed. 194, 105532 (2020). https://doi.org/10.1016/j.cmpb.2020.105532
23. Folorunso, S.O., Fashoto, S.G., Olaomi, J., Fashoto, O.Y.: A multi-label learning model for
psychotic diseases in Nigeria. Inf. Med. Unlocked 19(100326), 11 (2020). https://doi.org/10.
1016/j.imu.2020.100326
24. Matta, D.M., Saraf, M.K.: Prediction of COVID-19 using machine learning techniques (2020)
25. Ayyoubzadeh, S.M., Ayyoubzadeh, S.M., Zahedi, H., Ahmadi, M., Kalhori, S.R.N.: Predicting
COVID-19 incidence through analysis of google trends data in Iran: data mining and deep
learning pilot study. JMIR Public Health Surveill. 6(2), e18828 (2020)
26. Narin, A., Kaya, C., Pamuk, Z.: Automatic detection of coronavirus disease (Covid-19) using
X-ray images and deep convolutional neural networks (2020). arXiv preprint arXiv:2003.
10849
27. Awotunde, J.B., Jimoh, R.G., Oladipo, I.D., Abdulraheem, M.: Prediction of malaria fever
using long-short-term memory and big data. Communi. Comput. Inf. Sci. 1350, 41–53 (2021)
28. Kapata, N., Ihekweazu, C., Ntoumi, F., Raji, T., Chanda-Kapata, P., Mwaba, P., Mukonka, V.,
Bates, M., Tembo, J., Corman, V., Mfinanga, S.: Is Africa prepared for tackling the COVID-19
(SARS-CoV-2) epidemic. Lessons from past outbreaks, ongoing pan-African public health
efforts, and implications for the future. Int. J. Inf. Dis. 93, 233–236 (2020)
29. World Health Organization, & World health organization: Coronavirus disease (COVID-2019)
situation reports (2020)
30. Haider, N., Yavlinsky, A., Simons, D., Osman, A. Y., Ntoumi, F., Zumla, A., Kock, R.:
Passengers’ destinations from China: low risk of novel coronavirus (2019-nCoV) transmission
into Africa and South America. Epidemiol. Inf. 148 (2020)
31. World Health Organization: Importation pattern of COVID-19 cases in the WHO African
Region, 25 February–18 March 2020 (2020)
32. Nkengasong, J.: China’s response to a novel coronavirus stands in stark contrast to the 2002
SARS outbreak response. Nat. Med. 26(3), 310–311 (2020)
33. Bellizzi, S., Napodano, C.M.P., Fiamma, M., Maher, O.A.: Drought and Covid-19 in the
Eastern Mediterranean region of the WHO. Public Health (2020)
34. Nkengasong, J.N., Mankoula, W.: Looming threat of COVID-19 infection in Africa: act
collectively, and fast. The Lancet 395(10227), 841–842 (2020)
35. Gilbert, M., Pullano, G., Pinotti, F., Valdano, E., Poletto, C., Boëlle, P. Y., d’Ortenzio, E.,
Yazdanpanah, Y., Eholie, S.P., Altmann, M., Gutierrez, B.: Preparedness and vulnerability
of African countries against importations of COVID-19: a modelling study. The Lancet
395(10227), 871–877 (2020)
36. Dong, L., Hu, S., Gao, J.: Discovering drugs to treat coronavirus disease 2019 (COVID-19).
Drug Discov. Ther. 14(1), 58–60 (2020)
37. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M.,
Li, X.: A trial of Lopinavir–Ritonavir in adults hospitalized with severe Covid-19. N. Engl.
J. Med. (2020)
38. Parpia, A.S., Ndeffo-Mbah, M.L., Wenzel, N.S., Galvani, A.P.: Effects of response to 2014–
2015 Ebola outbreak on deaths from malaria, HIV/AIDS, and tuberculosis, West Africa.
Emerg. Inf. Dis. 22(3), 433 (2016)
39. Porcher, S.: Governments’ responses to COVID-19 (2020)
40. Loembé, M.M., Tshangela, A., Salyer, S.J., Varma, J.K., Ouma, A.E.O., Nkengasong, J.N.:
COVID-19 in Africa: the spread and response. Nat. Med. 1–4 (2020)
41. Ondoa, P., Kebede, Y., Loembe, M.M., Bhiman, J.N., Tessema, S.K., Sow, A., Nkengasong,
J.: COVID-19 testing in Africa: lessons learnt. The Lancet Microbe 1(3), e103–e104 (2020)
42. LLC, Forbidden Fruits: iAfrica—Ancient History UNTOLD. https://books.google.com/?

id=JA7tcmEx5lsC&pg=PT14&lpg=PT14&dq=origin+of+the+word+algeria+island#v=one
page. Forbidden Fruit Books LLC (2013)
43. Jansen, J.C.: Politics of remembrance, colonialism and the Algerian War of Independence in
France, pp. 275–293 (2010)
44. Reynolds, M.: What is coronavirus and how close is it to becoming a pandemic. Wired UK.
ISSN 1357-0978. Archived from the original on 5 March 2020. Retrieved 5 Sept 2020.
45. Boukhatem, M.N.: Novel coronavirus disease 2019 (COVID-19) Outbreak in Algeria: a new
challenge for prevention. J. Community Med. Health Care 5(1), 1035 (2020)
46. Jerome, J.T.J., Mercier, F., Mudgal, C.S., Arenas-Prat, J., Vinagre, G., Goorens, C.K., Rivera-
Chavarría, I.J., Sechachalam, S., Mofikoya, B., Thoma, A., Medina, C.: Perspectives and
consensus among international orthopaedic surgeons during initial and mid-lockdown phases
of coronavirus disease. J. Hand Microsurg. (2020)
47. Hamidouche, M.: COVID-19 Outbreak in Algeria: A model to predict cumulative cases. J.
Contemp. Stud. Epidemiol. Public Health 1(1) (2020)
48. Lounis, M.: A descriptive study of the current situation of COVID-19 in Algeria. Electron J.
Gen. Med. 17(6), em253 (2020)
49. Rouabah, M.T., Tounsi, A., Belaloui, N.E.: A mathematical epidemic model using genetic
fitting algorithm with cross-validation and application to early dynamics of COVID-19 in
Algeria. arXiv preprint arXiv:2005.13516 (2020)
50. Adesina, O.S., Onanaye, S.A., Okewole, D., Egere, A.C.: Forecasting of new cases of COVID-
19 in Nigeria using autoregressive fractionally integrated moving average models. Asian Res.
J. Math. 135–146 (2020)
51. Reuben, R.C., Danladi, M.M., Saleh, D.A., Ejembi, P.E.: Knowledge, attitudes, and practices
towards COVID-19: an epidemiological survey in North-Central Nigeria. J. community health,
1–14 (2020)
52. Oladipo, I.D., Babatunde, A.O., Awotunde, J.B., Abdulraheem, M.: An improved hybridiza-
tion in the diagnosis of diabetes mellitus using selected computational intelligence. Communi.
Comput. Inf. Sci. 1350, 272–285 (2021)
53. NCDC: An update of the COVID-19 outbreak in Nigeria. 01 August 2020.
Retrieved from https://ncdc.gov.ng/diseases/sitreps/?cat=14&name=An%20update%20of%
20COVID19%20outbreak%20in%20Nigeria (2020)
54. Van Zandvoort, K., Jarvis, C.I., Pearson, C., Davies, N.G., Russell, T.W., Kucharski, A.J., Jit,
M., Flasche, S., Eggo, R.M., Checchi, F., CMMID COVID-19 working group: Response strate-
gies for COVID-19 epidemics in African settings: a mathematical modeling study. MedRxiv
(2020)
55. Iwuoha, V.C., Aniche, E.T.: Covid-19 lockdown and physical distancing policies are elitist:
towards an indigenous (Afro-centred) approach to containing the pandemic in sub-urban slums
in Nigeria. Local Environ. 1–10 (2020)
56. World Health Organization. Emergencies preparedness, response. Pneumonia of unknown
origin–China. Dis. Outbreak news 5 (2020)
57. Winter, S., Dzombo, M.N., Barchi, F.: Exploring the complex relationship between women’s
sanitation practices and household diarrhea in the slums of Nairobi: a cross-sectional study.
BMC Infect. Dis. 19(1), 242 (2019)
58. Ioannidis, J.P.: Coronavirus disease 2019: the harms of exaggerated information and non-
evidence-based measures. Eur. J. Clin. Investig. 50(4), e13222 (2020)
59. Wong, G., Liu, W., Liu, Y., Zhou, B., Bi, Y., Gao, G.F.: MERS, SARS, and Ebola: the role of
super-spreaders in infectious disease. Cell Host Microbe 18(4), 398–401 (2015)
60. Ayinde, K., Lukman, A.F., Rauf, R.I., Alabi, O.O., Okon, C.E., Ayinde, O.E.: Modeling
Nigerian Covid-19 cases: a comparative analysis of models and estimators. Chaos, Solitons
Fractals 138(March), 1–16 (2020). https://doi.org/10.1016/j.chaos.2020.109911
61. Okuonghae, D., Omame, A.: Analysis of a mathematical model for COVID-19 population
dynamics in Lagos, Nigeria. Chaos, Solitons & Fractals 139, 110032 (2020)
62. Adams, S.O., Bamanga, M.A., Olanrewaju, S.O., Yahaya, H.U., Akano, R.O.: Modeling
COVID-19 cases in Nigeria using some selected count data regression models. Int. J.
Healthcare Med. Sci. 64, 64–73 (2020). https://doi.org/10.32861/ijhms.64.64.73
63. Iboi, E.A., Sharomi, O.O., Ngonghala, C.N., Gumel, A.B.: Mathematical modeling and
analysis of COVID-19 pandemic in Nigeria. medRxiv (2020)
64. Madubueze, C.E., Akabuike, N.M., Sambo, D.: The role of mathematical model in curbing
COVID-19 in Nigeria. medRxiv (2020)
65. Balah, B., Djeddou, M.: Forecasting COVID-19 new cases in Algeria using autoregressive
fractionally integrated moving average Models (ARFIMA). medRxiv (2020)
66. Corman, V.M., Landt, O., Kaiser, M., Molenkamp, R., Meijer, A., Chu, D.K., Bleicker,
T., Brünink, S., Schneider, J., Schmidt, M.L., Mulders, D.G., Mulders, D.G.: Detection of
2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25(3), 2000045
(2020)
67. World Health Organization.: Coronavirus disease 2019 (COVID-19): situation report, 72
(2020)
68. World Health Organization: Risk communication and community engagement readiness
and response to coronavirus disease (COVID-19): interim guidance, 19 March 2020 (No.
WHO/2019-nCoV/RCCE/2020.2). World Health Organization (2020)
the challenges. Int. J. Antimicrobial Agents 105924 (2020)
70. Umviligihozo, G., Mupfumi, L., Sonela, N., Naicker, D., Obuku, E. A., Koofhethile, C.,
Mogashoa, T., Kapaata, A., Ombati, G., Michelo, C.M., Makobu, K.: Sub-Saharan Africa
preparedness and response to the COVID-19 pandemic: a perspective of early career African
scientists. Wellcome Open Res. 5(163), 163 (2020)
71. Badu, K., Thorn, J.P., Goonoo, N., Dukhi, N., Sylverken, A.A.: Africa’s response to the
COVID-19 pandemic: a review of the nature of the virus, impacts and implications for
preparedness [version 1; peer review: awaiting peer review] (2020)
72. Bulled, N., Singer, M.: In the shadow of HIV & TB: a commentary on the COVID epidemic
in South Africa. Glob. Public Health, 1–13 (2020)
73. Dalu, M.T., Manyani, A.: Gender inclusivity and development in South African Public Urban
Spaces. Urban Geography in South Africa, pp. 239–250. Springer, Cham (2020)
74. Ahmed, S.F., Quadeer, A.A., McKay, M.R.: Preliminary identification of potential vaccine
targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological
studies. Viruses 12(3), 254 (2020)
75. Ali Hasab, A.: Flattening COVID-19 curve in Egypt: an epidemiological modelling. Depart-
ment of Epidemiology, High Institute of Public Health, Alexandria University (2020).
Preprints www.preprints.org. https://doi.org/10.20944/preprints202005.0156.v1
76. El Desouky, E.D.: Prediction of the Epidemic Peak of Covid19 in Egypt (2020). medRxiv
(2020)
77. Saba, A.I., Elsheikh, A.H.: Forecasting the prevalence of COVID-19 outbreak in Egypt using
nonlinear autoregressive artificial neural networks. Process Saf. Environ. Prot. (2020)
78. Hasab, A.A., El-Ghitany, E.M., Ahmed, N.N.: Situational analysis and epidemic modeling of
COVID-19 in Egypt. JHIPH 50(1), 46–51 (2020)
79. Asamoaha, J.K.K., Jina, Z., Seidub, B., Oduroc, F.T. d, Suna, G.Q., Alzahranie, F.: A mathe-
matical model and sensitivity assessment of COVID-19 outbreak for Ghana and Egypt. SSRN
Electron. J. (2020). https://doi.org/10.2139/ssrn.3612877
80. Shinde, G.R., Kalamkar, A.B., Mahalle, P.N., Dey, N., Chaki, J., Hassanien, A.E.: Forecasting
models for coronavirus disease (COVID-19): a survey of the state-of-the-art. SN Comput. Sci.
1(4), 1–15 (2020)
81. Anirudh, A.: Mathematical modeling and the transmission dynamics in predicting the Covid-
19-What next in combating the pandemic. Inf. Dis. Modell. 5, 366–374 (2020)
82. Singh, R.K., Rani, M., Bhagavathula, A.S., Sah, R., Rodriguez-Morales, A.J., Kalita, H.,
Nanda, C., Sharma, S., Sharma, Y.D., Rabaan, A.A. Rahmani, J Kumar, P.: Prediction of the
COVID-19 pandemic for the top 15 affected countries: advanced autoregressive integrated
moving average (ARIMA) model. JMIR Public Health Surveill. 6(2), e19115 (2020)
83. Guo, Y.R., Cao, Q.D., Hong, Z.S., Tan, Y.Y., Chen, S.D., Jin, H.J., Tan, K.S., Wang, D.Y., Yan,
Y.: The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19)
outbreak–an update on the status. Military Med. Res. 7(1), 1–10 (2020)
84. Chan, J.W.M., Ng, C.K., Chan, Y.H., Mok, T.Y.W., Lee, S., Chu, S.Y.Y., Law, W.L., Lee,
M.P., Li, P.C.K.: Short term outcome and risk factors for adverse clinical outcomes in adults
with severe acute respiratory syndrome (SARS). Thorax 58(8), 686–689 (2003)
85. Nguemdjo, U., Meno, F., Dongfack, A., Ventelou, B.: Simulating the progression of the
COVID-19 disease in Cameroon using SIR models. PloS One 15(8), e0237832 (2020)
86. Ob Sisay et al.: Planning for the worst and hoping for the best: forecasting Covid-19 for
Sub-Saharan Africa. Published at https://institute.global/advisory/planning (2020)
87. Ferner, R.E., Aronson, J.K.: Chloroquine and hydroxychloroquine in Covid-19 (2020)
88. Atangana, A.: Modelling the spread of COVID-19 with new fractal-fractional operators: can
the lockdown save mankind before vaccination? Chaos, Solitons & Fractals 136, 109860
(2020)
89. Prem, K., Liu, Y., Russell, T.W., Kucharski, A.J., Eggo, R.M., Davies, N., Flasche, S., Clifford,
S., Pearson, C.A., Munday, J.D., Abbott, S.: The effect of control strategies to reduce social
mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study. The
Lancet Public Health (2020)
90. Nkwayep, C.H., Bowong, S., Tewa, J.J., Kurths, J.: Short-term forecasts of the COVID-19
pandemic: a study case of Cameroon. Chaos, Solitons & Fractals 140, 110106 (2020)
91. Djaoue, S., Kolaye, G.G., Abboubakar, H., Ari, A.A.A., Damakoa, I.: Mathematical modeling,
analysis and numerical simulation of the COVID-19 transmission with mitigation of control
strategies used in Cameroon. Chaos, Solitons & Fractals, 110281 (2020)
92. Kouakep, Y.T., Tchoumi, S.Y., Fotsa, D.J.M., Kamba, F.G.T., Ngounou, D., Mboula, E.,
Kamla, V., Kamgang, J.C.: Modelling the anti-COVID19 individual or collective containment
strategies in Cameroon
93. Adela, N., Nkengazong, L., Ambe, L.A., Ebogo, J.T., Mba, F.M., Goni, H.O., Nyunai, N.,
Ngonde, M.C., Oyono, J.L.E.: Knowledge, attitudes, practices of/towards COVID 19 preven-
tive measures and symptoms: a cross-sectional study during the exponential rise of the
outbreak in Cameroon. PLoS Negl. Trop. Dis. 14(9), e0008700 (2020)
94. Bin, J.M., Ofeh, M.A., Che, S.B.: Impact of the corona pandemic on household welfare in
Cameroon. J. Econ. Manage. Sci. 3(3), p25–p25 (2020)
95. Wiah, E.N., Danso-Addo, E., Bentil, D.E.: Modelling the dynamics of COVID-19 disease
with contact tracing and isolation in Ghana. Math. Modell. Appl. 5(3), 146 (2020)
96. Asamoah, J.K.K., Owusu, M.A., Jin, Z., Oduro, F.T., Abidemi, A., Gyasi, E.O.: Global
stability and cost-effectiveness analysis of COVID-19 considering the impact of the
environment: using data from Ghana. Chaos, Solitons & Fractals 140, 110103 (2020)
97. Adekunle, I.A., Onanuga, A., Wahab, O., Akinola, O.O.: Modelling spatial variations of
coronavirus disease (COVID-19) in Africa. Sci. Total Environ. 138998 (2020)
98. Diop, B.Z., Ngom, M., Biyong, C.P., Biyong, J.N.P.: The relatively young and rural population
may limit the spread and severity of COVID-19 in Africa: a modelling study. BMJ Global
Health 5(5), e002699 (2020)
99. Lukman, A.F., Ayinde, K., Siok Kun, S., Adewuyi, E.T.: A modified new two-parameter
estimator in a linear regression model. Modell. Simul. Eng. 2019 (2019)
100. Lukman, A.F., Ayinde, K., Kibria, B.G., Adewuyi, E.T.: Modified ridge-type estimator for
the gamma regression model. Commun. Stat. Simul. Comput. 1–15 (2020)
101. Ayinde, K., Lukman, A.F., Arowolo, O.: Robust regression diagnostics of influential
observations in linear regression model. Open J. Stat. 5(04), 273 (2015)
102. Lukman, A.F., Osowole, O.I., Ayinde, K.: Two stage robust ridge method in a linear regression
model. J. Mod. Appl. Stat. Meth. 14(2), 8 (2015)
Modeling Covid-19 Cases in West
African Countries: A Comparative
Analysis of Quartic Curve Estimation
Models and Estimators
Kayode Ayinde, Hamidu Abimbola Bello, Rauf Ibrahim Rauf,

Omokova Mary Attah, Ugochinyere Ihuoma Nwosu,
Oluwatoyin Kikelomo Bodunwa, Oluwadare Olatunde Ojo,
Roseline Oluwaseun Ogundokun, Taiwo Stephen Fayose,
Rasaki Yinka Akinbo, Adebowale Olusola Adejumo, Oluwatosin Akinsola,
Abayomi Ayodele Akomolafe, Timothy Olabisi Olatayo,
Olabimpe Bodunde Aladeniyi, Emmanuel Idowu Olamide,
and Samuel Olayemi Olanrewaju
Abstract COVID-19 has remained and continued to be a severe pandemic threat-

ening the present and future health stability of all the countries, the West African
Countries inclusive. The challenge to avert the threat by modeling the reported cases
in each of these West African Countries becomes needful for future planning and a
K. Ayinde (B) · H. A. Bello · O. M. Attah · O. K. Bodunwa · O. O. Ojo · A. A. Akomolafe ·

O. B. Aladeniyi · E. I. Olamide
Department of Statistics, Federal University of Technology, Akure, Nigeria
e-mail: kayinde@futa.edu.ng
R. I. Rauf · S. O. Olanrewaju
Department of Statistics, University of Abuja, Abuja, Nigeria
U. I. Nwosu
Department of Statistics, Federal University of Technology, Owerri, Nigeria
R. O. Ogundokun
Department of Computer Science, Landmark University, Omu Aran, Nigeria
T. S. Fayose
Department of Mathematics and Statistics, Federal Polytechnic Ado Ekiti, Ekiti, Nigeria
R. Y. Akinbo
Department of Mathematics and Statistics, Federal Polytechnic Ilaro, Ilaro, Nigeria
A. O. Adejumo
Department of Statistics, University of Ilorin, Ilorin, Nigeria
O. Akinsola
Department of Community Health and Primary Care, College of Medicine, University of Lagos,
Lagos, Nigeria
T. O. Olatayo
Olabisi Onabanjo University, Ago-Iwoye, Nigeria
360 K. Ayinde et al.
concern in this book chapter. Consequently, COVID-19 data on daily confirmed and
death cases in each of the sixteen (16) countries in West Africa were collected from
European Centre for disease prevention and control (www.ecdc.europa.eu) begin-
ning from the first day of its occurrence until 25th September 2020. As at this time,
West African counties had recorded 181,376 confirmed cases and 2748 death cases.
It is intended to determine and use an appropriate curve estimation statistical model
to forecast for the remaining days of the year 2020; and establish the direction of
movement of the future forecast values for effective planning. The Quartic Curve Esti-
mation Model with autocorrelated error terms of order 1 (AR (1)) was found useful
with some estimators. The best estimator of the model parameters was identified to be
either the Cochrane Orcutt or the Hildreth-LU or the Prais-Winsten estimator. There
is an upward movement of forecast values of COVID-19 cumulative confirmed cases
towards the end of the year 2020 in Burkina Faso, Cape Verde, Code d’Ivoire, Liberia,
Mali, Mauritania, Nigeria, Senegal and Sierra Leone. So, the government in these
countries needs not to relax in their fight against the spread of COVI-19. Similarly,
there is an upward movement of forecast values of COVID-19 cumulative death cases
in Benin, Cape Verde, Guinea Bissau, Mali, Mauritania, Nigeria and Togo. So, these
countries would need to critically look after their COVID-19 confirmed patients so
as not to lose them to death. COVID-19 cases in Gambia, Ghana, Guinea and Niger
are expected to flatten out towards the year while they have to be approached with
all seriousness in Cape Verde, Mali, Mauritania and Nigeria.
Keywords West African countries · COVID-19 · Quartic curve estimation model ·

Autocorrelated error terms · Estimators · Forecast values
1 Introduction
The region of West Africa containing sixteen (16) countries namely; Benin, Burkina
Faso, Cape Verde, Gambia, Ghana, Guinea, Guinea Bissau, Ivory Coast (Cote
d’Ivoire), Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone and Togo
as well as Saint Hallen, has been reported to have some of its countries to be among
the poorest countries in the world. Its countries also have fewer than five (5) hospital
beds and two (2) medical doctors per 10,000 population, half of its countries have per
capita health expenditures lower than US$50 (based on WHO global health expendi-
ture data), and several of its countries have poorly resourced health system to measure
up with any epidemic challenges [1–3]. Another challenge being faced by countries
in the region is that of unprecedented food security. An estimated 12 million people
had food shortages in 2019 [4]. The emergence of COVID-19, a respiratory illness
reported to occur first in Wuhan City, Hubei Province, China on the 31st December
2019 [5–7], in West African region was later than other regions of the world. This was
much more attributed to the limited air traffic in West African Countries rather than
their region climatic condition. So, West African Countries experienced COVID-19
pandemic for the first time as different time [2].
Modeling Covid-19 Cases in West African Countries … 361
Learning from the 2014 Ebola epidemic in West Africa, most leaders were so
fast to put measures in place to prevent the health and prosperity of the countries
from being affected. In fact, few countries were able to put on measures against
the pandemic even before the first confirmed case was recorded [8]. International
flights were suspended, borders were closed, curfews were imposed, localities were
locked down, internal movements were restricted, schools, markets and non-essential
businesses were closed. In most West African Countries, most jobs and businesses
were done on an informal level. As a result, avoidance of face to face contact became
a severe challenge and so working from home to earn an income was practically very
scarce [5, 8–10]. Therefore, living became difficult and corruption again prevented
majority of the citizen to benefit from the assistance government proclaimed to give
them.
COVID-19 pandemic has continued to spread since the first reported case in each
country of West Africa. The minimum reported case in all the countries is zero (0)
except in Republic of Benin where its past COVID-19 confirmed case was corrected
on 20th May, 2020 by -209. Table 1 gives some vital information (descriptive statis-
tics) about the daily COVID-19 reported confirmed cases in all the West African
Counties from the 1st day of occurrence until 25th September 2020.
From the table, Nigeria was the first West African Country to record COVID-19
confirmed case on 28th February, 2020. This was followed by Senegal and Togo;
and before the end of the first week in March 2020 these three countries eventually
recorded at least forty (40) confirmed cases of COVID-19 of which most originated
from European countries [11, 12]. Sierra Leone, Guinea Bissau and Mali only expe-
rienced COVID-19 towards the end of March or early April, 2020 while Saint Helena
has not had any reported confirmed cases up till 25th September, 2020. The spread
of the pandemic has continued to increase all over the West African Countries except
in Benin, Gambia, Guinea Bissau and Mauritania in that zero confirmed cases were
reported for only few days (less than 70 days of the duration of data collection).
Moreover, the spread is most serious in Senegal, Code d’ivore, Mali, Nigeria and
Sierra Leone as non-zero confirmed cases were reported in not less than almost 90%
of the days of the data collection. The mean and the variance of confirmed cases for
each country are observed to differ greatly from one another. The widest variability in
the data sets is found in Ghana (84,582.785) while closet is found in Togo (66.649).
Niger has the least mean of 6 confirmed cases while Nigeria has the highest with 274
confirmed cases. Each mean is bigger than the mode and the median and thus, the
data set of each country is negatively skewed. As at 25th September, 2020; Nigeria,
Ghana, Code d’ivore, Senegal and Guinea had had over 10,000 of their population
affected by COVID-19. Meanwhile, three of these countries had earlier recorded
over 600 confirmed cases in day.
Table 2 provides some vital information (descriptive statistics) about the daily
COVID-19 reported death cases in all the West African Counties from the 1st day
of occurrence until 25th September 2020. From the table, it is obvious that the first
death reported case was recorded in Burkina Faso and it occurred on 19th March,
2020 while Guinea Bissau was last to experience the first death. Hitherto, there is
neither a confirmed nor death case in Saint Helena. Moreover, all the countries have
362
Table 1 Descriptive statistics of daily cOVID-19 confirmed cases in West African countries from 1st day of reported cases until 25th September, 2020
No Country’s name Date of 1st recorded case Duration of data Max Total Cases Mean Mode (frequency) Median Variance
[month/day/year] collection
in days (n)
1 Benin 3/17/2020 193 139 2325 12.0466 0(169) 0 954.295
2 Burkina Faso 3/11/2020 199 193 1950 9.799 0(37) 6 266.697
3 Cape Verde 3/21/2020 189 131 5479 28.9894 0(28) 24 759.5
4 Code d’ivore 3/12/2020 198 618 19,501 98.49 0(16) 55.5 12,494.129
5 Gambia 3/18/2020 192 416 3552 18.5 0(107) 0 2143.937
6 Ghana 3/13/2020 197 1513 46,222 234.6294 0(47) 124 84,582.785
7 Guinea 3/14/2020 190 204 10,478 55.4339 0(30) 50 1758.938
8 Guinea Bissau 3/27/2020 183 128 2303 12.5847 0(118) 0 610.046
9 Liberia 3/17/2020 193 45 1338 6.9326 0(44) 3 80.782
10 Mali 3/26/2020 184 110 3041 16.5272 0(16) 12.5 277.639
11 Mauritania 3/15/2020 195 590 7433 38.1179 0(104) 0 7500.837
12 Niger 3/21/2020 189 69 1194 6.32 0(69) 2 148.569
13 Nigeria 2/28/2020 211 790 57,849 274.1659 0(20 241 49,316.453
14 Senegal 3/3/2020 207 223 14,816 71.5749 0(8) 69 2557.857
15 Sierra Leone 4/1/2020 178 86 2188 12.2921 0(21) 9 144.592
16 Togo 3/7/2020 203 39 1707 8.4089 0(31) 6 66.649
17 Saint Helena No Reported Cases
Note Cumulative Confirmed cases in all the West African Countries as at 25th September, 2020 is 181,376
K. Ayinde et al.
Table 2 Descriptive statistics of daily COVID-19 death cases in West African countries from 1st day of reported cases until 25th September, 2020
No Country’s name Date of 1st recorded case Duration of data collection Max Total cases Mean Mode Median Variance
[month/day/year] in days (n) (frequency)
1 Benin 4/7/2020 172 3 40 0.2326 0(148) 0 0.413
2 Burkina Faso 3/19/2020 191 6 56 0.2932 0(157) 0 0.598
3 Cape Verde 3/25/2020 185 3 55 0.2973 0(139) 0 0.333
4 Code d’ivore 3/30/2020 180 4 120 0.6667 0(107) 0 0.95
5 Gambia 3/24/2020 186 14 110 0.5914 0(152) 0 3.292
6 Ghana 3/22/2020 188 15 299 1.5904 0(120) 0 7.965
7 Guinea 4/16/2020 163 3 65 0.3988 0(112) 0 0.429
8 Guinea Bissau 4/27/2020 152 4 39 0.2566 0(130) 0 0.536
9 Liberia 4/5/2020 174 15 82 0.4713 0(130) 0 1.892
Modeling Covid-19 Cases in West African Countries …
10 Mali 4/1/2020 178 7 130 0.7303 0(106) 0 1.317

11 Mauritania 4/3/2020 176 18 161 0.9148 0(136) 0 6.558
12 Niger 3/25/2020 185 5 69 0.37 0(141) 0 0.648
13 Nigeria 3/24/2020 186 31 1102 5.9247 0(23) 5 28.654
14 Senegal 4/2/2020 177 9 304 1.7175 0(56) 1 2.613
15 Sierra Leone 4/24/2020 155 5 72 0.4645 0(106) 0 0.692
16 Togo 3/28/2020 182 3 44 0.2419 0(148) 0 0.317
17 Saint Helena No reported cases
Note Cumulative Death Cases in all the West African Countries as at 25th September, 2020 is 2,748
363
zero (0) as the minimum daily reported case. Truly, West African countries have
not experienced immense death cases as the mean, mode and median of almost all
the countries revolve round zero. It is only in Ghana, Nigeria and Senegal that the
average daily death is more than 1 but not greater than 6. These 3 countries also have
total death cases more than the other countries. The variability in the daily data of
death cases is bigger in Ghana, Mauritania and Nigeria than any other countries. Up
till 25th Septemeber, 2020, the highest daily death reported case was 31 and this was
in Nigeria. Benin, Cape Verde, Guinea, and Togo have only reported 3 deaths on the
highest.
The spreads of COVID-19 over the West African Countries in term of cumulative
confirmed and death cases in the last six months are pictorially represented in Figs. 1,
2, 3, 4 and 5. The figures present good background to COVI-19 in these countries. It
is observed that there are differences in the patterns of movement of COVID-19 in
each of the West African Countries; and that none of the patterns is exactly the same.
From the figures, Nigeria, Ghana, Cote d’Ivoire, Senegal and Guinea are five (5)
significant countries with consistent increase in COVID-19 cumulative confirmed
cases in the last five months. However, in April, Burkina Faso only displaced Guinea
to be in the list of the five countries. Furthermore, it is also evident that Niger, Togo
and Liberia are more frequent in the list of five countries with low recorded cases
of COVID-19 in the last six (6) months. Cumulative death cases are observed to be
trivial especially when compared to the cumulative confirmed cases in most of the
counties. The seriousness and severity of COVID-19 in terms of confirmed and death
cases in Nigeria and Ghana become more evident than other countries from Figs. 1
and 5. The reported cumulative cases kept increasing as time increased. Meanwhile,
the increase is mild in countries like Benin, Burkina Faso, Cape Verde, Gambia,
Guinea, Guinea Bissau, Liberia, Mali, Mauritania, Niger, Senegal, Sierra Leone and
Togo.
In the light of the above, determining an appropriate model and the best estimator
for capturing the patterns and fluctuations of reported COVID-19 cases since its
first day of occurrence in each of the West African countries become needful and
essential. The model with the best estimator is intended to be used to predict future
values of COVID-19 in each country for the remaining days of the year. This is to
establish the direction of the movement of COVID-19 to enable the government to
plan effectively and do the needful against the pandemic. This chapter in the book
is further divided into four (4) sections. In Sect. 2, the history of COVID-19 as well
as some related works done on COVID-19 in each of the countries is presented.
Section 3 presents the methodology used to achieve the stated objectives while in
Sect. 4, the results from data analysis are presented and discussed. Lastly in Sect. 5,
the conclusion on the write-ups in the chapter is made.
160000
140000
120000 Togo
Sierra_Leone
Senegal
Nigeria
Cummulative Confirmed Cases
100000
Niger
Mauritania
Mali
80000
Liberia
Guinea_Bissau
Guinea
60000
Ghana
Gambia
Cote_dIvoire
40000 Cape_Verde
Burkina_Faso
Benin
20000
0
4/1/2020 5/1/2020 6/1/2020 7/1/2020 8/1/2020 9/1/2020
First Day of the Last Six Months
Fig. 1 COVID-19 cumulative confirmed cases in West African countries in the first day of the last
six months (April, May, June, July, August and September 2020)
2 COVID-19 in West African Countries and Related Works
The history of COVID-19 cases in each of the West African Countries and some
related works are reviewed as follows:
Ghana
Nigeria
Guinea
Confirmed Cases
Cote_dIvoire
Death Cases Senegal
Niger
Burkina_Faso
5/1/2020
Mali
Guinea_Bissau
Liberia
Sierra_Leone
Cape_Verde
Togo
Benin
Date And Country
Gambia
Mauritania
Burkina_Faso
Senegal
Cote_dIvoire
Ghana
Nigeria
Togo
Niger
4/1/2020
Mali
Guinea
Guinea_Bissau
Benin
Cape_Verde
Mauritania
Gambia
Liberia
Sierra_Leone
0 500 1000 1500 2000

Cummulative Cases
Fig. 2 COVID-19 cumulative confirmed and death cases in West African countries in the first day
of April and May 2020
2.1 COVID-19 in the Republic of Benin
The Republic of Benin, formerly known as Dahomey, bordered by Togo to the west,
Nigeria to the east, Burkina Faso to the north-west, and Niger to the north-east,
confirmed its first COVID-19 case in Porto-Novo, the capital of Benin on the 16th
March 2020 [13, 14]. It was a case of a 49-year-old male of Burkinabe nationality
who returned to Benin on 12th March 2020 [15].The second confirmed case that
happened was established three days after [13]. The first death recorded was the case
Confirmed Cases Nigeria

Ghana
Death Cases
Cote_dIvoire
Senegal
Guinea
Mauritania
Mali
7/1/2020
Guinea_Bissau
Sierra_Leone
Cape_Verde
Benin
Niger
Burkina_Faso
Liberia
Date And Country
Togo
Gambia
Nigeria
Ghana
Guinea
Senegal
Cote_dIvoire
Guinea_Bissau
Mali
6/1/2020
Niger
Burkina_Faso
Sierra_Leone
Mauritania
Togo
Cape_Verde
Liberia
Benin
Gambia
0 5000 10000 15000 20000 25000
Cummulative Cases
of June and July 2020
of a 43-year-old woman with sickle cell disease on 4th April 2020 [14]. As at 10th
April 2020, a total of thirty-five (35) cases was confirmed of which thirty-two (32)
were imported, and three (3) were locally transmitted. Furthermore, there were five
(5) recovered and one (1) death cases. The number of confirmed and death cases as
at 19th May 2020 stood at 135 and 3 respectively. On 5th June 2020, the number of
confirmed cases had jumped to 268 with 170 recovered and four deaths [14, 16].
Nigeria
Confirmed Cases
Ghana
Death Cases Cote_dIvoire
Senegal
Guinea
Mauritania
9/1/2020 Cape_Verde
Gambia
Mali
Guinea_Bissau
Benin
Sierra_Leone
Togo
Burkina_Faso
Date And Country
Liberia
Niger
Nigeria
Ghana
Cote_dIvoire
Senegal
Guinea
Mauritania
Mali
8/1/2020
Cape_Verde
Guinea_Bissau
Sierra_Leone
Benin
Liberia
Burkina_Faso
Niger
Togo
Gambia
0 10000 20000 30000 40000 50000 60000
Cummulative Cases
of August and September 2020
Following the confirmation of the first positive case, the United Nation Children
Education Fund (UNICEF) started working closely with the government and its
partners to prevent further proliferation of the COVID-19. Although the number of
reported cases was still low, it later started to increase relatively faster. The trans-
mission of the virus was local, with more than 80% of confirmed cases being locally
acquired [16]. Furthermore, the government of Benin of Republic put some measures
in place to combat the COVID-19 pandemic. Mitigating measures at first had been in
promoting hand washing along with social distancing. Hand washing equipment were
installed on the streets [14].There was also the compulsory wearing of face masks and
14 days isolation for all inbound travellers in selected hotels. “Cordon Sanitaires”
2500
Togo
Sierra_Leone
2000 Senegal
Cummulave Death Cases
Nigeria
Niger
1500
Mauritania
Mali
Liberia
1000
Guinea_Bissau
Guinea
500 Ghana
Gambia
Cote_dIvoire
0 Cape_Verde
Burkina_Faso
20
20
20
20
20
20
20
20
20
20
20
20
1/
1/
1/
1/
1/
1/
Benin
4/
5/
6/
7/
8/
9/
First Day of the Last Six Months
Fig. 5 COVID-19 cumulative death cases in West African countries in the first day of the last six
months (April, May, June, July, August and September 2020)
were also created around Cotonou, Aborney-Calari, Allada, Quidah, Seme-Podji,

Porto-Novo, So-Ava, Aguegues and Adjara. Travelling in/out of the Cordon Sani-
taires was prohibited from 30th March 2020 to 13th April 2020. Figure 6 shows
the Map of Republic of Benin with the demarcation of Sanitary Cordon Area, i.e.
Town and Cities concerned. It presents the sanitary cordon area of which there must
be compulsory wearing of a mask. There was free movement of people and goods
within the orange area. Movement of people from the orange area to the green area
was then prohibited (vice-versa). Furthermore, transportation within the two areas
was allowed.
Other measures adopted include the closure of religious places of worship,
schools, cultural sites and event centres. The schools’ closure was extended to 10th
May 2020 [16].
In addition to the above measures, the government of Benin prepared a COVID-
19 response plan for the US $672,095,179. The plan has the followings strategies
objectives namely; the improvement of health infrastructure and equipment, Risk
communication and community engagement, Provision of healthcare and capacity-
building for health professionals, journalists and community members, Strength-
ening capacities for preparedness, Minimizing inter-human transmission, Rein-
forcing capacities for intervention, Increasing resilience capacities for confirmed
cases, and Strengthening coordination and promoting research action[16].
Fig. 6 Benin COVID-19 sanitary condon response. Source https://www.worometer.info/corona

virus/country/benin/covid-19
The lockdown was eased on the 2nd June 2020 and government announced the
reopening of religious sites, restaurants and public transportation across the country.
There was also an extension of school holidays for pre-school and the first five years
of primary school and also the compulsory wearing of face masks [16, 17].
As a result of the ease of lockdown, there was a rapid spread of COVID-19
confirmed and death cases. As of 27th June 2020, the number of confirmed cases had
increased to 1,149 cases while that of deaths had jumped to 16. The fatality rate was
14% while the recovery remained around 37%. This situation was noted twelve days
after the lifting of restrictions by the government [15]. Figures 7a and b illustrate the
spread of COVID-19 concerning the number of confirmed and death cases within the
periods of the data collection. From Fig. 7a, negative daily record of confirmed cases
around 17th May 2020 (20th May, 2020 precisely) was noted to correct past records.
Furthermore, the pick of confirmed cases was 17th July 2020, and cases have started
a
17-09-20
17-08-20
17-07-20
Dates
17-06-20
Daily Confirmed Cases
17-05-20
17-04-20
17-03-20
-300 -200 -100 0 100 200
Number of Cases
b
22-09-20
01-09-20
11-08-20
21-07-20
Dates
30-06-20
Daily Death Cases
09-06-20
19-05-20
28-04-20
07-04-20
0 1 2 3 4
Number of Cases
Fig. 7 a Daily confirmed cases in Benin within 17th March and 25th September 2020 b daily death
cases in Benin within 7th April and 25th September 2020
reducing towards the end of the data collection. From Fig. 7b, it is observed that the
daily recorded cases of death had been between 1 and 3, while the number has also
been reducing toward the end of the period of the data collection.
2.2 COVID-19 in Burkina Faso
The COVID-19 pandemic in Burkina Faso was confirmed on 9th March 2020 in the
capital city Ouagadougou [18, 19]. The death of Rose Marie Compaoré, a member
of the National Assembly of Burkina Faso, on 18th March, 2020 marked the first
reported COVID-19 fatality not only in Burkina Faso but also in Sub-Saharan Africa
[19, 20]. Out of the 13 regions of Burkina Faso, nine were already affected by
Fig. 8 COVID-19
confirmed cases in Burkina
Faso as of July 2020. Source
Government site (https://
www.sante.gov.bf/)
22ndJuly 2020. These affected regions are Centre, Hauts-Bassins, Centre-Nord,

Boucle du Mouhoun, Plateau-Central, Cascades, Centre-Sud, Sud-Quest and Sahel.
However, it was still most serious in Ouagadougou [18]. COVID-19 has continued to
spread in the country and the situation as at 16th August 2020 is presented in Fig. 8.
As at 16th August 2020; there were a total number of 1,267 confirmed cases,
55 death cases, 199 active cases and 1,013 recovered cases [20]. Figures 9a and b
illustrate the spread of COVID-19 concerning the number of confirmed and death
cases for the periods of the data collection. From Fig. 9a, it is observed that the daily
recorded confirmed cases have always been less than 50 except for a day around
11th September when the daily recorded cases went up to around 200. According to
Fig. 9b, death cases were high only at the beginning of the COVID-19 in the country
and have reduced from six (6) to one (1) towards the end of the data collection.
Measures taken to curb the spread of the pandemic include closure of schools,
borders (land and air) and curfew. Shortage of water made Hygiene measures such
as frequent hand washing with soap and water difficult. Other measures, such as
wearing a mask and social distancing, did not translate into reality [21–23]. On the
27th May 2020, the Ministry of National Education, Literacy and National Languages
Promotion gave the announcement that schools would remain closed until the end of
the school year except for those students who had national exams. On the 1st June
and 3rd June 2020, the schools reopened, and a curfew was lifted respectively.
Furthermore, discussion on the reopening of borders (land and air) was brought
open in a state of health emergency meeting of 22nd June 2020. In July, all schools
were already functioning well. More so, the national exams started on 14th July 2020
[21, 22].
Modeling COVID-19 confirmed cases in Burkina Faso had been studied through
the use of Exponential Growth Model, Generalized Growth Model, Generalized
Logistic Growth Model and Richard Growth Model. The best one for prediction
a
11-09-20
11-08-20
11-07-20
Dates
11-06-20
11-05-20
11-04-20
11-03-20
0 50 100 150 200 250
Number of Cases
b
19-09-20
19-08-20
19-07-20
Dates
19-06-20
Daily Death Cases
19-05-20
19-04-20
19-03-20
0 2 4 6 8
Number of Cases
Fig. 9 a Daily confirmed cases in Burkina Faso within 11th March and September 2020 b daily
death cases in Burkina Faso within 19th March and September 2020
purpose was identified to be the Generalized Growth Model [24]. The impact of
COVID-19 pandemic has also been examined on Burkina Faso’s economy using a
single computable general equilibrium model with the other two alternative scenarios
based on the likely duration of the pandemic. The results obtained indicated signif-
icant impacts on both macroeconomic and sectoral level of household well-being
[25]. The potential impact of COVID-19 containment measures in Burkina Faso,
Sahel region, had been investigated. The study was based on ACAPS global vulnera-
bility to containment measures ‘analysis that highlighted how eight key factors could
shape the impact of COVID-19 containment measures. The factors are conflict and
security, scope and adaptability of social protection, reliance on informal economies,
commerce, remittance, cross border dynamics and migration, the rule of law, stan-
dard essential services, and social and cultural behaviour and level of community
adherence. Results revealed that, given these critical factors, the country is vulnerable
to COVID-19 containment measures [26].
2.3 COVID-19 in Cape Verde
Cape Verde; an Island country in the Central Atlantic Ocean, officially known as the
Republic of Cabo Verde, and one of the most developed and democratic countries
in Africa, reported its first case of COVID-19 on 20th March 2020 in Boa Vista
island with a 62-year-old British nationalist who arrived Boa Vista Island on 9th
March 2020. He started showing symptoms of cough and fever on 16th March 2020
and later died on 23rd March 2020. Two more cases were confirmed on 21st March
2020. Both cases were tourists, one from the Netherlands, aged 61 and the other
from the United Kingdom, aged 62. The former was staying in the same five-star
hotel (RiuKaramboa) that the Briton was lodged at and the later was a friend to the
first documented case of COVID-19 in the country [27–29]. The first three cases
of coronavirus in the country were in Boa Vista Island. After the first case tested
positive, the hotel where he was lodged, went under lockdown for 14 days. The
hotel had 640 tourists and 210 staff when it went into lockdown. Cape Verde’s Prime
Minister, Ulisses Correia Silva, also announced on 20th March 2020 that the island
of Boa Vista would go into lockdown until the 4th April 2020. On 25th March 2020,
the fourth case of COVID- 19 was discovered in the city’s capital, Praia. This was the
first reported case in the capital. It was a 43-year-old man, a citizen, who had returned
from Europe. On the following day, 26th March 2020, Cape Verde’s health minister
announced that the man’s wife also tested positive, thus being the first reported case
of local transmission [30–32].
On 19th March 2020, the Government of Cape Verde suspended commercial
passenger flights in and out of Cape Verde, including flights to Portugal, Senegal,
the United States, and other European countries, with limited exceptions for citi-
zens returning to their homes from Cape Verde and for medical emergencies. Also,
passengers onboard cruise ships and sailboats were not prevented and disallowed.
To allow the government to enforce social isolation and social-distancing measures
more strictly and oblige non-essential businesses to close, it declared a “State of
Emergency” that started midnight on 28th March 2020, and Inter-island passenger
travel was also prohibited. The state of emergency was meant to last for 20 days
ending on 17th April 2020. It was, however, extended until 2nd May 2020, for Boa
Vista, Sao Vicente. For the island of Santiago, it was extended until 29th May 2020.
The State of Emergency was lifted for the islands of Santo Antão, São Nicolau, Sal,
Maio, Fogo, and Brava on 26th April 2020. Citizens were also instructed to remain
at home unless they needed to carry out essential activities such as buying essential
goods, going to work (if unable to work from home) or medical facilities, caring for
an individual as well as walking their pets. They were also encouraged to wear face
masks [33–37].
Despite the measures undertaken by the government to mitigate the spread of
COVID- 19 in the country, there were 56 confirmed cases of the disease reported on
15th April 2020 of which 52 were from the island of Boa Vista, three from the city
of Praia and one from the island of Sao Vicente. This has continued to increase in the
country over time. As at 29th June 2020, only the islands of Fogo and Brava had not
recorded confirmed cases [38–42]. Figure 10a and b show the situation COVID-19
in the country in term of confirmed and death cases within the period of the data
collection. From Fig. 10a, it is evident that daily confirmed cases have generally
been on the increase over time and the numbers of death cases have been between 1
and 3, see Fig. 10b.
On work done about COVID-19, Susceptive Infected Removed (SIR) Model has
been used to simulate the propagation of COVID-19 in Santiago and Boavista Islands
a
05-09-20
15-08-20
25-07-20
04-07-20
Dates
13-06-20 Daily Confirmed Cases

23-05-20
02-05-20
11-04-20
21-03-20
0 50 100 150
Number of Cases
b
23-09-20
09-09-20
26-08-20
12-08-20
29-07-20
15-07-20
Dates
01-07-20
17-06-20 Daily Death Cases
03-06-20
20-05-20
06-05-20
22-04-20
08-04-20
25-03-20
0 1 2 3 4
Number of Cases
Fig. 10 a Daily confirmed cases in Cape Verde within 21st March and 25th September 2020 b daily
death cases in Cape Verde within 25th March and 25th September 2020
and then Cape Verde in general. It was observed that the date of simulations agreed
with the projections [43].
2.4 COVID-19 in Cote D’Ivoire
The Ministry of Public Health and Hygiene of Côte d’Ivoire confirmed the country’s
first case of COVID-19 on 11th March 2020. The individual who tested positive for
the virus was a forty-five-year-old Ivorian man who came back from Italy the week
prior and presented himself to public health authorities after developing symptoms.
The case was treated at the Treichville University Hospital in Abidjan. This made
Côte d’Ivoire, the eighth country in sub-Saharan Africa and the twelfth country in
Africa, to have a confirmed case of COVID-19.This came after several suspected
cases had been tested between January and March 2020 [44, 45]. As a result of
the confirmed case of COVID-19, health authorities immediately began tracing the
contacts that he had before being tested positive. This led to the individual’s wife
testing positive for COVID-19 the following day, bringing the total number of cases
to two. Days later, authorities announced three additional confirmed cases on 14th
March 2020. All were Ivorian citizens, and two had travelled abroad (to Italy and
France) in recent weeks. However, the third case was a health worker at a school
who had not recently been outside of Côte d’Ivoire, raising fears that community
transmissions were already occurring [44, 46].
Even though four of the cases at this time were directly linked to travel in
Europe, no travel restrictions were put into place. Around half a dozen direct flights
from Europe continued to arrive at Abidjan’s Félix-Houphouët-Boigny Interna-
tional Airport daily, each carrying hundreds of passengers. Ivorian authorities also
continued to allow passengers arriving from China unimpeded entry into the country
(though there were no direct flights to or from Abidjan and China). However, health
screening was put into place for all passengers arriving on international flights to
the country. The screening checked for symptoms such as fever and cough. It was
similar to those put in place during the Ebola epidemic in 2014. Before landing, all
passengers on the nearly full flight were given a disembarkation card to register them-
selves with the Ministry of Public Health and Hygiene, requiring them to describe
the length of their intended stay in Côte d’Ivoire and to provide multiple ways that
the government could contact them. Immediately after disembarking, all passengers
had to apply hand sanitizer before going through multiple rounds of health screening
that included a detailed examination of travel history, along with having temperatures
recorded. Some of those who exhibited symptoms or had a travel history to recent
hotspots were taken aside for additional screening. However, after passing through
screening, the passengers arriving from France, the country with the second-highest
number of COVID-19 cases in Europe after Italy as at the time, were able to disperse
into the most populous city in Côte d’Ivoire.
This occurred as the Ivorian public began to grapple with the impact that commu-
nity transmissions of COVID-19 could have on the country. At the urging of the
government, sanitation measures were taken, including placing hand sanitizer at the
entrance of many shops. At the same time, some restaurants attempted to have a
bottle of it at each table. Consequentially, pharmacies began to run out of both hand
sanitizer and soap, telling customers to come back the next morning. Some Ivorians
began to express worry that there might already be cases of COVID-19 transmit-
ting in-country, refusing to shake hands and attempting other measures of social
distancing. Despite these measures, life went on as usual throughout the city. Public
transport vehicles such as buses and shared taxis were full, schools and universities
continued to operate, and few people wore masks and other forms of protective gear.
Concern about COVID-19 was not felt by all Ivorians, some of whom believed
that the pandemic did not pose a threat. A security guard working at a mosque in
Abidjan’s Plateau commune insisted on shaking hands, saying, “There is no corona
here, look at the sun, it is warm here.” He was referencing an unproven theory that
in warm climates, COVID-19 is not easily transmitted as it is killed by the heat
[2, 9, 15]. Others said that people from outside of the country brought in the only
cases in Côte d’Ivoire. Therefore, it was not of concern to Ivorians who had not
traveled regularly. Further, some demonstrated a lack of general knowledge about
the pandemic. For instance, a taxi driver in Abidjan by the name of Simo was not
familiar with the terms COVID-19 or coronavirus but was simply aware that there
was a “disease from China” that was beginning to spread.
On the evening of 16th March 2020, Ivorian President, Alassane Ouattara,
announced that he had convened a meeting of the National Security Council to
discuss the country’s response to the pandemic, indicating the seriousness of the
government’s approach. That meeting led to the announcement that entry would
be denied to any foreigner attempting to enter Côte d’Ivoire from a country with
over one hundred confirmed cases of COVID-19, along with the “reinforcement” of
health screening at ports of entry. Most notable, however, were the social distancing
measures imposed within Côte d’Ivoire, including the suspension of all schools for
thirty days and the closure of all night clubs and cinemas for fifteen days, along
with banning gatherings of more than fifty people for two weeks[44].
The following day, little appeared to change in Abidjan. Two of the city’s largest
malls, Abidjan Mall and Playce Shopping Mall, were full of customers. However,
a significant number of them wore face masks and gloves. In the Carrefour market
at Playce Mall, people appeared to be partaking in panic-buying, purchasing large
quantities of non-perishable goods such as beans, rice, and pasta. However, this
behavior appeared to be limited to those of a middle or upper socioeconomic standing.
At the primary outdoor market in the relatively working-class commune of Koumassi,
concern about the pandemic was minimal. Children who were out of school assisted
their parents in crowded market stalls, people gathered around in close quarters in
drinking spots, and people ate communal dishes. Some night clubs also remained
open but were later shut down by the police and gendarmerie who were doing patrols.
When asked about the potential of having to close down market stalls during a
potential future lockdown, many said that would not be possible. A woman selling
dried fish in the market said, “I cannot stay home from work. If I do not sell my fish,
I do not have money to feed my children and then we will all die.” Around 30% of
Côte d’Ivoire’s population lives in extreme poverty and survives off of income made
each day, and even more of the population works in the informal economy. For this
segment of the country’s population, the notion of not being able to work every day
is not just difficult to comprehend—it would lead to unimaginable suffering. In some
countries, governments have attempted to assist workers in the informal economy
impacted by the pandemic. However, few believe that the Ivorian government has
such capacity. Others believe the political elite simply is not willing to make sacrifices
for Ivorians outside of their patronage networks, an indicator of the polarization that
still exists in the country after the civil war in 2011 that killed thousands.
The number of confirmed cases of COVID-19 continued to increase in Côte
d’Ivoire, rising to nine on 19th March 2020. The government responded by
announcing the cancellation of all international flights arriving at Abidjan Airport,
along with the closure of land and maritime borders. Quarantines were also mandated
for Ivorians returning to the country. As confirmed cases grew, so did the concern of
Ivorian citizens. Serge, who makes a living driving a taxi between the resort town
of Assinie-Mafia and Abidjan, wore a mask and was hesitant to shake hands. He
would have preferred not to be working at the time, saying “my wife told me not to
leave our home, but I have no choice: if I do not do this we will not eat.” He went
on to express deep worry about the impact COVID-19 could have on the country,
especially outside of major cities: “In many towns, the hospitals have no more than
five beds, and sometimes not even a single doctor. If this thing arrives here, we are
finished.” Even though Côte d’Ivoire was listed by the World Health Organization
(WHO) as one of eight countries in Africa prepared to respond to an outbreak of
COVID-19, it is clear that this confidence is not shared by all Ivorians [2, 47, 48].
On 20th March 2020, just over one week after the country’s first confirmed case,
Ivorian authorities announced five additional cases, bringing the total number of
infections to fourteen. On this same day, the government decided to close all borders
from midnight on 22nd March 2020 until further notice. The following day it rose
to seventeen. The government responded by limiting the number of people who can
utilize public transport and urged all Ivorians to take sanitation measures seriously.
Even with these measures, confirmed cases continued to rise, reaching eighty on the
25th March 2020. The President prohibited people travelling to and from Abidjan
as from 26th March 2020 unless by special exemption. Restaurants, maquis, bars,
night clubs, cinemas and places of entertainment remained closed, and gatherings
of more than 50 people were banned. The declaration also introduced a nationwide
curfew each night from 21 to 05 h. As cases climbed, the government put in place
strict measures. However, life during the day largely remained familiar with people
commuting to work and markets being packed, allowing plenty of opportunities for
community transmission.
Other measures taken by the government are discussed as follows: On 29th March
2020 until 15th April 2020, transportation between the greater Abidjan Burkina
Faso region (Abidjan Autonomous District, Dabou, Azaguié, Bingerville, Grand-
Bassam, Bonoua, Assinie-Mafia) and the rest of the country was banned. On 9th
April 2020, the National Security Council held an extraordinary meeting and decided
to make it compulsory to wear facemasks in greater Abidjan. On 15th April 2020,
the government extended the existing state of emergency until 30th April 2020 and
the closure of all schools until 17th May 2020. On 24th April 2020, the existing
night-time curfew was prolonged until 8th May 2020.
For the most part, the measures were being enforced with authorities arresting
those who violated it. However, it appeared that the measures did not equally apply
to all. Even though a period of quarantine was required for all Ivorians entering
the country, there were reports of individuals close to the government evading
the measures. Similarly, public anger emerged about Chinese nationals being able
to enter the country after the government banned foreigners from countries with
over 100 confirmed cases. Should the elite of the country be exempted from the
prevention measures, the consequences could be drastic. Other African states such
as Cameroon and have seen government officials become infected and transmitted
cases to others. Already, the Ivorian prime minister and ruling party presidential
candidate in this year’s elections went into self-isolation after coming in contact
with someone who had tested positive. Although he later tested negative, the poten-
tial consequences of COVID-19 impacting candidates in an election that many believe
could lead to a return to a conflict.
The relaxation policies taken by the government include only movement of food-
stuff, medicine, medical evacuations, fuel, utilities and vehicles with special autho-
rization between 29th March 2020 until 15th April 2020, lifting of restrictions outside
greater Abidjan, ending of night-time curfew in Abidjan on 15th May 2020, resump-
tion of domestic flights from 25th June 2020 and that of international flights from 1st
July 2020 while land and sea borders remain closed. Furthermore, Côte d’Ivoire has
taken measures to combat the spread of the COVID-19 pandemic within its borders,
both by imposing travel restrictions and limiting domestic movement. Whether those
actions came too late, and whether the Ivorian populations comply with the required
lockdown, remains to become evident. If they do not, coronavirus is likely to over-
whelm not only the country’s health systems, but the economics, politics, and stability
of the country. Figure 11a and b show the situation COVID-19 in the country in term
of confirmed and death cases within the period of the data collection. From Fig. 11a,
it is evident that the pandemic was severe between June and July 2020, and it is
already reducing towards the end of the data collection. Furthermore, according to
Fig. 11b, daily death cases have been between one (1) and four (4), and this is already
reducing toward the end of September.
2.5 COVID-19 in the Gambia
The Gambia, the smallest country within mainland Africa, surrounded by Senegal
except for its western coast on the Atlantic Ocean, situated on both sides of the
lower reaches of the Gambia River and the largest cities are Serekunda and Brikama,
officially called the Republic of The Gambia, registered its first case of COVID-19 on
Tuesday 17th March 2020, according to the health minister, Dr. Ahmadou Samateh
[49, 50]. The first case of COVID-19 was a woman of age 21 who had travelled
a
12-09-20
12-08-20
12-07-20
Dates
12-06-20
12-05-20
12-04-20
12-03-20
0 200 400 600 800
Number of Cases
b
14-09-20
24-08-20
03-08-20
13-07-20
Dates
22-06-20
Daily Death Cases
01-06-20
11-05-20
20-04-20
30-03-20
0 1 2 3 4 5
Number of Cases
Fig. 11 a Daily death cases in Côte d’Ivoire within 12th March and 25th September 2020 b daily
death cases in Côte d’Ivoire within 30th March and 25th September 2020
to the Gambia from the United Kingdom on 14th March 2020 and had transited
through Morocco before arriving in the Gambia on Sunday 15th March 2020. She
had gone into self-isolation after feeling feverish. She started receiving treatment
at the MRC Unit, The Gambia’s specialist clinic in Fajara [51, 52].The Ministry of
Health commenced the process of contacting and isolating all the passengers on the
flight who boarded the flight with the patient [53, 54]. This case was considered
imported and eventually increased to 3 confirmed cases (all imported) and one death
within the space of one week. The first death in the Gambia occurred on 23rd March
2020 [55]. The only facility with capacity for COVID-19 testing in the country is
MRC Unit, The Gambia; and testing is by appointment only. And this has to be
organized through a Ministry of Health specialist phone number [56].
Following these occurrences, Gambian President, Adama Barrow, on Tuesday

17th March 2020 announced the closure of all schools, including universities from
Wednesday 18th March 2020 for 21 days. Also, overseas travel by public officials
was suspended [55, 56]. On 18th March 2020, sessions of the National Assembly and
hearings for the Truth, Reconciliation and Reparations Commission were suspended
[56]. Furthermore, on 19th March 2020, flights from 13 countries were suspended,
and passengers arriving from 47 countries would have to undergo mandatory 14-day
quarantine before they were allowed into the country [57].
The governments of the Gambia and its sole neighbour, Senegal, agreed to close
their border for 21 days starting from 23rd March 2020 with exceptions for “essen-
tial services” and transporting food and medicine. The Gambia’s airspace was also
closed, with exceptions for medical flights and transporting goods [58]. Health
minister, Ahmadou Lamin Samateh, acknowledged that enforcing the border closure
was challenging, but the closure was necessary for fighting COVID-19 [59].
On 27th March 2020, President Adama Barrow declared a state of emergency,
ordering places of worship and non-essential businesses, prohibiting gatherings of
more than ten people, and limiting passengers on public transportation [59]. By the
end of March 2020, there had been four confirmed cases, 3 of which remained active
with one death toll [53].
Gambia’s National Assembly voted on Friday 3rd April 2020 to extend the current
State of Emergency for another 45 days. However, it was concluded that all non-
essential businesses be closed and restaurants were allowed to operate but only to
sell food for customers to take away. As at 3rd April 2020, four cases of COVID
19 and one associated fatality have been confirmed. At the end of April 2020, there
were 11 confirmed cases, seven additional. Out of the 11 cases, eight patients had
recovered, and the death toll remained one, and there were two active cases [53].
Gambian President further extended the country’s COVID-19 State of Emergency
by 21 days until 9th June 2020. In May 2020, there were 14 confirmed cases, bringing
the total number of confirmed cases to 25, 20 cases had recovered, leaving four active
cases.
On 4th June, 2020 in the Gambia President in consultation with his Special Cabinet
Sub-Committee on COVID-19 pandemic based on the advice by Health Experts’
Committee of the Ministry of Health decided to relax some of the COVI-19 Public
Health Emergency Restrictions. The relaxations were only to markets, houses of
worship and Grade-9 students about to sit for their transitional examinations to Senior
Secondary Schools. Religious services were allowed to resume with social distancing
measures in place and markets authorized to open between 06:00 and 18:00 (local
time). On Wednesday, 10th June 2020, the Gambia’s public health emergency also
made another extension of 21 days which ended on 1st July 2020. As at the end of
June, there were 24 confirmed cases, bringing the total number of confirmed cases
to 49, 27 patients had recovered, leaving 20 active cases with the death toll rose to 2
[56].
On 3rd July 2020, the Gambia extended a nationwide state of emergency for
another week as part of its fight against the novel Coronavirus and stressed the need
for people to stay home and to be guided by COVID-19 measures if any was to
venture outside. As at 6th July 2020, there were 61 confirmed cases, active cases
were 31, and the death toll rose to 3. Figure 12a and b show the situation COVID-19
collection. Figure 12a shows that COVID-19 became very serious between July and
September 2020. The pick was actually in August and eventually getting reduced
towards the end of the data of the period of the data collection. Similarly, according
to Fig. 12b, death was serious around August 2020 but started reducing towards
September 2020.
a 23-09-20
02-09-20
12-08-20
22-07-20
01-07-20
Dates

20-05-20
29-04-20
08-04-20
18-03-20
0 100 200 300 400 500
Number of Cases
b
08-09-20
18-08-20
28-07-20
07-07-20
Dates

26-05-20
05-05-20
14-04-20
24-03-20
0 5 10 15
Number of Cases
Fig. 12 a Daily confirmed cases in Côte d’Ivoire within 18th March and 25th September 2020
b daily death cases in Côte d’Ivoire within 24th March and 25th September 2020
2.6 COVID-19 in Ghana
Ghana, a western African country along the Gulf of Guinea, bordered to the north-
west and north by Burkina Faso, and to the east by Togo, and to the south by the
Atlantic Ocean, and the west by Cote d’Ivoire, recorded its first two COVID-19 cases
on 12th March, 2020 when two infected persons came from Turkey and Norway. The
first case was a senior officer at the Norwegian embassy in Ghana that returned from
Norway while the second case was a senior staff member at United Nations office in
Ghana that returned from Turkey [60, 61].
The first step the government of Ghana took was that cedi equivalent of US
$100 million should be made available to fight COVID-19. At the same time, bans
were placed on public gatherings such as funerals, political rallies, and religious
activities in order to reduce the spread of the virus. All Schools were closed while
the country’s borders were also closed for two weeks. However, some essential
services such as those who were involved in distribution, production of beverages,
foods, pharmaceuticals and media houses were exempted from restriction [62].
A further step by the Ghanaian government to curb COVID-19 was to disinfect
a significant market in the country. At the same time, the commencement of local
production of nose masks was announced. Different businesses and organizations
also enforced the use of nose masks in order to stop the spread of the virus. Other
measures taken by the Ghanaian government to prevent the spread of COVID-19
was pardoning of prisoners, those prisoners consist of people who had been arrested
for the first time, aged 70 and above, and seriously ill persons [63, 64].
The announcement of ease of several measures made by Ghanaian President in
order to limit the spread of COVID-19 pandemic was considered on 31st May 2020.
These involved reopening of schools for final year students, weddings, conferences,
burials and political activities, all with less than 100 people were permitted. Further-
more, closure of borders was extended indefinitely while bans also remained on
sporting activities, cinemas and night clubs [64]. Figure 13a and b show the situation
COVID-19 in the country in term of confirmed and death cases within the period of
the data collection. From Fig. 13a, it is evident that numbers of people affected were
on the increase between June and August 2020 and had been reducing towards the
period of the data collection. Also, from Fig. 13b, the daily death recorded was high
between June and August 2020.
Few works have been carried out on COVID-19 in Ghana, notable one focused on
the public’s awareness, knowledge, risk perception of COVID-19 and their influence
on the individual’s preparedness in Ghana [62]. The study further revealed that there
is a need for health authorities to timely and effectively disseminate COVID-19
prevention and control measures to the general public.
a
13-09-20
13-08-20
13-07-20
Dates
13-06-20
13-05-20
13-04-20
13-03-20
0 500 1000 1500 2000
Number of Cases
b 22-09-20
22-08-20
22-07-20
Dates
22-06-20
22-04-20
22-03-20
0 5 10 15 20
Number of Cases
Fig. 13 a Daily confirmed cases in Ghana within 13th March and 25th September 2020 b daily
death cases in Ghana within 22nd March and 25th September 2020
2.7 COVID-19 in Guinea
Guinea’s health ministry announced the first confirmed case of COVID-19 on Friday,
13th March 2020. The infected person was a Belgian resident who was 49 years old.
Since October 2018, she had a residence in Guinea working for the country’s Euro-
pean Union delegation [65]. On 15th February, she went to Brussels from Belgium for
a holiday, afterwards, visiting Nice in France for four days from 17th to 21st February
2020, before returning to Brussels, according to her. She then arrived on 3rd March
2020 at the city of Conakry in Guinea. She was put into solitary confinement at the
Disease Treatment Center in Congo, Conakry after her arrival and confirmation of
being infected with the disease. This was the 7th case in West Africa [66]. The first
COVID-19 death case in the country was registered on 15th April 2020. He was a
75-year-old Lebanese aged man who died in the country’s capital, Conakry, Guinea
while undergoing care at Donka hospital [67]. As of 30th June 2020, Guinea had
5,391 confirmed cases, 1,032 active cases, 4,326 recovered cases, and 33 deaths [68].
The death case was reported to be 31 hospital deaths since Guinea does not report
non-hospital deaths that are due to COVID-19 pandemic [69]. Figure 14a and b show
the situation COVID-19 in the country in term of confirmed and death cases within
a 14-09-20
14-08-20
Dates 14-07-20
14-06-20
14-05-20
14-04-20
14-03-20
0 50 100 150 200 250
Number of Cases
b
10-09-20
20-08-20
30-07-20
Dates
09-07-20
28-05-20
07-05-20
16-04-20
0 1 2 3 4
Number of Cases
Fig. 14 a Daily confirmed cases in Guinea 14th March and 25th September 2020 b daily death
cases in Guinea within 16th April and 25th September 2020
the period of the data collection. From Fig. 14a, it becomes clear that the confirmed
cases have been reducing towards the end of September 2020 and was at pick around
the middle of May 2020. Furthermore, from Fig. 14b, daily death cases have not been
more than three (3), and this was fading off towards the end of September 2020.
As part of a continuing crisis to stop the transmission of COVID-19 disease,
Guinea’s government enforced a national night-time curfew on 30th March 2020.
The curfew had been running from 21:00 to 05:00. The curfew accompanied a 30-day
contingency of the emergency on 26th March 2020. Following the announcement,
every single land, sea, and air boundaries were shut excluding for the transportation
of merchandise, with heightened screening steps for commercial transporters. Limits
were placed on the numeral of commercial transport buses in Conakry for the period
of the state of emergency at a given time, depending on the type of vehicle. The
Guinean government also directed all the schools and colleges to close for 14 days,
including pubs, eateries, game halls, movies, and other places of public meetings.
This warning started at 13:59 GMT on 1stApril 2020 and was scheduled to expire at
22:59 GMT on 30th April 2020 [70].
The larger Conakry city mandated that as from 18th April 2020, masks must be
worn in public spaces at all times. This undertaking was limited to education, work,
purchasing of essentials, health treatment, procurement of medications or delivery
about medicine, and critical conditions alone. Administration of Guinea shut land
boundaries altogether, and movement between Conakry and other metropolises was
prohibited. Mosques, Churches, enlightening establishments, restaurants, movies,
and other businesses in the service sector were instructed to be closed. The govern-
ment also reported that places of worship in prefectures would reopen if there were
no new cases of COVID-19 for 30 days. Each assembly/gathering was restricted
to 20 people. Various restrictions on the number of passengers were endorsed for
diverse kinds of automobiles. Colleges were intended to open for exam classes once
a comprehensive COVID-19 extenuation strategy has succumbed to the government
policy. Police officers carried out searches at major intersections in the capital of
Conakry, levying on suspects a fine of 30,000 francs of Guinean equal to 3 Euros.
Most residents of the inner suburbs appreciated this new measure, which they consid-
ered useful [71]. As of 29th June 2020, the Guinean Ministry of Health initiated a
COVID-19 hotline of number 115, which can be dialled from any handset or mobile
in Guinea. The administration of Guinea also executed improved examination and
isolation actions to decrease the transmission of the disease. The Health State of
Emergency had also been extended to 15th July 2020.
Furthermore, a restriction was made compulsory between 11 p.m. and 4 a.m. in the
broader region of Conakry. Markets were also instructed to close at 6 p.m. Specific
measures also implemented include a brief prohibition on Guinean diaspora leaders
returning to Guinea, the termination of diplomatic mission activities overseas, and
the implementation of public distancing standards. Governments might prolong the
emergency after the original 30 days and/or extend somewhat COVID-19-connected
limits with less to notice [72].
Flight journey was suspended to and fro of Guinea, and this became active on
Saturday 21st March 2020, 11.59 pm. The international airport of Conakry Gbessia
was shut indefinitely to all business persons. Every traveller to Guinea as well as
Guinean citizens had to be examined and tested negative of COVID-19 before
embarking on their journey and on arrival in Guinea, all passengers including Guinean
citizens were mandated to succumb to a fresh COVID-19 examination. Travellers
who tested negative and were asymptomatic were required to be on 14-day compul-
sory confinement at the Conakry Onomo hotel. Two more COVID-19 tests were
conducted on the travellers on confinement in the hotel within that14-days. When
tested negative, they were permitted to proceed from the hotel to their residence.
However, travellers tested positive for the COVID-19 disease were sent to Donka
Hospital each time they arrive in Guinea [72].
2.8 COVID-19 in Guinea Bissau
The prevalence and spread of COVID-19 in several countries of the world made
the government of Guinea-Bissau to shut down its borders (land and air), markets,
bars, restaurants and local public transport even before the first case was recorded
[73, 74]. The first two cases of COVI-19 pandemic were officially reported on 25th
March 2020. Within the next three weeks, the number of reported confirmed cases
increased unexpectedly from 50 to 1000 with transmission within these periods, also
moving from local to communities. As at 26th June, 2020, the total confirmed cases
was 11,614 with 317 recovered patients and 21 deaths. Guinea-Bissau is one of the
West African Countries with worrisome cases of COVID-19 pandemic [74–76].
A good number, nearly 10% (170 out of 2000), of health workers including those in
Intensive Care Units were infected with the pandemic due to overwhelming situation
the hospital became [74, 77]. The health condition in Guinea-Bissau is not acceptable,
and indeed discouraging, there is one doctor to every 5,964 citizens and one nurse
to every 1223 citizens. There is no ICU specialist, no fully equipped ICU bed and
no assurance of continuous supply of oxygen in the leading public hospitals. Even
two missionary hospitals offering assistance to COVID-19 patients still need to be
better equipped and coordinated. According to the Global Health Security Index,
Guinea-Bissau is second in the list of countries with the most fragile health system
[74, 78].
Measures put in place to cob the pandemic include the formation of an inter-
ministerial committee on Monday 6th April 2020 to monitor, among other things, the
30 measures of economic response plan of the government’s strategy to combat the
pandemic with the national health security agency, and that of a Task Force, UNICEF
Guinea COVID-19 Task Force, which meets regularly to evaluate situations of the
pandemic from time to time [79]. Figure 15a and b reveal the situation COVID-19
collection. From Fig. 15a, it is evident that COVID-19 confirmed cases had been
more prevalent in May 2020 and have been reducing towards the period of the data
collection. Furthermore, from Fig. 15b, daily death cases have been between zero
(0) and four (4) and have been reducing towards September 2020.
2.9 COVID-19 in Liberia
The first COVID-19 case in Liberia was confirmed on 16th March 2020 [80, 81]. He
was a government official who violated screening protocols on arriving the country’s
international airport while returning from Switzerland. The second case, recorded on
17th March 2020, had close contact with the first one while the third one, confirmed
on 20th March 2020, was also a returning traveller. As at 22nd May, 2020, the
number of COVID-19 confirmed, recovery and death cases in Liberia had risen to
249, 136 and 24, respectively [82]. Figure 16a and b reveal the situation COVID-19
a
11-09-20
21-08-20
31-07-20
10-07-20
Dates
19-06-20
29-05-20
08-05-20
17-04-20
27-03-20
0 50 100 150
Number of Cases
b
14-09-20
31-08-20
17-08-20
03-08-20
20-07-20
Dates
06-07-20
Daily Death Cases
22-06-20
08-06-20
25-05-20
11-05-20
27-04-20
0 1 2 3 4 5
Number of Cases
Fig. 15 a Daily confirmed cases in Guinea-Bissau within 27th March and 25th September 2020
b daily death cases in Guinea-Bissau within 27th April and 25th September 2020
collection. From Fig. 16a, it is clear that daily confirmed cases were on the increase
in June and July 2020 and had been reducing before the period of the data collection.
Furthermore, from Fig. 16b, the pick of the number of deaths occurred around 19th
July 2020 and death cases are already on the decline towards the period of the data
collection.
Consequently, the Ministry of Health and Social Affairs declared a national health
emergency on 22nd March, 2020. On 8th April, 2020, the Liberian President, George
Weah, declared a compulsory nationwide state of emergency which led to lockdown
in several regions including Monrovia, the capital city, to combat the spread of the
pandemic. Meanwhile, the Senate of the country had earlier approved extension
a
15-09-20
01-09-20
18-08-20
04-08-20
21-07-20
07-07-20
Dates
23-06-20
26-05-20
12-05-20
28-04-20
14-04-20
31-03-20
17-03-20
0 10 20 30 40 50
Number of Cases
b 20-09-20
30-08-20
09-08-20
19-07-20
Dates
28-06-20
17-05-20
26-04-20
05-04-20
0 5 10 15 20
Number of Cases
Fig. 16: a Daily confirmed cases in Liberia within 17th March and 25th September 2020 b daily
death cases in Liberia within 4th May and 25th September 2020
of a state of emergency throughout the nation for 90 days. Other measures put in
place include a ban on individuals coming into the country from countries with more
than 200 confirmed cases of COVID-19, the inauguration of National Multi-sectoral
Response Plan Public in coordination with United Union, the appointment of National
Coordinator of the Executive Committee and National Compliance Officer on coro-
navirus, recruitment of 200 contract tracers. Furthermore, the country received debt
service relief from International Monetary Fund on 13th April 2020, public service
non-essential workers enjoyed leave with pay, religious organizations and schools
put on the arrangement for regular hand washing, motorcyclists only carried on a
passenger while taxi drivers carried two, and free electricity and water supply to the
citizen within the pandemic periods[82]. The country focused its COVID-19 response
efforts on travel restrictions and implementations of lockdowns [83]. UNICEF also
provided assistances by airlifting 14 metric tonnes of vital health supplies, including
oxygen concentrators, pharmaceutical items, and personal protection equipment to
the country [84].
2.10 COVID-19 in Mali
Mali confirmed its first two COVID-19 cases on 25th March 2020 and had the cases
registered by the Ministry of Health and Social Affairs on 26th March 2020. This
was almost one month after the first case in the African Continent [85, 86]. Since
this time, the pandemic has continued to spread throughout the regions and districts
of the country. It was also observed to be spreading faster in the country than in
Algeria and Nigeria [86]. For the time being, all tests at the country level are carried
out in the four existing laboratories in Bamako as there are no yet testing facilities
outside the capital city. As of 30th June 2020, the cumulative number of confirmed
cases was 2181 of which 1474 recovered, representing a cure rate of 68%. One
hundred sixteen deaths were recorded, representing overall mortality of 5.3%. Nine
regions and 36 health districts were already affected [87]. The epidemic remains
concentrated in Bamako (47% of the total confirmed cases). However, the regions
of Timbuktu (23.4%) and Mopti (10.2%) experienced an explosion of cases in some
past weeks. Figure 17a and b reveal the situation COVID-19 in the country in term
of confirmed and death cases within the period of the data collection. From Fig. 17a,
it is observed that daily confirmed cases were on the increase between May and June
but had reduced towards the end of September. Furthermore, from Fig. 17b, daily
death cases were severe between May and June 2020. However, they had become
less severe towards the end of September 2020.
Like most sub-Saharan African countries, Mali has significant healthcare chal-
lenges in fighting the pandemics. At the beginning of the COVID-19, the country only
had 49 beds available in the hospital. At the same time, much other essential equip-
ment, including personal protective equipment, respirators, infrared thermometers
and laboratory reagents are very insufficient [86].
To address the pandemic in the country, the President of the Republic of Mali,
Ibrahim Boubacar Kéïta, declared a state of emergency and instituted a curfew from
9.00 p.m. to 5:00 a.m. On 18th March 2020, he further suspended flights from affected
countries, closed schools and banned large public gatherings. The planned elec-
tions in March–April were eventually postponed. The government also implemented
enhanced screening and quarantine measures, prohibited flights coming from coun-
tries with confirmed cases of COVID-19, closed land borders to passenger traffic and
that travellers need to be prepared for additional travel restrictions. Other measures
taken by the government of Mali include mandatory wearing of face masks in public,
a 24-09-20
10-09-20
27-08-20
13-08-20
30-07-20
16-07-20
02-07-20
Dates
18-06-20
04-06-20
21-05-20
07-05-20
23-04-20
09-04-20
26-03-20
0 20 40 60 80 100 120
Number of Cases
b 16-09-20
02-09-20
19-08-20
05-08-20
22-07-20
Dates
24-06-20
10-06-20
27-05-20
13-05-20
29-04-20
15-04-20
01-04-20
0 2 4 6 8
Number of Cases
Fig. 17 a Daily confirmed cases in Mali within 26th March and 25th September 2020 b daily
confirmed cases in Mali within 1stApril and 25th September 2020
ban of sporting events, festivals, and gatherings more massive than 50 people, closure
of bars and night clubs, social distancing among vehicle passengers, providing work
schedule for all government officers excluding those in defence, security and health to
be between 7:30 a.m. to 2:00 p.m., Monday through Friday. The General Directorate
for Commerce and Competition also set price limits for essential goods, including
sugar, rice, cooking oil, and bread. The daily curfew imposed on 26th March 2020
was eventually lifted on 9th May 2020.
2.11 COVID-19 in Mauritania
The index confirmed case of COVID-19 in Mauritania, a 40-year-old man, was

reported on Friday 13th March 2020 from an expatriate with a yet to be disclosed
country in the Mauritanian capital of Nouakchott. The second positive case, a 41-old
woman, was recorded on 18th March 2020 through an announcement by Mauritanian
Minister of Health of a foreign female employee who had arrived ten days prior to
the discovery [88]. After that, the demography of the third coronavirus case was
announced on 26th March 2020, a Mauritanian citizen of a 74-year-old man who
returned to the country from France. However, the country’s first mortality case
was recorded on 30th March 2020. Barely a month after, fewer than ten confirmed
cases were documented in the country of which six patients had recovered with one
death recorded. Also, within the first two months, despite partial ease of restrictions,
the total confirmed active cases had spiked to 480. As at 9th April 2020, 1,256
people were quarantined while 7 cases, including two recoveries and one death,
were recorded [89]. In more than one month, 25th May2020, the nation recorded
237 confirmed, 15 recovery and 6 death cases [90]. Figure 18a and b reveal the
situation COVID-19 in the country in term of confirmed and death cases within the
period of the data collection. From Fig. 18a, it is seen that daily confirmed cases
were severe between June and July 2020 and had reduced towards September 2020.
Furthermore, from Fig. 18b, death cases were severe in June 2020.
The government of Mauritania was so quick to address the health challenges
of COVID-19 once it started. Mauritania’s success in stamping out the new virus
has been attributed to its relative isolation and early preventative measures aimed at
shielding its ill-equipped medical system from a significant health crisis. The vast
desert country of just 4 million people has so far come out of the global health crisis
nearly unscathed, recording just 8 cases of the novel virus and one death, some of
the lowest numbers in the world [91]. It imposed a night curfew to prevent the spread
of the coronavirus after two cases were confirmed. The measure came into force on
Thursday at 8 p.m. local time. It lasted until 6 a.m. the following morning until further
notice. The initial measures taken ranged from the closure of harbours and airports
and later to border closure with Mali, Senegal and Morocco. The government also put
on quarantine measures for any traveller from coming countries where the pandemic
was raging. Also, it announced the closure of private and public schools, including
universities and institutes, restaurants and cafes, and the ban of all gatherings [90].
a
15-09-20
15-08-20
15-07-20
Death
15-06-20
15-05-20
15-04-20
15-03-20
0 200 400 600 800
Number of Cases
b
18-09-20
28-08-20
07-08-20
17-07-20
Dates
26-06-20
Daily Death Cases
05-06-20
15-05-20
24-04-20
03-04-20
0 5 10 15 20
Number of Cases
Fig. 18 a Daily confirmed cases in Mauritania within 15th March and 25th September 2020 b daily
death cases in Mauritania within 15th March and 25th September 2020
2.12 COVID-19 in Niger
On 19th March 2020, the first case in the country was confirmed on a 36-year-old man
from Nigerian Niamey. He had travelled to Lomé, Accra, Abidjan, and Ouagadougou
[92]. Niger reported a total of seven cases on 25th March 2020 including the first
death related to COVID-19 in the country which occurred on 24th March, 2020.
The death occurred on a 63-year-old Nigerian national in Niamey [93, 94]. Within
the first fifteen days of COVID-19 in Niger, a total number of 120 patients were
diagnosed and within two months, as of 19th May 2020, the country had recorded 909
confirmed cases and 55 reported deaths. Out of them, 714 people already recovered,
and 140 were under treatment. While the pandemic touches all regions, the most
affected regions remained Niamey, Dosso and Zinde. Zinde experienced the rapid
increase in the number of cases last. Following this announcement, the airports
in Niger and Zinder were closed to prevent the spread of the coronavirus [92, 95, 96].
Figure 19a and b reveal the situation COVID-19 in the country in term of confirmed
and death cases within the period of the data collection. From Fig. 19a, it is clear that
confirmed cases were most frequent in April 2020 but had reduced towards the end
of September. Furthermore, from Fig. 19b, the majority of the death cases happened
between April and May 2020 and death had become reduced towards the period of
the data collection.
Both in Niamey and the interior of the country, regular disinfection of health
centres, isolation and treatment centres, public infrastructures at risk of infection, and
supports compliance with the measures for the safe and dignified burial of patients
who have died from COVID-19 were carried out. Water hygiene and sanitation
facilities were set up in temporary structures, specially fitted out by UNICEF, to
increase the triage and isolation amenities and consequently, reinforce the capacities
of health structures in Niger. Mr. Brigi Rafini, Prime Minister, Head of Government,
visited the COVID-19 treatment system set up at the National Reference Hospital of
a 21-09-20
21-08-20
21-07-20
Dates
21-06-20
21-05-20
21-04-20
21-03-20
0 20 40 60 80
Number of Cases
b 25-09-20
25-08-20
25-07-20
Dates
25-06-20
25-04-20
25-03-20
0 1 2 3 4 5 6
Number of Cases
Fig. 19 a Daily confirmed cases in Niger within 21st March and 25th September 2020 b daily
death cases in Niger within 25th March and 25th September 2020
Niamey and paid particular attention to the temporary health facilities installed by
UNICEF, offering an additional capacity of 40 beds [95].
Several other measures were put in place to combat COVID-19 in the country.
These include the proclamation of a state of emergency in all parts of the country,
a curfew from 7.00 p.m. to 6.00 a.m. in Niamey, closure of international airports in
Niamey and Zinder and the land borders, closure of all educational institution, bars,
nightclubs, cinemas and places of entertainments, prohibition of any gathering whose
size is more than 50 people, the establishment of mandatory hygiene in markets,
shops, restaurants, public and private services, social distancing, recruitment of 1,500
additional health workers, and readjustment of working hours to be between 8.00
a.m. to 2.00 p.m. each working day of the week [97].
2.13 COVID-19 in Nigeria
Nigeria, the largest country in West Africa, announced the first case of coron-
avirus confirmed in Ogun State on Thursday 27th February 2020 through its Federal
Ministry of Health. The disease was found in an Italian resident employed at Lagos
who had lately returned from a journey to Milan (Italy). The patient was in a stable
condition and was held in solitary confinement at Yaba hospital (Lagos state). Health
officials tried to identify whoever had been in contact with the patient since reaching
Nigeria [98–100]. On 3rd March 2020, there was no new confirmed case, but a total of
17 suspected cases were identified across four states (Lagos, Ogun, FCT, and Kano).
The second and third cases of COVID-19 were established in Ogun and Ekiti states
on 9thand 16th March 2020 respectively. The cases continued to increase across the
states of Nigeria over time.
On Wednesday, 18th March 2020, Nigeria’s internal minister declared that
voyagers coming in from nations with 1000 and above cases of COVID-19 pandemic
would be barred from coming into Nigeria from Friday, 20th March 2020. The list
of these nations included the United States, China, the United Kingdom, Italy, Iran,
South Korea, Spain, Japan, France, Germany, Norway, the Netherlands, and Switzer-
land. The Government announced the stoppage of visa issuing to all passengers from
the disease infected nations upon arrival. The embargo was predicted to be lifted after
four weeks and could be shortened when necessary. Several federal regions imple-
mented strengthening steps to deter the transmission of the COVID-19 disease. Those
steps took effect from Friday 20th March 2020 [98, 99].
On 22nd March 2020, Nigeria announced its temporarily suspension of interna-
tional passenger flights to Lagos’ Muritala Muhammed International Airport (LOS)
and Abuja’s Nnamdi Azikiwe International Airport (ABV) from Monday 23rd March
2020 to Thursday 23rd April 2020 even though emergency and essential flights were
exempted. Export services to Enugu, Kano, and Port Harcourt were also suspended
[99, 100].
As of 8th July 2020, Nigeria was declared the 49th worldwide most infected
with COVID-19 with 29,789 confirmed cases, 669 death cases, 12, 108 recovered
cases, and 17, 012 active cases [101, 102]. Nigeria was also ranked the 3rd most
infected country with COVID-19 disease in Africa and 1st in West Africa as of 7th
July 2020 [103, 104]. As of September 2020, Nigeria had conducted above 436,231
sample test and had established above 55, 829 confirmed cases, 10, 944 active cases,
43,810 discharged cases, 1075 death cases [102, 104]. The pictorial representation
of COVID-19 cases, daily confirmed and death cases, in Nigeria within the period of
the data collection is presented in Fig. 20a and b. From Fig. 20a, it is evident that the
pandemic was most serious between May and August 2020 and had been reducing
towards the end of September 2020. Furthermore, from Fig. 20b, daily death cases
a 25-09-20
04-09-20
14-08-20
24-07-20
03-07-20
Dates
12-06-20
22-05-20
01-05-20
10-04-20
20-03-20
28-02-20
0 200 400 600 800 1000
Number of Cases
b 24-09-20
24-08-20
24-07-20
Dates
24-06-20
24-04-20
24-03-20
0 10 20 30 40
Number of Cases
Fig. 20 a Daily confirmed cases in Nigeria within 28th February and 25th September 2020 b daily
death cases in Nigeria within 24th March and 25th September 2020
were at the peak in June 2020 but had been reducing before the period of the data
collection.
Various works have been done on COVID-19 cases in Nigeria. The daily cumu-
lative confirmed, discharged, and death cases were subjected to nine (9) curve esti-
mation statistical models in simple, quadratic, cubic and quartic forms (making a
total of 36 models) in order to identify the best one for prediction purpose using
some estimators. The forecast values based on Quartic Linear Regression Model
with LAD estimator was recommended [98]. ARIMA (1,1,0) has also been iden-
tified to predict total confirmed cases in the country [105]. COVID-19 incidence
has also been reported to increase significantly with an increase in sea level pres-
sure and also decrease significantly with maximum temperature [106]. The impact
of various non-pharmaceutical control measures on the population dynamics of the
novel COVID-19 has been examined as well as its predictive tool for the cumulative
number of confirmed cases in Lagos, Nigeria [107]. Furthermore, travelling history
and contacts on the spread of COVID-19 cases has been observed to increase the
chances of people being infected [100].
2.14 COVID-19 in Senegal
The first case of COVID-19 was detected in Senegal on 2nd March 2020 in the Dakar
region of Senegal. The first case originated from France [108–110]. The first local
case appeared on 10th March 2020, following a contact traced from Italy’s case.
The first community-based case was detected on 20th March 2020. One month after
its onset in Senegal, 195 cases were recorded [111]. The evolution of the pandemic
seems slow, as for most African countries, unlike Europe and the Americas [111,
112]. Senegal experienced a 30% rise in COVID-19 infections on 11th May 2020.
As of 29th May 2020, there were 3,429 cases, 1,738 fully recovered and 41 deceased
persons with a significant increase in cases in the last weeks. 39 out of 79 health
districts were affected. As of 22nd June 2020, there were 5,970 cases, 3,953 fully
recovered and 86 deceased persons with a significant increase in cases in the last
weeks. 51 out of 79 health districts were affected but with the highest concentration of
cases in the regions of Dakar [109, 110, 112]. The pictorial representation of COVID-
19 cases in Senegal, within the period of the data collection, is presented in Fig. 21a
and b. From Fig. 21a, it can be seen that COVID-19 confirmed cases have been severe
in the country with the pick recently recorded in September 2020. Meanwhile, the
country has been noted for a high number of reported cases. Furthermore, from
Fig. 21b, the numbers of death cases have not been more than nine (9), but it rarely
occurs.
Senegal took less restrictive measures while maintaining good economic activity.
The hospitalization of cases, the use of hotels to isolate contact subjects for 14 days
combined with targeted quarantine measures for families or villages in rural areas are
adequate and appropriate mitigation measures [113–115]. All of this was facilitated at
the regional level by the Governor’s involvement from the beginning of the process
a
15-09-20
01-09-20
18-08-20
04-08-20
21-07-20
07-07-20
23-06-20
Dates

09-06-20
26-05-20
12-05-20
28-04-20
14-04-20
31-03-20
17-03-20
03-03-20
0 50 100 150 200 250
Number of Cases
b
17-09-20
27-08-20
06-08-20
16-07-20
Dates
25-06-20
Daily Death Cases
04-06-20
14-05-20
23-04-20
02-04-20
0 2 4 6 8 10
Number of Cases
Fig. 21 a Daily confirmed cases in Senegal within 3rd March and 25th September 2020 b daily
death cases in Senegal within 2nd April and 25th September 2020
through the decentralized management committees. The borders closure and the
suspension of air and sea lines seemed to work as there was imported case since 4th
April 2020. Social distance seems challenging to organize in Senegal [116].
Senegal also put in a comprehensive system to assist anybody in reporting the
illness. For example, monitoring teams from the health ministry are in action and
do arrive immediately to take samples when someone is reported ill. Clinics were
Table 3 Government of
Measures Date
Senegal measures in the
context of COVID-19 and Self-isolation on return from abroad 27/01/2020
their dates Barrier measures 10/02/2020
case-based self-isolation 02/03/2020
Ban on gatherings 14/03/2020
Closure of schools and universities 14/03/2020
Quarantine 18/03/2020
Border closure 20/03/2020
State of a health emergency 23/03/2020
Curfew 23/03/2020
Market closure 23/03/2020
Mosques closure 23/03/2020
Church closure 23/03/2020
prepared to receive patients. One of these is the infectious diseases clinic of the Centre
Hospitalier National et Universitaire de Fann. It is one of the only health facilities
in Senegal with the capacity to quarantine patients suspected of being infected.
However, there are concerns about gaps in Senegal’s ability to detect cases early. For
example, the fact that the first patient who tested positive came from abroad, mainly
by plane, has raised questions about the checking and prevention systems in place at
points of entry into the country. Due to this, at the Blaise-Diagne International Airport,
security was reinforced, with the deployment of infrared cameras that could detect
passengers whose body temperature is unusually high as one of the signs of COVID-
19 is fever. The infrared technology is used to detect people with a temperature
of 38 °C or more [117]. Other measures taken in the country, and the date of the
announcement is provided in Table 3 [109].
About related work done on COVID-19, a mathematical model with five compart-
ments was developed to simulate the evolution of the pandemic, retrieve the infec-
tion rate and necessary production number [118]. Results of Senegal’s response to
COVID-19 through a state of emergency and curfew were also reviewed [119].
2.15 COVID-19 in Sierra Leone
In mid-March of the year 2020, there were sensitizations about COVID-19 by

Dr. Chiyembekezo Kachimanga [120]. The President confirmed the country’s first
COVID-19 case on 31st March 2020 in a 37-year-old man who moved from France
on 16th March 2020 and the second case on 1st April 2020 [121]. Sierra Leone was
one of the last nations pointed out to have a high likelihood of not recording COVID-
19 in the world [122]. The news was predictable, given that the virus had existed
elsewhere in West Africa weeks before. Moreover, the country is one of those with
limited intensive care units capacity, very few ventilators, and a majority of people
whose incomes and lives would be directly affected by the strict social distancing
measures [120]. It also experienced a similar epidemic called Ebola in 2014, which
took about two years before the country was declared free [123]. As at 30th June
2020, there had been 1,462 confirmed cases, 428 active cases, 974 recovered cases
and 60 deaths [121]. The country was the 48th African country to record cases of
COVID-19 as well as the last in West Africa [124]. The pictorial representation of
COVID-19 cases, daily confirmed and death cases, in Sierra Leone within the period
of the data collection is presented in Fig. 22a and b. From Fig. 22a, it is noted that
the confirmed cases were more severe between the end of April and early July 2020.
Meanwhile, it has been reducing toward the end of the period of data collection.
Furthermore, from Fig. 22b, it is clear that the pick of death cases was in the middle
of May 2020.
Measures being taken by Sierra Leone were majorly information and trust as
used to combat Ebola [124]. These were seen in the spread of hand washing stations
a
16-09-20
26-08-20
05-08-20
15-07-20
Dates
24-06-20
03-06-20
13-05-20
22-04-20
01-04-20
0 20 40 60 80 100
Number of Cases
b 24-09-20
24-08-20
24-07-20
Dates

24-05-20
24-04-20
0 1 2 3 4 5 6
Number of Cases
Fig. 22 a Daily confirmed cases in Sierra Leone within 1st April and 25th September 2020 b daily
death cases in Sierra Leone within 24th April and 25th September 2020
all over the country; social distancing which seemed not practicable among the
people; improved health system with support from concern’s health response; school
closures and curfews [124]. The country also applied two full lockdowns between
5th–7th April 2020 and 3rd–5th May 2020 during which everyone was required to
stay home, also affecting the religious centres. On 23rd June 2020, the Government
lifted restrictions on inter-district travel for two weeks and also shortened the curfew
[124–127]. There was also the imposition of quarantine at the airport [124]. Though,
the President on 24th March 2020 had earlier declared a12 month national state of
emergency [126]. On 1st June 2020, the Government also declared a compulsory
wearing of face masks [128].
With the closure of Borders since 27th March 2020, it has been reported that
there would be effect on economic activity, poverty and hunger after COVID-19 [3].
The World Bank announced a $7.5 million grant to help Sierra Leone deal with the
pandemic [121, 126].
2.16 COVID-19 in Togo
On the 6th March 2020, Togolese authorities announced the first COVID-19 case, a
42-year-old Togolese woman who travelled between Germany, France, Turkey and
Benin before returning to Togo [129]. On this date, it was reported that she was
being treated in isolation and her condition was stable [130]. On 20th March 2020,
nine more cases were confirmed in Togo. On this day, the first case had recovered, as
indicated by the Ministry of Health [131, 132]. On 21st March 2020, seven more cases
were confirmed. On 27th March 2020, the first death occurred [133]. The pictorial
representation of COVID-19 cases, daily confirmed and death cases, in Togo within
the period of the data collection is presented in Fig. 23a and b. From Fig. 23a, it
is evident that the number of confirmed cases was severe daily, and the peak was
in August 2020. Furthermore, from Fig. 23b, it is noted that death cases had been
between one (1) and three (3) with the peak towards the end of September 2020.
On Monday, 16th March 2020, Togolese authorities announced that commercial
flights to and from countries positively affected by the coronavirus (COVID-19)
outbreak would be suspended as of Friday, 20th March 2020, for 15 days. While
the list of countries included in the suspension remains unclear, Togo’s government
website stated “it concerns most European countries [131, 132]". On Friday, 20th
March 2020, authorities announced the closure of all borders with immediate effect to
curtail the spread of the coronavirus (COVID-19). As such, all non-essential inbound
and outbound traffic and travel were prohibited, though cargo transportation was still
allowed. Additionally, in an attempt to control the spread of the virus, the cities of
Lome, Tsevie, Kpalime, and Sokode had quarantine measures for two weeks starting
on 20th March 2020. All non-residents or those who transited through those European
countries were not allowed to enter Togolese territory. Gatherings of more than 100
people were banned for three weeks immediately [134, 135]. The President, Faur
a 19-09-20
05-09-20
22-08-20
08-08-20
25-07-20
11-07-20
27-06-20
Dates
13-06-20
16-05-20
02-05-20
18-04-20
04-04-20
21-03-20
07-03-20
0 10 20 30 40 50
Number of Cases
b
28-08-20
28-07-20
Dates
28-06-20
Daily Death Cases
28-05-20
28-04-20
28-03-20
0 1 2 3 4
Number of Cases
Fig. 23 a Daily confirmed cases in Togo within 7th April and 25th September 2020 b daily
confirmed cases in Togo within 28th March and 25th September 2020
Gnassingbe, addressed the nation on Wednesday, 1st April 2020, to declare a three-
month nationwide emergency. He announced significant social-economic policies to
support the citizen during the emergency, including waiving charges for electricity
and water supplies. He also prepared ahead of the nation of curfew measure between
19:00 and 06:00 (local time), starting from Thursday, 2nd April 2020. He also created
a special anti-pandemic force composed of 5000 men [133].
After a great council of ministers on 16th March 2020, the Government announced
they would establish an XOF 2 billion fund to fight the pandemic. Other measures
established include suspending flights from Italy, France, Germany, and Spain;
cancelling all international events for three weeks; requiring people who were
recently in a high-risk country to self-isolate; closing their borders; and prohibiting
events with more than 100 people as from 19th March 2020 [136]. Following the
ban on large gatherings, the Togolese Football Federation suspended competitions on
18th March 2020. Other events were cancelled too, including the FILBLEU literature
festival [137].
2.17 COVID-19 in Saint Helena
No case of COVID-19 has been confirmed in Saint Helena up till the last day of the
data collection; although, the government on 27th March 2020 announced a suspected
case of COVID-19 in an individual who had been self-isolating for seven (7) days.
The COVID-19 status of the individual could not be immediately ascertained due
to lack of testing kits as at that time. The person later tested negative to COVID-19
[138].
The utmost priority of the Saint Helena government at this crucial period is to
make sure that the Island is kept safe from the ravaging threat of COVID-19. Constant
monitoring measure of the situation becomes essential for the government in order to
ensure that the preventive measures put in place are working and that regular updates
on the processes are provided to reflect changing circumstances. The Directorate of
Health is working harmoniously with England Public Health and the World Health
Organization (WHO) on curbing the spread of COVID-19 and the government is
doing everything within its ability to prevent the virus from reaching the Island. The
following precautionary measures were highlighted by the Saint Helena government
to prevent the occurrence and spread (if any) of COVID-19 [138].
i. Frequent washing of hands with soap and water or using alcohol-based sanitizer
if hands are not visibly dirty.
ii. Catch it, Kill it, Bin it – When coughing and sneezing, mouth and nose are to
be properly covered with flexed elbow or tissue paper in order to prevent the
spread of viruses. The tissue is to be discarded immediately into a closed bin
and hands cleaned with water and soap or alcohol-based hands rub.
iii. Hand touching many surfaces that might have been contaminated with viruses
should be discouraged.
iv. Anyone with fever, cough and difficulty in breathing should seek medical care
early.
The Saint Helenian government further assured and encouraged its citizenry on
protection, stating that the following steps should be adhered to if there comes a time
that COVID-19 is suspected or confirmed on the Island:
i. Do not panic.It should be seen as a mild, self-limiting infection for everybody.
ii. Self-isolation and calling dedicated phone number was given to be 25,707
iii. Practice of good hygiene
iv. Staying away from crowds and keeping distance from others
v. Getting information and regular updates through the appropriate channel
vi. Maintaining other healthy lifestyle practices [138].
3 Methodology
Capturing the patterns and fluctuations in data adequately remains very fundamental
in statistical modeling that aims at forecasting. The better the model is able to capture
the better the prediction by the model. COVID-19 data of all the affected counties in
the world are being collected daily by European Centre for Disease Prevention and
Control (ECDC) through its Epidemic Intelligence team since the commencement
of pandemic in Wuhan City, China, on December 2019 [139, 140]. Thus, the data to
model for forecasting purpose in this research, cumulative COVID-19 confirmed and
death cases obtained from the daily confirmed and death cases, for all the sixteen (16)
West African countries namely; Benin, Burkina Faso, Cape Verde, Gambia, Ghana,
Guinea, Guinea Bissau, Ivory Coast (Cote d’Ivoire), Liberia, Mali, Mauritania, Niger,
Nigeria, Senegal, Sierra Leone and Togo, were collected from ECDC website (www.
ecdc.europa.eu) since the beginning of the pandemic in each country until 25th
September 2020. Saint Hallen did not have any recorded confirmed and death cases.
With the cumulative data, the number of cases at a time t depends on previous time
t-1. So the quartic curve estimation model with an autoregressive model of order 1
(AR(1)) recently proposed, used and recommended out of sixteen (16) models was
adopted in this study [98]. The model is defined as:
yt = β0 + β1 t + β2 t 2 + β3 t 3 + β4 t 4 + μt (1)

where μt = ρμt−1 + εt , εt ∼ N 0, σ 2 , t = 1, 2, . . . n.
It should be noted that the starting date of COVID-19, either confirmed or death
cases, implies t = 1 and the last date of the data collection, 25th September 2020; is
when t = n. The dependent variable yt represents cumulative COVID-19 confirmed
or death cases for each of the countries at time t. The model regression parameters
are β0 , β1 , β2 , β3 , β4 and the auto-correlated parameter ρ.
The Ordinary Least Square (OLS) Estimator commonly used to estimate the
parameters of the Classical Linear Regression Model is best linear unbiased esti-
mator (BLUE) provided none of the assumptions of the model is violated [141–
143]. In model (1), the assumption that error terms are independent is violated and
thus resulting in autocorrelation problem. The use of the OLS estimator in this kind
of situation has been reported to produce unbiased but inefficient estimates [144,
145]. Consequently, estimators of a linear regression model with AR(1) have been
developed and these include the Cochrane Orcutt (CORC), Prais-Winsten (PW) and
Hildreth-LU (HILU) estimators [146–148]. The efficiency of these estimators has
been established to depend on the structure of the explanatory variables [144, 149].
Meanwhile, in order to determine the presence of AR(1) in the regression model after
the least square estimation, the Durbin Watson test statistic found relevance [150].
Furthermore, in modeling (1), the error terms are assumed to be normally distributed,
but this may not always be true. As a result, estimation, hypothesis testing and hence
inferences are affected. The Shapiro–Wilk (SW) test statistic is used to test for the
assumption of normality of error terms and the Least Absolute Deviation (LAD), a
robust estimation method originated by KF Gauss, used for the estimation. This is
often recommended for handling parameter estimation of models with non-normal
error terms or outliers [151–154]. Eventually, in this study, we adopted these six
(6) estimation methods, including the Weighted Least Square (WLS) estimator to
handle heteroscedasticity. We utilized a proportion of variation explained by each
estimator through their Adjusted coefficient of determination (Adj. R2 ) as a major
criterion for a model to be used prediction and forecast purpose. The forecast is done
with 99% Confidence Interval. The closeness of the DW statistic to 2, a state of
no autocorrelation, was also used to determine the best estimator. We used the Gretl
statistical software, version 1.7.1, to carry most of the estimations in this study [155].
4 Results and Discussion
The summary of the results of the estimation methods of each of the country is
provided and discussed as follows:
4.1 Data Analysis of the Republic of Benin
The results obtained when applying the six (6) estimation methods to data on cumu-
lative confirmed and death cases in the Republic of Benin are summarized in Table
4.
From Table 4, it can be observed that the results based on the OLS estimation
method of the cumulative conformed cases reveal that the error terms in model to
have the problem of non-normality (SW = 0.984503, p-value < 0.05), autocorrelation
(DW = 0.082539, p-value < 0.01) and heteroscedasticity (LM = 98.747066, p-value
< 0.01); and that all attempts to correct each of the problems only resulted into
identifying the HILU estimator as the best for prediction purpose. It has the highest
Adjusted Coefficient of determination (Adj. R2 = 0.99887) and its Durbin Watson
Statistic value (1.828381) is closest to 2. Although, the PW estimator also performs
very similarly. The fitted model with the actual values as well as the predicted values
for the rest of the year 2020 is graphically presented in Fig. 24a. From Fig. 24a, it
can be observed that the fitted model precisely captured the fluctuations in the data as
the Adjusted Coefficient of Determination reveals that the time variables explained
99.9% of the variation in the cumulative confirmed cases. The predicted values do not
show clearly that the COVID-19 would be overcome by December 2020 but rather
there is a slow and steady increase over the time. Consequently, the Government of
406
Table 4 Summary of results on cumulative COVID-19 confirmed and death cases in Benin
OLS WLS LAD CORC HILU PW
Confirmed cases F 3320.78 20,180.35 57.81342 48.82805 60.4199
(3.8e-173) (2.5e-246) (1.08e-31) (4.46e-28) (9.70e-33)
Adj. R2 0.985747 0.997627 0.9848 0.99887 0.99887 0.998864
SW-test 0.984503 0.882753 0.941837 0.736353 0.734717 0.722441
(0.0318949) (3.98e-011) (5.0e-007) (3.42e-017) (3.03e-017) (1.12e-017)
D-W test 0.082539 0.062643 0.074225 1.822496 1.828381 1.799164
(4.92e-016)
LM/ Mod. Glejeser test 98.747066 115.317
(3.16e-016) (0.000)
Death cases F 2724.803 3724.268 61.34470 58.62922 41.25890
(7.0e-151) (4.6e-162) (9.78e-32) (8.85e-31) (5.09e-24)
Adj. R2 0.984548 0.988648 0.984178 0.998679 0.998679 0.998630
SW-test 0.982196 0.994428 0.993138 0.745705 0.745066 0.704144
(0.0266982) (0.764387) (0.59679) (6.8e-016) (6.49e-016) (3.45e-017)
D-W test 0.092673 0.087600 1.843877 1.845962 1.777653
(4.94e-016)
(0.000938) (0.000)
K. Ayinde et al.
a 3000
99 percent interval
Cummulative_Con
forecast
2500
2000
1500
1000
500
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 200
99 percent interval
Cumulative_Deat
180 forecast
160
140
120
100
80
60
40
20
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 24 a The actual fitted and predicted values of cumulative COVID-19 confirmed cases in Benin
b the actual fitted and predicted values of cumulative COVID-19 death cases in Benin
Benin needs not to relax completely that COVID-19 has ultimately been defeated
but should continue in the various measures already put in place as lockdown is now
relaxed.
Furthermore from Table 4, the results from OLS estimation cumulative death cases
point to the existence of non-normality error terms ( SW = 0.982196, p-value < 0.05),
dependent error terms (DW = 0.092673, p-value < 0.01) and non-homogeneous error
variance (LM = 29.757974, p-value < 0.01) in the model; and that correcting for each
of the violations resulted into identifying the HILU estimator as the best, having the
Highest Coefficient of Determination (Adj. R2 = 0.998679) and the Durbin Waston
Statistic value (DW = 1.845962) closest to 2. The pictorial representation of the fitted
model to actual values is provided in Fig. 24b. From Fig. 24b, it becomes evident
that the model fit the data very well in that 99.9% of variations in the cumulative
death cases was explained by the time factors even though there appears not to be
significant death of people with COVID-19 as at present (also see Fig. 7b). However,
the increase is expected as time goes on and especially towards the end of the year
2020. Thus, the Government would need to put in serious measures to take care of
those already affected with COVID-19 to avert their in death as the year runs by.
4.2 Data Analysis of Burkina Faso
The summary of the results of the six (6) estimation methods on Burkina Faso’s
cumulative confirmed and death data are provided in Table 5.
Table 5 provides the results of the OLS estimation method on the cumulative
confirmed cases from which the error terms in model are observed to be non-normal
( SW = 0.972234, p-value < 0.01), dependent (DW = 0.179434, p-value < 0.01)
and heteroscedastic (LM = 102.76922, p-value < 0.01). The results of each of the
estimators used to correct these problems also reveal one further violation or the
other. For example, having corrected heteroscedastic problem with WLS there exist
non-normality of error terms. Of all the estimators used for correction, that of HILU
is best in that it provides the highest Adjusted Coefficient of determination (Adj. R2
= 0.998901 and its Durbin Watson Statistic value (2.00579) is closest to 2. Thus,
99.9% of variations in the cumulative confirmed cases are explained by the time
variables. Hence, it is used for the forecast purpose. However, the results of CORC
and PW are also very similar. The fitted model, actual values, as well as the predicted
values for the rest of the year 2020, is graphically presented in Fig. 25a.
From Fig. 25a, it can be observed that the fitted model captured the fluctuations
in the cumulative confirmed cases very well and this provides excellent and precise
support to the value of the Adjusted Coefficient of Determination obtained. The
predicted values steadily increase with time throughout the predicted periods. So,
COVID-19 confirmed cases would remain an issue of great concern throughout the
rest of the year except further drastic measures are put in place the Government.
Furthermore from Table 5, the results based on the OLS estimation reveal that
the error terms in the model are not normal (SW = 0.853384, p-value < 0.001),
dependent (DW = 0.208756, p-value < 0.01) and have non-constant variance (LM =
120.923861, p-value < 0.01), and that correcting for each these with an appropriate
estimator resulted into identifying the CORC or HILU estimator as the best, having
the Highest Coefficient of Determination (Adj. R2 = 0.998277). Moreover, PW
estimator does also not perform too differently. The pictorial representation of the
fitted model to actual values with CORC estimator is provided in Fig. 25b.
Table 5 Summary of results on cumulative COVID-19 confirmed and death cases in Burkina Faso
Confirmed cases F 7404.720 5725.728 570.0047 576.8014 234.3535
(7.7e-211) (4.4e-200) (1.2e-105) (4.0e-106) (4.23e-73)
Adj. R2 0.993359 0.991427 0.992963 0.998901 0.998901 0.998877
SW-test 0.972234 0.905732 0.883971 0.585579 0.586241 0.575598
(0.00056) (6.36e-010) (2.9e-011) (1.47e-021) (1.53e-021) (7.73e-022)
D-W test 0.179434 0.150042 0.148074 2.007161 2.005790 2.010811
(0.000)
(0.0000) (0.000)
Death cases F 4409.575 4392.901 710.9148 708.5986 11.99263

(4.9e-183) (6.9e-183) (4.4e-111) (5.8e-111) (1.08e-08)
Adj. R2 0.989340 0.9893 0.987424 0.998277 0.998277 0.997961
SW-test 0.853384 0.505242 0.581074 0.736951 0.736923 0.746829
(1.37e-012) (6.72e-023) (2.7e-021) (4.42e-017) (4.41e-017) (8.32e-017)
D-W test 0.208756 0.137267 0.167106 2.285828 2.286425 2.131208
(0.0000)
(0.000000) (0.000)
409
a 9000
99 percent interval
8000 Confirmed
forecast
7000
6000
5000
4000
3000
2000
1000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 60
99 percent interval
40 Death
forecast
20
-20
-40
-60
-80
-100
-120
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 25 a The actual, fitted and predicted values of cumulative COVID-19 confirmed cases in
Burkina Faso b the actual, fitted and predicted values of cumulative COVID-19 death cases in
Burkina Faso
From Fig. 25b, it is observed that the model fit the data well as 99.8% of vari-
ations in the cumulative death cases was explained by the time factors. The down-
ward movement of the predicted values for the rest of the year is an indication of
little or insignificant change in the cumulative death cases. Moreover, death cases in
the region have not even been too severe (see Fig. 9b). Consequently, the Govern-
ment is expected to continue and intensify its available measures to get this stability
maintained.
4.3 Data Analysis of Cape Verde
Table 6 provides a summary of the results of the six (6) estimation methods on Cape
Verde’s cumulative confirmed and death data. From the table, the results of the OLS
estimation method on the cumulative confirmed cases reveal the joint effect of time
variables to be highly significant (F = 44,023.91, p-value < 0.01) and that there
exist violations of assumptions of independence of error terms (DW = 0.112436,
Table 6 Summary of results on cumulative COVID-19 confirmed and death cases in Cape Verde
Confirmed F 44,023.91 72,529.99 1709.554 1579.691 1739.802
cases (4.8e-273) (5.6e-293) (1.1e-143) (1.2e-140) (5.8e-145)
Adj. R2 0.998934 0.999352 0.998916 0.999883 0.999883 0.999884
SW-test 0.988951 0.975769 0.982415 0.955483 0.955086 0.953747
(0.150634) (0.002281) (0.01787) (1.23e-005) (1.12e-005) (7.85e-006)
D-W 0.112436 0.108839 0.110250 1.771561 1.776007 1.767697
test (1.23e-017)
LM/ 39.58271 66.2126
Mod. (0.000042) (0.000)
Glejeser
test
Death F 7099.396 9828.606 241.0207 225.5932 255.5215
cases (7.7e-197) (1.8e-209) (6.55e-71) (9.30e-69) (4.67e-73)
Adj. R2 0.993561 0.995341 0.993361 0.998960 0.99896 0.998956
SW-test 0.982681 0.949229 88.6812 0.846087 0.84489 0.847037
(0.0216819) (3.65e-006) (0.000) (1.16e-012) (1.02e-012) (1.17e-012)
D-W 0.993561 0.161002 0.162079 1.833857 1.838460 1.813744
test (8.11e-01)
LM/ 77.242489 103.101
Mod. (0.000000) (0.000)
Glejeser
test
p-value < 0.01) and constant variance (LM = 39.58271, p-value < 0.01). Of all the
estimators used to correct the autocorrelation and heteroscedasticity problems, the
CORC, HILU and PW estimators provide better results in that they have the highest
Adjusted Coefficient of determination (Adj. R2 = 0.999883). More importantly, the
HILU is considered best because of its Durbin Watson Statistic value (1.776007)
which is closest to 2. Thus, the fitted model with HILU estimator can be considered
to be very good because the time variables explain 99.99% of variations in the
cumulative confirmed cases, and hence the model is used for the forecast purpose.
Moreover, the results from the CORC and PW estimators are also closely similar.
Figure 26a presents the fitted model, actual values as well as the predicted values for
the rest of the year 2020. From the figure, upward movement or a steady increase in
confirmed cases of COVID-19 for the rest of the year is evident, and this needs to
be critically considered by the Government so that more deliberate measures can be
put in place.
Furthermore from Table 6, the results from OLS estimation on the cumulative
death cases point to the presence of non-normality error terms (SW = 0.982681,
p-value < 0.05), related error terms (DW = 0.993561, p-value < 0.01) and hetero-
geneous error variance (LM = 77.242489, p-value < 0.01) in the model. Comparing
the results of the estimators for correction measures still reveal the HILU estimator
a 14000
99 percent interval
confirmed
12000 forecast
10000
8000
6000
4000
2000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 250
99 percent interval
Death
forecast
200
150
100
50
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 26 a The actual, fitted and predicted values of cumulative COVID-19 confirmed cases in Cape
Verde b the actual, fitted and predicted values of cumulative COVID-19 death cases in Cape Verde
as best because of its highest Co-efficient of Determination (Adj. R2 = 0.99896)

and the Durbin Waston Statistic value (DW = 1.83846) closest to 2. The graphical
representation of the fitted model to actual values is provided in Fig. 26b.
From Fig. 26b, the model fit the data very well, and this buttress 99.9% of vari-
ations in the cumulative death cases already reported to be explained by the time
factors. In addition to this from the figure, the upward movement or steady increase
cumulative death for the rest of the year should be of great concern to the Government
as further measures are expected to be put in place to reduce this.
4.4 Data Analysis of Code D’Ivoire
The summary of the results obtained from the six (6) estimation methods when
applied to data on cumulative confirmed and death cases in Code d’Ivoire is presented
in Table 7.
From the Table 7, it is observed that the OLS estimation results on the cumulative
confirmed cases reveal the presence of non-normality of error terms (SW = 0.971422,
p-value < 0.01), lack of independence of error terms (DW = 0.017445, p-value < 0.01)
and heterogeneity of error terms (LM = 69.357653, p-value < 0.01). Correcting each
of these problems with appropriate estimators reveals the HILU estimator as the best
having very high Adjusted Coefficient of determination (Adj. R2 = 0.999856) and
Durbin Watson Statistic value (1.966825) closest to 2. Consequently, the fitted model
with HILU estimator is used for prediction purpose in that 99.99% of variations in
the cumulative confirmed cases are explained by the time variables. Meanwhile, the
results obtained also from CORC, and PW estimators are very similar to that of
HILU. The graphical representation of actual values, fitted model and the forecast
values for the remaining days of the year 2020 are presented in Fig. 27a.
From the Fig. 27a, it can be observed the model fits the actual data very well and
that there is an upward movement or steady increase in the cumulative confirmed
cases of COVID-19 for the rest of the year. With this, there is a strong indication
that COVID-19 pandemic is still not over and that the Government needs to ensure
measures put in place are not relaxed but somewhat improved upon.
Furthermore from Table 7, the OLS estimation results on cumulative death cases
reveal that the effect of the time variables are jointly significant (F = 9927.955, p-
value < 0.01), and that there is violation of assumptions of independent error terms
(DW = 0.107617, p-value < 0.01) and constant error variances (LM = 53.230924,
p-value < 0.01). With the correction measures of the estimators, it is observed that
the PW estimator produces the highest Adjusted Coefficient of determination (Adj.
R2 = 0.999533) and Durbin Watson Statistic value (2.081992) closest to 2. So, it
is recognized as best and used for forecast purpose. The pictorial representation of
actual values, fitted model and the forecast values for the rest of the year 2020 are
presented in Fig. 27b. Meanwhile, these results are also very similar to those of
CORC and HILU estimators.
From Fig. 27b, it can be seen that the model fits well in that 99.95% of variations in
the cumulative death cases have been explained by the time variables. The downward
movement or steady decline in the forecast vales indicates that death cases based on
COVID-19 in the country would become trivial or insignificant before the end of the
year provided all measures current put in place are maintained or even improved by
the Government.
414
Table 7 Summary of results on cumulative COVID-19 confirmed and death cases in Code d’Ivoire
(3.5e-192) (2.8e-214) (1.30e-38) (5.81e-27) (2.85e-26)
Adj. R2 0.989899 0.994039 0.98943 0.999862 0.999856 0.999845
SW-test 0.971422 0.960929 0.965676 0.91745 0.95153 0.899634
(0.000459) (2.74e-005) (9.4e-005) (4.67e-009) (3.12e-006) (2.76e-010)
D-W test 0.017445 0.017462 0.017272 1.738078 1.966825 1.542078
(0.0000)
(0.0000) (0.0000)
Death cases F 9927.955 30,720.91 221.1110 229.5106 225.3521
(4.3e-205) (6.7e-248) (4.46e-67) (2.96e-68) (6.90e-68)
Adj. R2 0.995512 0.998545 0.99487 0.999530 0.999530 0.999533
SW-test 0.987442 0.974205 0.91911 0.919482 0.916457
(0.109851) (0.00202) (2.15e-008) (2.29e-008) (1.317e-008)
D-W test 0.107617 0.094477 0.090833 2.094321 2.092311 2.081992
(8.78e-017)
(0.0000) (0.0000)
K. Ayinde et al.
a 250000
99 percent interval
confirmed
forecast
200000
150000
100000
50000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 150
99 percent interval
death
forecast
100
50
-50
-100
-150
-200
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Code D’Ivoire b the actual, fitted and predicted values of cumulative COVID-19 death cases in
Code d’Ivoire
4.5 Data Analysis of Gambia
The summary of the results of the six (6) estimation methods on cumulative confirmed
and death cases in the Gambia is presented in Table 8.
From the Table 8, the results from OLS estimation on the cumulative confirmed
cases point to the violation of the assumptions of normality of error terms (SW =
0.979578, p-value < 0.01), independence of error terms (DW = 0.031277, p-value
< 0.01) and homogeneity of error terms (LM = 92.178157, p-value < 0.01). Using
416
Table 8 Summary of results on cumulative COVID-19 confirmed and death cases in the Gambia
(6.4e-132) (3.7e-133) (1.44e-21) (5.29e-18) (7.67e-19)
Adj. R2 0.961535 0.962691 0.999029 0.999029 0.998899
SW-test 0.979578 0.931854 0.879989 0.664331 0.661327 0.679126
(0.0066347) (7.89e-008) (3.02e-011) (3.01e-019) (2.5e-019) (6.79e-019)
D-W test 0.031277 0.029452 1.903135 1.912521 1.670655
(0.0000)
LM/ Mod. Glejeser test 92.178157
(0.000000)
Death cases F 698.6305 1360.048 24.78532 21.34089 19.07941
(7.9e-109) (8.1e-134) (2.34e-16) (2.02e-14) (4.14e-13)
Adj. R2 0.937826 0.967089 0.998286 0.998286 0.998149
SW-test 0.975923 0.905728 0.760597 0.654021 0.650016 0.640011
(0.0026624) (1.65e-009) (4.07e-016) (3.25e-019) (2.57e-019) (1.27e-019)
D-W test 0.031513 0.028849 1.761558 1.767210 1.628597
(0.0000)
(0.000000) (0.000)
K. Ayinde et al.
appropriate estimators to correct each of these problems reveals the HILU estimator
as the best estimator having the high Adjusted Coefficient of determination (Adj. R2
= 0.999029) and Durbin Watson Statistic value (1.912521) closest to 2. As a result,
the fitted model utilized the HILU estimator for parameter estimation and prediction.
Meanwhile, the results obtained also from CORC and PW estimators are also very
similar to that of HILU. In Fig. 28a, the actual values of cumulative confirmed cases,
fitted model and the forecast values for the rest of the year 2020 are presented.
Figure 28a reveals that the model fits well the actual cumulative confirmed cases,
and this further buttresses the 99.9% of variations in the cumulative confirmed cases
a 10000
99 percent interval
CONFIRMED
forecast
0
-10000
-20000
-30000
-40000
-50000
-60000
-70000
-80000
-90000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 500
99 percent interval
DEATH
forecast
0
-500
-1000
-1500
-2000
-2500
-3000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 28 a The actual, fitted and predicted values of cumulative COVID-19 confirmed cases in the
Gambia b the actual, fitted and predicted values of cumulative COVID-19 death cases in the Gambia
as explained by the time variables. The downward movement or steady decline in

the forecast values points to the fact that COVID-19 confirmed cases is expected
to become insignificant or trivial towards the rest of the year provided all current
measures are maintained.
Furthermore from Table 8, it is observed that the OLS estimation results of cumu-
lative death cases show the presence of non-normally distributed error terms (SW
= 0.975923, p-value < 0.01), dependent error terms (DW = 0.031513, p-value <
0.01) and non-constant variance of error terms (LM = 125.0746, p-value < 0.01).
Utilizing appropriate estimators for the correction of each of these problems reveals
the HILU estimator as the best estimator. It has the highest Adjusted Coefficient of
determination (Adj. R2 = 0.998286) and Durbin Watson Statistic value (1.76721)
closest to 2. So, the estimator is used to forecast cumulative death cases for the rest
of the year. Meanwhile, the results obtained from CORC and PW estimators are not
different those obtained from the HILU estimator. Figure 28b presents the actual
values of cumulative confirmed cases, the fitted model and the forecast values for
the rest of the year 2020.
Figure 28b reveals that the model fits well the actual cumulative death cases, and
this supports the 99.9% of variations in the cumulative death cases as explained by
the time variables. The downward movement or steady decline in the forecast values
of COVID-19 cumulative death cases for the rest of the year points to the fact that
the Gambia is expected to have an insignificant number of death cases provided all
the current measures are maintained and/or improved.
4.6 Data Analysis of Ghana
The results of the six (6) estimation methods on cumulative confirmed and death
cases in Ghana are summarily presented in Table 9.
In Table 9, the results of the OLS estimation on the cumulative confirmed cases
reveals the violation of the assumptions of normality of error terms (SW = 0.958871,
p-value < 0.01), independence of error terms (DW = 0.053672, p-value < 0.01) and
homogeneity of error terms (LM = 60.485371, p-value < 0.01). With the appropriate
correction of these violations, it is observed that among all the estimators, the CORC
is best having the highest Adjusted Coefficient of determination (Adj. R2 = 0.999824)
and Durbin Watson Statistic value (2.006155) closest to 2. Consequently, the fitted
model with CORC estimator is used for prediction purpose. Thus with this estimator,
99.98% of variations in the cumulative confirmed cases are explained by the time
variables. Meanwhile, the results obtained also from HILU and PW estimators are
perfectly in agreement with that of CORC. The graphical representation of actual
values, fitted model and the forecast values for the remaining days of the year 2020
are presented in Fig. 29a. From Fig. 29a, it is observed that the model fits well
the actual cumulative confirmed cases, and there is downward movement or steady
decline in the forecast values towards the end of the year. This points to the fact that
Table 9 Summary of results on cumulative COVID-19 confirmed and death cases in Ghana
Confirmed cases F 13,838.76 13,912.9 113.2946 72.31465 148.6963
(5.0e-235) (3.0e-235) (2.58e-49) (3.35e-37) (1.15e-57)
Adj. R2 0.996471 0.99649 0.996307 0.999824 0.999824 0.999824
SW-test 0.958871 0.930616 0.947694 0.901531 0.902802 0.902974
(1.732e-005) (4.57e-008) (1.34e-006) (4.23e-010) (5.1e-010) (4.86e-010)
D-W test 0.053672 0.045241 0.04642 2.006155 2.016356 1.99219
(0.0000)
LM/ Mod. Glejeser test 60.485371
(0.0000)
Death cases F 13,752.95 170,959.2 750.1037 750.1051 755.3157

(1.2e-225) (0.000000) (7.1e-112) (7.1e-112) (1.5e-112)
Adj. R2 0.996612 0.999727 0.996593 0.999381 0.999381 0.999385
SW-test 0.981812 0.98274 0.979729 0.886987 0.886987 0.886541
(0.0151505) (0.02038) (0.00787) (1.12e-010) (1.12e-010) (9.76e-011)
D-W test 0.19067 0.183519 0.188014 2.240926 2.240926 2.241519
(2.672e-016)
(0.000000) (0.000)
419
a 60000
99 percent interval
Cummulative_Con
forecast
40000
20000
-20000
-40000
-60000
-80000
-100000
-120000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 400
99 percent interval
Cummulative_Dea
forecast
200
-200
-400
-600
-800
-1000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Ghanab the actual, fitted and predicted values of cumulative COVID-19 death cases in Ghana
COVID-19 confirmed cases is expected to become insignificant or trivial over the

next few months provided all current measures are maintained.
Furthermore from Table 9, the OLS estimation of cumulative death cases show
the results to have non-normally distributed error terms (SW = 0.981812, p-value
< 0.01), dependent error terms (DW = 0.19067, p-value < 0.01) and heterogeneous
variance of error terms (LM = 77.207619, p-value < 0.01). With the use of appropriate
estimators for the correction of each of these problems, it is observed that with the
PW estimator 99.94% best explains the variation in the cumulative death cases.
Meanwhile, the results obtained from CORC and HILU estimators are also the same
as that of PW estimator. Figure 29b presents the actual values of cumulative confirmed
cases, the fitted model and the forecast values for the rest of the year 2020.
From Fig. 29b, the model is observed to fit well the actual cumulative confirmed
cases. Moreover, there is a downward movement or steady decline in the forecast
values as time increases towards the end of the year. This indicates that COVID-
19 confirmed cases is expected to become insignificant or trivial over the next few
months provided all current measures are consistently followed and perhaps, still
improved upon.
4.7 Data Analysis of Guinea
The summary of the results obtained from the six (6) estimation methods on
cumulative confirmed and death cases in Guinea are presented in Table 10.
From Table 10, the summary of the results of the six (6) estimation methods on
Guinea’s cumulative confirmed and death data is provided. The results of the OLS
estimation method reveal that the assumption of normality of error terms (SW =
0.962295, p-value < 0.01), independence of error terms (DW = 0.0529125, p-value
< 0.01) and non-constant variance (LM = 37.113827, p-value < 0.01) of error terms
are violated. Of all the estimators used to correct these problems, the CORC, HILU
and PW estimators provide better results having the highest Adjusted Coefficient
of determination (Adj. R2 = 0.99988). Moreover, the COCR estimator is used for
forecast purpose. Figure 30a presents the fitted model, actual values as well as the
predicted values for the rest of the year 2020.
From Fig. 30a, it is observed that the model fits the actual data well, and this
buttress the fact that the time variables have explained 99.99% of variations in the
cumulative confirmed cases. The downward movement or steady decrease of the
forecast values point to COVID-19 cases becoming insignificant or trivial before the
end of the year provided the Government keeps maintaining measures already in
place and if possible, improve them.
Furthermore from Table 10, the results of the OLS estimation method reveal that
the joint effect of all the time variables to be significant (F = 10,698.32, p-value
< 0.01) and that there is a problem of autocorrelation (DW = 0.323837, p-value <
0.01) and heteroscedasticity (LM = 36.520122, p-value < 0.01) in the model. Having
corrected for these problems, the best estimator is observed to be PW estimator
in that it has the highest Adjusted Coefficient Determination and the value of the
DubinWaston statistic closest to 2. The fitted model, actual values and the predicted
values for the rest of the year 2020 are presented in Fig. 30b.
Similarly, from Fig. 30b, it is seen that the model fits the actual data well, and
this support the 99.89% of variations in the cumulative death cases as explained by
the time variables. Also, the downward movement or steady decrease of the forecast
values point to the fact that COVID-19 death cases are expected to insignificant or
trivial as the year ends. Thus, the Government should keep maintaining measures
already in place and if possible, improve them.
422
Table 10 Summary of results on cumulative COVID-19 confirmed and death cases in Guinea
(1.4e-249) (7.6e-255) (9.54e-62) (1.03e-36) (1.34e-68)
Adj. R2 0.997588 0.997875 0.997371 0.99988 0.99988 0.999877
SW-test 0.962295 0.981225 0.992029 0.964874 0.962644 0.963777
(4.254e-005) (0.009985) (0.36022) (8.65e-005) (4.87e-005) (6.215e-005)
D-W test 0.0529125 0.051223 0.050049 2.231118 2.247872 2.159412
(0.000000)
(5.408e-005) (0.0000)
Death cases F 10,698.32 17,817.18 899.7124 899.7118 923.2843
(3.9e-191) (1.4e-208) (4.4e-107) (4.4e-107) (2.1e-108)
Adj. R2 0.996228 0.997732 0.996116 0.998855 0.998855 0.998877
SW-test 0.993543 0.99444 0.993485 0.86117 0.86117 0.862828
(0.687383) (0.79646) (0.68016) (4.49e-011) (4.49e-011) (4.905e-011)
D-W test 0.323837 0.307217 0.313002 1.934392 1.934392 1.940043
(1.855e-016)
(6.85e-005) (0.000)
K. Ayinde et al.
a 12000
99 percent interval
10000 Confirmed_cases
forecast
8000
6000
4000
2000
0
-2000
-4000
-6000
-8000
-10000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 80
99 percent interval
Death_cases
60
forecast
40
20
-20
-40
-60
-80
2020.6 2020.7 2020.8 2020.9 2021
Guinea b the actual, fitted and predicted values of cumulative COVID-19 death cases in Guinea
4.8 Data Analysis of Guinea Bissau
The results obtained from the six (6) estimation methods on cumulative confirmed
and death cases in Guinea Bissau are summarily presented in Table 11.
From Table 11, the results of the OLS estimation method reveal the violation of
assumption of normality of error terms (SW = 0.979326, p-value < 0.01), indepen-
dence of error terms (DW = 0.0649415, p-value < 0.01) and non-constant variance
(LM = 87.54525, p-value < 0.01) of error terms. Correcting each of these violations
with an appropriate estimator identifies the CORC, HILU and PW estimator to be
better because of their highest Adjusted Coefficient of determination (Adj. R2 =
0.9992). Meanwhile, the PW estimator is used for forecast purpose. It has the closest
value of Durbin Waston Statistic to 2. Figure 31a presents the fitted model, actual
values and the predicted values for the remaining days in the year 2020.
From Fig. 31a, it becomes evident that the model fits the actual data well, and this
supports the fact that the time variables explained 99.92% of variations in the cumu-
lative confirmed cases. The flattened downward movement of the forecast values
addresses that COVID-19 cases are expected to become insignificant or trivial before
424
Table 11 Summary of results on cumulative COVID-19 confirmed and death cases in Guinea Bissau
(3.9e-167) (1.3e-195) (2.46e-22) (1.10e-24) (3.96e-22)
Adj. R2 0.986879 0.993721 0.985741 0.999175 0.999174 0.999173
SW-test 0.979326 0.927917 0.928033 0.835627 0.837258 0.805935
(0.00812) (7.06e-008) (7.2e-008) (4.7e-013) (5.55e-013) (2.49e-014)
D-W test 0.0649415 0.054519 0.058081 2.094524 2.090137 2.057565
(0.000000)
(1.64e-014) (0.0000)
Death cases F 2669.615 9334.961 133.0199 132.2254 140.6630
(4.3e-136) (9.7e-176) (1.20e-47) (1.69e-47) (3.30e-49)
Adj. R2 0.986051 0.995972 0.985879 0.996660 0.996660 0.996712
SW-test 0.991316 0.994677 0.990193 0.617608 0.617169 0.608377
(0.480341) (0.855693) (0.3725) (3.34e-018) (3.27e-018) (1.811e-018)
D-W test 0.252077 0.234794 0.248592 2.076590 2.077273 2.067795
(3.003e-016)
(0.000642) (0.0000)
K. Ayinde et al.
a 2800
99 percent interval
Confirmed_cases
2600 forecast
2400
2200
2000
1800
1600
1400
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 220
99 percent interval
200 Death_cases
forecast
180
160
140
120
100
80
60
40
20
2020.55 2020.6 2020.65 2020.7 2020.75 2020.8 2020.85 2020.9 2020.95 2021
Fig. 31 a The actual, fitted and predicted values of cumulative COVID-19 Confirmed Cases in
Guinea Bissau b the actual, fitted and predicted values of cumulative COVID-19 death cases in
Guinea Bissau
the end of the year provided all current measures of the Government are not reduced
but are rather maintained or improved.
Furthermore from Table 11, the results of the OLS estimation method show the
significant joint effect of all the time variables (F = 2669.615, p-value < 0.01), and
that there is a serial correlation of the error terms (DW = 0.252077, p-value < 0.01)
and non-homogeneous variance (LM = 30.764657, p-value < 0.01) in the model. The
correction is done to reveal the best estimator to be the PW estimator with the highest
Adjusted Co-efficient Determination of 0.996712 and the value of the DubinWaston
statistic closest to 2. Thus, the time variables explain 99.67% of the variation in the
cumulative death cases. Figure 31b graphically show the fitted model, actual values
and the predicted values for the rest of the year 2020.
From Fig. 31b, it is seen that the model fits the actual data well. There is a
downward movement of the forecast values as the day increases. As a result, the
Government is expected to plan and put on measures to avoid an increase in the
death of COVID-19 patients as the year runs to an end and even after that.
4.9 Data Analysis of Liberia
Having applied the six (6) estimation methods to the data set on cumulative confirmed
and death cases in Liberia, Table 12 presents the summary results.
From Table 12, the OLS estimation results reveal the presence of non-normality
of error terms (SW = 0.979766, p-value < 0.01), autocorrelation (DW = 0.0245459,
p-value < 0.01) and heterogeneous error variance (LM = 64.826668, p-value < 0.01)
of error terms, and so, the OLS estimator is not appropriate. With the Correction
of the each of these violations using appropriate estimator, the best estimator is
the CORC estimator having the highest Adjusted Coefficient of determination (Adj.
R2 = 0.999794) and Durbin Waston Statistic value closest to 2. Meanwhile, the
results of HILU and PW estimators are not too different from that of CORC. The
actual values, the fitted model with the CORC estimator and the forecast values are
graphically presented in Fig. 32a.
From Fig. 32a, it becomes clear that the model fits the actual data very well and this
further buttresses the 99.98% variations in the cumulative confirmed cases explained
by the time variables. The upward movement of the forecast values indicates that
COVID-19 cases are expected to become very serious as the day increases towards
the end of the year. The Government is therefore expected to look more critically
into this by providing additional measures to avert coming increasing pandemic.
Furthermore from Table 12, the results of the OLS estimation method show that
there is a significant joint effect of all the time variables on the cumulative death
cases (F = 1716.387, p-value < 0.01), and that there are both autocorrelations (DW
= 0.0934471, p-value < 0.01) and heteroscedasticity problems (LM = 101.141477,
p-value < 0.01) in the model. With the corrections of each of these problems, the best
estimator is identified to be the HILU estimator with the highest Adjusted Co-efficient
Determination of 0.997773 and the value of the DubinWaston statistic closest to 2.
Thus, the time variables explain 99.78% of the variation in the cumulative death
cases. The appropriateness of the model with the actual value and the forecast values
for the rest of the year 2020 are shown in Fig. 32b.
From Fig. 32b, it can be seen that there is a downward expectation of the movement
of the forecast values for the remaining days of the year. This implies that death cases
would be insignificant or trivial in Liberia as the year ends provided all the measures
currently put in place are maintained and possibly improved by the Government.
4.10 Data Analysis of Mali
The six (6) estimation methods were applied to the data set on cumulative confirmed
and death cases in Mali, and the summary of results obtained are presented in Table
13.
From Table 13, it can be observed that the OLS estimation results of the cumulative
confirmed cases reveal that the error terms in the model are not normally distributed
Table 12 Summary of results on cumulative COVID-19 confirmed and death cases in Liberia
(7.1e-188) (2.3e-217) (5.15e-16) (6.98e-40) (3.52e-21)
Adj. R2 0.990064 0.995175 0.989453 0.999794 0.999366 0.999777
SW-test 0.979766 0.982097 0.973073 0.889018 0.979464 0.869668
(0.0068262) (0.014442) (0.0009) (9.88e-011) (0.0064) (7.69e-012)
D-W test 0.0245459 0.023182 0.021922 1.883716 3.462330 1.711921
(0.000000)
(1.161e-009) (0.0000)
Death cases F 1716.387 6492.413 23.61442 15.34098 25.96751

(1.2e-135) (8.4e-184) (1.66e-15) (1.03e-10) (8.69e-17)
Adj. R2 0.975407 0.993381 0.974918 0.997773 0.997773 0.997798
SW-test 0.985822 0.967678 0.970198 0.487345 0.481334 0.472534
(0.0755741) (0.000453) (0.00087) (3.35e-022) (2.59e-022) (1.547e-022)
D-W test 0.0934471 0.082294 0.088785 1.902105 1.915651 1.899974
(0.000000)
(3.21969e-017) (0.0000)
427
a 11000
99 percent interval
forecast
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 100
Death_cases
forecast
-100
-200
-300
-400
-500
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Liberia b the actual, fitted and predicted values of cumulative COVID-19 death cases in Liberia
( SW = 0.970162, p-value < 0.01) have autocorrelation (DW = 0.080702, p-value

< 0.01) and heteroscedasticity (LM = 55.676775, p-value < 0.01), and that after
correcting each of the problems the PW estimator is identified as best. It has the
highest Adjusted Coefficient of determination (Adj. R2 = 0.999812), and its Durbin
Watson Statistic value (1.933750) is closest to 2. Thus, it was used for prediction
purpose even though the HILU and CORC estimators perform very similarly. The
fitted model with the actual values as well as the predicted values for the rest of the
year 2020 is graphically presented in Fig. 33a. From Fig. 33a, it can be observed
that the fitted model precisely captured the fluctuations in the data as the Adjusted
Coefficient of Determination revealed that the time variables explained 99.98% of
the variation in the cumulative confirmed cases. The predicted values show clearly
that the COVID-19 would still be a severe issue even till the end of the year 2020.
There is an upward increase as time increases. Consequently, the Government of Mali
needs not to relax at all against their struggle to combat the pandemic. However, it
should continue and even improve the various measures already put in place.
Furthermore from Table 13, the results from OLS estimation point to the existence
of non-normality error terms (SW = 0.98202, p-value < 0.05), autocorrelated error
terms (DW = 0.128885, p-value < 0.01) and non-homogeneous error variance (LM =
28.561345, p-value < 0.01) in the model; and that correcting for each of the violations
resulted into identifying the PW estimator as the best, having the Highest Coefficient
Table 13 Summary of results on cumulative COVID-19 confirmed and death cases in Mali
(3.5e-233) (2.1e-262) (9.65e-94) (8.63e-99) (2.47e-67)
Adj. R2 0.997543 0.998841 0.997361 0.999811 0.999811 0.999812
SW-test 0.970162 0.958757 0.959473 0.853662 0.855134 0.845438
(0.0006) (3.21e-005) (3.8e-005) (2.90e-012) (3.38e-012) (1.08e-012)
D-W test 0.080702 0.070148 0.068491 1.929165 1.922426 1.933750
(0.0000) (0.0000) (0.0000) (0.0000) (0.0000)
(0.000000) (0.0000)
Death cases F 11,403.04 13,918.39 299.4662 264.7591 190.9927

(2.4e-207) (9.0e-215) (4.39e-76) (4.04e-72) (3.80e-62)
Adj. R2 0.996156 0.996848 0.995841 0.999523 0.999523 0.999530
SW-test 0.98202 0.993568 0.986892 0.890851 0.89044 0.891263
(0.0220203) (0.631884) (0.09833) (4.55e-010) (4.31e-010) (4.43e-010)
D-W test 0.128885 0.118987 0.118671 1.941712 1.948373 1.953790
(0.0000) (0.0000) (0.0000) (0.0000) (0.0000)
(0.001467) (0.0000)
429
a 14000
99 percent interval
CONFIRMED
forecast
12000
10000
8000
6000
4000
2000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 900
99 percent interval
SDEATH
800 forecast
700
600
500
400
300
200
100
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 33 a The actual, fitted and predicted values of cumulative COVID-19 confirmed cases in mali
b the actual, fitted and predicted values of cumulative COVID-19 death cases in Mali
of Determination (Adj. R2 = 0.999530) and the Durbin Waston Statistic value (DW
= 1.953790) closest to 2. The pictorial representation of the fitted model to actual
values is provided in Fig. 33b. From Fig. 33b, it is clear that the model fit the data
very well in that the time factors explained 99.95% of variations in the cumulative
death cases. There is also an upward movement of forecast values as time increases
towards the end of the year 2020. Thus, the Government would need to put in serious
measures to take of those already affected with COVID-19 to avert their increase in
their death as the year runs by.
4.11 Data Analysis of Mauritania
Results from the six (6) estimation methods applied to the data set on cumulative
confirmed and death cases in Mauritania are summarized in Table 14.
Table 14, among other results, presents the OLS estimation results of the cumu-
lative confirmed cases of Mauritania. It reveals that the error terms in model are not
normally distributed (SW = 0.963866, p-value < 0.01) have autocorrelation (DW
= 0.0354521, p-value < 0.01) and heteroscedasticity (LM = 93.930945, p-value <
0.01), and further identifies the CORC estimator as best for prediction purpose. It
has the highest Adjusted Coefficient of determination (Adj. R2 = 0.999344) with
Durbin Watson Statistic value (2.427432) closest to 2. Moreover, the results of the
HILU and PW estimators are also similar to that of CORC. The fitted model with the
actual values as well as the predicted values for the rest of the year 2020 is presented
in Fig. 34a. From Fig. 34a, it can be observed that the fitted model captured well the
fluctuations in the data as the Adjusted Coefficient of Determination revealed that the
time variables explained 99.93% of the variations in the cumulative confirmed cases.
The forecast values show upward movement as time increase, and this indicates that
COVID-19 would still be a serious issue even till the end of the year 2020. Conse-
quently, the Government needs not to relax that the pandemic has been overcome
but should rather assess the existing measures to maintain or improve them.
Furthermore from Table 14, the OLS estimation results of the cumulative death
cases reveals the presence of non-normality of error terms (SW = 0.95363, p-value
< 0.01) autocorrelation (DW = 0.05971, p-value < 0.01) and non-constant variance
(LM = 86.615447, p-value < 0.01). The HILU estimator, among others, is identified
as best for forecast purpose having the highest Adjusted Coefficient of determination
(Adj. R2 = 0.998899) with Durbin Watson Statistic value (2.34543) closest to 2.
Moreover, the results of the CORC and PW estimators are also similar to that of
HILU. In Fig. 34b, the fitted model with the actual values as well as the predicted
values for the rest of the year 2020 is presented. From Fig. 34b, it is observed that the
fitted model captured the fluctuations in the data very well as the Adjusted Coefficient
of Determination reveals that the time variables explained 99.89% of the variations
in the cumulative death cases. The forecast values show upward movement as day
increases and moves to the end of the year 2020. This indicates the expected severity
of COVID-19 death cases expected toward the end of the year. Consequently, the
Government needs to increase measures to manage COVID-19 confirmed cases to
reduce their possible increased deaths.
432
Table 14 Summary of results on cumulative COVID-19 confirmed and death cases in Mauritania
(7.1e-159) (9.8e-184) (4.56e-19) (3.92e-15) (1.11e-14)
Adj. R2 0.978934 0.988470 0.974958 0.999344 0.999344 0.999294
SW-test 0.963866 0.972334 0.905051 0.740244 0.739013 0.687456
(6.66e-005) (0.00067) (7.7e-010) (3.69e-017) (3.37e-017) (8.29e-019)
D-W test 0.0354521 0.031776 0.028231 2.427432 2.436713 2.245453
(0.000000)
(8.87e-016) (0.0000)
Death cases F 2006.464 3571.777 97.42699 100.6648 17.95763
(1.7e-142) (1.5e-163) (6.18e-43) (8.93e-44) (2.50e-12)
Adj. R2 0.978650 0.987896 0.995841 0.998899 0.998899 0.998813
SW-test 0.95363 0.868753 0.868808 0.709493 0.710719 0.677538
(1.539e-005) (2.96e-011) (2.9e-011) (3.46e-017) (3.75e-017) (3.96e-018)
D-W test 0.059710 0.051876 0.118671 2.347521 2.345430 2.224587
(0.000000)
(7.65e-014) (0.0000)
K. Ayinde et al.
a 80000
99 percent interval
forecast
60000
50000
40000
30000
20000
10000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 2500
99 percent interval
Death_cases
forecast
2000
1500
1000
500
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Mauritania b the actual, fitted and predicted values of cumulative COVID-19 death cases in
Mauritania
4.12 Data Analysis of the Republic of Niger
The summary results of the six (6) estimation methods to data on cumulative
confirmed and death cases in Niger are provided in Table 15.
From Table 15, it can be seen that the results based on the OLS estimation method
of the cumulative confirmed cases reveal that the error terms in the model are not
normally distributed (SW = 0.815294, p-value < 0.01), are related (DW = 0.073029,
p-value < 0.01) and possess non-constant error variances (LM = 116.028677, p-value
< 0.01); and that attempting to correct each of the problems resulted into identifying
the CORC estimator as the best estimator for prediction purpose. It has the highest
Statistic value (1.083594) is closer to 2. Moreover, the HILU and PW estimators
perform very similarly. The graphical representation of the fitted model with the
actual values as well as the predicted values for the rest of the year 2020 is presented
in Fig. 35a. From Fig. 35a, it is observed that the fitted model well captures the fluc-
tuations in the actual cumulative confirmed cases, and this supports the fact that the
time variables explained 99.9% of the variations in the cumulative confirmed cases.
The forecast values show clearly downward movement as time increase towards the
434
Table 15 Summary of results on cumulative COVID-19 confirmed and death cases in Niger
(5.1e-167) (3.3e-175) (2.01e-69) (9.96e-70) (0.068342)
Adj. R2 0.984847 0.987654 0.984559 0.999138 0.999138 0.999030
SW-test 0.815294 0.659812 0.766438 0.78273 0.783075 0.719413
(3.31e-014) (2.88e-019) (4.7e-016) (2.00e-015) (2.06e-015) (1.40e-017)
D-W test 0.073029 0.044719 0.065129 1.083594 1.083295 1.005977
(0.0000) (0.0000) (0.0000) (0.0000) (0.0000)
(0.0000) (0.0000)
Death cases F 2837.525 3084.688 49.47209 43.60875 8.018607
(2.3e-161) (1.4e-164) (5.50e-28) (1.63e-25) ( 5.69e-06)
Adj. R2 0.984042 0.985302 0.980271 0.999093 0.999093 0.999033
SW-test 0.970546 0.954147 0.937703 0.755898 0.755618 0.808831
(0.0006) (1.06e-005) (3.6e-007) (3.50e-016) (3.42e-016) (2.667e-014)
D-W test 0.064257 0.058495 0.054366 2.183816 2.188771 2.034946
(0.0000) (0.0000) (0.0000) (0.0000) (0.0000)
(0.0000) (0.0000)
K. Ayinde et al.
end of the year 2020. This implies that as time progresses towards the end of the
year, the curve would flatten out, meaning that an increase in the confirmed cases
would become insignificant or trivial. Consequently, the Government of Niger needs
not to relent on its measures against the virus but instead maintain or improve them.
Furthermore from Table 15, there is existence of non-normality error terms (SW
= 0.970546, p-value < 0.05), dependent error terms (DW = 0.064257, p-value <
0.01) and non homogeneous error variance (LM = 54.542983, p-value < 0.01) in the
model based on the OLS estimation of the model’s parameters. With each of these
problems corrected using appropriate estimators, the best estimator is identified to
a 2000 99 percent interval

confirmed
forecast
1000
-1000
-2000
-3000
-4000
-5000
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 80
99 percent interval
Death
forecast
60
40
20
-20
-40
-60
-80
-100
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Fig. 35 a The actual, fitted and predicted values of cumulative COVID-19 confirmed cases in Niger
b the actual, fitted and predicted values of cumulative COVID-19 death cases in Niger
be COCR having the Highest Coefficient of Determination (Adj. R2 = 0.999093)

and its Durbin Watson Statistic value (DW = 2.183816) closest to 2. The pictorial
representation of the fitted model to actual values and the forecast values are provided
in Fig. 35b. From Fig. 35b, it is apparent that the model fits the data very well in
that 99.91% of variations in the cumulative death cases explained by the time factors
are well supported. However, the downward movement of cumulative death cases
points to the expected insignificant or trivial cases before the end of the year. The
Government is as a result of this encouraged to continue with measures currently on
the ground and if possible, improve or increase them.
4.13 Data Analysis of Nigeria
confirmed and death cases in Nigeria are provided in Table 16.
Table 16 shows the results based on the OLS estimation method of the cumulative
confirmed cases, among other estimators. It is observed that there is violation of
assumptions of normality of error terms (SW = 0.981259, p-value < 0.01), indepen-
dence of error terms (DW = 0.0251698, p-value < 0.01) and constant variance of
error terms (LM = 122.000864, p-value < 0.01) in model. Among the estimators used
to correct each of these problems, the HILU estimator is best in that it has the highest
Statistic value (1.587732) is closest to 2. Moreover, the performances of the CORC
and PW estimators are also similar to that of HILU. The graphical representation of
the fitted model, the actual values and the predicted values for the rest of the year
2020 are presented in Fig. 36a.
From the Fig. 36a, it is clear that the fluctuations in the actual cumulative confirmed
cases are adequately and well captured by the fitted model, and this further buttresses
the fact that the time variables explained 99.998% of the variations in the cumulative
confirmed cases. The forecast values show clearly a slow upward movement as time
increase towards the end of the year 2020. With this, the Nigerian Government needs
not to relax against its COVID-19 measures but should somewhat improve them
drastically.
Furthermore from Table 16, there exist the problems of non-normality error terms
(SW = 0.984848, p-value < 0.05), autocorrelation (DW = 0.0997005, p-value < 0.01)
heterogeneous error variance (LM = 29.832720, p-value < 0.01) in the model based
on the OLS estimation of the parameters of the model. Having made various attempts
to correct these problems, With each of these problems corrected using appropriate
estimators, the best estimator is the HILU estimator having the Highest Coefficient
of Determination (Adj. R2 = 0.999893) and its Durbin Watson Statistic value (DW
= 1.788105) closest to 2. The graphical representation of the fitted model, the actual
values and the forecast values are provided in Fig. 36b.
From Fig. 36b, it is apparent that the model fits the data very well in that the
time variables explain 99.989% of variations in the cumulative death cases. Also,
Table 16 Summary of results on cumulative COVID-19 confirmed and death cases in Nigeria
(0.000000) (0.000000) (2.4e-135) (9.08e-89) (4.42e-97)
Adj. R2 0.999021 0.999328 0.998955 0.999983 0.999984 0.999980
SW-test 0.981259 0.898246 0.890493 0.98809 0.982816 0.969021
(0.00658) (8.69e-011) (2.83e-11) (0.077239) (0.01556) (0.000136)
D-W test 0.0251698 0.023976 0.024684 1.217637 1.587732 1.025496
(6.109e-017)
(7.173e-021) (0.0000)
Death cases F 39,657.58 55,276.83 1448.590 1140.894 615.6986

(4.0e-265) (3.6e-278) (1.1e-135) (1.2e-126) (3.5e-104)
Adj. R2 0.998835 0.999164 0.998816 0.999893 0.999893 0.999889
SW-test 0.984848 0.988874 0.990171 0.921425 0.91946 0.930608
(0.0422595) (0.154566) (0.2318) (2.06e-008) (1.49e-008) (9.28e-008)
D-W test 0.0997005 0.093045 0.097042 1.776774 1.788105 1.723664
(0.000000)
(0.00168) (0.0000)
437
a 160000
99 percent interval
Confirmed_cases
140000 forecast
120000
100000
80000
60000
40000
20000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 2000
99 percent interval
Death_Cases
forecast
1800
1600
1400
1200
1000
800
600
400
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Nigeria b the actual, fitted and predicted values of cumulative COVID-19 death cases in Nigeria
the upward movement of cumulative death cases indicates that death as a result of
COVID-19 is expected to increase as day increases towards the end of the year 2020.
As a result, the Government at this moment needs to know that with measures to be
further taken to ensure a reduction in COVID-19 confirmed cases.
4.14 Data Analysis of Senegal
confirmed and death cases in Senegal are provided in Table 17.
From Table 17, it can be seen that the results based on the OLS estimation method
of the cumulative confirmed cases reveal that the error terms in model are not normally
distributed (SW = 0.971506, p-value < 0.01), are related (DW = 0.0188515, p-
value < 0.01) and possess non-constant error variances (LM = 51.007703, p-value
< 0.01). Attempting to correct each of the problems resulted into recognizing the
CORC, HILU and PW estimators as best They have the highest Adjusted Coefficient
of determination (Adj. R2 = 1.0000). However, the PW estimator was used for
prediction because its Durbin Watson Statistic value is the closest to 2. The graphical
representation of the fitted model with the actual values as well as the predicted
values for the rest of the year 2020 is presented in Fig. 37a.
From Fig. 37a, it is observed that the fitted model fully captures the fluctuations
in the actual cumulative confirmed cases, and this supports the fact that the time
variables explained 100% of the variations in the cumulative confirmed cases. The
forecast values reveal upward movement as time increases towards the end of the
year 2020. Consequently, the Government of Senegal needs to intensify its measures
against the pandemic and possibly add more to combat this expected increase.
Furthermore from Table 17, it is observed that the results of the OLS estimation on
the cumulative death cases have non-normal error terms, (SW = 0.982927, p-value <
0.05), autocorrelation (DW = 0.145259, p-value < 0.01) and heteroscedasticity (LM
= 56.164394, p-value < 0.01); and that correcting each of the problems resulted into
identifying the HILU estimator as best estimator while the CORC and PW estimators
do not perform differently. The HILU estimator has the highest Adjusted Coefficient
of determination (Adj. R2 = 0.999870) and its Durbin Watson Statistic value closest
to 2. It was used for prediction purpose. The graphical representation of the fitted
model with the actual values as well as the predicted values for the rest of the year
2020 is presented in Fig. 37b.
From Fig. 37b, the fluctuations in the actual cumulative death cases are well
captured by the fitted model, and this supports the fact that the time variables
explained 99.99% of the variations in the cumulative death cases. The forecast values
show clearly downward movement as time increase towards the end of the year 2020.
This implies that as time progresses towards the end of the year, the curve is expected
to flatten out, meaning that an increase in the confirmed cases would become insignif-
icant or trivial. Consequently, the Government needs not to relent on its measures
440
Table 17 Summary of results on cumulative COVID-19 confirmed and death cases in Senegal
Confirmed cases F 5,004,566 5,153,275 159,453.4 112,680.9 111,340.4
(0.000000) (0.000000) (0.000000) (0.000000) (0.000000)
Adj. R2 0.99999 0.99999 0.999989 1.000000 1.000000 1.000000
SW-test 0.971506 0.983853 0.988186 0.94829 0.948499 0.985839
(0.000331) (0.01807) (0.08453) (9.34e-007) (9.78e-007) (0.03648)
D-W test 0.0188515 0.014971 0.017419 0.056090 0.056347 0.084396
(0.000000)
(1.741e-007) (0.0000)
Death cases F 47,082.27 236,418.7 1313.811 1331.775 15.91485
(3.3e-260) (0.000000) (3.5e-127) (1.1e-127) (4.49e-07)
Adj. R2 0.999066 0.999814 0.99975 0.999870 0.999870 0.999798
SW-test 0.982927 0.972952 0.980555 0.964751 0.964802 0.947056
(0.0290244) (0.001602) (0.01416) (0.0002) (0.000202) (3.677e-006)
D-W test 0.145259 0.137489 0.155486 2.131208 2.130257 1.423323
(1.367e-016)
(1.912e-008) (0.000)
K. Ayinde et al.
a 2.5e+006
99 percent interval
Confirmed_cases
forecast
2e+006
1.5e+006
1e+006
500000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 400
99 percent interval
Death_cases
forecast
200
-200
-400
-600
-800
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Senegal b the actual, fitted and predicted values of cumulative COVID-19 death cases in Senegal
to reduce the death of COVID-19 confirmed cases but rather maintain or improve
them.
4.15 Data Analysis of Sierra Leone
The summary of results obtained from the six (6) estimation methods on cumulative
confirmed and death cases in Sierra Leone are provided in Table 18.
From Table 18, the results based on the OLS estimation method of the cumula-
tive confirmed cases, among other estimators, is presented. It is observed that the
joint effects of the time variables on cumulative confirmed cases are significant (F
= 46,946.6, p-value < 0.01) and the assumptions of no serial correlation (W =
0.0251698, p-value < 0.01) and no heteroscedasticity (LM = 122.000864, p-value
< 0.01) are violated. Among the estimators used to correct each of these problems,
the HILU estimator is best in that it has the highest Adjusted Coefficient of deter-
mination (Adj. R2 = 0.999852) and its Durbin Watson Statistic value (2.191116) is
closest to 2. Moreover, the performances of the CORC and PW estimators are also
very similar. The graphical representation of the fitted model, the actual values and
the predicted values for the rest of the year 2020 are presented in Fig. 38a.
From Fig. 38a, the fluctuations in the actual cumulative confirmed cases are
adequately captured by the fitted model, and this supports the fact that the time
variables explained 99.99% of the variations in the cumulative confirmed cases. The
forecast values reveal upward movement as time increases towards the end of the year
2020. Consequently, the Government of Sierra Leone needs to advance its measures
against the spread of the pandemic and possibly intensify effort to combat the disease.
In addition from Table 18, the OLS estimation results on the cumulative death
cases reveal the presence of non-normality of error terms, (SW = 0.915169, p-
value < 0.01), autocorrelated error terms (DW = 0.173022, p-value < 0.01) and
heteroscedastic error variances (LM = 75.274977, p-value < 0.01) in the model.
Correcting each of the problems resulted in observing the HILU estimator as the
best estimator. In contrast, the CORC and PW estimators do not perform differently.
The HILU estimator having the highest Adjusted Coefficient of determination (Adj.
R2 = 0.998801) also has its Durbin Watson Statistic value closest to 2. It was used
to forecast the cumulative confirmed cases for the rest days in the year 2020. The
graphical representation of the fitted model, the actual values and the predicted values
for the rest of the year 2020 are presented in Fig. 38b.
From Fig. 38b, it is observed that the fluctuations in the actual cumulative death
cases are captured by the fitted model and this fact is well buttressed by 99.88%
of the variations in the cumulative death cases accounted for by the time variables.
The forecast values move downwardly as time increases towards the end of the year
2020. By implication, as time progresses towards the end of the year, the curve is
expected to flatten out and that any increase in the confirmed cases that are seen
would be insignificant or trivial. However, the Government needs not to relent on
its measures but rather maintain its measures and possibly improve them so that this
can be achieved.
Table 18 Summary of results on cumulative COVID-19 confirmed and death cases in Sierra Leone
(2.1e-261) (0.000000) (2.4e-147) (1.1e-147) (3.6e-127)
Adj. R2 0.999058 0.999826 0.999007 0.999852 0.999852 0.999851
SW-test 0.988295 0.986969 0.975891 0.887907 0.887975 0.893608
(0.148337) (0.098668) (0.0035) (2.853e-010) (2.88e-010) (5.58e-010)
D-W test 0.167486 0.156590 0.157260 2.192037 2.191116 2.213146
(0.000000)
(0.000003) (0.0000)
Death cases F 4994.727 2987.480 292.6383 277.3639 64.98794

(2.0e-158) (7.5e-142) (1.81e-69) (6.14e-68) (8.67e-32)
Adj. R2 0.992349 0.987273 0.992235 0.998801 0.998801 0.998758
SW-test 0.915169 0.880845 0.902394 0.866611 0.865654 0.865357
(7.074e-008) (7.95e-010) (1.1896e-008) (1.732e-010) (1.56e-010) (1.374e-010)
D-W test 0.173022 0.163785 0.171409 1.975324 1.980128 1.913837
(0.000000)
(4.21e-012) (0.0000)
443
a 14000
99 percent interval
Confirmed_cases
12000 forecast
10000
8000
6000
4000
2000
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 100
99 percent interval
Death_cases
forecast
50
-50
-100
-150
2020.55 2020.6 2020.65 2020.7 2020.75 2020.8 2020.85 2020.9 2020.95 2021
Fig. 38 a The Actual, fitted and predicted values of cumulative COVID-19 confirmed cases in
Sierra Leone b the actual, fitted and predicted values of cumulative COVID-19 death cases in Sierra
Leone
4.16 Data Analysis of Togo
confirmed and death cases in Togo are provided in Table 19.
From the Table 19, it is observed that the OLS estimation results on the cumulative
confirmed cases contain non-normal error terms (SW = 0.973454, p-value < 0.01),
Table 19 Summary of results on cumulative COVID-19 confirmed and death cases in Togo
(2.0e-234) (2.1e-287) (5.48e-51) (1.74e-42) (3.82e-63)
Adj. R2 0.995754 0.998762 0.99541 0.999819 0.999819 0.999819
SW-test 0.973454 0.975253 0.96863 0.908482 0.908612 0.905608
(0.00069) (0.00119) (0.00017) (7.83e-010) (7.8e-010) (4.681e-010)
D-W test 0.044862 0.040141 0.043585 1.781009 1.786412 1.755367
(0.000000)
(0.000000) (0.0000)
Death cases F 3052.835 4043.749 212.3877 215.6602 169.9608

(4.6e-162) (9.8e-173) (3.23e-66) (1.06e-66) (1.72e-59)
Adj. R2 0.985389 0.988931 0.983566 0.997455 0.997455 0.997444
SW-test 0.988094 0.94346 0.94697 (2.701e-006) 0.788256 0.789125 0.78618
(0.129677) (1.33e-006) (6.5e-015) (7.00e-015) (4.92e-015)
D-W test 0.183710 0.149998 0.159916 1.835966 1.834475 1.827901
(1.537e-017)
(3.367e-007) (0.0000)
445
autocorrelated error terms (DW = 0.044862, p-value < 0.01) and non-constant error
terms (LM = 75.086744, p-value < 0.01). Of all the estimators used in correcting each
of these problems, the CORC, HILU and PW estimators provide better results in that
they have the highest Adjusted Coefficient of determination (Adj. R2 = 0.999819).
More importantly, the HILU is considered best because of its result that removes
autocorrelation better than others, Durbin Watson Statistic value (1.786412) which
is closest to 2. Thus, HILU estimator was used to forecasting for the rest days of the
year 2020, as shown together with the fitted model and actual values of cumulative
confirmed cases in Fig. 39a.
From Fig. 39a, the fitted model can capture the fluctuations in the cumulative
confirmed cases very well, and this supports the fact that the time variables explain
a 2200 99 percent interval

2000 Confirmed
forecast
1800
1600
1400
1200
1000
800
600
400
200
2020.5 2020.6 2020.7 2020.8 2020.9 2021
b 140
99 percent interval
Death
forecast
120
100
80
60
40
20
0
2020.5 2020.6 2020.7 2020.8 2020.9 2021
Sierra Leone b the actual, fitted and predicted values of cumulative COVID-19 death cases in Togo
99.98% of the variations cumulative confirmed cases. The downward movement or

steady decrease in the forecast values points the COVID-19 confirmed cases were
becoming insignificant or trivial towards the end of the year. However, this does not
mean all measures put in place by the Government should be withdrawn but instead
be continued, maintained and if possible, improved.
Also from the Table 19, the OLS estimation results reveal that the joint effects
of the time variables on the cumulative death cases are significant (F = 3052.835,
p-value < 0.01), and that there is autocorrelation (DW = 0.183710, p-value < 0.01)
and heteroscedasticity (LM = 51.493617, p-value < 0.01) problems in the model.
Correcting these problems with appropriate estimators results into identifying the
COCR estimator as best, having the highest Adjusted Coefficient of determination
(Adj. R2 = 0.997455) and Durbin Watson Statistic value (1.835966) which is closest
to 2. Thus, the CORC estimator was used to forecast for the remaining days of the year
2020. This is shown together with the fitted model and actual values of cumulative
confirmed cases in Fig. 39b.
From Fig. 39b, the fitted model captures the fluctuations in the cumulative death
cases adequately, and this buttresses the finding that the time variables explain 99.75%
of the variations cumulative death cases. The upward movement in the forecast
values calls for severe measures by the Government to avert an increase in death of
COVID-19 confirmed cases towards the end of the year.
5 Summary and Conclusion
This chapter of the book has modeled COVID-19 cases, cumulative confirmed
and death cases, in all the sixteen (16) West African Countries namely; Benin,
Burkina Faso, Cape Verde, Gambia, Ghana, Guinea, Guinea Bissau, Ivory Coast
(Cote d’Ivoire), Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone
and Togo with Quartic Curve Estimation Model having autocorrelated error term of
order 1 (AR(1)). It provided the best estimator for forecasting for the rest of the year
for each of the countries and established the nature of the movement of the forecast
values between 26th September and 31st December 2020 as summarized in Table
20 so as to avert the threat of COVID-19 through effective monitoring and future
planning in the region.
From Table 20, COVID-19 confirmed cases are expected to be on the increase
towards the end of the year 2020 in Burkina Faso, Cape Verde, Code d’Ivoire, Liberia,
Mali, Mauritania, Nigeria, Senegal and Sierra Leone and as a result, the Government
in these countries need not relax in their fight against COVI-19. However, they need to
ensure that current measures are still maintained and additional ones are put in place
to avert the increase and spread. Furthermore, increase in COVID-19 death cases
are expected in Benin, CapeVerde, Guinea Bissau, Mali, Mauritania, Nigeria and
Togo towards the end of the year 2020; and as a result, these countries would need to
critically look after their COVID-19 confirmed cases and develop measures to ensure
their recovery rather than losing them to death. While COVID-19 cases in countries
Table 20 Estimators and nature of movement of COVID-19 forecast values in West African
Counties between 26th September and 31st December 2020
S/N Country’s name Forecast cumulative confirmed Forecast cumulative death cases
cases
Movement Estimator Movement Estimator
1 Benin Flattened downward HILU Upward HILU
2 Burkina Faso Upward HILU Downward CORC
3 Cape Verde Upward HILU Upward HILU
4 Code D’Ivoire Upward HILU Downward PW
5 The Gambia Downward HILU Downward HILU
6 Ghana Downward CORC Downward PW
7 Guinea Downward PW Downward PW
8 Guinea Bissau Flattened downward PW Upward PW
9 Liberia Upward COCR Downward HILU
10 Mali Upward PW Upward PW
11 Mauritania Upward CORC Upward HILU
12 Niger Downward COCR Downward CORC
13 Nigeria Upward HILU Upward HILU
14 Senegal Upward PW Downward HILU
15 Sierra Leone Upward HILU Downward HILU
16 Togo Downward HILU Upward CORC
like Gambia, Ghana, Guinea and Niger are expected to flatten out towards the year,
they are to be approached with all seriousness in Cape Verde, Mali, Mauritania and
Nigeria as these countries expect an increase in both confirmed and death cases.
References
1. Paul R. Masson, Catherine Anne Pattillo, “Monetary union in West Africa (ECOWAS): is it
desirable and how could it be achieved?” (Introduction). International Monetary Fund, 2001.
ISBN 1–58906–014–8
2. Lancet Glob Health COVID-19 Pandemic in West African. Published Online, April 1, 2020;
https://doi.org/10.1016/;S2214-109X(20)30123-6
3. Haider, N., Yavlinsky, A., Simons, D., Osman, A.Y., Ntoumi, F., Zumla, A., Kock, R.: Passen-
gers’ destinations from China: low risk of novel coronavirus (2019-nCoV) transmission into
Africa and South America. Epidemiology & Infection 148 (2020)
4. World Food Programme: Global Report on Food Crisis, 37 (2020)
5. Organization, W.H.: World Health Organization, 13 June (2020). Retrieved April 27, 2020.
https://www.who.int/csr/don/13-june-2016-lassa-fever-benin/en/
6. World Federation of Societies of Anaesthesiologists—Coronavirus. https://www.wfsahq.org/
resources/coronavirus. Retrieved 15 March 2020
7. WHO (2020). World Health Organization (Novel Coronavirus 2019–nCov): Available

at https://www.who.int/emergencies/disease/novel-coronavirus-2019. Accessed 7 February
2020
8. LoïcBisson and Thea Hambleton: COVID-19 Impact on West African Value Chains.
Clingendael, Netherlands Institute of International Relations (2020)
9. Edwin Nuwagira, C.M.: Is Sub- Saharan Africa prepared for Covid-19? Tropical Medicine
and Health 48, 18 (2020)
10. Paintsel, E.: Covid-19 threatens health systems in sub-Saharan Africa: the eye of the Crocodile.
J. clinical Investigation (2020)
11. Guo, Y., Cao, Q., Si, H., Yan, Y.: The origin, transmission and clinical therapies on coronavirus
disease (COVID-19) outbreak—an update on the status. Mil. Med. Res. 2019, 71 (2019).
https://doi.org/10.1186/s40779-020-00240.0
12. High consequences infectious diseases (HCID). Guidiance and information about high conse-
quence infectious diseases and their management in England. Gov.UK. Achived from the
original on 3rd March,2020. Retrieved 17th March,2020.
13. Coronavirus: Benin records second positive case. Panapress. 19th March,2020. Retrieved 19
March, 2020.
14. Coronavirus(Covid-19). Gouvernment de la Republique du Benin(in french). Retrieved 27
June, 2020.
15. BayaneBouraima, M., Zonon, B., Oiu, Y.: The first 100 days: Covid-19 Pandemic in the West
African Economic and Monetary Union (WAEMU). EJMI (2020). https://doi.org/10.14744/
ejmi.2020.61816
16. UNICEF: United Nation Children Education Funds. [Benin]: Covid-19 Situation Reports
(2020)
17. Domenico Cucinotta, M.V.: WHO declares Covid-19 a Pandemic. (E. O. Biomedica, Ed)
ActaBiomedica 91(1), 159–160 (2020)
18. Asiedu, K.: Four government ministers contacted coronavirus in Burkina Faso and it’s
spreading rapidly” Quartz Africa. Achieved from the original on 1 April 2020 (2020).
Retrieved 1 April, 2020
19. Burkina Faso reports Sub-Saharan Africa’s first coronavirus death as WHO warns ‘prepare for
worst’, France 24. 19 March, 2020. Achieved from the original on 30 March, 2020. Retrieved
1 April, 2020.
20. Wikipedia (2020). COVID-19 Pandemic in Burkina Faso. https://www.sante.gov.bf/
21. Burkina Faso: COVID-19 Situation Report #3, 27th May to 24th June, 2020
22. Burkina Faso: COVID-19 Situation Report #4, 25 June to 22 July, 2020
23. Prentice, A.: “Coronavirus Curfew Creates Water Shortage for Burkina Faso’s Poorest". US
News & World Report, 10 April 2020. Retrieved 11 April 2020
24. Rouamba, T., Samadoulougou, S., Bonnechère, B., Chiêm, B., Kirakoya-Samadoulougou, F.:
What Can We Learn from Burkina Faso COVID-19 Data? Using Phenomenological Models
to Characterize the Initial Growth Dynamic of the Outbreak and to Generate Short-Term
Forecasts (2020). https://doi.org/10.20944/preprints202004.0328.v1
25. Somlanare, R.K., Zidouemba, P.R., Ouedraogo, I.M.: How could the COVID-19 pandemic
impact the econmy of Burkina Faso? Economics Bullentin 40(3), 2034–2046 (2020)
26. ACAPS Thematic report: COVID-19 in the Sahel (2020). Burkina Faso, Mali and Niger:
Vulnerability to COVID-19 Containment Measures, April, 2020
27. https://www.macaubusiness.com/cabo-verde-first-case-of-covid-19-confirmed-boavista-isl
and-quarantined/
28. https://en.wikipedia.org/wiki/Cape_Verde#Development
29. https://en.wikipedia.org/wiki/COVID-19_pandemic_in_Cape_Verde
30. https://www.malaymail.com/news/world/2020/03/24/british-tourist-dies-in-cape-verde-aft
ercontracting-covid-19/1849850
31. https://cv.usembassy.gov/health-alert-government-of-cabo-verde-confirms-45-new-covid-
19-cases-on-boa-vista/
32. https://www.worldometers.info/coronavirus/country/cabo-verde/
33. https://www.worldaware.com/covid-19-alert-cape-verde-postpones-plans-resume-domestic-
flights-through-july-15
34. https://www.osac.gov/Content/Report/9583c290-ca68-44f4-bd0e-18d9ba87d45e
35. http://www.xinhuanet.com/english/2020-03/20/c_138898853.htm
36. https://www.express.co.uk/news/world/1259784/cape-verde-coronavirus-latest-British-tou
rist-deadcovid19-boa-vista
37. https://www.macaubusiness.com/cabo-verde-president-warns-of-covid-19-consequences-
on-development-in-africa/
38. https://www.inforpress.cv/wp-content/uploads/2020/05/Bairros-COVID-19.jpg
39. https://cv.usembassy.gov/health-alert-u-s-embassy-praia-cabo-verde-may-24-2020/
40. https://www.osac.gov/Content/Report/fb9e961e-ce14-48ef-9773-18af1e7b7b81
41. https://www.macaubusiness.com/cabo-verde-country-records-191-positive-coronavirus-
cases/
42. https://cv.usembassy.gov/health-alert-u-s-embassy-praia-cabo-verde-june-29-2020/
43. Adilson, da Silva (2020). Modeling COVID-19 in Cape Verde Islands- An Application of SIR
Model. Preprint Submitted to Elsevier
44. https://en.wikipedia.org/wiki/COVID-19_pandemic_in_Ivory_Coast.
45. Anjorin, A.A.: The coronavirus disease 2019 (COVID-19) pandemic: a review and an update
on cases in Africa. Asian Pac J Trop Med 13(5), 199–203 (2020)
46. Bone, M.: Watching the spread of coronavirus in Cote d’ Ivoire. Atlantic Council, Tuesday,
March 31, 2020. https://www.atlanticcouncil.org/blogs/africasource/watching-the-spread-of-
coronavirus-in-cote-divoire/
47. WHO:”Coronavirus disease (COVID-19) situation report 194” (PDF).1 August 2020. p. 5.
Retrieved 2 August 2020
48. Hoare, B.: The Kingfisher A-Z Encyclopedia, Kingfisher Publications. P.11 ISBN 0–7534–
5569–2 (2002)
49. Population of Cities in Gambia (2019)
50. https://www.garda.com
51. Confirmed Case of COVID-19 in The Gambia. MRC Unit the Gambia, 17 March 2020.
Retrieved 1 April 2020
52. Darboe, M.K.: Gambia confirms first Coronavirus case. Anadolu Agency, 18 March 2020.
Retrieved 1 April 2020.
53. Gambia confirms first Coronavirus case. The Jakarta Post, 18 March 2020. Retrieved 2
April 2020.
54. Gambia Suspends Overseas Travels By Public Officials To Curb Spread of Coronavirus.
Forroyaa, 13 March 2020. Retrieved 2 April 2020
55. Information on COVID-19 Testing at the MRC Unit The Gambia at LSHTM. MRC Unit the
Gambia, 18 March 2020. Retrieved 1 April 2020.
56. COVID-19: Gambia suspends flights from 13 countries. The Point, 20 March 2020. Retrieved 2
April 2020
57. COVID-19: Gambia, Senegal to close the border for 21 days. Retrieved 1 April 2020
58. Health Minister Calls on People to Respect the Border Closure. Foroyaa Newspaper, 28 March
2020. Retrieved 1 April 2020
59. Barrow declares a State of Emergency, amid Corona Infection cases in the Gambia. Mbai, Pa
Nderry (27 March 2020), Freedom Newspaper. Retrieved 1 April 2020
60. Duncan, J.: Two cases of coronavirus confirmed in Ghana. Citi Newsroom (2020). Retrieved
2 July 2020
61. Anyorigya, D.: Coronavirus: Norwegian embassy in Ghana shuts down after staff member
tested positive. Citi Newsroom (2020). Retrieved 3 July 2020
62. Serwaa, D., Lamptey, E., Appiah, A.B., Senkyire, E.K., Ameyaw, J., K. : Knowledge, risk
perception and preparedness towards coronavirus disease-2019(COVID-19) outbreak among
Ghanaians: a quick online cross-sectional survey. PanAfrican J. Med. 35, 2 (2020)
63. https://www.garda.com/crisis24/news-alerts/347306/ghana-authorities-announce-easing-of-
covid-19-restrictions-may-31-update-11
64. Abu-bashal, A.: Ghana pardons 794 prisoners to curb spread of COVID-19. Andolu Agency
(2020). Retrieved 8 July, 2020.
65. Tasamba T.: Guinea reports first confirmed COVID-19 case (2020). Retrieved on 1st July 2020
from https://www.aa.com.tr/en/africa/guinea-reports-first-confirmed-covid-19-case/1765526
66. Shaban A. R. A.: Sudan, Guinea record first cases of coronavirus. Africanews.com (2020).
Retrieve on 1st June 2020 from https://www.africanews.com/2020/03/13/sudan-guinea-rec
ord-first-cases-of-coronavirus/
67. Local Media Report, 2020. Guinean local media reports 1st COVID-19 death. Retrieved on
1st June 2020 from https://www.aa.com.tr/en/africa/guinean-local-media-reports-1st-covid-
19-death/1805369
68. Wikipedia, 2020.
69. U.S. Embassy in Guinea: COVID-19 Information (2020). Retrived on 1st June, 2020 from
https://gn.usembassy.gov/u-s-citizen-services/covid-19-information/
70. WorldAware: COVID-19 Alert: Guinea Declares Nightly Curfews as of March 30 (2020).
Retrieved on 1stApril, 2020 from https://www.worldaware.com/covid-19-alert-guinea-dec
lares-nightly-curfews-march-30
71. Africanews: COVID-19: Guinea’s compulsory mask wearing order takes effect (2020).
Retrieved on 1stJune 2020 from from https://www.africanews.com/2020/04/20/covid-19-gui
nea-s-compulsory-mask-wearing-order-takes-effect//
72. https://reliefweb.int/sites/reliefweb.int/files/resources/UNICEF%20Guinea%20COVID-
19%20Situation%20Report%20No.%209%20%2027%20May%20to%209%20June%202
020.pdf
73. COVID-19 Community Mobility Report (2020). https://www.gstatics.com/covid19/mobility/
2020-04-30_GW_Mobility_Report_en.pdf
74. Building Back Better Start Now: COVID-19 Social Economic Impact Analysis for Guinea
Bissau (2020). https://www.undp.org.Guinea_Bissau_SocialEconomicImpact_UN.pdf
75. Guinea-Bissau confirms first two cases of coronavirus. Reuters, 25th March,
2020.Retrieved 26 May 2020.
76. Guinea Bissau: COVID-19 Situation Report -#12, 20–26 June
77. Afican.cgtn.com. Retrieved 17th June, 2020.
78. Global Health Security Index: Building Collective Action and Accountability (2019). https://
www.ghsindex.org/wp-content/uploads/2020/04/2019-Global-Health-Security-Index.pdf
79. Guinea Bissau: COVID-19 Situation Report -#14
80. Wikipedia: COVID-19 pandemic in Guinea-Bissau—Wikipedia (2020). https://www.en.m.
wikipedia.org
81. Liberia braces for coronavirus with defunct health system. https://www.aljazeera.com.
Retrieved 26th May, 2020
82. ITUC-AFRICA: Covid-19 Response from Liberia (2020). https://www.ituc-africa.org.
83. COVIS-19 Promising Practice Liberia-v.10-phcpi. www.improvingphc.org
84. UNICEF Liberia COVID-19 (2020). https://www.unicef.org. Retrieved 20th September, 2020
85. Wikipedia: COVID-19 pandemic in Mali—Wikipedia (2020). https://www.en.m.wikipe
dia.org
86. Sagaon-Teyssier, L.„ Yattassaye, A., Bourrelly, M., Keita, B., Spire, B.: The COVID-19
response must integrate people living with HIV needs in Sub-Saharan Africa: The Case of
Mali.Tropical Medicine and Health, 41 (2020). https://doi.org/10.1186/s41182-020-00228-5
87. Mali: COVID-19 Situation Report- #04. Reporting period: 18th May–30th June, 2020. https://
www.unicef.org
88. Mauritania: UNDP in Africa. https://www.africa.undp.org
89. Mauritania: COVID-19 Situation Report No.3. https://www.unicef.org
90. Mauritania: Facing the pandemic of COVI-19-IYUC-Africa. https://www.itcu-africa.org
91. Gilbert, M., Pullano, G., Pinotti, F., Valdano, E., Poletto, C., Boelle, P., D’Ortenzio, E.,
Yazdanpanah, Y., Eholie, S.P., Altmann, M., Gutierrez, B., Kraemer, M.U.G., Colizza, V.:
Preparedness and vulnerability of African countries against importations of COVID-19: a
modelling study. The Lancet 395(10227), 871–877 (2020). https://doi.org/10.1016/S0140-
6736(20)30411-6
92. African Union: African Union Mobilizes Continent-Wide Response toCOVID-19 Outbreak
(2020). https://au.int/en/pressreleases/20200224/africanunion-mobilizes-continent-wide-res
ponse-covid-19-outbreak. Accessed 27 March 2020
93. Évolution du Coronavirus au Niger en temps réel—Coronavirus, Covid19. Retrieved 27
June 2020.
94. Niger: Civil society organisations call on authorities to end harassment of human rights
defenders www.amnesty.org. Retrieved 25 March 2020.
95. NIGER: COVID-19 Situation Report- #03
96. Wahid, B.K.A., Moustapha, D., Rabi, H.G., Bisso, S.: Contribution to the Mathematical
Modeling of COVID-19 in Niger. Appl. Math. 11, 427–435 (2020). https://doi.org/10.4236/
am.2020.116030
97. ITUC-AFRICA: Niger–even more vulnerable with the COVID-19 crisis (2020). www.ituc-
africa.org
98. Ayinde, K., Lukman A.F., Rauf, I.R., Alabi, O.O., Okon, C.E., Ayinde, O.E.: Modeling Nige-
rian Covid-19 Cases: A Comparative Analysis of Models and Estimators. Chaos, Solitons
and Fractals, 138 (2020). https://doi.org/10.1016/j.chaos.2020.109911
99. Gardaworld, 2020. New Alert full History. Retrieved on 8th July 2020 from https://www.
garda.com/crisis24/news-alert-full-history/HESSzegoWQCcJGQSp/nigeria-first-corona
virus-case-confirmed-in-nigeria-february-27
modelling of COVID-19 confirmed cases in Nigeria. Infectious Disease Modelling 5, 543–548
(2020)
101. Worldometers: COVID-19 Corona virus Pandemic (2020). Retrieved from https://www.wor
ldometers.info/coronavirus/#countries
102. Wikipedia: COVID-19 pandemic lockdowns (2020). Retrieved from https://en.wikipedia.org/
wiki/COVID-19_pandemic_lockdowns
103. NCDC: An update of the COVID-19 outbreak in Nigeria (2020). Retrieved
from https://ncdc.gov.ng/diseases/sitreps/?cat=14&name=An%20update%20of%20COVID-
19%20outbreak%20in%20Nigeria
104. Wikipedia: COVID-19 pandemic in Africa (2020). Retrieved from https://en.wikipedia.org/
wiki/COVID-19_pandemic_in_Africa
105. Rauf, R.I., OluwakemiOladipo, H.: Forecasting the spread of COVID-19 in Nigeria using
Box-Jenkins Modeling Procedure. MedRiv preprint (2020). https://doi.org/10.1101/2020.05.
20091686
106. Adeyeri, O.E., Oyekan, K.S.A., Ige, S.O, Akinbola, A., Okogbue, E.C.: Modelling COVID-19
cases in Nigeria: Forecast, uncertainties, projections and link with weather. Research Square
(2020). https://orcid.org/0000-0002-9735-0677.
107. Okuonghae, D., Omame, A.: Analysis of a Mathematical Model for COVID-19 population
dynamics in Lagos, Nigeria. Chaos, Solitons and Fractals, 139 (2020). https://doi.org/10.
1016/j.chaos.2020.110032
108. Ministry of Health and Social Action. Informations sur le corononavirus. MSAS: Ministere
de la Sante et de l’ Action sociale (2020)
109. General Directorate of Health (2020). National plan for preparing and responding to an
epidemic of the new coronavirus (COVID-19) February to July 2020. Dakar: DGS, January
2020
110. Senegal: COVID-19 Situation Report -#08 (24 July, 2020–17 August, 2020)
111. Adama F., El HadjMamadou N., Mamadou N., Jean P. D., Fatou B. D.: Epidemic Trend
of Corona Virus Disease 2019 (COVID-19) and Public Health Response in Senegal (2019).
https://doi.org/10.21203/rs.3.rs-32378/v1
112. Martnez-Alvarez, M., Jarde, A., Usuf, E.: COVID-19 Pandemic in West African. Lancet Glob
Health 8(5), e631–e632 (2020)
113. Hellewell, J., Gimma, A., Christopher, I.J.: Feasibility of controlling COVID-19 outbreaks
by isolation of cases and contacts. Lancet Glob. Health 8(4), E488–E496 (2020)
114. DOI: https://doi.org/10.1016/s2214-109X(20)30074-7
115. Hellewell J., Abbott S., Gimma A..: Feasibility of controlling COVID-19 outbreaks by
isolation of cases and contacts. Lancet Glob. Health. 8(4),e488–e496 (2020)
116. Ferguson, N.M., Laydon, D., Nedjati-Gilani, G.: Impact of non-pharmaceutical interventions
(NPIs) to reduce COVID-19 mortality and healthcare demand. London: Imperial College,
2020. A conict of interest statement (2020)
117. Faye, S.L.: Social distancing in Senegal, a remedy for Covid-19 which is struggling to
get through.The Conversation (2020). https://theconversation.com/la-distanciation-sociale-
au-senegal-un-remedeau-covid-19-qui-a-du-mal-a-passer-134810
118. Senegal: Govt Eases COVID Restrictions Tuesday, a Day After Surge in
Cases". allAfrica.com, 12 May 2020. Retrieved 13 June 2020
119. Diaby, M., Diop, O., Konte, A., Sene, A.: COVID-19 Propagation Mathematical Modeling:
The case of Senegal (2020). https://doi.org/10.20944/preprints202006.0224.v1
120. Faye, C., Tidiane, W. C., Dieye, S. Gomis, E.N.:. A review of results of Senegal’s
Response to the COVID-19 Pandemic Through State of Emergency and Curfew. Sumerianz
J. Biotechnology 3(5), 26–37 (2020). https://www.sumerianz.com
121. Facing COVID-19, Preparedness is Key in Sierra Leone. https://www.pih.org/article/facing-
covid-19-preparedness-key-sierra-leone (Accessed 30 June, 2020)
122. COVID-19 pandemic in Sierra Leone. Wikipedia, the free encyclopedia. www.facebook.com/
mic.go.sl. Accessed 30 June 2020
123. Gayawan, E. Awe, O., Oseni, B.M., Uzochukwu, I.C., Adekunle, A. Samuel, G., Eisen, D.P.,
Adegboye, O.A.: The spatio-temporal epidemic dynamics of COVID-19 outbreak in Africa.
medRxivpreprint. https://doi.org/10.1101/2020.04.21.20074435, this version posted April 25,
2020
124. COVID-19 and Ebola: Sierra Leone responds from experience. https://www.concernusa.org/
story/covid-19-ebola-sierra-leone/. Accessed 30 June 2020
125. Sierra Leone prez eases virus restrictions, places of worship remain closed.
Africanews. https://www.africanews.com/2020/06/23/virus-free-sierra-leone-records-covid-
19-scuffles-over-quarantine-at-airport. Accessed 30 June 2020
126. COVID-19 Alert: Sierra Leone Orders Lockdown From April 5–7. www.worldaware.com/
covid-19-alert-sierra-leone-orders-lockdown-april-5-7. Accessed 30 June 2020
127. Policy Response to COVID-19. https://www.imf.org/en/Topics/imf-and-covid19/Policy-Res
ponses-to-COVID-19. Accessed 30 June 2020
128. Sierra Leone: Country to Go Into Second Lockdown as COVID-19 Spirals. AllAfrica. https://
allafrica.com/stories/202005040237.html. Accessed 30 June 2020
129. Sierra Leone Tightens Restrictions After First 2 Coronavirus Cases | Voice of America -
English. www.voanews.com. Retrieved 4 April 2020; Accessed 30 June 2020
130. Togo confirms first case of Corona virus. Reuters. Archived from the original on 6 March
2020. Retrieved 6 March 2020
131. Togo confirms first case of Corona virus. The Jerusalem Post. Reuters. Archived fromthe
original on 8 March 2020. Retrieved 11 March 2020
132. First, Togo. “Corona virus: Togo reports 8 new cases”. www.togofirst.com. Retrieved 21
March 2020
133. Togo: 8 nouveaux cas de Corona virus confirmes. L-FRII (in French), 20 March 2020.
Retrieved 21 March 2020.
134. Médoune, SAMB (27 March 2020). “Corona virus: Journalist Dominique Aliziou, first case
of death linked to COVID-19 in Togo”. Panafrican News Agency. Retrieved 11 April 2020
135. Corona virus Update (Live): 301,100 Cases and 12,948 Deaths from COVID-19 Virus
Outbreak –Worldometer. Worldometers.info. Retrieved 21 March 2020.
136. Togo closes borders over corona virus—FAAPAFR. FAAPA. Retrieved 21 March2020.
137. Togolese Government puts in place an emergency fund to fight Corona virus. Togo First.
Retrieved 19 March 2020.
138. “Togolese Football Federation suspends all competitions due to the Corona virus threat”. Togo
First. Retrieved 19 March 2020.
139. Saint Helena Government Website: http://www.sainthelena.gov.sh
140. Coronavirus disease 2019 (COVID-19) Situation Report–94. https://www.who.int/docs/def

ault-source/coronaviruse/situation-reports/20200423-sitrep-94-covid-19.pdf.
141. https://www.ecdc.europa.eu/en/covid-19/data-collection
142. Ayinde, K., Lukman, A.F., Samuel, O.O., Omokova, M.A.: Some New Adjusted Ridge Estima-
tors of Linear Regression Model. International Journal of Civil Engineering and Technology
9(11), 2838–2852 (2018)
143. Lukman, A.F., Ayinde, K., Binuomote, S., Clement, O.A.: Modified Ridge-Type Estimator to
Combat Multicollinearity: Application to Chemical Data. J. Chemom. 2019, e3125 (2019).
https://doi.org/10.1002/cem.3125
144. Lukman, A.F., Ayinde, K., Aladeitan, B.B., Rasak, B.: An Unbiased Estimator withPriorIn-
formation. Arab Journal of Basic and Applied Sciences 27(1), 45–55 (2020)
145. Ayinde, K.: Performances of Some Estimators of Linear Model when Stochastic Regressors
are correlated with Autocorrelated Error Terms. Eur. J. Sci. Res. 20(3), 558–571 (2008)
146. Ayinde, K., Olaomi, J.O.: A Study of Robustness of Some Estimators of Linear Model with
Autocorrelated Error Terms When Stochastic Regressors Are Normally Distributed. J. Mod.
Appl. Stat. Methods 7(1), 246–252 (2008)
147. Cochrane, D., Orcutt, G.H.: Application of least square to relationship containing autocorre-
latederror terms. J. Am. Stat. Assoc. 44, 32–61 (1949)
148. Prais, G.J., Winsten, C.B.: Trend Estimates and Serial Correlation. Cowles Commission
Discussion Paper, Stat. No. 383, University of Chicago, Chicago (1954)
149. Hildreth, C., Lu, J.Y.: Demand relationships with autocorrelated disturbances. Agricultural
Experiment Statistical Bulletin 276. East Lansing, MI: Michigan State University (1960)
150. Kramer, W.: Finite sample efficiency of ordinary least squares in the linear regression model
with autocorrelated errors. J. Am. Stat. Assoc. 81, 150–154 (1980)
151. Durbin, J.: Estimation of Parameters in time – series regression models. Journal of the Royal
Statistical Society, B 22, 139–153 (1960)
152. Shapiro, S.S., Wilk, M.B.: An Analysis of variance Test for Normalty. Biometrika 52(3),
591–611 (1965)
153. Kuranga, J.O., Ayinde, K., Solomon, G.S.: Empirical Investigation of Type 1 Error Rate of
Some Normality Test Statistics. Int. J. Psychosoc. Rehabil. 24(4), 591–599 (2020). https://
doi.org/10.37200/IJPR/V24I4/PR201037
154. Portnoy, S., Koenker, R.: The Gaussian Hare and the Laplacian Tortoise: Computability of
Squared-error vs. Absolute-error Estimators with Discussion. Statistical Science 12, 279–300
(1997)
155. Lukman, A. F., Ayinde K., Alabi, O., Bamidele, R., Aladeitan, B. B. and Adagunodo, T.
A.(2019). Developing a New Estimator in Linear Regression Model. J. Phys.: Conf. Ser.
1299–012128. doi: https://doi.org/10.1088/1742-6596/1299/1/012128
Investigation of COVID-19 Using an
Artificial Intelligence Based Approach
Sayani Adak, Soovoojeet Jana, and T. K. Kar
Abstract The infectious disease COVID-19 is a disease caused by severe acute

respiratory syndrome coronavirus 2 (SARS-COV-2) which has become a pandemic.
RT-PCR test is implemented in most of the countries to diagnose the disease. Pri-
oritizing individuals for RT-PCR test is necessary in this pandemic situation. In this
scenario, we have attempted to propose and analyze two models on the vulnerability
of COVID-19 for a person using fuzzy inference system (FIS) based on whether or
not the person has a travelling history. To formulate these two models we have used
Mamdani type Fuzzy Inference System. In these two models, ‘Hygiene’, ‘Immu-
nity’, ‘Quarantine’ and ‘Home-isolation’ are taken as the inputs and ‘Vulnerability
to COVID-19’ is taken as the output variable. A thorough study of these two mod-
els using FIS is done which suggests in what percentage a person is vulnerable to
COVID-19.
Keywords Hygiene · Immunity · Quarantine · Home-isolation · Fuzzy inference

system · Fuzzy logic
1 Introduction
Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respira-

tory syndrome corona virus 2 (SARS-COV-2). Up to date, more than three hundred
million positive cases have been confirmed (with nearly 20 million closed cases and
one million deaths) [1]. The common symptoms of the disease are fever, cough,
dyspnoea, headache, myalgia, diarrhea, tiredness [2–5]. Determining whether a per-
son is infected with COVID-19 is not an easy task. The symptoms of COVID-19
has similarities with pneumonia. Many countries are diagnosing the positive case
S. Adak (B) · S. Jana

Department of Mathematics, Ramsaday College, Amta, Howrah 711401, India
S. Adak · T. K. Kar
Indian Institute of Engineering Science and Technology, Shibpur, Howrah 711103,
West Bengal, India
456 S. Adak et al.
of COVID-19 through an RT-PCR test [6]. Several physicians and experts analyzes
radiographic patterns of chest CT scan to determine if a person is infected with
COVID-19 [7]. Some researchers have applied both RT-PCR and chest CT scan to
determine the status of COVID-19 in a person. They have applied chest CT scan
based on one’s positive RT-PCR test [8].
In December 2019, the disease first occurred in Wuhan, capital of Hubei province,
China. On 31st December 2019, the virus has caused a significant number of cases of
unknown pneumonia in Wuhan which led to an investigation. In mid-January of 2020,
the virus started affecting other Chinese provinces as well. After China, Italy had its
first COVID confirmed cases from two tourists from China. Since then the disease
has affected countries like South Korea, the America, England, Russia, Germany,
Japan, India, Pakistan, Brazil, New Zealand and many more countries and territories
throughout the globe [1]. Noticing the deadly effects of this infectious disease, on 11
March, 2020 the World Health Organization (WHO) officially declared the COVID-
19 outbreak a pandemic and so far this is the first pandemic of the twenty-first
century.
With positive cases occurring every minute, it can be said that the COVID-19
cases are increasing at an exponential rate. The primary reason behind the high rate
of transmission is the contagious nature of the virus SARS-COV-2 causing COVID-
19. Initially, it was assumed that the origin of the virus was zoonotic. Then many
pieces of evidence of person to person transmission were found. Although the exact
nature of transmission is still to be determined completely, according to the Centers
for Disease Control and Prevention (CDC) the basic ways of disease transmission
have been found due to close contact and through respiratory droplets produced at the
time of coughing or sneezing or during breathing or even talking. According to WHO
[9] transmission of COVID-19 happens when a person shows symptoms. It can also
occur just before the onset of symptoms. Even a person who has never developed
a symptom can also transmit the virus. It is also reported that the virus can spread
when one touches their face, mouth, nose after touching contaminated surfaces like
plastic, stainless steel, copper, etc. Because the virus can remain infectious on these
surfaces for several hours which further depends on the temperature and humidity
of the respective place [10].
It has been observed that the person with travel history is more vulnerable to the
disease. South Korea had its first positive case in some tourists from Wuhan after
which an outbreak followed [9]. Italy faced its first coronavirus disease when two
Chinese tourists tested positive. The first patients of COVID-19 in India were three
students who returned from Wuhan. At present the disease COVID-19 has become
a pandemic throughout the world with its epicenter moving from one country to
another. However in the European countries the peak is slowly decreasing.
Due to the nature of the virus many control measures by governments were taken
all over the world. Restrictions in travelling, quarantines, isolation, curfews were
imposed. Even most of the governments have been implementing lockdown policies
to either eradicate the disease or to control the spread of the disease as much as
possible. As a result any type of places where any kind of gathering takes place
including public vehicles and all educational institutes are kept closed. Travelling was
Investigation of COVID-19 Using an Artificial Intelligence Based Approach 457
completely restricted. Although the lockdown policy may be the cause for imbalance
in the economy and human society but keeping the human life as first priority, most
of the countries have been implementing lockdown policy and it has been observed
that some of them are able to control the exponential growth of disease transmission.
But again lock down can not be kept forever. There are many limitations of complete
lock down. People of developing countries or economically poor countries are the
victims of this situation. This lead to lifting of lock down first partially and then fully.
Balancing both the economy and the number of COVID cases has become the main
challenge. That is why more testing are needed.
To combat the disease many countries used artificial intelligence techniques. Many
doctors and radiologists were helped by deep learning which was being used to
process and analyze the medical imaging data. Some experts are also applying deep
learning in diagnosis of COVID-19 using radiology images. Artificial intelligence
techniques are used not only in image processing. Hu et al. [11] proposed a deep
learning model to forecast number of confirmed cases in China. Ye et al. [12] proposed
an artificial intelligence based system to determine risk of infection in a geographical
area. They have collected various data like total cases, deaths, density of traffic,
demographic data, social media posts to construct the system. These models helped
officials to take proper action. Another aspect for using artificial intelligence is that
it saves time. CT scans or RT-PCR tests are time consuming. Whereas data obtained
from the temperature finger print sensor can be used for predicting fever level. Various
data obtained from smart phones’ sensors, collecting a person’s travelling history is
based on AI techniques. These data are valuable for machine learning algorithms
so that it can learn from the data and moreover can predict the infection risk for
every individual. Other than artificial techniques in order to prevent the disease
from infecting every person, ‘quarantine’ and ‘isolation’ is imposed in most of the
countries. ‘Quarantine’ is a state of isolation applied to those who were exposed to
the infectious people or contagious places. Quarantine is suggested for the people
who had travel history and persons with no travel history were suggested home
isolation. Keeping in mind the ways of transmission, CDCs are proposing an overall
good hygiene. Washing hands, sneezing and coughing with nose and mouth covered,
keeping a safe distance especially from the person with symptoms, keeping face
mask while going outside are advised [10]. It is interesting to note that not every
person coming into contact with a symptomatic or asymptomatic infected person
is being infected. So, there must be some factors behind this differentiation. We
take one’s immunity as the driving factor. From several works, it is found that age
and immunity are positively co-related. With decreasing age immunity of a person
decreases [13, 14]. From the epidemiological statistics, it is also noted that aged
persons are at more risk than the people belonging from the lower age groups. So, we
find it reasonable to take ‘immunity’ into consideration. These aspects are different
from the AI techniques. These restrictions has to be followed by an individual. In
this chapter we combine both of them. In this work we propose two models to see
how a person can be vulnerable to COVID-19 with respect to the factors ‘Hygiene’,
‘Immunity’ and ‘Quarantine’ (for the person with travel history) and ‘Hygiene’,
‘Immunity’ and ‘Home isolation’ (for the person with no travel history) so that a
458 S. Adak et al.
RT-PCR test can be performed. Prioritizing the places or individuals for RT-PCR test
is necessary for countries with huge population, not so stable or unstable economy.
Fuzzy Inference System is a process that captures non-linearity and ambiguity of
a problem very easily. Fuzzy Inference is used for those cases where there are no
available mathematical models for any physical problem. The essence of the Fuzzy
Inference System (FIS) lies in the natural language that is being used to formulate
the system. It is more of a knowledge-based system rather than data-based. One can
formulate the rules by simply using their common sense. That is why a person with
less mathematical background can also formulate the inference system. Fuzzy Infer-
ence System is a useful tool to recognize patterns of a problem which further helps
in taking control measures against that particular problem. Due to the completely
new nature of COVID-19 disease compared to similar type diseases like SARS and
MERS, various mathematical models are developed by many researchers [15, 16]. In
this chapter, we propose to use the artificial intelligence via Fuzzy Inference System
to see the effects of our input variables defined in the previous paragraph on COVID-
19 vulnerability. Fuzzy inference system consists of three steps. Firstly, the selected
inputs are defined in terms of fuzzy numbers. Then, some user-defined rules are given
which are typically in the ‘if-then’ format. Lastly, defuzzification is performed. There
are two types of Fuzzy Inference Systems (1) Mamdani type and (2) Sugeno type.
Although the steps used in both the Mamdani type and Sugeno type fuzzy inference
systems are similar, there is a difference in the way the outputs are determined. In
computing the output in Sugeno type Fuzzy inference system, the weighted average
of the rule’s consequents is used. So in this case no fuzziness is used. Whereas in
the counterpart a fuzzy membership function is used to define the output variable.
So, fuzziness is being used in Mamdani sense. Hence, Mamdani Fuzzy inference is
easier to interpret. Moreover, Mamdani Fuzzy Inference is intuitive and it is very
easy to formulate a model using Mamdani Fuzzy inference system. Hence, in our
work, we have used the Mamdani type Fuzzy Inference System. Although the use
of Fuzzy Inference System is new in epidemiology, there are other branches where
FIS is used fruitfully.
From these points of view, in this work, we aim to take the help of artificial
intelligence via fuzzy inference system instead of using natural intelligence to study
the behaviour and vulnerability of COVID-19. In any Fuzzy Inference System, one
may select inference, implication, aggregation, defuzzification methods in many
ways. Hence, in the development of any rule-based model finding the appropriate
mathematical model is one of the most vital topics. To reach this goal a primary study
and then selection of the appropriate input and output variables are done in Sect. 2.
In Sect. 3 the results on the surfaces generated by the two systems are done and in
Sect. 4 some computer simulation works are provided to explain the theoretical work
numerically. Finally, in last section we provide some key findings of our research
article.
2 Literature Review
In this section we present literature review of the works done so far using Fuzzy
inference system or related artificial intelligence technique (Table 1).
Table 1 Literature review

Authors Year Title
Alavi [17] 2013 Quality determination of Mozafati dates using Mamdani fuzzy
inference system for crop suitability
Afrinaldi and Zhang [18] 2014 A fuzzy logic based aggregation method for life cycle impact
assessment
Chang and Lai [4] 2014 Adaptive neuro-fuzzy inference system for the prediction of
monthly shoreline changes in northeastern Taiwan
Wua et al. [19] 2015 Measuring the performance of thermal power firms in China
via fuzzy enhanced Russell measure model with undesirable
outputs
Saikia and Dutta [20] 2016 Early diagnosis of dengue disease using fuzzy inference system
Abualigah et al. [21] 2016 A krill herd algorithm for efficient text documents clustering
Abualigah et al. [22] 2017 Text feature selection with a robust weight scheme and
dynamic dimension reduction to text document clustering
Putti et al. [23] 2017 A Fuzzy mathematical model to estimate the effects of global
warming on the vitality of Laelia purpurata orchids
Khatua et al. [24] 2020 A fuzzy rule-based model to assess the effects of global
warming, pollution and harvesting on the production of Hilsa
fishes
Adak and Jana [25] 2020 A study on stegomyia indices in dengue control: a fuzzy
approach
Adak and Jana [26] 2020 A model to asses to dengue using type 2 fuzzy inference system
Nabati et al. [27] 2020 GIS-based agro-ecological zoning for r crop suitability using
fuzzy inference system in semi-arid regions
Chowdhury and De [28] 2020 FIS-RGSO: dynamic fuzzy inference system based reverse
glowworm swarm optimization of energy and coverage in
green mobile wireless sensor networks
Ebrahimi and Qaderi 2021 Determination of the most effective control methods of SO2
[29] pollution in tehran based on adaptive neuro-fuzzy inference
system
Raeihagh et al. [30] 2020 Risk assessment of sour gas inter-phase onshore pipeline using
ANN and fuzzy inference system—case study: the South Pars
gas field
460 S. Adak et al.
3 Materials and Methods
In this section, we formulate two mathematical models using Fuzzy Inference Sys-
tem. For the first system, we take ‘Hygiene’, ‘Immunity’ and ‘Quarantine’ as input
variables and ‘Vulnerability to COVID-19’ as output variable and in the second
system input variables are ‘Hygiene’, ‘Immunity’, ‘Home isolation’, and the same
parameter ‘Vulnerability to COVID-19’ is taken as the output variable. The reason
behind proposing two models is that ‘Quarantine’ are to be implemented for the
person having a travel history; whereas ‘Home isolation’ should be advised for the
person with no travel history. Basic structure of fuzzy inference system is shown in
Fig. 1.
In this work, we use Matlab Fuzzy Logic Toolbox to work with our proposed
models. To define the three input variables of the first system, trapezoidal type mem-
bership functions have been used for the first two inputs ‘Hygiene’, ‘Immunity’ and
for the output ‘Vulnerability to COVID-19’ whereas triangular type membership
functions have been used for the third input ‘Quarantine’. On the other hand for
the second system only trapezoidal type membership function is used to define the
corresponding inputs and output.
Equation (1) represents a trapezoidal type fuzzy set with four points (x1 , x2 , x3 , x4 )
⎧ x−x1
⎪
⎪ x2 −x1
x1 ≤ x ≤ x2
⎪
⎨1 x2 ≤ x ≤ x3
f (x; x1 , x2 , x3 , x4 ) = x4 −x (1)
⎪
⎪ x3 ≤ x ≤ x4
⎪
⎩ x4 −x3
0 otherwise
Fig. 1 Fuzzy logic structure

Hygiene (3)
system1
(mamdani)
Immunity (3)
18 rules
VunlnurabilityToCorona (3)
Quarantine (2)
System system1: 3 inputs, 1 outputs, 18 rules
Fig. 2 Fuzzy rules based system 1
The triangular type membership function with three points (x1 , x2 , x3 ) defined in the
following way (2)
⎧ x−x
⎪
⎨ x2 −x1 x1 ≤ x ≤ x2
1
−x
f (x; x1 , x2 , x3 ) = xx33−x x2 ≤ x ≤ x3 (2)
⎪
⎩ 2
0 otherwise
From (1) and (2), it has been observed that the functional value of f always lies in
the interval [0,1].
The two Fuzzy Inference systems are shown in Figs. 2 and 3 respectively.
3.1 Choosing the Input and Output Variables
In this section we discuss about input and output variables and corresponding mem-
bership functions for both the inference systems.
462 S. Adak et al.
Hygiene (3)
system3
(mamdani)
Immunity (3)
27 rules
VulnerabilityToCorona (3)
HomeIsolation (3)
System system3: 3 inputs, 1 outputs, 27 rules
Fig. 3 Fuzzy rules based system 2
3.1.1 Hygiene
As it is studied and mentioned previously that the virus transmits from touching
one’s face, nose after coming into contact with some contaminated object or from
respiratory droplets due to coughing, sneezing, talking, or coming into contact with
an infected person, keeping a good hygiene is necessary. By the word ‘Hygiene’
we mean washing hands for 20 s, using a face mask, not to touch face or nose by
hand, washing of clothes with detergent, using sanitizer etc [10]. Hence, we take
‘Hygiene’ as one of the input variables of our fuzzy inference systems. Since, there
is no particular measurement or unit for hygiene we take the range of ‘Hygiene’ as
[0, 1]. We divide the membership functions into ‘low’, ‘medium’ and ‘high’ and
trapezoidal fuzzy number is used to describe the membership functions. By ‘low’
we mean poor sense of hygiene, so the instructions on hygiene are seldom followed.
By ‘medium’ we mean knowing the instructions proposed by several agencies like
WHO and CDC, but does not follow it thoroughly and by ‘high’ we mean the habits
strictly instructed by WHO and CDC are followed. The functional form of this input
variable is defined in (1), tabular form is in Table 2 and pictorial representation is
shown in Fig. 4.
Table 2 Degree of membership of hygiene

Fuzzy set M.F. type Limiter
Low Trapezoidal [−0.3 −0.04 0.04 0.36]
Medium Trapezoidal [0.14 0.46 0.54 0.86]
High Trapezoidal [0.64 0.96 1.04 1.36]
low medium high

1
0.8
Degree of membership
0.6
0.4
0.2
0 0.2 0.4 0.6 0.8 1

Hygiene
Fig. 4 Degree of membership function of the input variable hygiene
3.1.2 Immunity
A quantitative characteristics of a person, immunity is a property of an organism

to protect itself from some biotic or abiotic pathogens. There exists two types of
immunity in the human body (1) innate immunity and (2) adaptive immunity. Other
than these two types there are active immunity and passive immunity. Since, the
nature of the virus is new, no vaccination is discovered so far. Therefore, we emphasis
on improving self-immunity. There is a work due to Cooper et al. which describes
a positive relation of innate immunity with nutrition. It has also been stated that
nutrition can also influence acquired immunity [31]. Claus et al. have found nutrition,
age, stress as contributing factors on one’s immunity [32]. In this account, we take
‘immunity’ as one of the input variables in order to emphasis on betterment of
lifestyle. Since there is no particular measurement of immunity we take the range of
‘immunity’ as a closed interval [0, 1] and divide it into ‘low’, ‘medium’ and ‘high’.
We take a trapezoidal type fuzzy number to describe the membership functions. The
functional form of this fuzzy input is defined in (1) and explained graphically in
Fig. 5 and Table 3.
464 S. Adak et al.
low medium high

1
0.8
0.6
0.4
0.2
0 0.2 0.4 0.6 0.8 1

Immunity
Fig. 5 Degree of membership function of the input variable immunity
Table 3 Degree of membership of immunity

Low Trapezoidal [−0.3 −0.04 0.04 0.36]
3.1.3 Quarantine
Another vital factor of the pandemic COVID-19 transmission is coming into contact
with the infected. Hence, we have taken ‘Quarantine’ as one of the input variables. It
is advised by the doctors and experts of the field for the people exposed to COVID-19
affected people or COVID-19 affected area, at least 14 days of Quarantine is manda-
tory. It should be noted that in Hubei province, China a case was reported with the
27 days incubation period [33]. Therefore, the exact time for the quarantine period
of COVID-19 pandemic may vary from one place to another, one community to
another. But for most cases, it has been observed that the 27 days quarantine period
is sufficient. Hence, we take the range of the input variable as [0–27]. Instead of
considering the trapezoidal type membership function, here we divide the member-
ship functions into ‘low’ and ‘high’ only. Furthermore, we use triangular type fuzzy
number to describe the membership functions. While choosing membership function
for ‘Quarantine’ we take account the matter of being quarantined for a person with
travel history very strictly. Here we take the 14 days measurement in a rigid way
to impose the seriousness of the matter. Also it is to be noted that the change of
Table 4 Degree of membership of quarantine

Low Triangular [−2 0 15.75]
High Triangular [14.62 27 30.75]
low high
1
0.8
0.6
0.4
0.2
0 5 10 15 20
Quarantine
Fig. 6 Degree of membership function of the input variable quarantine
quarantine days with respect to time is linear which led us to taking the membership
functions as triangular type fuzzy number. The functional form is defined in (2) and
is illustrated in Table 4 and Fig. 6.
3.1.4 Home-Isolation
Since there is no accurate vaccination and treatment policy developed yet, therefore
it is prescribed that social distancing is the chief architect of controlling COVID-
19. The main reason behind keeping one Home-isolated is to keep the susceptible
population away from both the exposed and infected population so that they can
not come into COVID-19 positive patients. From this perspective, we have taken
the range of corresponding home-isolation as the closed interval [0–1] and divided
the membership functions into ‘low’, ‘medium’ and ‘high’. The functional form is
defined in (1) and in the corresponding graphical demonstration is provided in Table 5
and Fig. 7.
466 S. Adak et al.
Table 5 Degree of membership of home-isolation

Low Trapezoidal [−2 0 15.75]
High Trapezoidal [14.62 27 30.75]
low medium high

1
0.8
0.6
0.4
0.2
0 0.2 0.4 0.6 0.8 1

HomeIsolation
Fig. 7 Degree of membership function of the input variable home-isolation
3.1.5 Vulnerability to COVID-19
Our objective is to find out whether a person would be affected by COVID-19 or not
when all the corresponding associated inputs are known. Hence, the output variable
chosen here is named as ‘Vulnerability to COVID-19’. Since, there is no particular
measurement of vulnerability, the range of the output variable for defining member-
ship functions is taken as closed interval [0, 1] and the corresponding membership
function is divided into three categories namely ‘low’, ‘medium’ and ‘high’. Obvi-
ously the ‘low’ category determines that the associated person is not in danger of
COVID-19 whereas the ‘high’ category determines that there is a significant reason
behind the person being affected by COVID-19. The functional form is defined in
(1) and is graphically illustrated in Table 6 and Fig. 8.
Table 6 Degree of membership of vulnerability to COVID-19

Low Trapezoidal [−0.3 −0.04 0.04 0.36]
Fig. 8 Degree of membership function of the output variable vulnerability to COVID-19
3.2 Rules for Fuzzy Inference Systems
The ‘if-then’ rules are the main determinant of the output variable. These rules
approximate the required output. So, more the number of rules, better the approxi-
mation. Here we define the rules for the two systems separately. We have considered
all possible combinations of input variables and 18 rules for 1st system and 27 rules
for 2nd system are generated. The rules are in if-then format. For example
If (Hygiene is low) and (Immunity is low) and (Quarantine is low) then (Vulner-
ability to COVID-19 is high).
If (Hygiene is high) and (Immunity is high) and (Home-Isolation is high) then
(Vulnerability to COVID-19 is low) etc.
The rules for system 1 and system 2 are shown in Tables 7 and 8 respectively.
468 S. Adak et al.
Table 7 If-Then rules for fuzzy inference system 1

S. No. Hygiene Immunity Quarantine Vulnerability to
COVID-19
1 Low Low Low High
2 Low Low High High
3 Low Medium Low High
4 Low Medium High high
5 Low High Low High
6 Low High High Medium
7 Medium Low Low High
8 Medium Low High high
9 Medium medium Low High
10 Medium medium High Medium
11 Medium High Low Medium
12 Medium High high Low
13 High Low Low High
14 High Low High High
15 High Medium Low High
16 High Medium High Low
17 High high Low Medium
18 High High High Low
3.3 Defuzzification of the Fuzzy Output
In this subsection we defuzzify the corresponding fuzzy output. The fuzzy numbers
can not be written in an order which makes it incomparable. Hence, we turn the
fuzzy outputs into crisp outputs to make the comparison by defuzzification. For both
the systems we have used ‘center of gravity’ method for defuzzification. The rule of
defuzzification of a fuzzy set ‘A’ is given by

xµ A (x)
z̄ = (when x is discrete) (3)
µ A (x)
and
xµ A (x)d x
z̄ = (when x is continuous ) (4)
µ A (x)d x
where z̄ and µ A (x) denote the final output value and membership function of the
input variable respectively.
Table 8 If-Then rules for fuzzy inference system 2

S. No. Hygiene Immunity Home-isolation Vulnerability to
COVID-19
1 Low Low Low High
2 Low Low Medium High
3 Low Low High High
4 Low Medium Low High
5 Low Medium Medium Medium
6 Low Medium High Medium
7 Low High Low High
8 Low High Medium Medium
9 Low High high Low
10 Medium Low Low High
11 Medium Low Medium Medium
12 Medium Low High Medium
13 Medium Medium Low High
14 Medium Medium Medium Medium
15 Medium Medium High Low
16 Medium High Low Medium
17 Medium High Medium Medium
18 Medium High high Low
19 High Low Low High
20 High Low Medium Medium
21 High Low High Low
22 High Medium Low High
23 High Medium Medium Medium
24 High Medium High Low
25 High High Low Medium
26 High High Medium Low
27 High High High Low
4 Results
After defining the input and output variables and implementing the rules we get some
surfaces generated from the two systems. Below we find the relation of the output
variable with the input variables for both of the two systems.
470 S. Adak et al.
4.1 Analysis of 1st System
At first, we consider the first system (i.e. the system where the associated population
has travel history) where the inputs are hygiene, immunity, and quarantine with
the output vulnerability to COVID-19. In Fig. 9a, b, we plot the corresponding
relation considering hygiene and immunity are two inputs and the figure is drawn
incorporating the above-defined fuzzy rules.
It is seen from Fig. 9a, b that when hygiene is low, one is highly vulnerable to
COVID-19 even if one has high immunity power. Also, it can be said from the figure
that if one has medium to high sense of hygiene, but high immunity, the chances that
he/she gets infected by COVID-19 reduce in a significant amount. Hence, a good
immunity power with a good sense of hygiene reduces the chances of infection of
the virus SARS-COV-2. Next, in Fig. 10, we study the significance of the inputs
quarantine and hygiene against the output vulnerable to COVID-19.
0.85
0.9
0.8 0.8
0.7
0.85 0.75
VunlnurabilityToCorona
0.8 0.6
Immunity
0.75 0.7
0.5
0.7
0.4 0.65
0.65
0.6 0.3
0 0.6
0.55 0.2 0.2
0.5 0.4 0.55
1 0.6 0.1
0.8
0.6 0.8 Immunity
0.4 0 0.5
0.2 1 0 0.2 0.4 0.6 0.8 1
Hygiene 0
Hygiene
(a) (b)
Fig. 9 a Vulnerability to COVID-19 with respect to hygiene and immunity for the system 1. b The
contour map of Vulnerability to COVID-19 with respect to hygiene and immunity
0.62
20 0.6
0.6 0.58
15
Quarantine
0.55 0.56
10
0.5 0.54
1
0
0.8 5
5
0.6 0.52
10
0.4
15
Hygiene 0.2 20 Quarantine 0 0.5
0 0 0.2 0.4 0.6 0.8 1
Hygiene
(a) (b)
Fig. 10 a Vulnerability to COVID-19 with respect to hygiene and quarantine for the system 1. b
The contour map of Vulnerability to COVID-19 with respect to hygiene and quarantine
0.85
20 0.8
0.75
0.7
0.8 15
Quarantine
0.65
0.7
0.6
10
0.6
0.55
0.5 0
0.5
0.2 5
0.4 0.4 0.45
0 0.6
5
10 0.8 0.4
15 Immunity 0
20 1 0 0.2 0.4 0.6 0.8 1
Quarantine
Immunity
(a) (b)
Fig. 11 a Vulnerability to COVID-19 with respect to immunity and quarantine for the system 1. b
The contour map of vulnerability to COVID-19 with respect to immunity and quarantine
It is observed from Fig. 10a, b that if one is quarantined for less than 15 days,
he/she becomes vulnerable to the disease even if he/she has a good sense of hygiene.
On the contrary, if a person is fully quarantined then the chances reduce from high
to medium even when the hygiene is poor. But, a higher quarantine period and well
hygienic maintenance may reduce the percentage of positive COVID-19 significantly.
Hence, the persons are advised to be quarantined so that the disease does not spread.
For the system 1, lastly, we study the Vulnerability to COVID-19 against quarantine
and immunity in Fig. 11a, b.
It is concluded from Fig. 11a, b, that if a person who was exposed to the infected
population and has poor immunity, quarantine up to 27 days is not useful for him/her
from avoiding the infection of COVID-19. But, it will help susceptible from get-
ting infected. Also, it is notifiable that with good immunity and at least 15 days of
quarantine one can be less vulnerable to the disease COVID-19.
4.2 Analysis of 2nd System
Next we analyze the 2nd System i.e. the community of population with no travel
history or very marginal travel history. We study the vulnerability to COVID-19 with
respect to three input parameters namely immunity, hygiene and home-isolation. At
first we draw the Fig. 12a, b to study the vulnerability to COVID-19 against the input
parameters namely immunity and hygiene.
Figure 12a, b represent the change in the output ‘Vulnerability to COVID-19’
with respect to the two input parameters namely hygiene and immunity. It can be
seen from the two graphs of Fig, 12, that the chances of getting infected are medium
to high if we take account only immunity and hygiene. We see that a person has
a high chance of getting the infection even if he has a medium to high immunity
472 S. Adak et al.
1
0.85
0.9
0.8 0.8
0.7
0.75
VulnerabilityToCorona
0.6
0.8
Immunity
0.7
0.5
0.7
0.4 0.65
0.6 0 0.3
0.2 0.6
0.2
0 0.4
0.2 0.6 0.55
0.4 Hygiene 0.1
0.6 0.8
0.8 0
Immunity 1 1 0 0.2 0.4 0.6 0.8 1
Hygiene
(a) (b)
Fig. 12 a Vulnerability to COVID-19 with respect to hygiene and immunity for the system 2. b
The contour map of Vulnerability to COVID-19 with respect to hygiene and immunity
0.9 0.8
0.8 0.8
0.7
0.7
0.7
0.6
0.6
HomeIsolation
0.5 0.6
0.4
0.5 0.5
0.3
0.2 0.4
0.4
0 0.3
0.2 0.3
0.2
0.4
0 0.2
0.6 0.2 0.1
0.4
HomeIsolation 0.8 0.6
0.8 Immunity 0
1 1 0 0.2 0.4 0.6 0.8 1
Immunity
(a) (b)
Fig. 13 a Vulnerability to COVID-19 with respect to home-isolation and immunity for the system
2. b The contour map of Vulnerability to COVID-19 with respect to home-isolation and immunity
but a poor sense of hygiene. But, the chances of getting the infection reduce when
proper hygiene is maintained. It is interesting to see that the effects of hygiene and
immunity on a person with no travelling history are almost same as that for a person
with a travelling background. Next in Fig. 13a, b, we examine the vulnerability to
COVID-19 against the two input parameters immunity and home-isolation.
From the two graphs of Fig. 13a, b, we can easily verify the effect of the parameters
immunity and home-isolation on the proposed output vulnerability to COVID-19.
It is observed from the figures that home-isolation is a very important parameter to
reduce the chances of getting the infection. A person with poor immunity has the
highest chance of getting the infection if he/she does not maintain home-isolation
fully. Further, it is clearly seen from the figure that both immunity and home-isolation
are inversely proportional to the chance of getting the infection. A person with a strong
immunity system has a low risk of getting infected if he/she is home isolated.
1
0.62
0.9
0.8
0.6
0.7
0.6 0.58
HomeIsolation
0.6
0.55 0.5
0.56
0.4
0.5
0 0.54
0.3
0.2 0
0.2 0.2
0.4
0.4 0.52
0.6 0.1
0.6
HomeIsolation 0.8 Hygiene
0.8
0 0.5
1 1 0 0.2 0.4 0.6 0.8 1
Hygiene
(a) (b)
Fig. 14 a Vulnerability to COVID-19 with respect to hygiene and home-isolation for the system
2. b The contour map of vulnerability to COVID-19 with respect to hygiene and home-isolation
output variable Vulnerability to COVID-19 in Fig. 14a, b. From the two graphs
of Fig. 14, we see that if home-isolation is not followed at all, chances of getting the
infection is medium even if he/she maintains proper hygiene. But, if home-isolation
is maintained the chances of getting the infection reduce. Like earlier case, the input
parameter home-isolation is inversely proportional with the other input parameter
hygiene on accounting vulnerability to COVID-19.
5 Numerical Simulation
In this section, we examine the compatibility of the two proposed systems numeri-
cally. In this work one of the common inputs between the two systems is ‘Immunity’.
There is no direct method to determine one’s immunity. However, depending on age,
history of previous infectious diseases, their lifestyle, stress (see, [32]), we may deter-
mine the status of immunity level of a particular person. In a similar manner, we can
categorize the input parameter ‘Hygiene’. A person obeying proper hygienic status
should be categorized as having ‘high’ hygiene and the person who is not maintain-
ing hygienic status as prescribed by the doctors and medical professionals should
belong to the ‘low’ hygiene category. Thus based on a person’s financial background,
their lifestyle the status of the inputs ‘immunity’ and ‘hygiene’ can be assumed. On
the other hand ‘Quarantine‘ and ‘home-isolation’, both are measurable in the sense
that one can say for how many days he/she followed isolation. Although the third
input variable can be measured to see the effect of all the three input variables on the
output, we have considered literature review and taken hypothetical data to perform
the simulation.
Let us assume that 10% of the total population has travel history and another
90 % has no travel history. If a person has a travel history then system 1 is to be
implemented and if the person has no travel history or a marginal travel history in the
474 S. Adak et al.
Table 9 Numerical simulation for the 1st fuzzy inference system

S. No. Hygiene Immunity Quarantine Vulnerability Remarks
to COVID-19
1 0.3 0.8 16.5 0.5 Medium
2 0.7 0.8 16.5 0.415 Low
3 0.7 0.8 5 0.544 Medium
4 0.2 0.3 5 0.859 High
5 0.2 0.3 17 0.59 Medium/High
6 0.886 0.765 23.3 0.148 Low
7 0.5 0.6 15 0.662 High
8 0.5 0.65 14 0.706 High
Table 10 Numerical simulation for the 2nd fuzzy inference system

S. No. Hygiene Immunity Quarantine Vulnerability Remarks
to COVID-19
1 0.3 0.8 0.7 0.395 Medium
2 0.7 0.8 0.7 0.395 Low
3 0.7 0.8 0.5 0.439 Medium
4 0.2 0.3 0.3 0.843 High
5 0.2 0.3 0.7 0.842 Medium/High
6 0.8 0.7 0.8 0.157 Low
7 0.5 0.6 0.4 0.5 High
8 0.5 0.65 0.8 0.493 High
COVID-19 free region, then system 2 will work. Now, we take some values of the
input variables in both the systems and observe how the outputs of both the systems
change with changing input.
From Table 9, it can be seen that when one has a poor sense of hygiene but high
immunity and was in quarantine for more than 15 days, he/she has a medium chance
of getting infection even if his/her immunity is strong (Sl 1, Table 9 , output = 0.5).
But, good hygiene reduces these chances (Sl no. 2, Table 9, output = 0.415). But if
quarantine is not followed one becomes vulnerable even if one has strong immunity
and maintains a proper hygiene (Sl no. 3, Table 9, output = 0.544). Hence, it is
concluded from Table 9, that if a person having travel history with good immunity
system maintains proper hygiene throughout the quarantine time of at least 15 days
is very much safe from COVID-19.
Next, it is observed from Table 10, the output variable changes in almost the same
way in system 2. Here we have taken the same values corresponding to the input
variables ‘Hygiene’ and ‘Immunity’. In the 2nd system also if a person with a good
sense of hygiene, high immunity system remains home isolated then he/she is less
vulnerable to the infection. It is interesting to note that the outputs generated by
system 2 in each case is less than the output generated by the system 1. Hence, it can
be said that the person with no travelling history is less vulnerable to the infection
compared to the one with a travelling history.
6 Discussion
In the present work, we have developed a rule-based Fuzzy Inference System (FIS)
to see how much a person is vulnerable to the COVID-19 disease based on the
parameters ‘Hygiene’, ‘Immunity’, ‘Quarantine’, ‘Home-isolation’. In this regard,
we formulate two separate FISs depending on the travel history of a person. A person
with normal immunity system and a good sense of hygiene is likely to be less affected
by the virus if he/she avoids direct contact with an infected person. We have also
found that the person with travel history is much more vulnerable to the disease hence
they should be quarantined for at least 14 days. Also, it has been established that a
person with the same immunity and hygiene is less vulnerable to the COVID-19 if
he/she has no travelling history in the COVID-19 affected regions.
In this work we have formulated an FIS system to develop the percentage of chance
of getting infected by COVID-19 for a single person. Thus it is expected that the
proposed systems can be applied to study both quantitative and qualitative behavior
of a COVID-19 affected region and the region which is susceptible to COVID-19
pandemic. On receiving the output from the proposed FIS systems, we can take the
necessary steps in advance to control COVID-19. Further we know that RT-PCR test
is implemented to diagnose the disease COVID-19 but in a high populated region that
test may not be done to all susceptible population. In this regard, using the artificial
intelligence techniques used in this article, we first sort out more vulnerable humans
for the disease and the RT-PCR test can be done on those selected persons only.
This procedure can be useful in reducing both cost and testing time of COVID-19
diagnose.
7 Conclusion
COVID-19 being a new type of coronavirus caused disease, different information

about the virus are derived every day. Hence, in this work we consider the most
important parameters as input variables to study the affect of these parameters on
the disease which if maintained can beat COVID-19. In future, we can consider
other method like Type 2 Fuzzy Inference System or ANFIS or Artificial Neural
Network etc. other than FIS to study the nature of COVID-19. In 1918 the world has
faced a pandemic Spanish flu. Back then technology was not developed. At present
technology has come a long way. At this situation technology should be used at its
best. Hospitals, several organizations are trying their best to use technologies in their
work. In this process AI is used everywhere. It should be fully exploited and imple-
476 S. Adak et al.
mented to combat this battle. AI can be used in many ways. It can be utilized for the
preparedness and response activities against the unprecedented national and global
crisis. For example, AI can be used to create robots which will be more efficient. In
such pandemic situation autonomous machines can be made for disinfection purpose
which can also be used for delivering medicines, foods to the patients. In another way
to better understand public behaviour or public response to some strategies NLP tools
can be used to undertake better strategies. Many NLP technologies can also be used
to develop chatbot systems that can communicate with patients who are suggested
to be home isolated. It can be used to provide consultations to them. AI can be used
to eradicate fake news which circulates on social media platforms which will ensure
reliable information about the pandemic such as scientific evidences relevant to the
virus, governmental policies or other pandemic prevention and control measures. In
spite of many possibilities, there are some drawbacks of using AI. AI requires lots of
data which are required for training, testing and for validation. In present day when
data are in our hands choosing the right one is difficult. When an AI techniques are
being implemented for the betterment of human race or any living being we must
keep in mind that it should be safe, well examined and protected. Most importantly
it must provide a positive impact on society.
Acknowledgements The work of is financially supported by the Department of Science and

Technology & Biotechnology, Govt. of West Bengal (vide memo no. 201 (Sanc.)/ST/P/S&T/16G-
12/2018 dated 19-02-2019). Moreover, the authors are very much grateful to the anonymous review-
ers and the editor Prof. Ahmad Taher Azar for their constructive comments and helpful suggestions
to improve both the quality and presentation of the manuscript significantly.
References
1. https://www.worldometers.info/coronavirus
2. Ghinani, I., McPherson, T.D., Hunter, J.C., Kirking, H.L., Christiansen, D., Joshi, K., Lay-
den, J.E., et al.: First known person-to-person transmission of severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2) in the USA. Lancet (2020). https://doi.org/10.1016/
s0140-6736(20)30607-3
3. Lupia, T., Scabini, S., Pinna, S.M., Perri, G., Rosa, F.G., Corcione, S.: 2019 Novel coronavirus
(2019-nCoV) outbreak: a new challenge. J. Glob. Antimicrobial Resistance (2020). https://doi.
org/10.1016/j.jgar.2020.02.021
4. Chang, F.-J., Lai, H.-C.: Adaptive neuro-fuzzy inference system for the prediction of monthly
shoreline changes in northeastern Taiwan. Ocean Eng. 84, 145–156 (2014)
5. Mandal, M., Jana, S., Nandi, S.K., Khatua, A., Adak, S., Kar, T.K.: A model based study on the
dynamics of COVID-19: prediction and control. Chaos Solit. Fract. https://doi.org/10.1016/j.
chaos.109889 (2020)
6. How is the COVID-19 Virus Detected using Real Time RT-PCR? IAEA. 27 March 2020.
Retrieved 5 May 2020
7. Butt, C., Gill, J., Chun, D., Babu, B.A.: Deep learning system to screen coronavirus disease:
2019 pneumonia. Appl. Intell. https://doi.org/10.1007/s10489-020-01714-3 (2020)
8. Ai, T., Yang, Z., Hou, H., Zhan, C., Chen, C., Lv, W., Taao, Q., Sun, Z., Xia, L.: Correlation of
chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of
1014 cases. Radiology (2019). https://doi.org/10.1148/radiol.2020200642 (2020)
9. WHO|Novel Coronavirus-China. http://www.who.int (2020)

10. Coronavirus Disease 2019(COVID-19)-Transmission. Centers for Disease Control and Pre-
vention. http://www.cdc.gov. (2020)
11. Hu, Z., Ge, Q., Jin, L., and Xiong, M. : Artificial intelligence forecasting of COVID-19 in
China. arXiv:2002.07112 (2020)
12. Ye, Y., Hou, S., Fan, Y., Qian, Y., Zhang, Y., Sun, S., Peng, Q., Laparo, K.: K-satellite: an
AI-driven system and benchmark datasets for hierarchical community-level risk assessment to
help combat COVID-19. arXiv:2003.12232 (2020)
13. Whiting, C.C., Siebert, J., Newman, A.M., Du, H.W., Alizadeh, A.A., Goronzy, J., et al.: Large-
scale and comprehensive immune profiling and functional analysis of normal human aging.
PLoS ONE 10(7) (2015). https://doi.org/10.1371/journal.pone.0133627
14. Smetana, J., Chlibek, R., Hanovcova, I., Sosovickova, R., Smetanova, L., Gal, P., et al.: Decreas-
ing seroprevalence of measles antibodies after vaccination ± possible gap in measles protection
in adults in the Czech Republic. PLoS ONE 12(1), e0170257 (2017). https://doi.org/10.1371/
journal.v
15. Piccolominib, E.L., Zamaa, F.: Preliminary analysis of COVID-19 spread in Italy with an
adaptive SEIRD model. arXiv:2003.09909v1 [q-bio.PE] (2020)
16. Lin, Q., Zhao, S., Gao, D., Lou, Y., Yang, S., Musa, S.S., He, D.: A conceptual model for the
outbreak of Coronavirus disease 2019 (COVID-19) in Wuhan, China with individual reaction
and governmental action. Int. J. Infect. Diseases (2020). https://doi.org/10.1016/j.ijid.2020.02.
058
17. Alavi, N.: Quality determination of Mozafati dates using Mamdani fuzzy inference system. J.
Saudi Soc. Agric. Sci 12, 137–142 (2013)
18. Afrinaldi, F., Zhang, H.C.: A fuzzy logic based aggregation method for life cycle impact
assessment. J. Clean. Prod. 67, 159–172 (2014)
19. Wua, J., Xionga, B., Anb, Q., Zhua, Q., Lianga, L.: Measuring the performance of thermal
power firms in China via fuzzy enhanced Russell measure model with undesirable outputs. J.
Clean. Prod. 102, 237–245 (2015)
20. Saikia, D., Dutta, J.C.: Early diagnosis of dengue disease using fuzzy inference system (2016)
21. Abualigah, L.M., Khader, A.T., Al-Betar, M.A., Awadallah, M.A.: A krill herd algorithm for
efficient text documents clustering. In IEEE Symposium on Computer Applications and Indus-
trial Electronics (ISCAIE), pp. 67–72 (2016)
22. Abualigah, L.M., Khader, A.T., Al-Betar, M.A., Alomari, O.A.: Text feature selection with a
robust weight scheme and dynamic dimension reduction to text document clustering. Expert
Syst. Appl. 84, 24–36 (2017)
23. Putti, F.F., Filho, L.R.A.G., Gabriel, C.P.C., Neto, A.B., Bonini, C., dos S.B., Reis, A.R.: A
fuzzy mathematical model to estimate the effects of global warming on the vitality of Laelia
purpurata orchids. Math. Biosci. (2017). https://doi.org/10.1016/j.mbs.2017.03.005
24. Khatua, A., Jana, S., Kar, T.K.: A fuzzy rule-based model to assess the effects of global warming,
pollution and harvesting on the production of Hilsa fishes. Ecol. Inf. 57 (2020)
25. Adak, S., Jana, S.: A study on stegomyia indices in dengue control: a fuzzy approach. Soft
Comput. (2020)
26. Adak, S., Jana, S.: A model to assess dengue using type 2 fuzzy inference system (2020).
https://doi.org/10.1016/j.bspc.2020.102121
27. Nabati, J., Nezami, A., Neamatollahi, E., Akbari, M.: GIS-based agro-ecological zoning for
crop suitability using fuzzy inference system in semi-arid regions. Ecol. Indicators 117, (2020).
https://doi.org/10.1016/j.ecolind.2020.106646
28. Chowdhury, A., De, D.: FIS-RGSO: dynamic fuzzy inference system based reverse glowworm
swarm optimization of energy and coverage in green mobile wireless sensor networks. Comput.
Commun. 163, 12–34 (2020). https://doi.org/10.1016/j.comcom.2020.09.002
29. Ebrahimi, M., Qaderi, F.: Determination of the most effective control methods of SO2 pollution
in Tehran based on adaptive neuro-fuzzy inference system. Chemosphere 263 (2021). https://
doi.org/10.1016/j.chemosphere.2020.128002
478 S. Adak et al.
30. Raeihagh, H., Behbahaninia, A., Aleagha, M.M.: Risk assessment of sour gas inter-phase
onshore pipeline using ANN and fuzzy inference system—Case study: The South Pars Gas
field. J. Loss Prevent. Process Ind. 104238 (2020). https://doi.org/10.1016/j.jlp.2020.104238
31. Cooper, E.L., Ma, M.J.: Understanding nutrition and immunity in disease management. J. Trad.
Complementary Med. 1–6 (2016). https://doi.org/10.1016/j.jtcme.2016.12.002
32. Claus, M., Dychus, N., Ebel, M., Damaschke, J., Maydych, V., Wolf, O.T., Kleinsorge, T.,
Watzl, C.: Measuring the immune system: a comprehensive approach for the analysis of immune
functions in humans (2016). https://doi.org/10.1007/s00204-016-1809-5
33. Jiang, X., Niu, Y., Li, X., Li, L., Cai, W., Chen, Y., Liao, B., Wang, E.: Is a 14-day quarantine
period optimal for effectively controlling coronavirus disease 2019 (COVID-19) https://doi.
org/10.1101/2020.03.15.20036533
the challenges. Int. J. Antimicrobial Agents (2020). https://doi.org/10.1016/j.ijantimicag.2020.
105924
35. https://www.icmr.gov.in/
Optimal Control Design of Impulsive
SQEIAR Epidemic Models
with Application to COVID-19
Zohreh Abbasi, Mohsen Shafieirad, Amir Hossein Amiri Mehra,

Iman Zamani, and Asier Ibeas
Abstract According to the great importance and effectiveness of quarantine in the

COVID-19 epidemic, this chapter presents a SEIAR-type model considering quar-
antined individuals (Q), called SQEIAR model. The main factor that has played a
major role in the outbreak of COVID-19 around the world is traveling and immigra-
tion of people, which add to the population size impulsively. Therefore, an impulsive
epidemic model of SQEIAR is considered to deal with the potential sudden increase
in population caused by immigration or travel. Optimal control theory is presented
to control and reduce the rate of disease spread in society within an optimal time.
Optimal control is used to minimize an objective (cost) function over a free terminal
time. Also, quarantine and antiviral treatment are used as control inputs. In the
following, numerical simulations are given to prove the accuracy of the theoretical
claims and applied to this infection’s particular data. Moreover, numerical computa-
tions of the COVID-19 are compared with diseases like Ebola and Influenza. In addi-
tion, the controller is evaluated with system parameters identified by using actual data
of China. Finally, the controller tuned with the estimated parameters of the Chinese
data is applied to Spain’s actual data to compare the quarantine and treatment policies
in both countries.
Z. Abbasi · M. Shafieirad (B) · A. H. Amiri Mehra

Department of Electrical and Computer Engineering, University of Kashan, Kashan, Iran
e-mail: m.shafieirad@kashanu.ac.ir
Z. Abbasi
e-mail: abbasi.z@grad.kashanu.ac.ir
A. H. Amiri Mehra
e-mail: a.amirimehra@grad.kashanu.ac.ir
I. Zamani
Electrical and Electronic Engineering Department, Shahed University, Tehran, Iran
e-mail: zamaniiman@shahed.ac.ir
A. Ibeas
Telecomunicació I Enginyeria de Sistemes by Telecomunicació i Enginyeria de Sistemes,
Escolad’Enginyeria by Escola d’Enginyeria, Universitat Autònoma de Barcelona, Barcelona,
Spain
e-mail: asier.ibeas@uab.cat
480 Z. Abbasi et al.
Keywords COVID-19 · Impulsive epidemic model · Mathematical model ·

Optimal control · SQEIAR model · Quarantined people
1 Introduction
Coronaviruses are a group of viruses that cause infection ranging from a usual
cold to Severe Acute Respiratory Syndrome (SARS) [1]. According to the World
Health Organization, the current coronavirus disease (COVID-19) was first reported
in Wuhan, China, on 31 December 2019. General symptoms of this infection are
respiratory symptoms such as cough, fever, breathing problems, and shortness of
breath. In more critical cases, pneumonia, kidney failure, severe acute respiratory
syndrome, and even death have also been reported [2]. Given that COVID-19 is an
unknown disease, it is understandable that its development and spread cause nervous-
ness and fear. As a result, we decided to represent a more completed model than the
other works used, [1], and control the infection with an optimal control strategy.
According to [3], which presents a new (SEIAR) model for influenza, we introduce a
related and new model with a difference in the present chapter. Since the coronavirus
(or any similar infection) does not have a vaccine yet, in our new model, in addi-
tion to Susceptible, Exposed, Infected, Asymptomatic, and Recovered individuals
(SEIAR), we added a new group of people called “people in quarantine”. In addition
to continuous-time systems, system dynamics can also be described by discrete-time
SEIR epidemic models [4, 5]. For more study about discrete-time SEIR epidemic
models with time delay, readers are referred to [6].
Transportation among regions has a strong impact on the dynamic evolution of a
disease that can spread the infection on a large scale. Thus, [7] considers an SEIR
epidemic model and investigated the impact of transport-related infection between
two cities. Generally, the number of the population may grow because of travel or
immigration during a period. Therefore, impulsive change of population should be
considered, which is generates an impulsive epidemic model. The phenomena of the
‘impulsive epidemic model’ have important biological meaning in epidemic models.
Impulse is included in epidemic disease models, which greatly improves biological
background [8]. Some studies are examining this subject, including [9], where a
system of impulsive functional differential equations is studied using new compu-
tational techniques for impulsive differential equations and [10], which investigated
the stability of impulsive delayed nonlinear hybrid differential systems. Accordingly,
in this chapter, we consider some susceptible, infected, asymptomatic, and exposed
individuals as an impulsive additive population to the community on a daily basis,
which describes the fact that the coronavirus is spread by the travel of people unaware
of the disease that is added to the population impulsively. Among these models which
have used impulsive strategy, impulsive control has attracted many interests, which
in these papers can be seen as an example of this impulsive control [11–14]. Optimal
control methods are used to control numerous kinds of models, especially dynamic
epidemic models [15–20]. The adaptability and relative simplicity of optimal control
Optimal Control Design of Impulsive SQEIAR Epidemic Models … 481
methods can lead to the improvement of the strategies to control the different kinds
of diseases [21, 22]. Human mobility is a critical issue in epidemic models. Thus,
for studying the transmission of infectious diseases and improving epidemic control,
we also can use large-scale systems. We refer to [23] that deals with the application
of optimal control in large-scale systems that can also be used in epidemic systems.
Therefore, in this chapter, the optimal control strategy is applied to the SQEIAR
model to decrease the number of susceptible, infected, exposed, and asymptomatic
individuals in the optimal time. It has been proved that as a result of this that the
number of people in quarantine and the total population is increased. China, where
the virus first began to spread in late 2019, has seen an obvious reduction in its rate
of new cases, and people are known to be infected have since recovered, this is only
for strict quarantine and treatment of infected people. Also, Spain is another country
hit by COVID-19. Therefore, in this study, the accuracy of the controller designed on
the estimated parameters using real data of China has also been examined, and the
process of controlling COVID-19 in both countries will be investigated. Accordingly,
in this chapter, it was decided to compare the results of the study with the actual data
to evaluate the performance of this controller.
This chapter is divided into seven sections: In the first section, we introduce and
explain the SEIAR model in detail. The optimal control strategy is applied to the
SQEIAR dynamic model in Sect. 2. Also, an impulsive SQEIAR epidemic model
is introduced in Sect. 3. In Sect. 4 the proposed controller applied to the impulsive
SQEIAR epidemic model. In the following and in the finfth section, the results of
simulations under different cases are presented. The comparison of the results of this
study with other diseases and actual data is mentioned in Sect. 6. Finally, in Sect. 8
the chapter ends with conclusions.
2 SEIAR Epidemic Model Description
In this section, we explain the SEIAR epidemic model taken from [3], but we skipped
births and natural mortality (because of the low μ rate in [3]). This assumption is
feasible since the total population does not change significantly during the spreading
time, and we aim at controlling the disease as quickly as possible. The nonlinear
SEIAR epidemiological model includes five non-negative state variables S(t), E(t),
I(t), A(t) and R(t) that are defined as Susceptible, Exposed, Infected, Asymptomatic,
and Recovered people, respectively. Here, S(t) represents the number of individuals
who are susceptible to the infection (i.e., they are not infected yet). When a susceptible
individual gets infected (i.e. becomes exposed to the infection, they move to the
exposed people group (E(t)) that denotes the number of individuals who are exposed
to infection (they are infected, but cannot transmit the virus). Finally, they reach a level
that can transmit the disease at the rate of κ but a fraction of them have symptoms,
and the other fraction does not have any visible symptoms. We call them infected and
asymptomatic, and they are denoted by I (t) and A(t), respectively. The fraction p
of exposed people moves to the infected people group, and can transmit the infection
to the others and the fraction (1 − p) of them goes to the asymptomatic people group
who have infected with no symptoms of infection (A(t)). The fraction f of infected
people become recovered at the rate of α and the remaining of them (the fraction
(1 − f )) will die because of the infection. The fraction z of asymptomatic people
will be recovered at the rate of η and the rest of them (the fraction (1 − z)) will be
infected. Therefore, R(t) denotes the recovered people from the virus, and finally,
N (t) is the total population size. Figure 1 shows a flow diagram of SEIAR dynamic
model. The dynamic model is mathematically described as:
Ṡ(t) = −β(t)S(t) (1a)
Ė(t) = β(t)S(t) − κ E(t) (1b)
I˙(t) = (1 − z)η A(t) − α I (t) + pκ E(t) (1c)
Ȧ(t) = (1 − p)κ E(t) − η A(t) (1d)
Ṙ(t) = zηA(t) + f α I (t) (1e)
Here, N (t) = S(t) + E(t) + I (t) + A(t) + R(t), (t) = εE(t) + (1 − q)I (t) +
δ A(t) in which ε is infectivity reduction factor for the exposed people, q is contact
reduction by isolation and δ is infectivity reduction factor for the asymptomatic
people. The non-negative initial conditions are (S(0), E(0), I (0), A(0), R(0)) =
(S0 , E 0 , I0 , A0 , R0 ). The state variables and parameters are positive values. For
further study, view [3, 24].
Fig.1 Conceptual flow

diagram of the SEIAR
dynamic epidemic model
3 The Optimal Control Strategy of SEIAR
Since the vaccines we have fought against the virus do not work, and recovery
depends on the strength of the immune system, many of those who have died were
already in poor health. So, at the moment, the best way to prevent the spread of
the virus is to quarantine susceptible people against the infection. Therefore, in this
section, we want to use optimal control theory to eradicate the epidemic within the
shortest pre-defined period of time (for example, ten days) by quarantining suscep-
tible people and by applying antiviral therapies to infected people. A number of
susceptible people must become quarantined at the rate of λ(t), that means they
move to a group called quarantined people, described by Q(t). After eradication of
the disease, the total size of people almost includes the quarantined, and recovered
people (R(t) + Q(t) ∼ = N (t)), because a percentage of infected people will die
because of infection and not all of them recover. Figure 2 shows the flow diagram of
SQEIAR dynamic model in the presence of the controller (i.e., the addition of the
extra state Q(t) is indeed a control action on the SEAIR model describing the spread
of the infection). The dynamic model with the controller is given by:
Ṡ(t) = −(β(t) + λ(t))S(t) (2a)
Q̇(t) = λ(t)S(t) (2b)
Ė(t) = β(t)S(t) − κ E(t) (2c)
I˙(t) = (1 − z)η A(t) − α I (t) + pκ E(t) − U (t)I (t) (2d)
Ȧ(t) = (1 − p)κ E(t) − η A(t) (2e)
Ṙ(t) = zηA(t) + f α I (t) + U (t)I (t) (2f)

diagram of the SQEIAR
dynamic model with the
proposed controller
where,N (t) = S(t) + Q(t) + E(t) + I (t) + A(t) + R(t).

In optimal control theory, the main objective is the minimization of the number of
the susceptible, infected, exposed, and asymptomatic population while minimizing
the cost of applying the controls U (t) (0 ≤ U (t) ≤ 1, treatment), and controls λ(t)
(0 ≤ λ(t) ≤ 1, quarantine) in an optimal time interval. Therefore, the problem is
to minimize the cost function J with a free terminal time control:
⎡ ⎤
T A1 I (t) + A2 A(t) + A3 E(t) + A4 S(t)
J (U (t), λ(t), T ) = ⎣ A5 A6 ⎦dt + ∅(T )
+ U (t)2 + λ(t)2
0 2 2
(3)
A1 , A2 , A3 , and A4 are the gains of the infected, asymptomatic, exposed, and

susceptible individuals, respectively. Also, A5 and A6 are the gains of controllers. ∅(t)
is a positive increasing function such that lim ∅(t) = ∞. In other words, we want
t→∞
∗ ∗
(U (t), λ (t)) in an optimal terminal
to reach the optimal controls time (T ∗ ) such
that J (U (t), T ) = min J (U (t),T )|U (t) ∈ U1 , T ∈ R and J (λ∗ (t), T ∗ ) =
∗ ∗ +
min J (λ(t), T )|λ(t) ∈ U2 , T ∈ R+ . The set of admissible controls defined by U1

and U2 as U1 = {U (t)|U (t) is measurable, 0 ≤ U (t) ≤ Umax = 1, t ∈ [0, T ]} and
similarly U2 = {λ(t)|λ(t) is measurable, 0 ≤ λ(t) ≤ λmax = 1, t ∈ [0, T ]}. The
necessary conditions for optimality are expressed by:

T
∂∅
∇x∅f − p(T ) δx f + H (x(T ), U (T ), λ(T ), p(T ), T ) + δT = 0 (4)
∂T

here, the gradient ∇x∅f is the derivative of ∅ x f , T with respect to x f , and T
is final time. Since x(T ) is constant value (The final value of all states is known)
then δx f = 0 and H is Hamiltonian, given as:
H = g + p T (t) f (5)
where, p(t) = [ p1 (t), p2 (t), p3 (t), p4 (t), p5 (t), p6 (t)] such that
p1 (t), p2 (t), p3 (t), p4 (t), p5 (t), and p6 (t) are adjoint variables and
g = A1 I (t) + A2 A(t) + A3 E(t) + A4 S(t) + A25 U (t)2 + A26 λ(t)2 and
T
˙
f = ẋ = Ṡ(t), Q̇(t), Ė(t), I (t), Ȧ(t), Ṙ(t) . Therefore, in this study the
Hamiltonian yields as:
A5
H = A1 I (t) + A2 A(t) + A3 E(t) + A4 S(t) + U (t)2
2
A6
+ λ(t)2 + p1 (t) Ṡ(t) + p2 (t) Q̇(t) + p3 (t) Ė(t)
2
+ p4 (t) I˙(t) + p5 (t) Ȧ(t) + p6 (t) Ṙ(t) (6)
also,

∂H ∂H ∂H ∂H ∂H ∂H ∂H T
ṗ(t) = − = − ,− ,− ,− ,− ,−
∂ x(t) ∂ S(t) ∂ Q(t) ∂ E(t) ∂ I (t) ∂ A(t) ∂ R(t)
(7)
To calculate the necessary conditions, we use Pontryagin’s maximum principle

as follows:
Theorem Given optimal controls (U ∗ (t), λ∗ (t)) and solutions

∗ ∗ ∗ ∗ ∗ ∗
S (t), Q (t), E (t), I (t), A (t), and R (t) of the corresponding system,
there exists adjoint variables p1 (t), p2 (t), p3 (t), p4 (t), p5 (t), and p6 (t) that satisfy.
∂H
ṗ1 (t) = − = −A4 + λ(t)[ p1 (t) − p2 (t)]
∂ S(t)
+ (β(1 − q)I (t) + βεE(t) + βδ A(t))[ p1 (t) − p3 (t)] (8a)
∂H
ṗ2 (t) = − =0 (8b)
∂ Q(t)
∂H
ṗ3 (t) = − = −A3 + βεS(t)[ p1 (t) − p3 (t)]
∂ E(t)
+ κ[ p3 (t) − p5 (t)] + pκ[ p5 (t) − p4 (t)] (8c)
∂H
ṗ4 (t) = − = −A1 + β(1 − q)S(t)[ p1 (t) − p3 (t)]
∂ I (t)
+ U (t)[ p4 (t) − p6 (t)] + α[ p4 (t) − p6 (t) f ] (8d)
∂H
ṗ5 (t) = − = −A2 + η[ p5 (t) − p4 (t)]
∂ A(t)
+ zη[ p4 (t) − p6 (t)] + βδS(t)[ p1 (t) − p3 (t)] (8e)
∂H
ṗ6 (t) = − =0 (8f)
∂ R(t)
where, pi (T ) = 0 , i = 1, . . . , 6. By using the optimality conditions, we can

solve the optimal controls as ∇UH(t) = 0 and ∇λ(t)
H
= 0. Therefore:
I ∗ (t)[ p4 (t) − p6 (t)]

U ∗ (t) = (9)
A5
and
S ∗ (t)[ p1 (t) − p2 (t)]

λ∗ (t) = (10)
A6
therefore,
⎧ I ∗ (t)[ p4 (t)− p6 (t)]
⎪
⎨ 1 A5
≥1
I ∗ (t)[ p4 (t)− p6 (t)] I ∗ (t)[ p4 (t)− p6 (t)]
U ∗ (t) = 0 < < 1 (11)
⎪
⎩
A5 A5
I ∗ (t)[ p4 (t)− p6 (t)]
0 A5
≤ 0
and
⎧ S ∗ (t)[ p1(t) − p2 (t)]
⎪
⎨ 1 A6
≥1
S ∗ (t)[ p1 (t)− p2 (t)] S ∗ (t)[ p1 (t)− p2 (t)]
λ∗ (t) = 0 < < 1 (12)
⎪
⎩
A6 A6
S ∗ (t)[ p1 (t)− p2 (t)]
0 A6
≤ 0
so, the optimal controls are written as:

∗
∗ I (t)[ p4 (t) − p6 (t)]
U (t) = max min , Umax , 0 (13)
A5
and
∗
∗ S (t)[ p1 (t) − p2 (t)]
λ (t) = max min , λmax , 0 (14)
A6
and we can calculate the optimal final time (T ∗ ) by:
∂φ ∗
H S ∗ (t), Q ∗ (t), E ∗ (t), I ∗ (t), A∗ (t), R ∗ (t), U ∗ (t), λ∗ (t), T ∗ + T =0
∂t
(15)
thus,
∂φ ∗
T = −H S ∗ (t), Q ∗ (t), E ∗ (t), I ∗ (t), A∗ (t), R ∗ (t), U ∗ (t), λ∗ (t), T ∗
∂t
(16)
therefore, by applying using the characterization of the optimal control, the

following optimality system to optimal control is obtained as:
∗
∗ S (t)[ p1 (t) − p2 (t)]
Ṡ (t) = − β(t) + max min , λmax , 0 S ∗ (t)
A6
(17a)
∗
S (t)[ p1 (t) − p2 (t)]
Q̇ ∗ (t) = max min , λmax , 0 S ∗ (t) (17b)
A6
Ė ∗ (t) = β(t)S ∗ (t) − κ E ∗ (t) (17c)
I˙∗ (t) = (1 − z)η A∗ (t) − α I ∗ (t) + pκ E ∗ (t)

∗
I (t)[ p4 (t) − p6 (t)]
− max min , Umax , 0 I ∗ (t) (17d)
A4
Ȧ∗ (t) = (1 − p)κ E ∗ (t) − η A∗ (t) (17e)
Ṙ ∗ (t) = zη A∗ (t) + f α I ∗ (t)

∗
I (t)[ p4 (t) − p6 (t)]
+ max min , Umax , 0 I ∗ (t) (17f)
A4
The adjoint equation are also obtained as:
∂H
ṗ1 (t) =−
∂ S(t)
∗
S (t)[ p1 (t) − p2 (t)]
= −A4 + max min , λmax , 0 [ p1 (t) − p2 (t)]
A6

+ β(1 − q)I (t) + βεE (t) + βδ A∗ (t) [ p1 − p3 ]
∗ ∗
(18a)
∂H
ṗ2 (t) = − =0 (18b)
∂ Q(t)
∂H
ṗ3 (t) = − = −A3 + βεS ∗ (t)[ p1 (t) − p3 (t)]
∂ E(t)
+ κ[ p3 (t) − p5 (t)] + pκ[ p5 (t) − p4 (t)] (18c)
∂H
ṗ4 (t) = − = −A1 + β(1 − q)S ∗ (t)[ p1 (t) − p3 (t)] + α[ p4 (t) − p6 (t) f ]
∂ I (t)
∗
I (t)[ p4 (t) − p6 (t)]
+ max min , Umax , 0 [ p4 (t) − p6 (t)] (18d)
A5
∂H
ṗ5 (t) = − = −A2 + η[ p5 (t) − p4 (t)]
∂ A(t)
+ zη[ p4 (t) − p6 (t)] + βδS ∗ (t) [ p1 (t) − p3 (t)] (18e)
∂H
ṗ6 (t) = − =0 (18f)
∂ R(t)
Remark 1 Considering that Ṡ(t) = −(β(t) + λ(t))S(t) then we can write

Ṡ(t) = −ϑ(t)S(t) in which ϑ(t) > 0 (because of the positivity of parameters
and states), therefore, S(t) changes are subtractive. Since S(0) > 0 then, S(t)
converges asymptotically to zero in the finite time. By zeroing S(t) it can be
concluded that β S(t)(t) = 0 and Eq. (2c) turns into Ė(t) = −κ E(t) where
κ > 0 and E(0) > 0, thereupon, E(t) converges exponentially to zero. And so on,
A(t) = −η A(t)(η > 0, A(0) > 0) then it will become zero over time. According
to the zeroing of A(t) and E(t) the Eq. (2d) rewrite as I˙(t) = −(α + U (t))I (t)
in which α + U (t) > 0 therefore I (t) → 0. Also, the change of Q(t) is also zero
and remains at its maximum value as a result of zeroing S(t). R(t) converges to its
maximum value as well indirectly because of zeroing the infected and asymptomatic
people. Consequently, the control objective is attained.
Remark 2 To control the pandemic diseases, disease time control has more priority,
and we should be able to drive the disease model to the disease-free equilibrium
point in the shortest possible time. Our purpose is to minimize the number of suscep-
tible, exposed, infected, and asymptomatic people in the optimal time. Therefore,
we considered the cost function with a free terminal time control. By minimizing the
cost function, the rates (quarantine and treatment rates) computed that give us input
optimal controls, that is, if we quarantine the people at the rate λ(t) and treat them
at the rate U (t). Then, we can eradicate the disease in the shortest possible time.
4 The Impulsive SEIAR Epidemic Model
In this section, an impulsive SEIAR epidemic model is introduced due to sudden

changes that may occur for any reason, including travel and immigration for the
whole population of the study area. Figure 3 displays the diagram of the impulsive
the SEIAR dynamic model. The dynamic of SEIAR model changes as follows:

diagram of impulsive SEIAR
dynamic model
⎧
⎪
⎪ Ṡ(t) = −β(t)S(t)
⎪
⎪
⎪
⎨ Ė(t) = β(t)S(t) − κ E(t)
I˙(t) = (1 − z)η A(t) − α I (t) + pκ E(t) , t ∈ / tk (19a)
⎪
⎪
⎪
⎪ Ȧ(t) = (1 − p)κ E(t) − η A(t)
⎪
⎩ Ṙ(t) = zη A(t) + f α I (t)
⎧
⎪
⎪ Ṡ tk+ = −β(t)S(t) + θ1 (t)S(t)
⎪
⎪
⎪ +
⎨ Ė tk = β(t)S(t) − κ E(t) + θ2 (t)S(t)
I˙ tk =
+
+(1 − z)η A(t) − α I (t) + pκ E(t) + θ3 (t)S(t)
, t ∈ tk (19b)
⎪
⎪
⎪
⎪ Ȧ t = (1 − p)κ E(t) − η A(t) + θ (t)S(t)
⎪
⎩
k 4
Ṙ tk+ = zη A(t) + f α I (t)
where tk are integer numbers in which k = 1, 2, . . . , p, . . . and θi (t) which

indicates the rate of new people being impulsively added to the population.
Remark 3 Travel or immigration is the reason for this sudden change in population
to groups (S, E, I, A) that is modeled as impulsive action in the model system. These
individuals are added to the groups of the population once a day. In the real world,
the people who are added include susceptible, infected, exposed, and asymptomatic
people. As a result, this population affects most of the groups, and they add a popu-
lation to each of these groups on a daily basis. The controller must also be able to
counteract the effects of this sudden and daily increase in this population.
5 The Optimal Control Strategy of Impulsive SEIAR
In this section, the controller design equations for the new model are modified. Also,
Fig. 4 shows the applied controller on impulsive SQEIAR epidemic model. In this
way, Eq. (19a and b) is changed as follows:

diagram of impulsive
SQEIAR dynamic model
with the proposed controller

[t]
Ṡ(t) = −(β(t) + λ(t))S(t) + θ1 (t)S(t) (20a)
t
Q̇(t) = λ(t)S(t) (20b)

[t]
Ė(t) = β S(t)(t) − κ E(t) + θ2 (t)E(t) (20c)
t

[t]
I˙(t) = (1 − z)η A(t) − α I (t) + pκ E(t) − U (t)I (t) + θ3 (t)I (t) (20d)
t

[t]
Ȧ(t) = (1 − p)κ E(t) − η A(t) + θ4 (t)A(t) (20e)
t
Ṙ(t) = zηA(t) + f α I (t) + U (t)I (t) (20f)
[t]such
that [.] is floor function. If t ∈ / tk (tk indicates
[t] the day), then the term
t
θ1 (t)S(t) will be eliminated and if t ∈ t k , term t
θ1 (t)S(t) is added to the
model as an impulsive. Similarly, this is true for Eqs.(20c–e).
Similarly to the previous section, the problem is to minimize the cost function J
that is written as Eq. 3. So, the optimal controls are written as:
∗
∗ I (t)[ p4 (t) − p6 (t)]
U (t) = max min , Umax , 0
A5
and
∗
∗ S (t)[ p1 (t) − p2 (t)]
λ (t) = max min , λmax , 0
A6
therefore, the adjoint equation are also obtained as:
∂H
ṗ1 (t) = − = −A4
∂ S(t)
∗
S (t)[ p1 (t) − p2 (t)]
+ max min , λmax , 0 [ p1 (t) − p2 (t)]
A6

[t]
− θ1 (t) p1 (t) + β(1 − q)I ∗ (t) + βεE ∗ (t) + βδ A∗ (t) [ p1 (t) − p3 (t)]
t
(21a)
∂H
ṗ2 (t) = − =0 (21b)
∂ Q(t)
∂H
ṗ3 (t) = − = −A3 + βεS ∗ (t)[ p1 (t) − p3 (t)] + κ[ p3 (t) − p5 (t)]
∂ E(t)

[t]
+ pκ[ p5 (t) − p4 (t)] − θ2 (t) p3 (t) (21c)
t
∂H
ṗ4 (t) = − = −A1 + β(1 − q)S ∗ (t)[ p1 (t) − p3 (t)] + α[ p4 (t) − p6 (t) f ]
∂ I (t)
∗
[t] I (t)[ p4 (t) − p6 (t)]
− θ3 (t) p4 (t) + max min , Umax , 0
t A5
(21d)
∂H
ṗ5 (t) = − = −A2 + η[ p5 (t) − p4 (t)]
∂ A(t)
(21e)
[t]
+zη[ p4 (t) − p6 (t)] + βδS ∗ (t) [ p1 (t) − p3 (t)] − θ4 (t) p5 (t)
t
∂H
ṗ6 (t) = − =0 (21f)
∂ R(t)
Remark
4 According to Ṡ(t) = (−βεE(t) − β(1 − q)I (t) − βδ A(t) − λ(t) +
[t]
θ1 (t))S(t), if we can prove (βεE(t) + β(1 − q)I (t) + βδ A(t) + λ(t)) >
[t]
t
t
θ1 (t) then, the change of S(t) is also decreasing and converges to zero.
Proof of Remark 4
1. If t ∈
/ tk , then βεE(t) + β(1 − q)I (t) + βδ A(t) + λ(t) > 0 fact that according
to the positivity of parameters and states, is always true.
2. If t ∈ tk , then βεE(t) + β(1 − q)I (t) + βδ A(t) + λ(t) > θ1 (t), since λ(t)
is the control input and when needed, it can appear at its maximum value
(0 ≤ λ(t) ≤ 1) then λmax (t) = 1, So in the worst case, that the impulsive
population add to the population the same size as the number of each group
(θ1 (t) = θmax (t) = 1), we can write βεE(t) + β(1 − q)I (t) + βδ A(t) + 1 > 1,
given that the states and parameters are positive, βεE(t) + β(1 − q)I (t) +
βδ A(t) + λ(t) > θ1 (t) is always true.
Then change of S(t) is also decreasing and converges to zero.
Remark 5 When S → 0 then Eq. (20c) changes as:

[t]
Ė(t) = −k + θ2 (t) E(t) (22)
t
[t] t2
if we can prove k > t
θ2 (t) then ∫ Ė(t)dt < 0 and E(t2 ) −
f or all t f or all t t1
E(t1 ) < 0 also, since t2 > t1 (because t is time) then, the change of E(t) is decreasing
and converges to zero E(t) → 0.
[t]
To proof of k > t
θ2 (t), first, we suppose there is w w ≥ 1
f or all t f or all t
day and each day is divided into w (w ≥ 1) sections. Now the impact of the whole
period is investigated:
Proof of Remark 5
(1) if

[t]
k> θ2 (t) (23)
t

and knowing that in each part of a day (not a whole day, t ∈ / tk ) then [t]t = 0,
therefore,
[t] Eq. (23) changes to k > 0 and in every day (one single day, t ∈ tk ), then
t
= 1, therefore, Eq. (23) changes to k > θ2 (t).
If we add up Eq. (23) for all t (t ∈/ tk and t ∈ tk ) for w days that we have w
sections per day then we can write:

w

w kw > θ2 (i) (24)
i=1
Eq. (24) can be written as:

w
i=1 θ2 (i)
k> (25)
w w

w
In the worst case (θ2 (i) = 1 for all i) then θ2 (i) = w and the Eq. (25) rewrite
i=1
as:
w 1
k>
= (26)
ww w
Since the S Q E I A R dynamic is in continuous time, then the number of parts of
a day is a large number w → ∞ then k > 0, that is always true. As a result, the Eq.
(24) exist in the whole period then it can be concluded that the change of E(t) is also
decreasing and converges to zero.
(2) if

[t]
k< θ2 (t) (27)
t
We need to examine the validity of the following equation:


w

w kw < θ2 (i) (28)
i=1
w
(a) If θ2 (i) = 0 then i=1 θ2 (i) = 0. Therefore, w kw < 0, which is never true
because of all three parameters are positive.
w
(b) If θ2 (i) = 1 then i=1 θ2 (i) = 0. Therefore, w kw < w , thereupon kw < 1
and since w → ∞ and k is positive, as a result, kw < 1 is never true.
From (a) and (b), Eq. (28) is not true.
So, it can be concluded, when Eq. (28) is not true then Eq. 24) is definitely and
always true.
Remark 6 As a result of this, the change of E(t) is also decreasing and converges to
zero (E(t) → 0). Since, we proved the number of susceptible and exposed coverage
to zero, therefore, the dynamics of the asymptomatic (Eq. 20e) changes as follows:

[t]
Ȧ(t) = −η + θ4 (t) A(t) (29)
t
[t] [t]

w
in similar way, if η > t
θ4 (t) or η < t
θ4 (t), therefore, w ηw > θ4 (i)
i=1
and the change of A(t) is also decreasing and converges to zero (A(t) → 0).
Remark 7: Since A(t) and E(t) converge to zero, then it is possible to deduce Eq.
(20d) reformed as:

[t]
I˙(t) = −α − U (t) + θ3 (t) I (t) (30)
t

If we can prove (α + U (t)) > [t]t θ3 (t) then, the change of I (t) decreases and
converges to zero. In similar way for susceptible people:
Proof of Remark 7
1. / tk then α + U (t) > 0.
According to positivity of parameters, therefore, If t ∈
Therefore, this equation is always true.
2. If t ∈ tk then α + U (t) > θ3 (t).
Since U (t) is the control input and (0 ≤ U (t) ≤ 1) then Umax (t) = 1, So in the
worst case (θmax (t) = 1) we can write α + 1 > 1, therefore, this equation is always
true.
We proved the number of infected (I ), susceptible (S), exposed (E) converged to
zero then the Eqs. (20b) and (20f) reformed as Q̇(t) = 0, Ṙ(t) = 0, it is noticeable
that when the change of them is zero, then they remain on their maximum value.
After investigating the effect of the proposed controller on SQEIAR and impulsive
SQEIAR model, we should simulate our result. Therefore, we outlined the results of
our work in the next section as a simulation result.
6 Simulation Results of Two Dynamic Models
In this section, a numerical result is given to corroborate the theoretical results

presented in the two previous sections. Section 5.A illustrates the result of optimal
control applied on the SQEIAR dynamic model, while Sect. 5.B investigates the
impact of the controller on sudden population change on this dynamic and presents
the results. The initial parameter values of the SQEIAR epidemic model are shown
in Table 1 and the model is applied to the case of SARS-Cov-2. Also, the values of
the parameters in our epidemic model based on experimental data are from [25] and
[26]. Some values have changed based on the specific case of COVID-19 according
to [2] (Table 2).
Table 1 Initial values of the

State Initial value
SQEIAR epidemic model
variable
S0 8000
Q0 0
E0 1000
I0 500
A0 500
R0 0
N0 10,000
Table 2 Parameters values of

Parameter Values
the SQEIAR epidemic model
κ 0.54/day
α 0.3/day
η 0.3/day
p 0.1
f 0.965
ε 0
δ 1
q 0.5
z 0.02
(A) Simulation Results of the SQEIAR Epidemic Model
The Figures below show the difference between the number of people from all
of the groups in both cases of absence and the controller’s presence over the period
shown. The graph of people without any control is illustrated in red, while the diagram
of people with control is shown in blue. Figure 5 compares the number of asymp-
tomatic people without any control applied and the number of them with control
(including quarantining the susceptible people and antiviral treatment of infected
people). It is clear that the number of asymptomatic people decreased rapidly to
zero (in approximately 20 days). Also, the peak difference between the number of
people when the infection is uncontrolled by the time, we applied the controller
on the dynamics is almost 1400. This indicates that the controller has been able to
reduce the number of asymptomatic people involved. As shown in Fig. 6 the number
of infected people increased from 500 to just over 2200 only in 10 days when there
wasn’t any control of them. But when we applied the controller, the infected people
have also been going down and converge to zero in about 15 days, and the process
of control has not caused to exceed the number of infected over 500.
In Fig. 7, from the first day to day five, there was a significant increase in exposed
people’s number. By contrast, there was a considerable fall in the number of them
controlled by the proposed controller in almost ten days. Figure 8 gives information
about the number of susceptible people with and without control in 15 days. It is
noticeable that control the infection by quarantining susceptible people has been
effective; therefore, the number of susceptible people fell by 8000 to zero in around
five days.
Figure 9 compares the number of recovered individuals with and without the
proposed controller. We can see a decrease in the number of recovered individuals
with the controller over the 35 days. It is noticeable that in almost 15 days only about
2500
A without control
A with control
2000
Number of humans
1500
1000
500
0
0 2 4 6 8 10 12 14 16 18 20
Time(days)
Fig.5 Changes in population number of asymptomatic individuals over time with and without
control
2500
I without control
I with control
2000
Number of humans
1500
1000
500
0
0 5 10 15
Time(days)
Fig.6 Changes in population number of infected individuals over time with and without control
1800
E without control
1600 E with control
1400
Number of humans
1200
1000
800
600
400
200
0
0 5 10 15
Time (days)
Fig.7 Changes in population number of exposed individuals over time with and without control
2500 of them are recovered and remained at 2500. This is obvious because when
people are put into quarantine, fewer get infected; therefore, fewer will be recovered,
which is discussed in greater detail in Fig. 13. Figure 10 also shows the impact of
quarantine on the number of people in the quarantine group. When there is no control
over the outbreak, it is evident that the number of quarantined individuals is zero;
therefore, after applying the controller, their number gradually increases.
As shown in Fig. 11, when the controller is applied to the dynamic, more people
survive because the total population equals the number of recovered and quarantined
8000
S without control
7000 S with control
Number of humans 6000
5000
4000
3000
2000
1000
0
0 5 10 15
Time (days)
Fig.8 Changes in population number of susceptible individuals over time with and without control
10000
9000
R without control
8000 R with control
7000
Number of humans
6000
5000
4000
3000
2000
1000
0
0 5 10 15 20 25 30 35
Time (days)
Fig.9 Changes in population number of recovered individuals over time with and without control
people. Since 3.5% of infected people die from their infection; therefore, the total
number of people is not exactly equal to 10,000. Figure 12 shows the absolute
difference between N (t) with and without the controller; it can be concluded that
the difference between them reaches a constant value (approximately 315), meaning
the controller has kept 315 more people alive.
In Fig. 13, there are two separate cases: with no control and with control. More
than half of the recovered people went down in the controlled case while quarantined
people are almost 7200; therefore, a total of them is approximately 10,000 (∼
=9970). It
is noticeable that most susceptible people are quarantined and there are fewer infected
8000
7000
Q without control
Q with control
6000
Number of humans
5000
4000
3000
2000
1000
0
0 3 6 9 12 15
Time (days)
Fig.10 Changes in population number of quarantined individuals over time with and without control
10000
9950
N with control
N without control
9900
Number of humans
9850
9800
9750
9700
9650
0 5 10 15 20 25 30
Time(days)
Fig.11 Changes in total number of populations over time with and without control
people to become recovered. While in the case of people without the controller, the
number of recovered people rose to around 9660 and there are not any quarantined
people; therefore, a total of them is about 9660. as a result, the total number of alive
people with control is more than the case without control. Approximately 200 more
people have survived from infection when the infection is under control, which is
very significant in a community of 10,000 people.
350
Absolute(N without control - N with control)
300
250
Number of humans
200
150
100
50
0
0 5 10 15 20 25 30
Time(days)
Fig.12 Comparison between total population (N (t)) with and without the controller
10000
9000
8000
7000
Number of humans
R with control
R without control
6000
Q with control
Q without control
5000
R+Q with control
R+Q without control
4000
3000
2000
1000
0
0 5 10 15 20 25 30
Time(days)
Fig.13 Comparison between the recovered and quarantined individuals and a total of them with
and without control
(B) Simulation Results of the Impulsive SQEIAR Epidemic

In this section, the effects of daily suddenly injection at variable rates θi (t) to
susceptible, exposed, infected, and asymptomatic individuals in both cases, with and
without the controller, are investigated. This means the number of these people will
never be zero, but the controller has overcome this population growth and eradicate
the disease. Some asymptomatic travelers and migrants enter society at variable
rates and add to the asymptomatic group every day. Therefore, this injection does
not allow declining the population of asymptomatic individuals. They also affect
the persistence of the epidemic. So, we must prevent it from spreading disease in
the community with proper and optimal control. Figure 14 illustrates the number of
asymptomatic people decreasing daily and eventually reaches 250 and remains stable.
This stationery is because of daily changes in the population that prevent this decline.
On the other hand, the blue line shows that the controller has overcome this population
stagnation and reduce their numbers. The daily added people (including infected
people) to the whole population (by travel or immigration) has profoundly affected
the disease spread and the number of present infected people. The controller was
also able to reduce the number of infected people because if the infected population
were not controlled, approximately 500 people in the community would infect and
spread the disease daily. As infected people are adding to the population daily, some
recover and go to the recovered group and some die from the infection; therefore,
the population almost reaches stability and remains constant. It can be controlled,
and the number of infected people has finally fallen to zero, as shown in Fig. 15.
In Figs. 16 and 17, it can be observed the impact of the sudden population increase
on the number of exposed and susceptible individuals, respectively. The controller
reduced the population of susceptible individuals to zero within five days and the
population of exposed individuals to the lowest possible extent.
As previously mentioned, the number of individuals in quarantine is equal to zero
when there is no control over the disease, but when we implement the controller, the
number of people in quarantine increases. It is noticeable in Fig. 13 when no popula-
tion enters the community, the number of people in quarantine is approximately 7200.
Whereas, if people who come into the community have susceptible people, the same
number must also be quarantined daily (Fig. 18). Thus, the number of them increase
about the number 700, and the number of people in quarantine went up to approxi-
mately under 8000. The sudden injection in the population increases the number of
2500
A without control
A with control
2000
Number of humans
1500
1000
500
0
0 5 10 15 20 25 30
Time(days)
Fig.14 Time evolution of asymptomatic people with and without controls with the impulsive rate
of growth
3000
I without control
I with control
2500
Number of humans
2000
1500
1000
500
0
0 5 10 15 20 25 30 35
Time(days)
Fig.15 Time evolution of infected people with and without controls with the impulsive rate of
growth
2000
E without control
1800 E with control
1600
1400
Number of humans
1200
1000
800
600
400
200
0
0 5 10 15 20 25 30 35
Time (days)
Fig.16 Time evolution of exposed people with and without controls with the impulsive rate of
growth
recovered people. Because those who enter the community include infected people
too, therefore, more infected people will be recovered and the number of recovered
people group will be increased. Without any control over the community, the injected
people (including infected people) add more infected people to society; therefore,
more infected people will be recovered, and the number of recovered people grows.
Whereas by applying controller, the susceptible individuals are rapidly quarantined;
8000
S without control
S with control
7000
6000
Number of humans
5000
4000
3000
2000
1000
0
0 5 10 15 20 25 30 35
Time (days)
Fig.17 Time evolution of susceptible people with and without controls with the impulsive rate of
growth
12000
10000
Number of humans
8000
R with control
R without control
6000 Q with control
Q without control
R+Q with control
4000 R+Q without control
2000
0
0 5 10 15 20 25 30 35
Time(days)
Fig.18 Time evolution of recovered and quarantined people and a total of them with and without
controls with the impulsive rate of growth
therefore, fewer people get infected and eventually recovered. The total number of
people in the quarantine and the recovered ones in the controlled case is higher than
their number without control. Because there are no quarantined people in the uncon-
trolled case, whereas, in the controlled case, the people in the quarantine are all
healthy and more people are alive. The daily increase
number of R(t) + Q(t)
in the
is due to the community’s dynamic population Ṅ (t) = 0 .
11400
N with control
N without control
11200
11000
Number of humans
10800
10600
10400
10200
10000
0 5 10 15 20 25 30 35
Time(days)
Fig.19 Time evolution of total population of people with and without controls with the impulsive
rate of growth
Figure 19 shows the changes in the total population size with and without proposed
optimal control daily. As shown, we were able to keep more of the population alive
with the controller than when the infection was spreading without any control.
Figure 20 shows the absolute difference between the whole population with and
without the controller. The difference between them is a constant value (equal to
350
Absolute(N without control - N with control)
300
250
Number of humans
200
150
100
50
0
0 5 10 15 20 25 30 35
Time(days)
Fig.20 The absolute of total population of people with and without controls with the impulsive
rate of growth
350), meaning the controller has managed to keep 350 more people alive per unit of
time.
7 Comparison with Other Diseases and with Actual Data
This section is divided into four sub-section; in the first and second sub-section (A
and B, respectively), the results of the controller applied to the impulsive epidemic
model are compared for two different diseases (Ebola Virus Disease (EVD) and
influenza). In the following sub-section C, the simulation result for three types of
infections (COVID-19, Ebola, and Influenza) are compared together. Finally, the
comparison of simulation results with real data of China and Spain is also given in
the last sub-section. The parameters of each disease are represented in Table 3.
(A) Ebola Virus Disease (EVD)
As it can be seen in Fig. 21, the number of susceptible people is reduced in only
five days when the controller is applied to the impulsive epidemic model. There is a
significant fall in the number of exposed people when the controller is applied to the
dynamic, and this reduction is acceptable for Ebola disease because the rate of (κ)
is low; that is, the exposed people go to the infected and asymptomatic group at a
lower rate. Also, since the population is considered dynamic, some people are added
every day (whether traveling or migrating), and it prevents the population of groups
from declining rapidly. Although the Ebola virus disease is severe and often fatal in
humans due to its fatality rate (90%), the controller could still reduce the number
of infected significantly. When the recovered people were controlled, the number of
them is increased by almost 550 and reached nearly 1300 in 40 days.
Table 3 Parameters values of

Diseases
the SQEIAR epidemic model
Parameter Ebola [27] Influenza(H2N2) [24] COVID-19
κ 0.0023 0.526 0.54
α 0.178 0.244 0.3
η 0.178 0.244 0.3
p 0.76 0.667 0.1
f 0.26 0.98 0.965
ε 0 0 0
δ 1 1 1
q 0.5 0.5 0.5
z 0.02 0.9 0.02
8000
S without control
Number of humans
6000
S with control
4000
2000
0
0 5 10 15 20 25 30 35 40
Time (days)
8000
Number of humans
6000 E without control

E with control
4000
2000
0
0 5 10 15 20 25 30 35 40
Time (days)
600
Number of humans
I without control
400 I with control
200
0
0 5 10 15 20 25 30 35 40
Time(days)
Fig.21 The Comparison between (S(t), Q(t), E(t), I (t), A(t), R(t)) with and without the
controller in Ebola
Number of humans 600
A without control
400
A with control
200
0
0 5 10 15 20 25 30 35 40
Time(days)
1500
Number of humans
1000 R without control

R with control
500
0
0 5 10 15 20 25 30 35 40
Time(days)
8000
Q without control
6000
Number of humans
Q with control
4000
2000
0
0 5 10 15 20 25 30 35 40
Time(days)
Fig.21 (continued)
(B) Influenza (H2N2)
According to Fig. 22 and as stated in detail in the preceding sections, the controller
could properly control the susceptible individuals and move them to the quarantined
people group. Also, the number of infected and exposed people converged to zero
in only ten days with the controller. There is no direct control on the number of
asymptomatic people. Converging them to zero is due to the other groups, which
8000
S without control
6000 S with control
Number of humans
4000
2000
0
0 5 10 15 20 25 30 35
Time (days)
1500
E without control
Number of humans
E with control
1000
500
0
0 5 10 15 20 25 30 35
Time (days)
2000
I without control
Number of humans
1500 I with control
1000
500
0
0 5 10 15 20 25 30 35
Time(days)
Fig.22 The Comparison between (S(t), Q(t), E(t), I (t), A(t), R(t)) with and without the
controller in Influenza
are discussed in detail in Remark 6. Therefore, it takes more time to reach zero.
Eventually, the number of them with the controller has also reached its lowest level.
In the case of without the controller, more people get infected, then more people
will be recovered. Whereas the number of infected people in the presence of the
controller is reduced, therefore, the recovered number of them will be less. In the
end, the number of people in quarantine with controllers has reached its peak. Since
1000
A without control
A with control
Number of humans
500
0
0 5 10 15 20 25 30 35
Time(days)
10000
R without control
Number of humans
R with control
5000
0
0 5 10 15 20 25 30 35
Time(days)
8000
Q without control
6000
Number of humans
Q with control
4000
2000
0
0 5 10 15 20 25 30 35
Time(days)
Fig.22 (continued)
the death rate in influenza is less than Ebola, fewer people died in influenza, and
more people will be recovered compared to Ebola.
(C) Comparison of Three Types of Diseases (COVID-19, Ebola, and Influenza)
As it can be seen in Fig. 23a, the controller was able to control the dynamic and
the susceptible individuals are quarantined in all three disease groups. In Fig. 23b,
the number of exposed people in both influenza and corona groups is converged to
8000
S (Ebola)
Number of humans
6000 S (Influenza)
S (Corona)
4000
2000
0
0 5 10 15 20 25 30 35
Time (days)
(a)
1500
Number of humans
E (Ebola)
1000 E (Influenza)
E (Corona)
500
0
0 5 10 15 20 25 30 35
Time (days)
(b)
600
I (Ebola)
Number of humans
I (Influenza)
400
I (Corona)
200
0
0 5 10 15 20 25 30 35
Time (days)
(c)
Fig.23 The comparison between different groups of people in one community against three types
of disease like Influenza, Coronavirus, and Ebola (S(t), Q(t), E(t), I (t), A(t), R(t))
zero by the controller in ten days. But the number of exposed people in the Ebola
disease group is reached to zero later because the rate of κ in this disease is lower
than the other group and prevents exposed individuals from joining groups A and I
rapidly. In Remark 5, it is proved that E eventually reaches zero. Figure 23c shows
the number of infected people went down by controller, and according to Fig. 23d
in every three groups, the number of asymptomatic people converged to zero later
1000
A (Ebola)
Number of humans
A (Influenza)
A (Corona)
500
0
0 5 10 15 20 25 30 35
Time (days)
(d)
4000
R (Ebola)
Number of humans
R (Influenza)
3000
R (Corona)
2000
1000
0
0 5 10 15 20 25 30 35
Time (days)
(e)
8000
Number of humans
Q (Ebola)
6000
Q (Influenza)
Q (Corona)
4000
2000
0
0 5 10 15 20 25 30 35
Time (days)
(f)
Fig.23 (continued)
because there was no direct controller on them, but in the end, according to the
evidence in Remark 6, they eventually got to zero. Since exposed people have a
higher rate of infection (κ) in coronavirus (according to Table 3), so more of them
get infected, and eventually more of them will be recovered, which is quite evident
in Fig. 23.e. The number of recovered people in Ebola is lower than the other two
groups, this reduction is acceptable for Ebola disease because the mortality rate ( f )
is very high therefore there are fewer infected people; as a result, fewer recovered
people. Finally, in Fig. 23.f, the susceptible individuals are well quarantined, and the
number of people in the quarantine group is increased.
(D) Comparison of the Simulation Results with Actual Data of China and
Spain
In this sub-section, divided into two parts (1 and 2), designed controller’s accuracy
is examined by the actual data of China. Then, the controller, whose parameters were
estimated using China’s actual data, is applied to the actual data of Spain to show
the applicability of quarantine and treatment policies in both countries.
(1) China
To evaluate the SQEIAR epidemic model, we need to study a successful model of

this type of operation (quarantine and treatment). China has been one of those coun-
tries involved with the virus that has been able to control and eventually eradicate it.
Therefore, in this part, the results of this study are compared to China’s actual data,
to find out the efficiency of the designed controller. If we look at the total popula-
tion of cities infected with coronavirus in China, they are approximately 80,000,000
people. The number of those who have tested positive for the coronavirus and recov-
ered people given by the National Health Commission of the People’s Republic of
China (from 22 January 2020 to 22 March 2020) [28] shown in Fig. 24, respectively.
According to [29], about 20% of those who have tested positive for the coronavirus
have no symptoms of the disease (asymptomatic people), and the rest of them are
infected.
The number of other states can be estimated by using this real data [30]. Since
R0 (Basic Reproduction Number [3, 31]) equal to 2 then the value of E(t) can be
calculated as E(t) ≈ 2I (t) + 2 A(t), that is, each person, whether asymptomatic or
infected, can infect two other people and by assuming 98% of people are quarantined,
the number of susceptible people can easily be calculated as S(t) = N (t) − Q(t) −
E(t) − I (t) − A(t) − R(t).
If the model output is considered as the total number of quarantined
and recovered people, therefore, the parameters of the system can be identi-
fied by actual data given from [27]. For this purpose, we consider y(t) =
T
010 001 S(t) Q(t) E(t) I (t) A(t) R(t) which implies y(t) =
Q(t) + R(t). By using Eq. (2b), Q̇(t) = λ(t)S(t) that is equivalent to d Q(t) =
t t dt
λ(t)S(t) and then d Q(t) = λ(t)S(t)dt and 0 d Q(t) = 0 λ(t)S(t)dt. By assuming
t
λ is stationary, then Q(t) − Q(0) = λ 0 S(t)dt. Since Q(0) = 0 then finally
t
Q(t) = λ 0 S(t)dt. In the same way and by assuming U is stationary, since
t t
Ṙ(t) = zηA(t) + ( f α + U )I (t) then R(t) = zη 0 A(t)dt + ( f α + U ) 0 I (t)dt.
Since the actual data used reported daily, then the model is changed to a discrete-time
model. By this fact it can be deduced

k
k
k
yk = zη Ai + ( f α + U ) Ii + λ Si (31)
i=0 i=0 i=0
60000
positive tested people
50000
Number of humans
40000
30000
20000
10000
0
0 10 20 30 40 50 60 70 80
Time (days)
96000
R with actual data

80000
Number of humans
64000
48000
32000
16000
0
0 10 20 30 40 50 60 70 80
Time (days)
Fig.24 The number of people who has tested positive for the virus and recovered people in China
where yk is the output of k th day, therefore:

⎡ ⎤
zη

k
k
k
yk = Ai Ii Si ⎣ f α + U ⎦ (32)
i=0 i=0 i=0
λ
Define the parameter vectors θ , and the information vectors ϕk as

T T T
θ = θ1 θ2 θ3 = zη f α + U λ and ϕk = ϕ1 ϕ2 ϕ3 =

T
k k k
i=0 Ai i=0 Ii i=0 Si , respectively. We obtain the following evaluations:
yk = ϕkT θ (33)
define a quadratic criterion function:
ℵ
ℵ
2
J (θ ) = [ek ] =
2
yi − ϕkT θ = (Yk − k θ )T (Yk − k θ ) (34)
k=0 k=0
where ℵ is the total number of samples and the vector Yk and the matrix k
⎡ ⎤ ⎡ T ⎤
y1 ϕ1
⎢ y2 ⎥ ⎢ ϕT ⎥
⎢ ⎥ ⎢ 2 ⎥
are defined as Y = ⎢ . ⎥ ∈ Rℵ and = ⎢ . ⎥ ∈ Rℵ×3 . By minimizing the
⎣ .. ⎦ ⎣ .. ⎦
yℵ ϕℵT
criterion function J , the least-squares estimate of θ is obtained as:
−1
θ = T T Y (35)
However, since and Y are known, it is possible to directly calculate the param-
eter estimation vector θ via the above equation. Replacing the obtained parameters in
this study’s model and comparing the responses, the following results are obtained.
If new data is added to the system while the system is estimating simultaneously, it
should be used recursive identification described in detail in [32]. Considering partial
differential equations (PDE) instead of the ordinary differential equation (ODE), [33]
can be used. As seen in Fig. 25, the results of applying the controller on the original
model are compared to a model whose parameters are estimated using real data, and
the total number is scaled for a population of 10,000. In part (a), when the controller
is applied to the model using the identified parameters, the rate of reduction of the
susceptible individuals is lower than before (when the controller is applied to the
original model), which is also justified in reality but ultimately achieved zero. Part
(b) shows the exposed people’s diagram, when the model parameters were identified
by using real data, initially had a peak, but the controller converged it to zero in about
twenty days. Part (c) of Fig. 25 shows that unlike quarantine and treatment in the
real-world, the peak in the number of infected people does not show up in modeling,
but eventually converges to zero. In part (d), similar to part (c), the diagrams of the
asymptomatic population have a higher peak than people in the modeling, and have
growth about 1800 in people, but have finally become zero by the 30th day. A valid
point can be found in part (e) is the reduction in the population of recovered people
(with real data) and the reason for this is that the recovery time is actually longer
and more delayed in real-world society. Part (f) shows the quarantine of individuals
at a rate of 98 percent, which is equal in both cases, and 98 percent of the total
population (10,000) are quarantined successfully. As can be seen from the results of
these studies and since China, where the virus originated from, have implemented
quarantines and got good results and also quarantine is by far one of the most effec-
tive ways to prevent the spread of the disease like coronavirus that there is still no
8000
S with actual data
Number of humans
6000 S with proposed control
4000
2000
0
0 5 10 15 20 25 30 35
Time (days)
(a)
1500
E with actual data
Number of humans
E with proposed control

1000
500
0
0 5 10 15 20 25 30 35
Time (days)
(b)
600
I with actual data
Number of humans
I with proposed control

400
200
0
0 5 10 15 20 25 30 35
Time(days)
(c)
Fig.25 The comparison between different groups of people in one community with proposed
control and actual data (S(t), Q(t), E(t), I (t), A(t), R(t))
vaccine for them. So, it is concluded that the disease spreads very rapidly without
the quarantine and will be highly fatal and catastrophic.
(2) Spain
In this part, similar to part 1 process, the results obtained from applying the
desired controller to the disease and the actual data are compared. In part 1, unknown
parameters are estimated using real data from China. In Fig. 26, 2 diagrams are
2000
A with actual data
Number of humans
1500 A with proposed control
1000
500
0
0 5 10 15 20 25 30 35
Time(days)
(d)
3000
Number of humans
R with actual data

2000 R with proposed control
1000
0
0 5 10 15 20 25 30 35
Time(days)
(e)
10000
Number of humans
8000 Q with actual data
Q with proposed control
6000
4000
0
0 5 10 15 20 25 30 35
Time(days)
(f)
Fig.25 (continued)
compared. The blue diagram shows the number of confirmed cases in Spain, which
is based on actual data extracted from the Health Alert and Emergency Coordination
Centre (from 24 February to 29 May 2020) [34]. The red graph shows the number of
declining trends in the number of infected people when the controller is applied. The
controller parameters are estimated by the actual data from China. As it is known, if
Spain had taken the process of controlling the COVID-19, it could have controlled
the disease well and within about 20 days. In the case that the desired controller
112500
I with actual data
I with proposed control
100000
87500
Number of humans
75000
62500
50000
37500
25000
12500
0
0 10 20 30 40 50 60 70 80 90 100
Time(days)
Fig.26 The comparison between the number of infected people in Spain with and without the
proposed controller
applied to the model, the number of infected people has finally reached approximately
62,500, but in the case without the controller, the number of infected people has
reached 100,000 and has an upward trend after 85 days, which has reached zero in the
shortest time in the controlled case. It is essential to note that this chapter’s evidence,
given from modeling studies, proves how quarantine affects the COVID-19 outbreak.
Putting quarantine in place early and combining it with medical treatment is critical
and effective to control the spread of COVID-19. Also, the quarantining of travelers
from a country involved with COVID-19 reduces disease transmission and deaths and
makes more significant cost savings. However, suppose the government enacts strict
laws to ban rallies and quarantine and other different ways to getting people away
from gatherings like isolation, social distancing, community containment, driving
ban, etc., in the shortest possible time. In that case, it can be expected that the
COVID-19 prevalence will decline in the next few months.
8 Discussion
Since the spread of COVID-19 has not still stopped and the second peak has been
observed in some countries or is expected in the near future, putting quarantine
in place timely and combining it with medical treatment is critical to prevent the
spreading. As is clear from the simulation results, the proposed optimal control
method can also be used for the next peaks of COVID-19. In addition to causing
catastrophic deaths, COVID-19 can also affect countries’ economies, which, if
left unchecked, will have far-reaching consequences for the economies. Therefore,
quarantine’s importance and effectiveness can also be realized, which significantly
reduces the incidence of the disease. Therefore, governments should make strict roles
to make social distancing, isolation, travel banning, and quarantine to prevent the
COVID-19 outbreak around the world.
9 Conclusion
In this chapter, in the first step, the SEIAR dynamic epidemic model was extended
to SQEIAR considering a new group of people called quarantined people. Then,
the impulsive SQEIAR epidemic model was also considered caused by the sudden
growth in population. This chapter aims to provide a method to eradicate the Coro-
navirus disease by decreasing the number of infected, exposed, and asymptomatic
people and to put the susceptible people into quarantine in the absence of an effec-
tive vaccine using the optimal control strategy. Quarantine and treatment were two
control actions employed to achieve this objective. Pontryagin’s maximum principle
was also used to find control inputs in an optimal time. The simulation results of the
COVID-19 were compared with Ebola and Influenza. In the second step, the system
parameters were estimated by using actual data of China. Also, the quarantine and
treatment procedures of China and Spain were compared by applying the controller
with the estimated parameters. Eventually, numerical simulation corroborated our
theoretical results.
Acknowledgements This work was supported in part by the Basque Government through project
IT1207-19.
References
1. Tahir, M., Shah, S.I.A., Zaman, G., Khan, T.: Prevention Strategies for Mathematical Model
MERS-Corona Virus with Stability Analysis and Optimal Control. J. Nanosci. Nanotechnol.
2, 401 (2018)
2. World Health Organization (WHO), Coronavirus (2020)
3. Amiri Mehra, A H., Zamani, I., Abbasi, Z.,Ibeas, A.: Observer-based adaptive PI sliding
mode control of developed uncertain SEIAR influenza epidemic model considering dynamic
population, J. Theoretical Biol. 482, 109984 (2019)
4. Ibeas, A., de la Sen, M., Alonso-Quesada, S.,Zamani, I.: Stability Analysis and Observer Design
for Discrete-Time SEIR Epidemic Models. Adv. in Diff. Equ. 2015 (1), 122 (2015)
5. Ibeas, A., de la Sen, M., Alonso-Quesada, S., Zamani, I.,Shafiee, M.: Observer Design for
SEIR Discrete-Time Epidemic Models. In 2014 13th International Conference on Control
Automation Robotics & Vision (ICARCV), pp. 1321–1326 (2014)
6. Zamani, I., Shafiee, M.: Stability Analysis of Uncertain Switched Singular Time-Delay Systems
with Discrete and Distributed Delays. Optimal Control Appli. Methods 36(1), 1–28 (2015)
7. Jana, S., Haldar, P., Kar, T.: Optimal Control and Stability Analysis of an Epidemic Model with
Population Dispersal. Chaos, Solitons Fractals 83, 67–81 (2016)
8. Zhang, T., Teng, Z.: An Impulsive Delayed SEIRS Epidemic Model with Saturation Incidence.
J. Biol. Dyn. 2(1), 64–84 (2008)
9. Meng, X., Li, Z., Wang, X.: Dynamics of a Novel Nonlinear SIR Model with Double Epidemic
Hypothesis and Impulsive Effects. J. Biol. Dyn. 59(3), 503–513 (2010)
10. Jia, Q., Xia, C.: Exponential stability of impulsive delayed nonlinear hybrid differential systems.
Archives of Electrical Engineering 68(3).
11. Zamani, I., Shafiee, M., Ibeas, A., de la Sen, M.: Switched impulsive control of the endocrine
disruptor diethylstilbestrol singular model. In AIP Conference Proceedings, 2014, vol. 1637,
no. 1, pp. 1218–1227. American Institute of Physics.
12. Zamani, I., Amiri Mehra, A H., Abbasi, Z., Shafiee, M.: Robust stability for affine TS fuzzy
impulsive control systems subject to parametric uncertainties. In 2019 27th Iranian Conference
on Electrical Engineering (ICEE), pp. 1102–1107 (2019)
13. Zamani, I., Shafiee, M., Ibeas, A.: On Singular Hybrid Switched and Impulsive Systems. Int.
J. Robust Nonlinear Control 28(2), 437–465 (2018)
14. Zamani, I., Shafie, M.: Fuzzy Impulsive Control with Application to Chaos Control’. IEEE
International Conference on Fuzzy Systems 2009, 338–343 (2009)
15. Stengel, R.F., Ghigliazza, R., Kulkarni, N., Laplace, O.: Optimal Control of Innate Immune
Response. Optimal Control Applications and Methods 23(2), 91–104 (2002)
16. Lhous, M., Rachik, M., Larrache, A.: Free Optimal Time Control Problem for a SEIR-Epidemic
Model with Immigration of Infective. International Journal of Computer Applications 159(3),
1–5 (2017)
17. Abdelhadi, A., Hassan, L.: Optimal control strategy for SEIR with latent period and a saturated
incidence rate, ISRN Applied Mathematics (2013)
18. Zamani, I., Zaynali, M., Shafiee, M.,Afshar, A.: Optimal control of singular large-scale linear
systems. In 2011 19th Iranian Conference on Electrical Engineering, pp. 1–5 (2011)
19. Di Giamberardino, P., Iacoviello, D.: Optimal Control of SIR Epidemic Model with State
Dependent Switching Cost Index. Biomed. Signal Process. Control 31, 377–380 (2017)
20. Sharomi, O., Malik, T.: Optimal Control in Epidemiology. Ann. Oper. Res. 251(1–2), 55–71
(2017)
21. Rachah, A.: Analysis, Simulation and Optimal Control of a SEIR Model for Ebola Virus with
Demographic Effects. Communications Faculty of Sciences University of Ankara Series A1
Mathematics and Statistics, 67(1), 179–197 (2018)
22. Area, I., NdaÏrou, F., Nieto, J.J., Silva, C.J., Torres, D.: Ebola model and optimal control with
vaccination constraints. arXiv (2017)
23. Zamani, I., Shafiee, M., Shafieirad, M., Zeinali, M.: Optimal Control of Large-Scale Singular
Linear Systems Via Hierarchical Strategy. Transactions of the Institute of Measurement Control
41(8), 2250–2267 (2019)
24. Arino, J., Brauer, F., Van Den Driessche, P., Watmough, J., Wu, J.: A Model for Influenza with
Vaccination and Antiviral Treatment. J. Theor. Biol. 253(1), 118–130 (2008)
25. Riou, J., Althaus, C. L.: Pattern of Early Human-to-Human Transmission of Wuhan 2019 Novel
Coronavirus (2019-nCoV), December 2019 to January 2020. Eurosurveillance 25(4) (2020)
26. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K. S., Lau, E. H.,Wong, J.
Y.: ‘Early transmission dynamics in Wuhan, China, of novel coronavirus–infected Pneumonia.
The New England Journal of Medicine (2020)
27. Althaus, C.L.: Estimating the Reproduction Number of Ebola Virus (EBOV) During the 2014
Outbreak in West Africa. PLoS currents 6 (2014)
28. National Health Commission of the People’s Republic of China (NHC) (2020)
29. Mizumoto, K., Kagaya, K., Zarebski, A.,Chowell, G.: Estimating the Asymptomatic Proportion
of Coronavirus Disease 2019 (COVID-19) Cases on Board the Diamond Princess Cruise Ship,
Yokohama, Japan, 2020. Eurosurveillance 25(10), 2000180 (2020)
30. Amiri Mehra, A.H., Shafieirad, M, Abbasi, Z. and Zamani, I.: Parameter Estimation and Predic-
tion of COVID-19 Epidemic Turning Point and Ending Time of a Case Study on SIR/SQAIR
Epidemic Models. Computational and Mathematical Methods in Medicine (2020)
31. Van den Driessche, P., Watmough, J.: Reproduction Numbers and Sub-Threshold Endemic
Equilibria For Compartmental Models of Disease Transmission. Math. Biosci. 180(1), 29–48
(2002)
32. Shafieirad, M., Shafiee, M., Abedi, M.: Recursive Identification of Continuous Two-
Dimensional Systems in the Presence of Additive Colored Noise. IETE J. Res. 60(1), 74–84
(2014)
33. Shafieirad, M., Shafiee, M., Abedi, M.: Identification of Linear Partial Difference Equations
with Constant Coefficients. J. Basic Appl. Sci. Res 3(1), 655–660 (2013)
34. Health Alert and Emergency Coordination Centre (2020)
Siddha Medicine and Computer
Modeling: A Treasure for SARS-CoV-2
Treatment
M. S. Shree Devi, P. Sathiyarajeswaran, D. Thirumal Kumar,

S. Udhaya Kumar, R. Siva, George Priya Doss, and K. Kanakavalli
Abstract The SARS-CoV-2 was identified in December 2019 and spread quickly
around the globe. Around 218 countries with 61,468,916 cases have been diag-
nosed as of November 27, 2020. The epidemic quarantine and symptomatic care
plan control are the first step of the treatment in the absence of medicines and
vaccines. The need for treatments/therapeutics is in high demand. Pharma companies
are working around the clock to develop these treatments/therapeutics. Several tradi-
tional medicines are also followed as the treatments/therapeutics across the globe.
In India, the traditional medicine system ranks to be one of the topmost promising
treatments/therapeutics for ages. In COVID-19, the medicinal products for treatment,
prophylaxis, and convalescence were listed based on the Siddha Medicine advisory
provided by the Ministry of AYUSH. These drugs are recommended for the treat-
ment and prophylaxis of symptoms. In reality, however, these medications have been
in vogue for infectious diseases like Dengue and Chikungunya for the past two
decades. In parallel, the in silico studies are positively helping in the drug discovery
and unravel the drug mechanisms. The computational protein modeling techniques
also play a significant role in identifying all the reference genome’s proteins. This
chapter discussed Siddha and Quarantine’s traditional insight in viral diseases, Virus-
based drug repurposing for coronaviruses, and various treatment, including signifi-
cant drug repurposing and BSAA combination therapy. We have also used compu-
tational modeling techniques to identify and model the individual protein structures
from the whole genome of SARS CoV-2. Finally, this chapter will explain the steps
M. S. S. Devi (B) · P. Sathiyarajeswaran

Siddha Central Research Institute (CCRS), Chennai, India
e-mail: ms.shreedevi@gov.in
D. T. Kumar
Meenakshi Academy of Higher Education and Research, Chennai, India
S. U. Kumar · R. Siva · G. P. Doss
School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
K. Kanakavalli
Central Council for Research in Siddha, Chennai, India
522 M. S. S. Devi et al.
taken to develop and repurpose Kabasura Kudineer as a drug to inhibit the COVID-19
pandemic.
Keywords Siddha medicine · AYUSH · COVID-19 · Computational modelling ·

Drug repurposing · Kabasura kudineer
1 Introduction
The novel corona-virus disease-2019 (COVID-19) is an ongoing corona-virus

ailment pandemic prompted with the aid of corona-virus two (SARS-CoV-2) as a
Severe Acute Respiratory Syndrome [1]. WHO coined the phrase COVID-19 after it
used to be widely agreed [2–4]. The disorder was first detected in Wuhan in China in
December 2019 and had unfolded globally, ensuing in the modern-day pandemic [5,
6]. World Health Organization (WHO) reported on January 30 that the 2019-nCoV
outburst is a public fitness emergency of global difficulty [7]. Around 218 coun-
tries with 61,468,916 cases have been diagnosed as of November 27, 2020, with the
numbers rising by means of the hour. The following things need to be implemented
(1) slow the spread of illness; (2) provide time better to prepare health care systems
and the general public to be ready if widespread transmission with substantially
associated condition arises; and (3) better illustrate 2019-nCoV to monitor public
health commendations and the expansion of therapeutic countermeasures including
diagnostics and vaccines [7–10]. Isolation, treatment based on symptoms, is the
current management pattern because of the non –availability of suitable antiviral
drugs [11]. Repurposed therapeutic agents targeting COVID-19 is essential [12].
The Indian government recorded 93,51,224 confirmed cases and 1,36,238 deaths on
November 11, 2020. Despite allopathic medicines, Siddha Medication could also be
a safer option for this COVID-19 infection as an alternative/supplement treatment
[13]. The potential for these forms lies in the herbs used in the Siddha medicine
system. During earlier epidemics of vector-borne diseases and HIV, Siddha litera-
ture’s compound formulations were tested [14–16]. Herbal remedies have made a
comeback, making use of herbal ingredients with limited or no side effects. Due to
pharmacological proof of protection, effectiveness, the manufacturing of standard-
ized dosage forms, and high-quality manipulate measures, and they are recognized
[17]. The Siddha remedy is also described as science. In South India, the outstanding
restoration artwork originated, flourished, and practiced by each normal and ancestral
method [18]. Classically, relying on the patient’s medical symptoms, indication, and
adjuvant remedy is referred to in traditional literature. It states that the Siddha method
of medicine (sastric preparation) can also be clinically used for viral infections. Treat-
ment can differ according to its behavior and symptoms, referring to a category of
diseases [19]. The selection of the specific Siddha medicine (sastric preparation/novel
formulation) would depend on the disease’s indication [20]. COVID-19 correlated
with kaphasuram [21]. Based on the symptoms, germ theory is not new to Siddha
Medicine as terms like kirumi existed significantly earlier [22]. The diseases like
Siddha Medicine and Computer Modeling: A Treasure … 523
gonorrhea, leucohorrea, scabies, anorectal abscess, and worm infestations are dealt
with under communicable diseases. Multi targeted approach using external thera-
pies like steam inhalation, nasal fumigation, external oil application, herbal inhalers,
breathing practices, and antiviral medications, which are repurposed, are used to
control COVID-19 [23]. Siddhars emphasized the identification of root cause and
to treat the root cause than the symptoms [24]. The immune role is a component of
pitta thathu, as per Siddha literature [21]. Possessing good immunity encounters all
the signs when this comes into action. In low immune status, pitta thathu is reduced
iyam escalate precipitating respiratory symptoms. Siddhars have explained this in
the verses “Thanamulla sethumanthan ilagil veppu.” If not treated at that stage, it
gradually transfers to a stage of Sanni. Focused group discussion and Siddha’s task
force feel appropriate to use kaphasuram as a Siddha diagnosis for the early stage
[21]. Severe and complicated stages will be moving towards sanni. This method is
recognized for thirty-two kinds of preparations, each for internal administration and
32 types of external applications. The herbal, animal, and metal-mineral compounds
used to treat various ailments are based on many single drugs and compound formu-
lations. Besides manuscripts and palm-leaf texts, there are more than thousands of
original works. In south India, Siddha medicine is ordinary for treating more than a
few viral diseases, such as chickenpox, mumps, influenza, dengue, and prophylaxis
[25]. The most common antiviral Siddha formulation, nilavembu kudineer, supported
an immense set of victims and aided from dengue outbreaks. Siddha treatment offers
a plethora of charming defensive potentials for victims due to the truth of this. The
efficacy of Siddha medicine in controlling sickness outbreaks such as dengue and
chikungunya fever. In the last segment of the 12 months of 2012, an outbreak of
dengue in Tamil Nadu.
The Government of Tamil Nadu launched public fitness commercials advertising
nilavembu kudineer as defensive and controlling the public’s morbidity degree on
contracting viral fever [26]. The Government of Tamil Nadu issued public health clas-
sified ads advertising nilavembu kudineer as preventive and controlling the public’s
morbidity stage on contracting viral fever [26]. The Ministry of AYUSH also advo-
cated the use of Siddha formulations to deal with these viral pandemics. On the other
hand, modern drugs intend to destroy the virus and do not intend to enhance host
immunity to conflict illness simultaneously [27]. Evidence is required to document
a medicinal drug to work towards COVID-19. It has been proven that Siddha drug
treatments act on each pathogen and host immunity, mainly due to the fact these drugs
are the formula of quite a several energetic components that can work on many condi-
tions of the sickness at the identical time [28]. It is nevertheless a challenge, however,
to display screen various Siddha formulations to deal with COVID-19 rapidly exper-
imental. On a parallel event, the Computer-aided drug discovery also plays a signif-
icant role in identifying the disease/drug mechanism and identifying a new drug to
treat the COVID-19 [29]. This chapter discusses the traditional Siddha practices on
antiviral infections, the essential proteins protein for drug repurposing using the in
silico approach to aid Siddha, and finally, the various therapeutic strategies.
2 The Traditional Insight of Siddha and Quarantine

Measures in Viral Diseases
The latest phenomenon in India is holistic processes closer to viral infections, envi-
ronmental sanitation, and quarantine. In literature, Tholkappium mentions quaran-
tining troopers who sustained conflict wounds that are infectious and adopted quar-
antine methods via connecting neem leaves to the public in these rooms. During
gatherings such as spiritual festivals, particularly in the summer season and autumn,
to keep away from the outbreak of viral diseases. A chord (Kodi Maram) will be
hooked up two weeks earlier than the festival’s beginning. Humans will no longer be
in a position to go out, or others will no longer let in, greater importantly, containing
infectious diseases. During these festivals, anyone would spray medicated water from
turmeric powder and neem leaf paste in all the roads, which is additionally predicted
to include viruses and bacterial spread.
The public is typically cautioned to keep self-hygiene and have restricted meals
and be prompted to stay away from non-vegetarian foods. However, plenty of greens
and a healthy diet are offered, which will take care of the concern’s immunity. A pot
of water is put in every residence in the home’s entry factor (Muttram), the place
human beings can sanitize themselves earlier than getting into the house, leaving their
footwear besides. All the data mentioned above is from the traditional knowledge that
is now interpreted as quarantine, strategies of handwashing, and climate strategies.
3 Natural Products and Siddha Medicine for COVID-19
Natural products used in Siddha medicine are reported as immunomodulators. The

complementary these natural products possess antiviral properties. To face the chal-
lenges of containment of COVID-19 the below-listed herbs from Siddha medicine
play a very vital role by their activities such as Withania somnifera, Tinospora cordi-
folia, Phyllanthus embelica, Moringa oliefera, and Glycyrrhiza glabra, might be
taken for prophylaxis and as a supplementary treatment for COVID-19 [30]. These
herbs have been used in Siddha over the centuries, either alone or in combination,
and have proved their effectiveness when subject to thorough scientific examina-
tion. They also play a significant role in discovering and developing many antiviral
medicines based on their structural moiety. WHO funds and welcomes innovations
in scientifically proven traditional medicine around the globe. The potential role
of Siddha in the treatment of COVID-19 through immune pathways was recently
established.
In the case of SARS-CoV-2, the AYUSH Ministry recommended the formu-
lation of Kabasura Kudineer consisting of 15 plants, namely, Zingiber offic-
inale, Piper longum, Syzygium aromaticum, Tragia involucrata, Anacyclus
pyrethrum, Hygrophilla auriculata, Terminalia chebula, Adhatoda vasica, Plectran-
thus amboinicus, Saussurea costus, Tinospora cordifolia, Clerodendrum serratum,
Andrographis paniculate, Sida acuta, and Cyperus rotundus (6.6% each). The posi-
tive side of the concoction based on this plant holds the levels of infection at bay.
There is failure to determine the chemical composition or mode of action in these
plants [30, 31]. Major medicinal compounds and natural products, such as inhibiting
viral 3CL protease and blocking viral RNA-dependent RNA polymerase activity,
have exhibited various antiviral mechanisms against SARS-CoV, thus preventing
early infection, including viral attachment and penetration [32, 33]. Table 1 shows
the list of individual plants and their pharmacological activity for repurposing.
4 Virus Structure-Based Drug Repurposing

for SARS-CoV-2
Virus-based antiviral marketers target specific virus proteins. The SARS-CoV-2

genome’s critical open analysis frame, ORF 1ab, encodes the large replicase polypro-
tein pp 1ab that types the non-structural proteins, NSP1-16. By way of contrast, the
structural proteins consist of S, E, M, and N8-10. By using two cysteine proteases,
specifically the most crucial protease (Mpro) or 3C-like protease (3CLpro) and the
secondary papain-like protease two (PL2pro), a complicated replicase that involves
the processing of pp1ab allows viral replication. Mpro cleaves at eleven websites
in the central and C-terminal regions, while PL2pro cleaves at three web pages in
the N-terminal polyprotein regions. The mainstream of the proteins and enzymes of
CoVs needed for the replication technique are potential drug pursuits [30, 31, 47–
49]. The Mpro is a hopeful viral objective for the proposal of SARS / MERS drugs,
as the Mpro’s polyprotein cleavage facilitates the RNA-dependent RNA polymerase
(RdRp) and helicase integral viral replication proteins. CoVs have a glycoprotein
(S) floor structural spike essential for interaction with the host phone receptor and
ensuing access of the virus into the host. Two subunits make up the S protein, the
S1 (receptor binding) and the S2 (membrane fusion), to bind a few viral glyco-
proteins. Kabasura Kudineer and Nilavembu Kudineer recorded antiviral recreation
(Unpublished Data).
Separate host variables are used for entry and replication CoVs. In vitro and
in vivo studies have been reported on the anti-CoV potential of monoclonal antibodies
against the receptor-binding region (RBD) [50]. The angiotensin-converting-enzyme
two (ACE2) host receptor is ideally used by the SARS-CoVs, while MERS-CoV5
uses dipeptidyl peptidase four (DPP4) [51]. In the extra entry of CoVs into host
cells, the cell phone floor and endosomal pathways cleave and prompt the viral S
protein by host proteases such as transmembrane protease serine two (TMPRSS2)
are concerned. This proteolytic cleavage can of these host proteases, partly blocking
entry [52].
Table 1 List of individual plants and their pharmacological activity for repurposing [34, 35, 44–46,
36–43]
Botanical name Pharmacological activity
Zingiber officinale Antioxidant, Anticancer, Anti-inflammatory, Antiemetic,
Antipyretic, Analgesic, Anti-Inflammatory, Antiviral,
Antimicrobial, Immunomodulatory, Expectorant, Hepatoprotective
Piperlongum L Antifungal, Ant Amoebic, Antimicrobial, Respiratory Stimulation,
Antiasthmatic, Antioxidant, Immunomodulatory, Bioavailability
Enhancement, Antiviral, Expectorant, Hepatoprotective
Syzygiumaromaticum Antimicrobial, Analgesic, Antioxidant, Anticancer, Anthelmintic,
Antiulcer, Anti-Inflammatory, Anti-Depressant, Bone Preserving,
Antipyretic, Antithrombotic, Expectorant
TragiainvolucrataL Anti-Inflammatory, Analgesic, Diuretic and Anthelmintic,
Antimicrobial
Anacycluspyrethrum Anti-inflammatory, Antioxidant, Antimicrobial,
Immunomodulatory, Antipyretic
Andrographispaniculata Anticancer, Anti-Inflammatory, Angiogenic, Antivenom,
Antidiabetic, Antimalarial, Antimicrobial
Hygrophilaauriculata Antimicrobial, Antipyretic, Anti-inflammatory
Terminaliachebula Antiviral, Antimicrobial, Immunomodulatory, Expectorant
JusticiaadhatodaL Antimicrobial, Antipyretic, Expectorant, Bronchodilator
Plectranthus amboinicus Antimicrobial
Saussurea lappa Antiviral, Antimicrobial, Antipyretic
Tinosporacordifolia Antiviral, Antimicrobial, Immunomodulatory, Antipyretic,
Clerodendrumserratum Antimicrobial, Expectorant
SidaacutaBurm.f.L Antiviral, Antimicrobial, Antipyretic
Cypreusrotundus L Antiviral, Antimicrobial, Antipyretic
Justiciaadathoda L Antimicrobial, Expectorant
Carica papaya Anti-bacterial, Antioxidant, Antipyretic, Insecticidal, Antimicrobial
Andrographispaniculata Antiviral, Antipyretic
Ocimumtenuiflorum Antibacterial, Antiviral, Antifungal, Antiprotozoal, Antimalarial,
Anthelmintic, Antidiarrheal, Analgesic, Antipyretic,
Anti-inflammatory, Antiallergic, Antihypertensive, Cardio
Protective, Central Nervous System (CNS) Depressant, Memory
Enhancer, Anti-Hyper Cholesterolaemic, Hepatoprotective,
Antidiabetic, Antiasthmatic, Antithyroid, Antioxidant, Anticancer,
Chemopreventive, Radioprotective, Immunomodulatory
Vetiveria zizanioides Anti-inflammatory, Antibacterial, Antifungal, And Anti-Malarial,
Anti-Tubercular, Anti-Hyperglycaemic, Anti-Hepatoprotective,
And Antioxidant Activity
Santalum album Antipyretic, Antiscabietic, Diuretic, Expectorant, Stimulant,
Anti-Inflammatory, Anti-Mitotic, Antiviral
(continued)
Table 1 (continued)
Botanical name Pharmacological activity
Piper nigrum Antihypertensive, Antiplatelet, Antioxidant, Antitumor,
Anti-Asthmatics, Analgesic, Anti-Inflammatory, Anti-Diarrheal,
Antispasmodic, Antidepressants, Immunomodulatory
Hedyotis corymbose Antibacterial, Antioxidant, Analgesic, Hepatoprotective,
Anticancer
Plectranthus vettiveroides Antioxidant Activity, Anticancer
Trichosanthes cucumerina Anti-inflammatory
5 Computational SARS-CoV-2 Target Modeling in Drug

Discovery
The selection of a target for drug interaction is the most crucial in therapeutics.
There are 100 s of SARS-CoV-2 protein structures deposited in the public databases
today. However, the first crystal structure of SARS-CoV-2 main protease monomer
in complex with an inhibitor N3 was deposited in the Protein Data Bank on 2020–
02-05 with PDB ID: 6LU7 at a resolution of 2.16 Å [53]. The other related species’
protease proteins are always dimer, and the crystal structure of SARS-CoV-2 being
a monomer is found to be a limitation in structure [54]. The drug discovery relies
on the 3D structure of the protein targets, but X-ray or NMR techniques to obtain
the crystallographic structure could be time and cost consuming. The alternative
method to overcome these time and cost could promisingly be computer-aided protein
modeling techniques [55]. Here we illustrate an overall pipeline to obtain a 3D
structure of the computer-aided drug designing proteins. This can be done quicker,
especially in cases like the COVID19 pandemic, where there is a need for the drug
in a shorter duration.
NCBI protein BLAST algorithm was performed utilizing the information obtained
from the QHO62876 sequence to identify the possible drug targets based on the
polyprotein [56]. This was one of the earliest sequence data, which was available
on 21 January 2020. The name of the proteins, accession number, and description
has been tabulated along with the E-value in Table 2. The graphical visualization
of the protein products is shown in Fig. 1. The interval values between the first and
last amino acids were taken as the protein sequence for further modeling. We have
formatted each protein sequence in FASTA format (Supplementary data 1).
Coronaviridae family of viruses consists of a single-stranded, positive-sense RNA
genome. The length of whose genome ranges from around 26 to 32 kilobases [57].
We have developed the 3D models of all the proteins identified from the BLAST
search and submitted as supplementary data, which could help further drug discovery
studies. Each protein’s atomic coordinates were modeled utilizing the online Swiss
Model Server [58]. These models were validated for Ramachandran plot predictions
using the PROCHECK server [59]. The template ID of each query protein and its
identity percentage, the ligand present, and q-mean value is tabulated in Table 3. We
Table 2 The list of COVID-19 proteins obtained from the NCBI BLAST with NCBI accession
number QH062876.1 as a query. The table provides a detailed list of the product’s identified names,
accession number, description, intervals between the first and last amino acids, and the E-value
NSP11 pfam06471 NSP11; This region of 5928–6520 0.00E + 00
coronavirus polyproteins
encodes the NSP11
protein
Corona_RPol_N pfam06478 Coronavirus RPol 4406–4758 0.00E + 00
N-terminus; This family
covers the N-terminal
region of the coronavirus
NSP13 pfam06460 Coronavirus NSP13; 6800–7095 0.00E + 00
This family covers the
NSP13 region of the
coronavirus polyprotein
Peptidase_C30 pfam05409 Coronavirus 3292–3569 7.45E-162
endopeptidase C30;
Corresponds to Merops
family C30
Viral_protease pfam08715 Papain like viral 1564–1880 4.03E-132
protease; This family of
viral proteases are
similar to the papain
protease
nsp8 pfam08717 nsp8 replicase; Viral 3943–4140 1.83E-113
nsp8 (non-structural
protein 8) forms a
hexadecameric
supercomplex
SUD-M pfam11633 Single-stranded poly(A) 1351–1493 2.73E-75
binding domain; This
family of proteins
represents Nsp3c
NSP10 pfam09401 RNA synthesis protein 4265–4384 1.05E-71
NSP10; Non-structural
protein 10 (NSP10) is
involved in RNA
synthesis
Nsp1 pfam11501 Non-structural protein 13–127 4.02E-62
Nsp1; Nsp1 is the
N-terminal cleavage
product from the viral
replicase
nsp9 pfam08710 nsp9 replicase; nsp9 is a 4141–4253 6.90E-55
single-stranded
RNA-binding viral
protein
(continued)
Table 2 (continued)
Corona_NSP4_C pfam16348 Coronavirus 3169–3261 4.00E-43
non-structural protein 4
C-terminus; This is the
C-terminal domain
nsp7 pfam08716 nsp7 replicase; nsp7 3860–3942 1.32E-38
(non-structural protein
7) has been implicated
in viral RNA replication
Nsp3_PL2pro pfam12124 Coronavirus polyprotein 1498–1561 1.42E-27
cleavage domain; This
domain is found in
SARS coronaviruses
Macro pfam01661 Macro domain; This 1058–1165 2.31E-22
domain is an
ADP-ribose binding
module
Macro_Af1521_BAL_like cd02907 Macro domain, Af1521- 1038–1169 1.57E-21
and BAL-like family.
The macro domain is a
high-affinity
ADP-ribose
DEXXQc_Upf1-like cd17934 DEXXQ-box helicase 5596–5767 9.68E-20
domain of Upf1-like
helicase; The Upf1-like
helicase family includes
UPF1, …
PRK00431 PRK00431 RNase III inhibitor; 1056–1196 1.34E-17
Provisional
A1pp smart00506 Appr-1"-p processing 1051–1164 3.71E-15
enzyme; Function
determined by Martzen
et al
DUF3655 pfam12379 The protein of unknown 920–987 1.83E-14
function (DUF3655);
This domain family is
found in viruses
DNA2 COG1112 Superfamily I DNA 5647–5916 3.79E-13
and/or RNA helicase
Replication,
recombination, and
repair]
(continued)
Table 2 (continued)
NAR pfam16251 Nucleic acid-binding 1907–2019 2.26E-12
domain (NAR); This
domain, approximately
100 residues in length
SF1_C_Upf1 cd18808 C-terminal helicase 5768–5905 6.21E-12
domain of Upf1-like
family helicases
AAA_12 pfam13087 AAA domain; This 5767–5904 1.84E-11
family of domains
contains a P-loop motif
that is characteristic of
the AAA
YmdB COG2110 O-acetyl-ADP-ribose 1035–1192 2.99E-11
deacetylase (regulator of
RNase III) contains a
Macro domain
AAA_11 pfam13086 AAA domain; This 5604–5661 2.39E-05
family of domains
contains a P-loop motif
that
is characteristic of the
AAA
AAA smart00382 ATPases associated with 5604–5736 4.12E-03
a variety of cellular
activities
have deposited the 3D structure of the proteins as 3D coordinate files in PDB format
as Supplementary data 2.
The Ramachandran plot validation of understanding the percentage of residues in
most favored regions, in additional allowed regions, in generously allowed regions,
and in disallowed regions of each individual modeled proteins are tabulated in Table
4.
6 Repurposing of Siddha Formulations as Antivirals

Against COVID-19
Quarantine is the current therapeutic factor, and there is a symptomatic treatment plan
for disease control and no antiviral drugs or vaccine therapy. Therefore, treatment
for COVID-19 needs to be developed. Based on the Siddha medicine framework,
the Ministry of AYUSH’s advisory gave India the stages of care, prophylaxis, and
associated recovery listed for COVID-19. These medications are recommended for
both the treatment of symptoms and the prophylaxis scenario.
Fig. 1 Graphical representation of the SARS-CoV-2 proteins list obtained from the NCBI BLAST
with NCBI accession number QH062876 as a query
However, for the past two decades, these drugs have been in vogue for infec-
tious diseases such as Dengue and Chikungunya. The official Siddha formula-
tions mentioned in the CittaVaittiyattirattu Siddha manuscript include both Kaba-
sura Kudineer and Nilavembu Kudineer. These are used for hemorrhagic fevers
(pitthacuram) and are a safe treatment for Siddha fever [60]. These are used for
phlegmatic fever (Aiyacuram). Due to its Neuraminidase inhibition ability against
inactivated influenza virus H1N1 (Patent No. 201741016901 A, Dated 18.05.2018),
we studied additional proprietary herbal formulations called ‘JACOM,’ a coded
novel medication [61]. The effectiveness of herbal medicine can be used effi-
ciently during viral outbreaks with the implementation of modern and more reliable
Table 3 Name of the COVID-19 proteins with the respective template ID and identity of the
template proteins taken for 3D modeling using the Swiss Model server. The Q-mean score obtained
from the Swiss Model server is included
S.No Protein name Template ID Identity Ligand QMEAN
(%)
1 A1pp 2fav.2.A 80.18 None −1.64
(Replicase
polyprotein 1ab
(pp1ab)
(ORF1AB))
2 AAA 6jyt.2.A 100.00 None −5.24
(Helicase)
3 AAA_11 6jyt.2.A 100.00 None −2.75
(Helicase)
4 AAA_12 6jyt.2.A 99.28 None −7.55
(Helicase)
5 Corona_NSP4_C 3vcb.1.A 61.18 None −1.11
(RNA-directed
RNA
polymerase)
6 Corona_Rpol_N 6nur.1.A 93.77 zinc −0.19
(NSP12)
7 DEXXQc_Upf1-like 6jyt.2.A 100.00 None −4.97
8 DNA2 6jyt.2.A 99.63 None −8.3
9 DUFF3655 No template – – –
10 Macro 2fav.2.A 81.48 None −1.86
11 Macro_Af1521_BAL_like 2acf.2.A 76.52 None −0.93
(Replicase
polyprotein 1ab)
12 NAR 2k87.1.A 82.30 None −1.14
(Non-structural
protein 3 of
Replicase
polyprotein 1a)
13 Nsp1 2hsx.1.A 85.96 None −4.29
(Leader protein;
p65 homolog;
NSP1 (EC
3.4.22.-))
14 Nsp3_PL2pro 2kaf.1.A 73.44 None −2.34
(Non−structural
protein 3)
(continued)
Table 3 (continued)
S.No Protein name Template ID Identity Ligand QMEAN
(%)
15 nsp7 1ysy.1.A 98.80 None −5.44
(Replicase
polyprotein 1ab
(pp1ab)
(ORF1AB))
16 nsp8 2ahm.1.H 97.47 None 1.08
(Replicase
polyprotein 1ab,
heavy chain)
17 nsp9 1qz8.1.A 97.35 None −1.39
(polyprotein
1ab)
18 NSP10 5nfy.1.B 98.33 zinc −1.74
(Polyprotein
1ab)
19 NSP11 5nfy.1.A 94.86 zinc −3.15
(Polyprotein
1ab)
20 NSP13 3r24.1.A 93.58 S-Adenosylmethionine −2.57
(2’-O-methyl
transferase)
21 Peptidase_C30 2alv.1.A 94.95 None −0.9
(Replicase
polyprotein 1ab)
22 PRK00431 2fav.2.A 75.91 None −1.16
(Replicase
polyprotein 1ab
(pp1ab)
(ORF1AB))
23 SF1_C_Upf1 6jyt.2.A 99.28 None −7.59
(Helicase)
24 SUD-M 2rnk.1.A 79.14 None −2.01
(Replicase
polyprotein 1ab)
25 Viral_protease 5tl6.1.A 82.86 zinc −0.14
(Replicase
polyprotein 1ab)
26 YmdB 2acf.2.A 73.42 None −0.38
(Replicase
polyprotein 1ab)
Table 4 The detailed percentage list of amino acids in the modeled COVID-19 proteins obtained
from Ramachandran plot evaluation using PROCHECK server
S.No Protein name Residues in Residues in Residues in Residues in
most favored additional generously disallowed
regions (%) allowed allowed regions (%)
regions (%) regions (%)
1 A1pp 94.6 4.3 1.1 0
2 AAA 76.1 17.1 5.1 1.7
3 AAA_11 74.5 21.3 2.1 2.1
4 AAA-12 68.3 24.6 4 3.2
5 Corona_NSP4_C 93.8 5.6 0.6 0
6 Corona_Rpol_N 90.7 9.3 0 0
7 DEXXQc_Upf1-like 79.3 14 4.7 2
8 DNA2 70.7 23.6 3.7 2
9 Macro 94.4 4.4 1.1 0
10 Macro_Af1521_BAL_like 92 6.2 1.8 0
11 NAR 84.7 14.3 1 0
12 Nsp1 78.9 16.8 3.2 1.1
13 Nsp3_PL2pro 82.1 14.3 1.8 1.8
14 nsp7 72.5 22.5 3.8 1.2
15 nsp8 94.4 5.6 0 0
16 nsp9 88.2 10.7 0.5 0.5
17 NSP10 90 10 0 0
18 NSP11 86 11.8 1.5 0.6
19 NSP13 91.2 7.7 1.2 0
20 Peptidase_C30 88.8 9.6 0.8 0.8
21 PRK00431 95.8 3.4 0.8 0
22 SF1_C_Upf1 67.5 25.4 4 3.2
23 SUD-M 84 13.6 0.8 1.6
24 Viral_protease 90.1 9.6 0.4 0
25 YmdB 94.2 4.3 1.4 0
screening assays and prediction methods [62]. In silico studies in kabasura kudi-
neer, JACOM, and nilavembu kudineer have been conducted against SARS-CoV-
2, encouraging and extending the reach of these drugs in drug repurposing areas
[21, 63]. The in silico methods with the phytochemical components of kabasura
kudineer, nilavembu kudineer, JACOM were targeted against the SPIKE and RNA
Dependent RNA Polymerase (RdRp) of SARS-CoV-2 [64]. In preprints, the compu-
tational screening is done on kabasura kudineer, and thonthasura kudineer showed
evidence for corona viral drug targeted coronavirus spike (s) glycoprotein. In silico
studies were performed on Ammaiyar Koondhal Kudineer and Nilavembu Kudineer
(Siddha Herbal infusion) against SARA-CoV-2 Spike Protein and its ACE2 Receptor
Complex [65–67]. The screening of Siddha herbs containing anti-coronavirus (2019-
nCoV) compounds is a challenge. A combination of herbs can act simultaneously
on multiple targets to provide complete relief [68].
7 BSAA Combination Therapy
The low potency of hit compounds as single agents is one downside of phenotypic
screens, as their maximum tolerated dose is frequently sub-therapeutic for the new
indications being pursued [69]. The crucial way to evade this issue is to test two or
more drugs with limited redundancy on various cellular signaling pathways involving
viral replication. Another tool helping scientists narrow down individual antimicro-
bials’ scope is the high-throughput screening of compound libraries for synergistic
host-virus interactome-level combinations for emerging and re-emerging infectious
diseases. These approaches promise to address BSAAs’ sometimes low actions by
improving efficacy while potentially reducing doses, reducing duration, drug devel-
opment pipeline costs, reducing toxicity, and minimizing the emergence of secondary
resistance [70, 71].
The plant kingdom remains largely unexplored in this situation and can contain
several bioactive molecules that are therapeutically important. In a recent review,
traditional Chinese medicine’s role in treating patients with SARS-CoV-2 is under-
lined (72). There are no such systematic studies in countries with a long history
of medicinal plant use since ancient times to treat broad-spectrum diseases. For
example, under distinct domain names like Ayurveda, Siddha, Unani, etc., India
relied primarily on plant-based medicines. While the introduction of allopathic drugs
has cornered the prevalence of plant-dependent therapies, the current pandemic has
been. It stresses the need for revisiting and researching individual plants using
advanced methods and approaches. It is a scientific challenge to analyze plants’
therapeutic benefits to identify sufficient phytochemical compounds that could act
as potential molecules in SARS-CoV-2 therapy. The research sheds light on plants
and plant-based drugs for use in the treatment of COVID-199 in this context. It
recognizes the medicines used to treat various viral infections that are plant-based.
There have been convincing proof of the need to identify new plant biomolecules
which could be used for targeted therapy. We point out that unique compounds can
work in combination with synthetic drugs to improve antiviral activity.
8 Future Prospective
Despite advanced medical research, there are several diseases worldwide with unmet
therapeutic options that challenge scientists to find effective therapeutic alternatives.
In this sense, the principle of repurposing a drug provides a broad reach for exploring
and recycling the hidden potential behind the drug. While researchers are lucky
enough to be equipped with such computational tools in this period, there is still a
particular gap to be filled to solve the post-prediction deficiencies in optimizing the
dosing schedule, formulation and target population selection, etc. The significance of
drug repurposing in silico approaches has gained prominence in drug development in
current pharmaceutical industries, despite the hiccups during the process. In different
clinical trials, a variety of repurposed drugs are currently being tested, but the primary
therapy for COVID-19 has been mostly supportive to date. In broad trials, medicines
such as chloroquine and hydroxychloroquine (CQ and HCQ) showed no benefits in
reducing hospitalized patients’ mortality rates. Therefore, the WHO recommended
that their further use be suspended from treating SARS-CoV-2 infections. To find
a safe and successful therapy to combat COVID-19, several mega clinical trials are
currently underway. To address this COVID-19 pandemic, complementary efforts
need to be made by health agencies, non-governmental organizations, and funding
bodies all over the world. Accelerated drug/vaccine approval strategies that take
both effectiveness and safety into account need to be placed to further flatten the
worldwide COVID-19 incidence curve.
The SARS CoV2 has only been identified for a few months and a few months,
Yet a book on drug repurposing could already be published; efforts have caused the
COVID-19 pandemic. Every computer in the armamentarium of drug developers has
been engaged, from in the wet laboratory, high throughput screening for the most
the in silico tools varied. There is no time to waste in a pandemic arising from a
new pathogen, and many drug production prerogatives are open. They’ve brushed
aside. This is a big drug market for But it could prove to be a double-edged sword,
too: If minimal effectiveness (of the sort we have seen so far) is exchanged for,
Severe side effects, especially those that only manifest later or later, As may be the
case with cardiac conduction, they are permanent, Seen with hydroxychloroquine
anomalies. During the months to come, many aspects of daily life during COVID-19
will change, and maybe years; maybe the months to come, too, will change. We
analyze the repurposing of drugs: predictive safety evaluations Might prove to be as
important.
9 Conclusion
The treatment of COVID-19 with repurposed medicines depends on the drug’s ability
to prevent proliferation by binding to the enzyme’s active sites, terminating the viral
chain, and activating molecular pathways. For example, ritonavir and lopinavir are
thought to bind at the active enzyme site. They are used together to inhibit SARS-
CoV-2 replication because the cytochrome P450 enzyme is susceptible to oxidation
metabolism by lopinavir alone. In contrast, the addition of ritonavir will inhibit
the activity of the P450 3A4 enzyme. Therefore, to maintain drug efficacy for the
treatment of COVID-19, the combination of ritonavir and lopinavir is necessary. In
contrast to the above, the 4 Siddha Medicines like kabasura kudineer, nilavembu
kudineer, thonthasura kudineer, and ammaiyar koondhal kudineer discussed in this

drug repurposing chapter were initially used to treat influenza and SARS by acting as
neuraminidase blockers and activating the cascade of inflammation such as blocking
the release of endogenous inflammatory mediators, TNF-alpha, IL-6, and IL-8 to
avoid the mechanism of action of inflammation rather than the termination of the RNA
chain. New drugs that are effective for COVID-19 therapy are either being developed
or are in clinical trials. This analysis offers a basis for a deeper understanding of the
mechanism of action and participation of repurposed drugs and Siddha Medicines in
the molecular pathway to prevent viral replication, such as SARS or MERS. However,
our results are limited since there is still a lack of concrete evidence for the drug’s
action mechanisms and its curative effect on COVID-19. To provide more concrete
proof, more experimental validation is needed. We assume natural products may play
an important role and contribute to the production of antiviral drugs. It seems to be
a realistic choice for handling this medical crisis to investigate antiviral medicinal
plants as an adjunct or supportive therapy. Natural products could treat symptoms
such as fever, coughing, and improve immunity in patients with COVID-19. Detailed
research should be carried out alone or in conjunction with antiviral therapy on
possible natural products to examine their role in the battle against COVID-19.
Therefore, to achieve the general aim of seeking a cure for COVID-19 earliest, it is
essential to work parallel to various techniques such as genetic engineering, in silico
approach, herbal remedies, and drug repositioning.
Acknowledgements Authors thank CCRS, Chennai and VIT, Vellore for providing facilities to
carryout this work.
Funding No national or international fundings obtained for the study.
Competing Interests The authors declare that they have no conflict of interest.
Availability of Data and Materials All the data generated during this study are included in this
published article (and its supplementary information files).
References
1. Coronavirus Disease (COVID-19) Situation Reports [Internet]. November 29 2020. Available

from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
2. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al.: A novel coronavirus from
patients with pneumonia in China, 2019. N. Engl. J. Med. (2020)
3. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., et al.: Early transmission dynamics in
Wuhan, China, of novel coronavirus-infected pneumonia. N. Engl. J. Med. 382(13), 1199–1207
(2020)
4. Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., et al.: Clinical Characteristics of 138
Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
JAMA—J Am Med Assoc. 323(11), 1061–1069 (2020)
5. Hui, D.S., Azhar, E., Madani, T.A., Ntoumi, F., Kock, R., Dar, O., et al.: The continuing
2019-nCoV epidemic threat of novel coronaviruses to global health—The latest 2019 novel
coronavirus outbreak in Wuhan, China. Int. J. Infect. Diseases (2020)
6. WHO Director-General’s opening remarks at the media briefing on COVID-19 - 11 March

2020 [Internet], November 29, 2020. Available from: https://www.who.int/director-general/
speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-
19---11-march-2020
7. Patel, A., Jernigan, D.B., Abdirizak, F., Abedi, G., Aggarwal, S., Albina, D., et al.: Initial public
health response and interim clinical guidance for the 2019 novel coronavirus outbreak—United
States. American J. Trans. 20, 889–895, December 31, 2019–February 4, 2020 (2020)
8. Preventing the spread of the coronavirus - Harvard Health [Internet], November 29, 2020. Avail-
able from: https://www.health.harvard.edu/diseases-and-conditions/preventing-the-spread-of-
the-coronavirus
9. Kumar, S.U., Kumar, D.T., Christopher, B.P., Doss, C.G.P.: The rise and impact of COVID-19
in India. Front Med. 7 (2020)
10. Udhaya Kumar, S., Thirumal Kumar, D., Siva, R., George Priya Doss, C.: Kerala, India’s front
runner in novel coronavirus disease (COVID-19). Front Med. 7 (2020)
11. Torneri, A, Libin, P., Vanderlocht, J., Vandamme, A.M., Neyts, J., Hens, N.: A prospect on the
use of antiviral drugs to control local outbreaks of COVID-19. BMC Med. 18(1) (2020)
12. Singh, T.U., Parida, S., Lingaraju, M.C., Kesavan, M., Kumar, D., Singh, R.K.: Drug
repurposing approach to fight COVID-19. Pharmacological Reports (2020)
13. Alagu Lakshmi, S., Shafreen, R.M.B., Priya, A., Shunmugiah, K.P.: Ethnomedicines of Indian
origin for combating COVID-19 infection by hampering the viral replication: using structure-
based drug discovery approach. J. Biomol. Struct. Dyn. (2020)
14. Jain, J., Pai, S., Sunil, S.: Standardization of in vitro assays to evaluate the activity of polyherbal
siddha formulations against Chikungunya virus infection. VirusDisease (2018)
15. Jain, J., Kumar, A., Narayanan, V., Ramaswamy, R.S., Sathiyarajeswaran, P., Shree Devi,
M.S., et al.: Antiviral activity of ethanolic extract of Nilavembu Kudineer against dengue and
chikungunya virus through in vitro evaluation. J. Ayurveda. Integr. Med. 11(3), 329–335 (2020)
16. Jain, J., Narayanan, V., Chaturvedi, S., Pai, S., Sunil, S.: In Vivo evaluation of Withania
somnifera–Based Indian traditional formulation (Amukkara Choornam), Against Chikungunya
virus–induced morbidity and Arthralgia. J. Evidence-Based Integr. Med. 23 (2018)
17. Moshi, M.J., Mhame, P.P.: Legislation on medicinal plants in Africa. In: Medicinal plant
research in Africa: Pharmacology and chemistry (2013)
18. Karunamoorthi, K., Jegajeevanram, K., Xavier, J., Vijayalakshmi, J., Melita, L.: Tamil
traditional medicinal system—siddha: an indigenous health practice in the international
perspectives. Tang [Humanitas Med. 2(2), 12.1–12.11 (2020)
19. Ravishankar, B., Shukla, V.J.: Indian systems of medicine: A brief profile
[Internet]. African Journal of Traditional, Complementary and Alternative Medicines.
African Ethnomedicines Net. 4, 319–337, November 29 2020. Available from:
https://pmc/articles/PMC2816487/?report=abstract
20. Ram, A., Arul Joseph, D., Balachandar, S., Pal Singh, V.: Medicinal plants from Siddha system
of medicine useful for treating respiratory diseases. Int. J. Pharm. Anal. [Internet]. 1(2), 975–
3079. Available from: http://www.impcops.org/
21. Kiran, G., Karthik, L., Shree Devi, M.S., Sathiyarajeswaran, P., Kanakavalli, K., Kumar, K.M.,
et al.: In Silico computational screening of Kabasura Kudineer - Official Siddha Formulation
and JACOM against SARS-CoV-2 spike protein. J. Ayurveda Integr. Med. (2020)
22. Unique Perspective through Ayurveda: Are Epidemics and Pandemics mere a Germ Theory?
| Ayurved Sadhana [Internet]. [cited 2020 Nov 29]. Available from: https://www.ayurvedsa
dhana.com/unique-perspective-through-ayurveda/
23. (No Title) [Internet], cited 29 Novenber 2020. Available from: https://pib.gov.in/PressRelease
IframePage.aspx?PRID=1653759
24. Lalitha, N.: Protecting traditional knowledge in Siddha system of medicine. J. Intellect. Prop.
Rights. 18(3), 272–282 (2013)
25. Shailaja, R., Sugunthan, S., Pitchaiah Kumar, M.: A review on polyherbal formulation- Visha-
sura Kudineer chooranam-A classical anti-viral drug used in Siddha system of medicine. Eur.
J. Pharm. Med. Res. [Internet] 4(9), 184–192. Available from: https://www.ejpmr.com/home/
abstract_id/2862
26. Pitha Suram (Dengue Fever) |National Health Portal of India [Internet], 29 November 2020.
Available from: https://www.nhp.gov.in/pitha-suram-dengue-fever-_mtl
27. Why vaccines are a better bet against coronavirus than drugs [Internet], 29 November 2020.
Available from: https://theprint.in/health/why-vaccines-are-a-better-bet-against-coronavirus-
than-drugs/502710/
28. Rakulini Raveendran, K.S.: Siddha prospective aspect of immune boosters against COVID-19.
Int. J. Recent Adv. Multidiscip Res. 7(5), 5801–5806 (2020)
29. Onawole, A.T., Sulaiman, K.O., Kolapo, T.U., Akinde, F.O., Adegoke, R.O.: COVID-19:
CADD to the rescue. Virus Res. [Internet] 285, 198022, 1 August 2020, cited 29 November
2020. Available from: https://pmc/articles/PMC7228740/?report=abstract/
30. Thiel, V., Herold, J., Schelle, B., Siddell, S.G.: Viral Replicase Gene Products Suffice for
Coronavirus Discontinuous Transcription. J. Virol. 75(14), 6676–6681 (2001)
31. Lee, T.W., Cherney, M.M., Huitema, C., Liu, J., James, K.E., Powers, J.C., et al.: Crystal
structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like
aza-peptide epoxide. J. Mol. Biol. 353(5), 1137–1151 (2005)
32. Balasubramani, S.P., Venkatasubramanian, P., Kukkupuni, S.K., Patwardhan, B.: Plant-based
Rasayana drugs from Ayurveda. Chinese J. Integrative Medi. 17, 88–94 (2011)
33. Tillu, G., Chaturvedi, S., Chopra, A., Patwardhan, B.: Public health approach of Ayurveda
and Yoga for COVID-19 Prophylaxis. J. Alternative and Complementary Medi. 26, 360–364
(2020)
34. Gyawali, R., Paudel, P., Basyal, D., Setzer, W., Lamichhane, S., Paudel M., et al.: A review
on Ayurvedic medicinal herbs as remedial perspective for COVID-19. J. Karnali Acad. Heal.
Sci. [Internet] 3(May), 1–21 (2020). Available from: https://www.jkahs.org.np/jkahs/index.
php/jkahs/article/view/237
35. Mani, J.S., Johnson, J.B., Steel, J.C., Broszczak, D.A., Neilsen. P.M., Walsh, K.B., et al.:
Natural product-derived phytochemicals as potential agents against coronaviruses: A review.
Virus Res. 284 (2020)
36. Mishra, R.K., Kumar, A., Kumar, A.: Pharmacological activity of Zingiber officinale. Int J.
Pharm. Chem. Sci. [Internet] 1(3), 1073–1078 (2012). Available from: www.ijpcsonline.com
37. Zaveri, M., Khandhar, A., Patel, S., Patel, A.: Chemistry and pharmacology of Piper longum
L. Int. J. Pharm. Sci. Rev. Res. 5(1), 67–76 (2010)
38. Mittal, M., Gupta, N., Parashar, P., Mehra, V., Khatri, M.: Phytochemical evaluation and phar-
macological activity of syzygium aromaticum: A comprehensive review. Int. J. Pharmacy and
Pharmaceutical Sci. 6, 67–72 (2014)
39. Venkat Rao, N., Benoy, K., Hemamalini, K., Shanta Kumar, S.M., Satyanarayana, S.: Anti-
diabetic activity of root extracts of Tragia involucrata. Pharmacologyonline. 2, 203–217 (2007)
40. Manouze, H., Bouchatta, O., Gadhi, A.C., Bennis, M., Sokar, Z., Ba-M’hamed, S.: Anti-
inflammatory, antinociceptive, and antioxidant activities of methanol and aqueous extracts
of Anacyclus pyrethrum roots. Front Pharmacol. 8(SEP), (2017)
41. Sujeethasai, K: A review on Pharmacological activity of Kabasura decoction. Int. J. Sci. Res
Publ. (2020)
42. Priyadarshi, A., Ram, B.: A review on pharmacognosy, phytochemistry and pharmacological
activity of carica papaya (LINN.) leaf. Int. J. Pharm. Sci. Res. (2018)
43. Pandey, G., Madhuri, S.: Article-009.pdf. 5(1), 61–66 (2010)
44. Zahoor, S., Shahid, S., Fatima, U.: Review of pharmacological activities of Vetiveria zizanoide
(Linn) Nash. J. Basic Appl. Sci. 14, 235–238 (2018)
45. Damanhouri, Z.A.: A review on therapeutic potential of Piper nigrum L. (Black Pepper): The
king of spices. Med. Aromat Plants 3(3) (2014)
46. S.S.K.: A review on phytochemical and pharmacological profile of hedyotis corymbosa linn.
Int. J. Pharm. Sci. Rev. Res. (2014)
47. Chan, J.F.W., Lau, S.K.P., To, K.K.W., Cheng, V.C.C., Woo, P.C.Y., Yue, K.Y.: Middle East
Respiratory syndrome coronavirus: Another zoonotic betacoronavirus causing SARS-like
disease. Clin. Microbiol. Rev. 28(2), 465–522 (2015)
48. Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., et al.: Genomic characterisation and epidemi-
ology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet
395(10224), 565–574 (2020)
49. Zumla, A., Chan, J.F.W., Azhar, E., Hui, D.S.C., Yuen, K.Y.: Coronaviruses-drug discovery
and therapeutic options. Nature Rev. Drug Dis., 327–347 (2016)
50. Rattanapisit, K., Shanmugaraj, B., Manopwisedjaroen, S., Purwono, P.B., Siriwattananon, K.,
Khorattanakulchai, N., et al.: Rapid production of SARS-CoV-2 receptor binding domain
(RBD) and spike specific monoclonal antibody CR3022 in Nicotiana benthamiana. Sci Rep.
(2020)
51. Zhang, H., Penninger, J.M., Li, Y., Zhong, N., Slutsky, A.S.: Angiotensin-converting enzyme
2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.
Intensive Care Med. (2020)
52. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., et al.:
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven
protease inhibitor. Cell (2020)
53. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., et al.: Structure of Mpro from SARS-CoV-2
and discovery of its inhibitors. Nature 582(7811), 289–293 (2020)
54. Pettit, S.C., Gulnik, S., Everitt, L., Kaplan, A.H.: The dimer interfaces of protease and extra-
protease domains influence the activation of protease and the specificity of GagPol cleavage.
J. Virol. 77(1), 366–374 (2003)
55. Thirumal Kumar, D., George Priya Doss, C., Sneha, P., Tayubi, I.A., Siva, R., Chakraborty,
C., et al.: Influence of V54M mutation in giant muscle protein titin: a computational screening
and molecular dynamics approach. J. Biomol. Struct. Dyn. [Internet]. 35(5), 917–928, 7 June
(2017). Available from: http://www.ncbi.nlm.nih.gov/pubmed/27125723
56. Camacho, C., Coulouris, G., Avagyan, V., Ma, N., Papadopoulos, J., Bealer. K., et al.: BLAST+:
architecture and applications. BMC Bioinformatics [Internet]. 10, 421 (2009). Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20003500
57. Su, S., Wong, G., Shi, W., Liu, J., Lai, A.C.K., Zhou, J., et al.: Epidemiology, genetic
recombination, and pathogenesis of coronaviruses. Trends in Microbiology (2016)
58. Guex, N., Peitsch, M.C.: SWISS-model and the Swiss-PDBViewer: an environment for compar-
ative protein modeling. Electrophoresis [Internet]. 18(15), 2714–2723 (1997). Available from:
http://www.ncbi.nlm.nih.gov/pubmed/9504803
59. Laskowski, R.A., MacArthur, M.W., Moss, D.S., Thornton, J.M.: Procheck: a program to check
the stereochemical quality of protein structures. J Appl Crystallogr [Internet]. 26(2), 283–289
(1993). Available from: http://scripts.iucr.org/cgi-bin/paper?gl0276
60. The Siddha Formulary of India—India. Ministry of Health and Family Welfare—Google Books
[Internet], 29 November 2020. Available from: https://books.google.co.in/books/about/The_
Siddha_Formulary_of_India.html?id=4P5sAAAAMAAJ&redir_esc=y
61. Ramaswamy, R.S., Sathiyarajeswaran, P., Devi, M.S.S., Srinivasan, V.M., Devi, C.S.: Simple
and low cost process for the preparation of synergistic bio active compound jacom for the.
Indian Pat. Appl., 18pp (2018)
62. Kim, K.J., Liu, X., Komabayashi, T., Jeong, S., Selli, S.: Natural products for infectious
diseases. Evidence-based Complementary and Alternative Medicine. Hindawi Limited (2016)
63. Walter, T.M., Justinraj, C.S., Nandini, V.S.: Effect of Nilavembu kudineer in the prevention
and management of COVID–19 by inhibiting ACE2 Receptor. ResearchgateNet [Internet],
15 (2020). Available from: https://www.researchgate.net/profile/DrThomas_M_Walter/
publication/340250132_Effect_of_Nilavembu_kudineer_in_the_Prevention_and_Manage
ment_of_COVID_-19_by_inhibiting_ACE2_Receptor/links/5e7f3920299bf1a91b82d306/
Effect-of-Nilavembu-kudineer-in-the-Preventi
64. Sivaraman, D., Pradeep, P.S.: Affiliations. revealing anti-viral potential of Bio-active therapeu-
tics targeting SARS-CoV2-polymerase (RdRp) in combating COVID-19: Molecular investi-
gation on Indian traditional medicines. 31 March 2020, 29 November 2020. Available from:
www.preprints.org
65. Kumar, P.M., Meenakshi Sundaram, K., Ramasamy, M.S.: Coronavirus Spike (S) Glycoprotein
(2019-Ncov) targeted siddha medicines kabasura kudineer and thonthasura kudineer-In silico
evidence for corona viral drug. Asian J. Pharm. Res. Heal. Care [Internet]. 11(2), 1460–2250
(2019). Available from: www.informaticsjournals.org/index.php/ajprhc
66. Krishnasamy, R., Baba, T.A., Bharath, M., Phuntsho, J., Arunachalam, D., et al.: In Silico
analysis of active compounds from Siddha herbal infusion of Ammaiyar Koondhal Kudineer
(Akk) against SARS-CoV-2 Spike protein and its ACE2 receptor complex. SSRN Electron J.
[Internet], 1 May 2020, cited 29 November 2020. Available from: https://papers.ssrn.com/abs
tract=3578294
67. Sivaraman, D., Pradeep, P.S.: Scope of phytotherapeutics in targeting ACE2 mediated Host-
Viral Interface of SARS-CoV2 that causes COVID-19. ChemRxiv. (2020)
68. Drug Discovery and Development, Volume 2: Drug Development | Wiley [Internet], 29
November 2020. Available from: https://www.wiley.com/en-us/Drug+Discovery+and+Develo
pment%2C+Volume+2%3A+Drug+Development-p-9780471398479
69. Sun, W., Sanderson, P.E., Zheng, W.: Drug combination therapy increases successful drug
repositioning. Drug Discovery Today 21, 1189–1195 (2016)
70. Cheng, Y.S., Williamson, P.R., Zheng, W.: Improving therapy of severe infections through drug
repurposing of synergistic combinations. Current Opinion in Pharma. 48, 92–98 (2019)
71. Zheng, W., Sun, W., Simeonov, A.: Drug repurposing screens and synergistic drug-
combinations for infectious diseases. British J. Pharma. 175, 181–191 (2018)
72. Yang, Y., Islam, M.S., Wang, J., Li, Y., Chen, X.: Traditional Chinese medicine in the treatment
of patients infected with 2019-new coronavirus (SARS-CoV-2): A review and perspective. Int.
J. Biological Sci., 16, 1708–1717 (2020)
Modeling SARS-CoV-2: Mitigation
Interventions and Increased Mobility
Events
Mario Santana-Cibrian, Manuel A. Acuña-Zegarra, Marco Tulio Angulo,

Andreu Comas-García, Esteban A. Hernández-Vargas,
and Jorge X. Velasco-Hernandez
Abstract From the beginning of the SARS-CoV-2 pandemic, mathematical mod-

els have been developed to describe, predict, and control its evolution. This chapter
presents a set of useful mathematical tools to understand the epidemic dynamics.
First, to obtain a rough approximation to the magnitude of the epidemic, the basic
and effective reproduction numbers are estimated. Then, several growth models are
applied to estimate the peak and final size of the epidemic. The results show that
mitigation measures were able to flatten the epidemic curve, at the cost of extending
it more than expected. Nonetheless, these heuristic models have limitations. Thus a
mechanistic Kermack-McKendrick model is used to explore transmission and super-
spreading events. Our results show that these events can delay the peak incidence or
drive the epidemic into a long plateau with relatively constant but high incidence.
This highlights the need to monitor and anticipate atypical mobility events. Also,
M. Santana-Cibrian (B) · M. T. Angulo

CONACYT- Instituto de Matematicas UNAM-Juriquilla, Boulevard Juriquilla 3001, 76230
Juriquilla, Queretaro, Mexico
e-mail: msantana@im.unam.mx
M. T. Angulo
e-mail: mangulo@im.unam.mx
M. A. Acuña-Zegarra
Departamento de Matematicas, Universidad de Sonora, Blvd. Luis Encinas y Rosales S/N, Col.
Centro, 83000 Hermosillo, Sonora, Mexico
e-mail: adrian.acuna@unison.mx
A. Comas-García
Departamento de Microbiología de la Facultad de Medicina y Centro de Investigación en Ciencias
de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí. Avenida Venustiano,
Carranza, 2405. Colonia Los Filtros, 78210 San Luis Potosí, S.L.P., Mexico
E. A. Hernández-Vargas · J. X. Velasco-Hernandez
Instituto de Matematicas, UNAM-Juriquilla, Boulevard Juriquilla 3001, 76230 Juriquilla,
Queretaro, Mexico
e-mail: esteban@im.unam.mx
J. X. Velasco-Hernandez
e-mail: jx.velasco@im.unam.mx
544 M. Santana-Cibrian et al.
our projections of the pandemic trend for the last part of 2020 and the beginning of
2021, show that temporary immunity and an increase in the effective contact rate
may generate an epidemic rebound by the end of 2020. Data from Mexico is used to
exemplify the estimation and limitations of all the models. Although Mexico is our
case study, the methodology can be extended to other regions.
Keywords COVID-19 · Mathematical model · Basic reproduction number ·

Nonpharmaceutical interventions · Superspreading · Kermack-McKendrick ·
Reinfection
1 Introduction
COVID-19 is a respiratory disease caused by the SARS-CoV-2 virus. It is more

accurately a syndrome that mainly affects the respiratory tract, but that has health
consequences in various physiological subsystems of the human being. We defer its
description to the appropriate sources that detail the wealth of manifestations of this
disease (e.g. [23, 27, 33]). In this chapter, we present a set of mathematical tools,
models, and also review of some published results, geared to analyze and understand
the evolution of the epidemic caused by the SARS-CoV-2 virus. As a case study, we
use the Mexican Republic and Mexico City, in particular, to exemplify our results
and scenarios.
The chapter covers two central topics: (1) the modeling of the early phase of the
epidemic, and (2) the mechanisms of local transmission of COVID-19 disease. For
the first part, epidemiological measures such as the basic and effective reproduction
numbers and population growth models are analyzed and estimated. These tools are
classical subjects in epidemiology. Growth models are a set of heuristic approxima-
tions to the epidemic curve whose main objective is to estimate its initial growth rate,
the time of maximum incidence, and the total epidemic size [25, 52]. In the con-
text of the SARS-CoV-2, these heuristic approaches have been useful and practical
tools to measure and evaluate the impact of the diverse and most common mitiga-
tion strategies that were implemented in many countries to control de epidemic. The
classical approaches comprise generalizations or extensions of the logistic growth
or Richards curve [8, 24, 52], and the Gompertz curve [31, 42]. These models pos-
tulate different hypotheses regarding the shape of the epidemic curve, but all rely on
exponential growth, exponential decay, or single epidemic peak assumptions. How-
ever, in many world regions, the epidemic has shown linear or power law rather than
exponential growth [45, 47]. There exists several alternatives to model this atypical
form of dynamics (e.g. [19, 41, 43]). The one that we have chosen and applied to
the epidemic in Mexico City, in particular, is the method developed by Adam et al.
[2] and Tsallis and Tirnakli [46] which is a generalization of the Boltzman model of
statistical mechanics.
On the other hand, variants of the Kermack-McKendrick model to the problems
we address in this chapter are abundant in the recent literature (e.g. [5–7, 11–13, 16,
Modeling SARS-CoV-2: Mitigation Interventions and Increased Mobility Events 545
26, 28]). We particularly review results in which the lockdown strategies are approx-
imated by splitting the human population into two subpopulations defined in terms
of their members’ compliance with the mitigation and other sanitary governmental
instructions. This approach on splitting the total population into subgroups to model
confinement, risk of infection or to characterize differences within the host popula-
tion have been explored in other papers (e.g. [4, 54]) but with different objectives.
For example [54] have described staggered release strategies that would guarantee
disease mitigation and eradication. However, one issue that we address in this work
and not directly treated in this reference is the role of increased population mobil-
ity events during confinement prior to the release. Likewise, [4] presents a strategy
for population release defining risk groups rather than ages without considering the
effect of perturbations (high mobility events) occurring before the release. We, in
particular, highlight the role of increased mobility events and disease superspreading
on the epidemic curve shape, whose impact on the epidemic growth has also been
studied by other authors (e.g. [2, 22]) in the case of Hong Kong . In this respect,
another important paper is the one by Sanche et al. [37] which underlines the need
to understand superspreading events for the success of control strategies. Our group
has also worked on topics such as within-host dynamics of SARS-CoV-2 [15], and
the design of optimal intervention strategies for mitigation [3] that are not discussed
in this chapter.
For the second central topic of the chapter, to study the role of human behavior
as characterized by mobility, and strategies to reduce the effective contact rate on
the local transmission mechanisms of COVID-19 disease, we present a mathematical
model of the Kermack-McKendrick type modified to account for the aforementioned
behavioral factors. This model is not intended to generate precise estimations and pre-
dictions but, rather, it seeks to present plausible scenarios that may help to design,
establish and evaluate public health policies to mitigate the epidemic. Kermack-
McKendrick SEIR equations are the basic building blocks of a large proportion of
the models that are being used to simulate and forecast COVID-19 epidemic all
over the world. This is a well-known set of mathematical equations used to model
epidemics that date back to the early 20th century [18]. The generality and basic
properties of this type of models make their application straightforward. They have
been extensively used to generate scenarios, explore tendencies and provide pro-
jections and forecasts of the present pandemic’s evolution . However, in this last
respect, naive approaches focusing on curve fitting and parameter estimation, some-
times using highly sophisticated statistical methods, rather than on the epidemiology
of the problem have resulted in a failure or lack of precision for their disregard of
conceptual biological mechanisms.
Data gathered about the epidemic shows, in many regions of the world, a plateau-
like behavior in their epidemic curve after the initial growth had been altered by the
mitigation strategies. This plateau has occurred in places where the lifting of mobility
restrictions was implemented early or in places where thier enforcement was not
strict, as in the case of Mexico, where mobility restrictions and other social-distancing
strategies are not mandatory, generating a poor reduction of the effective contact rate.
The existence of a plateau can be explained by the presence of superspreading events
that are related to periods of increased mobility [1, 39, 48], as we argue in this chapter.
Motivated by such explanation, we have used the mathematical model mentioned
before to explore the effect on the epidemic curve shape of atypical events related to
high mobility. We present model-generated long-term scenarios when considering
several superspreading events that have or are occurring in the final months of the
year. We have not introduced vaccination in the models we describe here.
To put into context the contents of this chapter and to conclude this introduction,
a brief description of the evolution of the coronavirus pandemic in Mexico is given.
At the end of December of 2019, the novel coronavirus SARS-CoV-2, was detected
in adults with pneumonia in Wuhan, Hubei Province, China. This new virus rapidly
spread from the Hubei Province to all China [27, 33, 50, 51, 53]. By January 22,
2020, the virus had been detected in South Korea, Taiwan, Thailand, Macao, and the
USA. Mexico recorded its first case on February 22, 2020.
On March 18, 2020, the Mexican Health Secretariat reported that a total of 250,656
COVID-19 cases were expected in the country which amounts to roughly a 0.0019
of the total population of Mexico (estimated, in 2018, around 130.8 million by the
United Nations Population Division). This figure proved to be an extreme underes-
timation. Mexico, to the date of writing, has exceeded 600,000 reported cases and
close to 68,000 COVID-19 related deaths.
On March 23, 2020, a Sanitary Emergency was declared in Mexico, ordering
the suspension of all non-essential activities in the public and private sectors, a
suspension that would last until April 30, 2020, date that was later corrected to be
on May 30. The containment measures lowered the transmission rate to manageable
levels in terms of the expected number of critical cases [1, 26].
All of the recommendations indicated both in the Healthy Distance and the Emer-
gency Sanitary orders affect basic aspects of individual and social human behavior
(washing hands, keeping cough/sneeze etiquette, avoiding handshakes, keeping dis-
tance from other people, working at home) and, therefore, have a learning curve
and can be forgotten, relaxed or incompletely adopted in any given population. The
epidemic curve in Mexico has shown very slow growth, as described in Sect. 3 and,
in particular in Mexico City, the epidemic curve has remained essentially flat for
many months. Only in recent times (by the middle of October 2020) the incidence
has shown a tendency to increase providing worrisome signs of an epidemic rebound
to occur by the end of the year if not earlier.
The chapter is organized as follows. Sect. 2 covers tools used at the start of
the pandemic as well as a brief commentary on available data at this stage. Then,
Sect. 3 presents a general model that considers the effect of nonpharmaceutical
interventions (NPIs) by splitting the total population into two groups: one that follows
the mitigation measures and one that does not. Sect. 4 uses a variant of the base model
to study the effect of atypical transmission events on the epidemic curve behavior. In
Sect. 5, the effect of future high mobility events for Mexico City, is explored. Finally,
the discussion of the results and final conclusions can be found in Sects. 6 and 7,
respectively.
2 Initial Description of the Epidemic
To characterize the evolution of an epidemic it is necessary to estimate its growth

rate, the day of maximum incidence and the expected total epidemic size. Because
the robustness of the results obtained from the use of any given methodology is
closely related to the type and quality of the data, this section is dedicated to explore
the type of data available during the pandemic.
2.1 The Data
During an epidemic, daily suspected new cases are collected, then tested and, if
confirmed, they are reported on a daily or weekly basis. These cases are reported
using different dates of reference. For example, for COVID-19 in Mexico, cases are
grouped by date of symptoms onset, date of registration to a health care facility,
and date of test confirmation. Each of these time series can be used to construct
an incidence and cumulative cases curve. Therefore, these data types can be used to
describe the disease but each provides different information. Incidence by symptoms
onset is the time series that better represents the progression of the active infections
since a subject starts spreading the disease just before symptoms appear. Te main
source of variability in this case is the certainty of the date. Incidence by hospital
registration is important for beds and ICU occupation, and has an additional source
of variability because individuals decide whether or not to seek medical care based
on their health condition and idiosyncrasy. Finally, incidence by test confirmation
informs weakly on incidence and has the most variability because testing is affected
by the available resources, laboratory protocols and the state of the epidemic.
We work in this chapter with a publicly available Mexican data base that records
incidence, deaths and other variabls from February 28 to September 20, 2020.
Figure 1 shows confirmed cumulative and daily cases reported by date of symp-
toms onset, by date of arrival to a hospital, and by date of test confirmation from
February 22, 2020 to September 5, 2020. Notice that the last fifteen days of data have
been omitted since these records are incomplete due to lags in test confirmation, lab-
oratory procedures and other sources. The growth pattern of each curve is slightly
different. For example, if we focus on cases reported by date of test confirmation
(green line), the cumulative cases show a slower growth at the beginning of the epi-
demic, but a faster growth at the end. On the other hand, for the cases reported by
symptoms onset (blue line), cumulative cases show a linear rather than exponential
growth. Note the drop, each weekend, in the number of cases reported by hospital
registration and test confirmation. This drop is not related to the disease dynamics,
but to delays in sampling or data processing by the laboratories and health care units.
There is not a constant rate of sampling/data processing in a given week. The rate is
lower during weekends and Mondays.
10k
8k
By symptoms onset
By hospital registration
By test confirmation
6k
Daily cases
4k
2k
Mar 2020 Apr 2020 May 2020 Jun 2020 Jul 2020 Aug 2020 Sep 2020
700k
600k
By symptoms onset
By hospital registration
500k By test confirmation
Cumulative cases
400k
300k
200k
100k
Fig. 1 Daily and cumulative confirmed COVID-19 cases in Mexico from February 22, 2020 to
September 5, 2020, presented in three different forms: by symptoms onset (blue line), by date of
arrival to hospitals (orange line), and by date when tests were confirmed (green line)
It is important to keep in mind these differences when using the data to describe
the epidemic since calculations such as the basic and the instantaneous reproduction
numbers can provide substantially different results depending upon the particular
series used.
Suspected cases are also reported, i.e. those individuals that present COVID-19
related symptoms but are still waiting for test results. These can be reported either by
symptoms onset or by hospital registration. Figure 2 shows the number of confirmed
and suspected cases by symptoms onset for Mexico from February 22, 2020 to
September 20, 2020. Note that, in this case, the last 15 days of data were not omitted
Fig. 2 Daily confirmed and 10k

suspected COVID-19 cases
in Mexico from February 22,
8k
2020 to September 20, 2020. Confirmed + Suspected
Confirmed
Blue bars represent cases by
symptoms onset, orange bars
Daily cases
6k
confirmed cases plus
suspected cases
4k
2k
0
Fig. 3 Total COVID-19

tests per thousand people in 0.12
Mexico from February 22,
Daily tests per thousand people
2020 to September 5, 2020 0.1
0.08
0.06
0.04
0.02
0
to show that, in fact, these records should not be used as they are incomplete. For
example, at September 20, 2020, there were 79,150 suspected cases, which amounts
to 11.3% of the 697,658 confirmed cases at the same date. Certainly, not all suspected
cases were confirmed as COVID-19 cases. Given that the positivity rate in Mexico is
approximately 40% at this point in time, then 31,660 of those 79,150 suspects could
be confirmed, a number that represents 4.5% of the total cases. The quantification
of the suspected cases is important to accurately determine the current trend of the
epidemic, especially in countries similar to Mexico where there is an important lack
and lag in test confirmation.
Incidence data is strongly related to the number of tests. In the case of Mexico,
testing is very limited and it is only performed on individuals that either present
symptoms and are directed to a medical care unit, or individuals that can afford to
pay for a test in a private laboratory. An approximation to the daily number of test
conducted in Mexico is shown in Fig. 3 where the daily number of individuals that
arrive to a hospital with influenza-like illness symptoms is shown.
Records on daily deaths are also available. In principle, mortality should constitute
the most reliable data since the date of death can be registered with no error. However,
120
1400
Daily cases by symptoms onset
1200 100
1000 80
Daily deaths
800
60
600
40
400
20
200
0 0
Mar 2020 Apr 2020 May 2020 Jun 2020 Jul 2020 Aug 2020 Sep 2020 Mar 2020 Apr 2020 May 2020 Jun 2020 Jul 2020 Aug 2020 Sep 2020
Fig. 4 Daily cases by symptoms onset (blue bars) and daily deaths (red bars) in Mexico City from
February 22 to September 5, 2020. Observe in both graphs the marked tendency to remain in a
plateau. In the case of the incidence, this behavior is observed right after lockdown termination; in
the case of deaths, the plateau occurs until early August after several weeks since the start of the
partial reopening of the economy
for a number of reasons, not all COVID-19 deaths are registered, leading to an
underestimation of the daily numbers. Figure 4 shows daily cases by symptoms
onset and daily deaths in Mexico City from February 22, 2020 to September 5, 2020.
Observe how the number of deaths started to decrease around mid May 2020 and
stabilized around August 2020, while the number of cases stayed on a relatively
stable plateau since mid May. It is not clear if this curious phenomenon is due to the
unreported deaths, to changes in the management of COVID-19 patients, to changes
in the susceptible population or, indeed, to the effectiveness of mitigation measures,
among other possible explanations. In any case, it is important to keep in mind that
records of deaths can be inexact.
2.2 Basic and Effective Reproduction Numbers
The basic reproduction number R0 and the instantaneous reproduction number Rt are
mathematical tools that can be used to determine if an infectious disease will spread in
the population or not at a certain point in time. Both of these numbers roughly estimate
the proportion of individuals that must be immunized to eradicate the disease. R0
is defined as the expected number of secondary infections that will be generated
by one infectious individual while in his/her infectious period, when introduced in a
completely susceptible population. On the other hand, the instantaneous reproduction
number indicates the expected number of secondary infections produced by one
infected individual at time t [10, 44]. The basic reproduction number for the epidemic
in the whole country was estimated using techniques implemented in [30]. Table 1
shows the estimates obtained using two methods for each of the time series described
in the previous section: daily cases by symptoms onset, by hospital registration and by
test confirmation. Note that the R0 estimated using daily cases by test confirmation,
Table 1 Estimates of the basic reproduction number for Mexico (country) using data from February
29 to March 23, 2020. Mean estimate and 95% confidence intervals are reported for three different
time series: daily cases by symptoms onset, daily cases by date of hospital registration and daily
cases by date of test confirmation
Symptoms onset Hospital registration Test confirmation
Lower Mean Upper Lower Mean Upper Lower Mean Upper
Exponential growth 1.82 1.88 1.95 2.06 2.17 2.29 2.54 2.80 3.10
Maximum likelihood 1.59 1.70 1.82 1.61 1.77 1.93 2.02 2.35 2.71
Fig. 5 Instantaneous reproduction number Rt for Mexico from March 11, 2020 to September 5,
2020. A median serial interval of 4.7 days was used following the study presented in [29]
is substantially higher than the one estimated using daily cases by symptoms onset.
The difference exists because the time series of reported cases grows later and faster
due to the lag in test results. Also note that for each column in the Table 1, both of
the methods render confidence intervals that barely overlap which each other. This
indicates that the choice of the time series to estimate R0 as well as the methodology
are indeed important, specially at the beginning of the epidemic.
On the other hand, Fig. 5 shows the evolution of the instantaneous reproduction
number Rt in Mexico from February 22, 2020, to September 5, 2020, computed using
the methodology and software presented in [10, 44] with a mean intergenerational
period of 4.7 days [29]. Notice that Rt is noisy and has important variability which
makes its interpretation difficult. Moreover, its estimates are sensitive to the inter-
generational period, the time between a primary and a secondary infections, which
is typically unknown and difficult to estimate as it requires contact tracing which is
extremely limited in Mexico.
Although R0 and Rt can be estimated using incidence data, the estimates can vary
considerably depending on the methodology used and the quality of the data. For
this reason, it is important to complement the estimates of the reproduction numbers
with other measurements and analysis.
2.3 Population Growth Models
Population growth models are tools that provide estimates of several key quantities
such as the date of maximum incidence, the duration of the epidemic and the final
epidemic size. These models also are capable of short term forecasts for the trend and
magnitude of the epidemic. Classical models such as exponential growth, logistic
growth, generalized logistic growth, Richards curve and Gompertz are commonly
used in life sciences [8, 24, 31, 42, 52]. Other, more recent approach such as the one
presented in [46], called the Tsallis-Tirnakli model for the purposes of this work, is
based on complex systems approximations used in statistical physics. In this section,
the use of three models is exemplified: generalized logistic growth (GLM), Richards
curve and Tsallis-Tirnakli model.
The generalized logistic growth model [8] assumes that the number of confirmed
cumulative cases, C(t), can be described by the solution of the equation

C(t)
C (t) = rC(t) p 1 − . (1)
K
Here, r is the epidemic growth rate, K is the final epidemic size, and p is a scaling
parameter that allows the curve to describe exponential growth ( p = 1), constant
growth ( p = 0) and sub-exponential growth (0 < p < 1).
On the other hand, Richards model [34] similarly assumes that C(t) is described
by the solution of the equation

C(t) a
C (t) = rC(t) 1 − , (2)
K
where r and K are as before, and a is a scaling parameter to account for the asymmetry
of the epidemic curve. Both models are extensions of the simple logistic growth
model and both have been used to predict cumulative COVID-19 cases in China
[36]. The parameters a, K , r , and p must be estimated from the observed data.
Despite the simplicity of these models, the estimation is challenging since, typically
at the beginning of the epidemic, there is no information available on the final size
of the epidemic K . Furthermore, the parameters a and p are highly correlated with
the growth rate r and this fact can cause instability of the estimates.
The third model [46] has been used to model COVID-19 active cases in several
countries. It has its origins in statistical thermodynamics, particularly in the study
of thermodynamic properties of complex systems. For more details, we refer the
Fig. 6 Growth models fit to daily COVID-19 cases by symptoms onset in Mexico. Data from March
23, 2020 to September 5, 2020 was used to fit each model. Median estimates for the expected value
of the epidemic curve are represented by solid lines and 95% pointwise probability intervals are
shown with colored bands. Gray bars represent observed data
interested reader to the reference mentioned above. For now it suffices to say that the
model assumes that the number of confirmed daily cases, D(t) is given by equation
γ K (t − t0 )α
D(t) = K (t − t0 )α e−β(t−t0 ) = , (3)
[1 + (q − 1)β(t − t0 )γ ]1/(q−1)
where exp{−β(t − t0 )γ } is the q-exponential factor (a generalization of the Boltzman

factor) with C, α, βγ > 0, q > 1 and t0 ≥ 0. According to the authors, C is related
to the size of the population at risk, (α, β) depend on the public health measures
undertaken to mitigate the epidemic whereas (γ , q) are possibly related to the virus
biological properties. The increase of the epidemic curve is described as a power law
increment with exponent α, and the decrease is also a power law but with exponent
α − γ /(q − 1).
To understand and compare the characteristics of these three models, Fig. 6 shows
how each of them fits Mexican incidence data from March 23, 2020 to September
5, 2020. Bayesian inference is used to estimate the parameters of each model (see
Sect. 2.4). In this case, the data contains information past the peak of the curve and
it similarly bell shaped. Richards and GLM models provide similar estimates of the
epidemic curve. Tsallis-Tirnakli predicts a completely different curve which shows
a plateau, likely due to the stabilization of the number of cases during August 2020.
Figure 7 shows the fit of the same three models using Mexican data but only until
May 31, 2020. In this case, the data does not contain the peak and each model give
a different projection for when the peak will occur. Notice that the Tsallis-Tirnakli
Fig. 7 Growth models fit to daily COVID-19 cases by symptoms onset in Mexico. Data from March
23, 2020, to September 5, 2020, was used to fit each model. Median estimates are represented by solid
lines and 95% pointwise probability intervals are shown with colored bands. Gray bars represent
observed data while yellow bars are available data that was not used to estimate the parameters
model is not the best option in this case because it overestimates the epidemic curve.
Richards and GLM models do a better job describing what will truly happen, although
the variability of GLM is large in comparison to the other approaches.
Now, if we focus on Mexico City, Fig. 8 shows the fit of each model from March
23, 2020 to September 5, 2020. In Mexico City, the epidemic curve entered in a
long plateau on or about May 2020. In this case, Tsallis model does a better job
recovering the characteristics of the epidemic curve. Richards and GLM models can
only reproduce bell like shapes with longer tails to the right and, therefore, produce
rather inaccurate projections. Growth models provide information regarding the peak
date of the outbreak and the maximum cumulative incidence (epidemic size). In the
case of the epidemic size, the estimates tend to have too much variability since they
are long term predictions. This is particularly problematic at the beginning of the
epidemic when the data does not contain information about the peak. For example,
in Fig. 7, Richards model estimates that the the final epidemic size in Mexico as a
whole is 662,076 confirmed cases (median estimate) with a 95% probability interval
of (507,231, 837,032). As of September 20, 2020, there are 697,658 confirmed cases
which is in the range of the interval.
These models can also be used to roughly estimate the reduction in growth rate
that nonpharmaceutical interventions (NPIs) have on the disease transmission. By
fitting, for example, Richards model before and after the NPIs, it is possible to
evaluate the effectiveness of such interventions. At the national level, on March 23,
2020, the Mexican Federal government officially established mitigation measures to
control the COVID-19 epidemic and one week later, on March 30, 2020, a Sanitary
Fig. 8 Growth models fit to daily COVID-19 cases by symptoms onset in Mexico City. Data from
March 23, 2020 to September 5, 2020 was used to fit each model. Median estimates are represented
by solid lines and 95% pointwise probability intervals are shown with colored bands. Gray bars
represent observed data while yellow bars are available data that was not used to estimate the
parameters
Table 2 Parameter median estimates and 95% posterior probability intervals before and after March
23, 2020 for Mexico City. Here, r is the growth rate, K is the final size of the outbreak and a is a
scaling factor
February 29–March 22 March 23–April 30
Lower Median Upper Lower Median Upper
a 0.017 0.103 1.757 0.012 0.324 1.125
r 0.193 0.455 1.889 0.092 0.127 1.458
K 934 57062 420711 21214 65782 404054
Emergency was declared, ordering the suspension of all nonessential activities in

the public and private sectors. To approximate the reduction in the growth rate r
for the case of Mexico City, resulting from the social distancing measures, Richards
model is fitted to the epidemic curve for two different periods: from February 29 to
March 22, 2020, and from March 23 to April 30, 2020. Table 2 shows the parameter
estimates for each period. Before the start of social distancing on March 23, 2020,
the growth rate was approximately 0.455 with a 95% interval (0.193, 1.889). After
March 23, 2020, the growth rate is 0.127 with a 95% interval of (0.092, 1.458). If we
compare the median values of r for each period, then the reduction of the epidemic
growth rate in the early days of the implementation of social distancing measures is
around 72% approximately. Notice that the probability intervals are wide, signaling
the lack of information regarding the final size of the epidemic at this early stage.
Growth models can provide a rough estimate of the intensity of the disease trans-
mission, but they are limited tools to describe the dynamics of an epidemic. It is not
possible to incorporate specific characteristics such as the presence of two types of
infected individuals, asymptomatic and symptomatic, which play an important role
in COVID-19. Also, growth models assume that the epidemic characteristics do not
change in time, not a realistic assumption. More sophisticated and ad hoc tools are
compartmental models as will be show in the following sections.
2.4 Parameter Estimation for the Growth Models
In this subsection, the process to estimate the parameters of the growth models in
Sect. 2.3 is explained. A Bayesian approach was used for each case. The case of
Richards curve is presented as example since the process is very similar for GLM
and Tsallis-Tirnakli models.
Let Y j , for j =, 2, ..., n, be the number of observed daily cases at time t j , with
t j given in days. We assume that Y j follows a Negative Binomial distribution with
mean value μ j = C(t j |a, r, K ) − C(t j−1 |a, r, K ) and dispersion parameter s. Here,
C(t j |a, r, K ) is the number of cumulative cases at time t j , and it is obtained by
solving Eq. 1. Assuming that, given the parameters, the observations Y2 , Y3 , . . . , Yn
are conditionally independent, then
E[Y j |a, r, K , α] = μ j , (4)

V ar [Y j |a, r, K , α] = μ j + μ2j /s. (5)
The Negative Binomial distribution allows to control the variability of the data by
considering over-dispersion, which is common for epidemiological data. If s → ∞,
then we recover the Poisson model, which is often used in this context.
Let θ = (a, r, K , s) be the vector of parameters to estimate. The inclusion of
the parameter α, which is related to the variability of the data, not to the Richards
model, is necessary since in practice this variability is unknown. Then, the likelihood
function, which represents how likely it is to observe the data under the Negative
Binomial assumption and Richards model if we knew the parameters, is given by

n s y j
(y j + s) s μj
π(y1 , . . . , yn |θ ) = . (6)
j=2
(y j + 1)(s) s + μj s + μj
Consider the parameters a, r , K , and s as random variables. Assuming prior inde-

pendence, the joint prior distribution for vector θ is
π(θ ) = π(a)π(r )π(K )π(s),

where π(a) is the probability density function (pdf) of a Uniform(0,2) distribution,

π(r ) is the pdf of a Uniform(0,2), π(K ) is the pdf of a Uniform(K min , K max ), and
π(s) is the pdf of a Gamma(shape = 2, scale = 0.5). To select the prior for parameter
r , we consider that values already reported for r are close to 0.3 [36]. In addition,
there is no available prior information regarding the final size of the outbreak K . This
is a critical parameter in the model and, to avoid bias, we assume a uniform prior
over K min and K max . To set K min we consider that the minimum number of confirmed
cases is the current observed cases Y (tn ) times 2, i.e. K min = 2yn . To set the upper
bound for K , we consider a fraction of the total population K max = 0.05N , where
N is the population size of the region of interest.
Then, the posterior distribution of the parameters of interest is
π(θ|y1 , . . . , yn ) ∝ π(y1 , . . . , yn |θ)π(θ ),
and it does not have an analytical form because the likelihood function depends on
the solution of the Richards model, which is nonlinear in the parameters. We analyze
the posterior distribution using an MCMC algorithm that does not require tuning
called t-walk [9]. This algorithm generates samples from the posterior distribution
that can be used to estimate marginal posterior densities, mean, variance, quantiles,
etc.
The methodology to estimate parameters for GLM model is almost identical to
the one presented above. The only changes are: (1) C(t j |a, r, K ) will be replaced by
C(t j | p, r, K ) given by Eq. 2; (2) the prior for parameter a will be replaced for the
prior for parameter p which is Uniform in (0,1).
For Tsallis-Tirnakli model, the same ideas apply. The expected values μ j in Eq. 6
will be replaced by the corresponding Tsallis-Tirnakli (Eq. 3). A few more changes
are required for the joint prior distribution. Here, the vector of parameters that must
be estimated is ψ = (α, β, γ , q, s). Parameter C will be fixed to 1/N , where N is
the population size of the region of interest as before. Then, the joint prior for ψ is
given by
π(ψ) = π(α)π(β)π(γ )π(α)π(s), (7)
where π(α) is the pdf of a Uniform distribution in (1,20), π(β) is the pdf of a Uniform
distribution in (0,0.001), π(γ ) and π(s) are the pdf of a Gamma distribution with
shape parameter 2 and scale parameter 1, and π(q) is the pdf of a truncated Gamma
distribution in (1, ∞) with shape parameter 2 and scale parameter 1.
We refer the reader to [35] for more details on MCMC methods and to [17] for
an introduction to Bayesian inference with differential equations.
3 A General Model for NPIs
At the beginning of the COVID-19 epidemic, except for China, the first stage of the
epidemic was driven by imported cases. Several days later, local transmission started.
The pandemic transited to Phase 2. In the absence of a vaccine or treatment, many
countries implemented non-pharmaceutical interventions to mitigate the spread of
the disease. In Sect. 2.3 we pointed out that, in the case of Mexico, these measures
started on March 23, 2020 and that, given our estimates from the Richards curve, they
were effective in flattening the epidemic curve. However, to understand in detail the
effect of NPIs, it is necessary to formulate mechanistic models that take into account
the changes in the dynamics induced by these interventions [38, 48, 54].
In this subsection, an extension of a classical Kermack-McKendrick model is
presented. The objective is to explore the effect of the NPIs on the disease dynamics
of COVID-19. It represents a general approach that can be used to answer several
questions, as shown in the following sections. The model is based on the work
developed by [1, 39]. The compartmental diagram is depicted in Fig. 9.
Fig. 9 Diagram of the SEIR model extension. S, E, Ia , Is , R, Ir , and D represent the populations
of susceptible, exposed, asymptomatically infected, symptomatically infected, reported infected,
recovered and dead individuals, respectively. The orange rectangle represents the population dynam-
ics previous to the implementation of mobility restrictions. After this event, the general population
is split into two subgroups representing a low (yellow) and high (blue) compliance on NPIs. See
the text for a more detailed description of model parameters and properties
3.1 Mathematical Model Formulation
Let S, E, Ia , Is , Ir , R, and D represent the number of susceptible, exposed, asymp-

tomatically infected, symptomatically infected, reported infected, recovered, and
death individuals, respectively. Note that the class Ir represents those individuals
that, once confirmed, are registered and isolated. Ir does not participate in the dis-
ease transmission.
To model the implementation of mitigation measures, we postulate the following
hypotheses:
• disease transmission dynamics is split into two subgroups upon the implementation
of mitigation measures;
• one group complies better with the NPIs measures than the other group;
• the difference in compliance is reflected in the time-dependent effective contact
rates.
In this section we do not include vital dynamics nor temporary immunity since
we are looking at a time horizon of less than a year. The mathematical model valid
in the period previous to the implementation of mitigation measures is:
S
S = −b (Is + Ia ) ,
N∗
S
E = b (Is + Ia ) ∗ − γ E,
N
Ia = ργ E − ηa Ia ,
(8)
Is = (1 − ρ)γ E − (ηs + δs ) Is ,
Ir = δs Is − δr Ir ,
R = ηa Ia + ηs Is + (1 − μ) δr Ir ,
D = μδr Ir ,
where N ∗ = S + E + Ia + Is + R. Parameter definitions are given in Table 3.

The effective contact rate b is the product of the number of contacts between
infected and susceptible individuals, and the probability that these contacts result in
infection. The viral load is similar for both asymptomatically and symptomatically
infected individuals [21, 56]. Then, it is reasonable to assume that the probabilities of
infection by a symptomatic or by an asymptomatic individual are similar. Likewise,
we assume that symptomatic and asymptomatic individuals have the same mobility
until the symptomatic cases are reported and isolated. This allows us to postulate
that both classes have approximately the same number of effective contacts per unit
time with the same contact rate b for both infectious classes (asymptomatic and
symptomatic). This simplification helps to reduce the number of parameters in the
model without affecting the main results. Mitigation measures are implemented at
time T . After this time, the population is split into two subgroups: one that complies
with NPIs (social distancing, use of face masks, mobility restrictions, etc.), and
Table 3 Parameters for system in Eq. 8

Parameters Definition
b Effective contact rate
γ −1 Incubation period
ρ Proportion of individuals that become asymptomatic infected
ηa−1 Average recovery time for asymptomatic individuals
ηs−1 Average recovery time for symptomatic individuals
δs−1 Average time that takes one individual to seek medical attention
δr−1 Average time until recovery or death for a reported case
μ Proportion of reported individuals that die
another group with a lower compliance. The disease dynamics after the interventions
are described by the equations:
Si = μh (Si + E i + Iai + Isi ) + [(2 − i) q + (i − 1) (1 − q)] μh (Ir + R)

Si
− βi (t) (Isi + Iai ) ∗ + (−1)i ω(t)S1 − μh Si + (1 − i)i χr R,
N
Si
E i = βi (t) (Isi + Iai ) ∗ − γ E i + (−1)i ω(t)E 1 − μh E i ,
N
Iai = ργ E i − ηa Iai + (−1)i ω(t)Ia1 − μh Iai , (9)
Isi = (1 − ρ)γ E i − (ηs + δs ) Isi + (−1)i ω(t)Is1 − μh Isi ,
Ir = δs (Is1 + Is2 ) − δr Ir − μh Ir ,
R = ηa (Ia1 + Ia2 ) + ηs (Is1 + Is2 ) + (1 − μ) δr Ir − μh R − χr R,
D = μδr Ir ,
2
where N ∗ = i=1 (Si + E i + Iai + Isi ) + R, i = 1, 2. The index i = 1 denotes the
population that complies better with the control measures, while i = 2 indicates that
with a lower compliance. For t > T we introduce the parameters μh , that represents
both the birth rate and natural death rate of the population, and χr−1 , the average time
that a recovered individual remains immune. We assume that NPIs are not perfect
and individuals can abandon the group with higher compliance at a rate ω, defined
here as the compliance-failure rate. All other parameters are defined in Table 3.
The effective contact rates for each group, βi (t), decrease after the implementation
of the NPIs. However, the reduction is not necessarily the same for each subpopula-
tion. For example, the group higher NPIs compliance, consist mainly of individuals
that can work at home. This group will limit its mobility and, therefore, will consid-
erably reduce its contact rate. On the other hand, the group with lower compliance
consists of essential workers, those that keep functioning the basic and most funda-
mental aspects of the economy, and people that work in the informal economy. This
group may take certain measures, such as the use of face masks for example, and thus
it can reduce its contact rate, but not as much as the other group since their mobility
is higher. There are many alternatives to model this behavior in the effective contact
transmission rate. For example:

bq1 , if t < T ;
βi (t) = (10)
bq2 , if t ≥ T,
where q1 , q2 ∈ [0, 1] and (1 − qi ) × 100 are the percentage reduction of the original
contact rate b for each group. Equation 10 is a step function, but it can be modified to
consider other characteristics of the epidemic [54] as we will show in later sections.
4 Short Duration Superspreading Events
Given that mitigation measures are focused on non-pharmaceutical interventions,

it is expected that an increase in population mobility during a few days weakens
the strength of the NPIs and, therefore, may have an impact on disease transmis-
sion. Superspreading events are defined as situations where transmission is increased
above a baseline value determined by the average Rt during a given time interval.
Superspreading correlates with periods of significant increased mobility. This section
focuses on the analysis of the effect of short term superspreading that occurs dur-
ing the confinement period. It will be shown that these sporadic events can have an
important impact and that they are a possible explanation of the plateau-like behavior
of the epidemic curve that many countries around the world have shown, as it is the
case of Mexico, Panama, and Sweden, among others.
Using Eqs. 8 and 9, the atypical increases in mobility are modeled as follows:
• it is assumed that the increase in mobility lasts only for a period of τ days.
• the change in mobility on these days is reflected by increasing the compliance-
failure rate ω0 by a factor k, i.e., for the superspreading period, the new compliance-
failure rate is kω0 ;
• behavioral change is not instantaneous. The effective contact rates are modeled by

b − (1−q
θ
i)
b (t − T ) , T ≤ t < T + θ,
βi (t) = (11)
qi b, t ≥ T + θ,
where θ is the period where the contact rate declines, and qi is the proportion of
reduction for each subpopulation. The index i = 1 represents the population with
high compliance, while i = 2 indicates the one with low compliance.
As a first approximation we set χr = 0 (no reinfections). Figure 10a illustrates
the effect of one atypical event where mobility increases for three days by a fac-
tor of k = 10 times the baseline failure rate, i.e. ω = 10ω0 , with ω0 = 0.005). The
events occur either before or after the baseline (no increased mobility periods) inci-
(a)
(b) (c)
Fig. 10 Impact of different times of mobility increase on the epidemic curve. Mobility increase is
given by 10ω0 (ω0 = 0.005). The green line is the baseline epidemic curve. Blue, black, red, and
yellow discontinuous lines illustrate the scenarios when the mobility event starts four weeks before,
a week before, a week after, and four weeks after peak incidence, respectively
dence peak. The green solid line represents the baseline epidemic curve. Note that
the worst-case scenario (blue dashed line) occurs when the atypical event is located
on the exponential growth phase of the curve and relatively far from the maximum
incidence. A less extreme scenario occurs when the increase in population mobility
is located after the incidence peak (dashed yellow line). Note that, when the super-
spreading event occurs just after the peak of the curve, a plateau that lasts several
weeks is formed. Figure 10b gives the cumulative incidence for each perturbation
and shows that, regardless of the timing of increased mobility, there is a similar incre-
ment in cases. Moreover, the worst-scenario in terms of extra number of new cases,
occurs when the plateau is formed (dashed red line). The plateau scenario shows a
10% increase of cases when compared to the baseline (solid green line). Figure 10c
illustrates the dynamics of both effective transmission contact rates (Eq. 11) with
q1 = 0.23, q2 = 0.34, and θ = 150 days.
Next, let us exemplify the above results for the case of Mexico City. Consider
the scenario where 70% of the general population is confined and 30% is not. The
low compliance population includes workers with essential economic activities in
government and industry or individuals in the informal economy. In Mexico City, the
informal economy represents 22% of the economically active population [14]. This
split of the population occurs when social distancing measures are implemented on
March 23, 2020.
In Mexico, there were three important holidays (in terms of population mobility)
within the confinement period: April 30 (children’s day), May 3 (holy cross day),
and May 10 (mother’s day). There exists evidence that population mobility increased
[39, 40] in these periods. To study the effect of these holidays, one period of high
mobility, from April 29 to May 10, is used were the confinement-failure rate is κω0 ,
with κ = 1.5, 3, 4.5, and 6. The magnitude of k is chosen arbitrarily.
To mimic the daily COVID-19 cases in Mexico City, the effective transmission
rate has two periods of linear decay at different speeds. Thus, Eq. 11 becomes
⎧ (1−q1i )
⎪
⎪ b− b (t − T ) , T ≤ t < T + θ1i ,
⎨ θ1i
βi (t) = q b − (q1iθ−q 2i )
b (t − T − θ1i ) , T + θ1i ≤ t < T + θ1i + θ2i , (12)
⎪ 1i
⎪ 2i
⎩
q2i b, T + θ1i + θ2i ≤ t,
where 0 ≤ q1i , q2i ≤ 1 are two different reductions in the contact rate, and θ1i , θ2i
are two periods of reduction, for i = 1, 2. Figure 11a illustrates the effect of high
mobility events when the value of parameter κ, the increase in the failure rate ω,
varies. Here, solid green line represents the baseline epidemic curve. Dashed blue,
black, red, and yellow lines illustrate the scenarios when mobility increases by 1.5,
3, 4.5, and 6 times, respectively. Yellow bars represent confirmed cases by hospital
registration and blue bars represent daily suspected cases, respectively. Only data
from February 22 to July 15 is used for this analysis. As expected, a higher increase
in mobility causes a higher incidence peak (dashed yellow line), which happens
after the original baseline peak . However, if the mobility increase is moderate,
κ = 3, a plateau-like behavior is observed, which is consistent with the data until
July 15, 2020. This shows that the model can recreate the observed data. Figure 11b
illustrates the cumulative incidence for each perturbation. On September 5, 2020,
the dashed black line corresponds to a 26% increase in incidence when compared
to the baseline. Moreover, a worst-scenario (dashed yellow line) shows a 118%
increase regarding the baseline. Fortunately, this scenario did not happen. Figure 11c
illustrates the dynamics of both effective transmission contact rates (Eq. 12) using
the parameters q21 = 0.2, q22 = 0.3, and θ21 = θ22 = 113 days. Other parameters
are given in Table 4.
Note that, even if the black curve in Figure 11 provides a good description of
the observed data until July 15, 2020 for Mexico City, it decreases shortly after this
date, under the assumption that the conditions of the epidemic do not change, i.e.
the contact rates will remain constant and there are no further atypical transmission
events. However, inspecting the available data up to September 5, 2020 (c.f. Sect. 2),
the incidence shows, rather, a slight increase. To approximate the situation occur-
ring here, Fig. 12 shows a variant of the previous model where one more period of
high mobility is postulated to have occurred from July 26 to August 19, 2020. This
particular event is not associated with any specific public health related instruction
(a)
(b) (c)
Fig. 11 Impact of different increases of mobility on the epidemic curve of Mexico City. Blue bars
shows daily confirmed cases by hospital registration while yellow bars show suspected cases from
February 22, 2020 to July 15, 2020. Mobility increases from April 29, 2020 to May 10, 2020 and it is
represented by κω0 , with (ω0 = 0.005). Discontinuous blue, black, red, and yellow lines illustrate
the scenarios when the mobility increases 1.5, 3, 4.5, and 6 times, respectively. The scenario that
better describes the situation of Mexico City for this period is κ = 3
Table 4 Baseline parameter values used to fit data from Mexico city. These values will be used for
all the following scenarios, unless otherwise stated
Parameter Value Parameter Value Parameter Value
b 0.888 γ −1 5.1 q11 0.6
ρ 0.699 ηa−1 6.0 θ11 18.0
δr−1 12.1 ηs−1 7.0 q12 0.7
q 0.7 δs−1 4.0 θ12 18.0
μ 0.11 q 0.7 T 30.0
released at the time. We argue that the existence of this period is consequence of
the need to reactivate the economic activity. Officially, the reopening started on June
1, 2020, and it has been followed every fifteen days by executive orders to allow
the reincorporation (or continued closure) of different classes of business and public
places. These orders are not mandatory, but only recommendations for the general
public. This paused way of reopening the economy and the need of many people to
earn their day, can support the hypothesis of increased transmission related to the
observed incidence in the data during the postulated dates.
(a) (b)
Fig. 12 a Mexico City data and model projected trajectory from February 22, 2020 to September
5, 2020. Note that this is not an statistical fit but, rather, a projected trajectory under the hypothesis
described in the text. Two periods of high mobility are considered: (1) from April 29, 2020, to May
10, 2020 with a failure rate of (6.5ω0 ), and (2) from July 26, 2020, to August 19, 2020 with a failure
rate of (11ω0 ). Blue bars shows daily confirmed cases by hospital registration while yellow bars
show suspected cases. The black line shows the fit of the model. b Behavior of the contact rates for
the subpopulation with higher (blue line) and lower (black line) compliance
5 Dynamics Induced by Superspreading Events
In this section, the long-term behavior of the epidemic curve is explored in a situation
where there are multiple events of high transmission and the possibility of reinfection
exists. The goal is to anticipate possible changes in the dynamic of the COVID-
19 epidemic through the exploration of scenarios that may be affected by future
(possible) superdispersion events.
5.1 Anticipating Superspreading Events
Mexico City is again used to motivate the timing and duration of the superspreading
events. There are two other periods on the second semester of the year that can cause
high transmission events: independence day celebrated on September 15, 2020, and
the Buen Fin, a Mexican equivalent to the Black Friday in the USA. The event usually
lasts four days but to reactivate the economy in 2020, it will take place in the period
9-20 November.
For the scenarios that will be shown later, four periods of high mobility and
their corresponding perturbation on the compliance-failure rate will be used: (1)
from April 29–May 10, 2020 with κ = 6.5ω0 , (2) from July 26–August 19, 2020
with κ = 11ω0 , (3) from September 13–16, 2020 with κ = 19.5ω0 , and (4) from
November 9–20, 2020 with κ = 19.5ω0 . Here, ω0 = 0.003. Lifetime immunity will
be considered for now, which means χr = 0. We also make additional changes to
the effective transmission contact rates. Thus, Eq. 11 becomes:
⎧
⎪
⎪ b − (1−q
θ1i
1i )
b (t − T ) , T ≤ t < T + θ1i ,
⎪
⎪
⎪
⎪
⎪
⎪ q b − (q1iθ−q 2i )
b (t − T − θ1i ) , T + θ1i ≤ t < T + T1i ,
⎨ 1i 2i
βi (t) = q2i b, T + T1i ≤ t < T + T2i , (13)

⎪
⎪
⎪
⎪
⎪
⎪ q2i b + (q3iθ−q 2i )
b (t − T − T2i ) , T + T2i ≤ t < T + T3i ,
⎪
⎪ 4i
⎩
q3i b, T + T3i ≤ t,
where T1i = θ1i + θ2i , T2i = T1i + θ3i , and T3i = T2i + θ4i . Equation 13 can be inter-
preted as follow:
• if q2i < q3i , then there is an increase in the effective transmission contact rate in
[T2i , T3i ]. After this interval, βi (t) is constant;
• if q2i = q3i , then the effective transmission contact rate is constant from T1i ;
• if q2i > q3i , then there is a decrease in the effective transmission contact rate in
the interval [T2i , T3i ]. After that, βi (t) is constant.
Figure 13 shows some scenarios for different effective transmission rates. The
model incorporates the periods of high mobility just mentioned above. Baseline
parameters are given in Tables 4 and 5. Also, in Fig. 13a, we employ q31 = 0.18
and q32 = 0.22, while for Fig. 13b, we use q31 = 0.28 and q32 = 0.32. Figure 13a
illustrates the scenario corresponding to contact rates decreasing from September
16 to November 9, 2020, and then settling into a constant. The solid black line
represents the baseline epidemic curve, with no increased mobility during September
and November. The dashed black line shows the case where high mobility occurs
only in September, while the dotted black line shows high mobility in September and
November. Pink and gray areas highlight the difference between these curves. This is
an optimistic scenario where, even during the high mobility periods, the population
reinforces the use of face mask and social-distancing. Under these assumptions,
the number of reported cases is always low. On the other hand, Fig. 13c shows the
behavior of the epidemic curve if the contact rate is slightly increased from September
16 to November 9, 2020. In this situation, the projections indicate that the epidemic
will increase, and its magnitude will depend on how‘ many events of high mobility
occur during this period. The meaning of lines and shadowed areas is similar to
those in Fig. 13a. Finally, Figs. 13b and d show the effective transmission contact
rates. Blue and black lines are associated with the compliant and low-compliance
populations, respectively. The orange area indicates the period when the effective
contact rates are different.
(a) (b)
(c) (d)
Fig. 13 Impact of several periods of high mobility and changes in the behavior of the effective
transmission contact rates. Blue bars represent the daily confirmed cases by hospital registration
and yellow bars show suspected cases for Mexico City from February 22, 2020 to September 5,
2020. In a, c, the black line shows the scenario when only two events of high mobility occur in
April 29 - May 10, 2020, with a perturbation of κ = 6.5ω0 , and in July 26 - August 19, 2020 with
κ = 11ω0 . A black dashed line shows the effect on the epidemic curve of one superdispersion event
occurring from September 13–16, 2020 with κ = 19.5ω0 . A black dotted line depicts the effect of
one extra superdispersion event from November 9-20, 2020 with κ = 19.5ω0 . Here, ω0 = 0.003.
Pink and gray areas highlight the differences among this curves. b shows a 5% drop in the effective
contact rates from September 16 to November 9, 2020 and is associated to subplot a. d shows a 5%
increase in the effective contact rates from September 16 to November 9, 2020 and is associated to
c. The orange shadow shows periods when the effective contact ates differ
Table 5 Baseline parameters values for Eq. 13, used in the simulations presented in Sect. 5
Parameters Values Parameters Values
q21 0.23 q22 0.27
θ21 80 θ22 156
θ31 79 θ32 3
θ41 54 θ42 54
6 Discussion
This section is organized around the main topics explored in this chapter. We start
with observations on our application of epidemic growth formulas and proceed to
looking more closely at examples that illustrate the main points arising from our
mechanistic models when applied to the specific case of Mexico City.
6.1 On Growth Models
Growth models can be very useful to check for consistency between parameter esti-
mates and data. It is tempting to use, for example, estimated values of R0 or the
generation time Tg from Wuhan or elsewhere, and assume that these are valid in a
widely different regional or national context. The estimation of growth rates and,
at least, comparison with the observed doubling time is necessary to evaluate the
appropriateness of their use.
Table 6 shows estimated parameters deduced from available data and our previous
estimates in Tables 1 and 2. For example, the observed doubling time of the epidemic
in Mexico (country) is 4.24 days, as reported in [32] for the Mexican epidemic up
to March 30. Using this doubling time we obtain an estimate of the growth rate of
r = 0.16. Using the formula [49]
R0 = 1 + r Tg ,
where Tg is the generation interval and r the growth rate, we can readily see from
Table 1 that, for R0 = 1.88 and a generation time of 4.7 days [29], we deduce a
growth rate r = 0.16 rendering a doubling time of 3.7 days. For R0 = 1.7, using the
Table 6 Parameters for Mexico (country) and Mexico City using a doubling time of 4.24 days
observed for the whole country from data (see main text). This doubling time corresponds to
a growth rate r = 0.16. In the Table, Td is the doubling time and Tg is the generation time. For
Mexico (country), Tg was obtained using the formula R0 = 1 + r Tg [49]. The first column indicates
the method used to estimate R0 (from Table 1: exponential or maximum likelihood). For Mexico
City, the first row indicates the doubling time Td before the lockdown; the second row is Td after
lockdown, derived from the growth rates given in Table 2 and estimated from incidence data. For
Mexico City the above formula was used to estimate R0 before and after lockdown. Given the
values of R0 estimated for the whole country from incidence data, the R0 ’s for Mexico City must
be considered upper bounds
Mexico (country) R0 Tg Mexico City R0
Exp. 1.88 3.7 Td = 1.5 before 3.04
ML 1.70 4.6 Td = 5.4 after 1.57
Average 1.79 4.15
same generation time, we obtain r = 0.14 and a doubling time of 4.6 days. Both
estimates are reasonable approximations to the observed doubling time of 4.24 days.
Using these approximations to R0 we can conclude that the generation time for the
whole country is in the interval [3.7, 4.6] days at the start of the epidemic. Recall
the widely use estimate of Tg = 4.7 from [29]. A similar analysis for Mexico City,
now using Table 2 and an estimated generation time of Tg = 4.5 days, we deduce
that before the lockdown the doubling time was of 1.5 days, with a corresponding
R0 ≈ 3.04. In the first weeks after lockdown, the doubling time is estimated to have
been of 5.4 days, with an R0 ≈ 1.57. Mexico City is one of the most populated cities
in the World and it is reasonable to expect a higher reproduction number than the
national one that, in fact, averages the incidence over the whole national territory.
Nevertheless, given the magnitudes of R0 estimated for the whole country directly
from incidence data, the R0 for Mexico City must be cautiously considered to be an
upper bound. These computations show that social-distancing measures were indeed
effective in reducing transmission in Mexico City as evidenced by the reduction of
the epidemic growth rate, the reduction of R0 and the increased doubling time, during
the first week after March 23, 2020. We conclude our discussion on these estimates
pointing out that although the reduction of the growth rate was indeed effective, it
had an interesting side effect not projected by the initial models: the reduction of
R0 delayed the occurrence of the epidemic peak too far, unintentionally making it to
coincide with the date that the government had determined for the reopening of the
economy. This had important consequences for the later evolution of the epidemic
making it longer than expected.
6.2 On the Dynamics of Temporal Immunity
At the date of writing, there is little information regarding the temporal immunity
for the SARS-CoV-2 virus and whether or not COVID-19 will become a seasonal
disease. There is some inconclusive evidence that immunity against SARS-CoV-2
starts to wane one month after recovery [23, 55]. Using the ideas of the previous
section, the effect of three periods of natural immunity will be explored: six, twelve
and twenty four months.
Figure 14 corresponds to twelve moths of temporal immunity (χ −1 = 365 days).
Notice that the epidemic curve evolution depends on the assumptions regarding
the behavior of the two subpopulations with high and low compliance. For example,
Fig. 14a assumes that the contact rates decrease 5% from September 16 to November
9, 2020, which results in the extinction of the epidemic sometime in 2021. Figure 14b
considers constant contact rates since September 13, 2020, for the low compliance
group, and since June 29, 2020 for the high compliance group. This projects that
the epidemic will enter a long plateau. Moreover, Fig. 14c shows that the epidemic
will oscillate if the contact rates are allowed to increase a 5% from September 16 to
November 9, 2020. Here, lines and shadowed areas keep the same meanings as in
Fig. 13. Notice that, regardless of whether or not the perturbations of September and
(a)
(b)
(c)
Fig. 14 Daily reported cases when considering temporal immunity equal to twelve months
(χr = 1/365 days). a Dynamics when effective transmission contact rates are decreased 5% from
September 16 to November 9, 2020. This is obtained by setting 0.23 = q21 > q31 = 0.18, and
0.27 = q22 > q32 = 0.22 in Eq. 13. b Dynamics when effective transmission contact rates are held
constant since September 13, 2020, for the low compliance group, and since June 29, 2020 for
the compliant group, that is q21 = q31 = 0.23, and q22 = q32 = 0.27. c Dynamics when effective
transmission contact rates are increased 5% from September 16 to November 9, 2020, that is,
0.23 = q21 < q31 = 0.28, and 0.28 = q22 < q32 = 0.32
November of 2020 occur, the general behavior of each scenario is the same. This
means that the long-term behavior of the epidemic curve described by this scenarios,
in the case where immunity lasts one year, is largely determined by the changes in
the contact rates, and the atypical transmission events only affects the magnitude of
the epidemic curves.
Figure 15 shows the epidemic curve when temporal immunity lasts six months
(χr−1 = 182 days). All the other parameters are identical to the scenarios of Fig. 14.
Subplot (a) held the contact rates constant. Here it is clear that the occurrence of
atypical transmission events does change the behavior of the epidemic curve. Subplot
(b), on the other hand, shows the consequences of assuming a 5% increase in contact
rates. Notice that the increment in incidence during 2021 is dramatically different;
the level of the peak is almost three times as high as the maximum incidence observed
until September 5, 2020.
Finally, Fig. 16 shows the cases when temporal immunity lasts twenty four months
(χr−1 = 730 days) and constant or increased contact rates as in Fig. 15. The behavior
of this scenarios is very similar to those presented when immunity lasts one year.
(a)
(b)
Fig. 15 Daily reported cases dynamics when considering temporal immunity equal to six months
(χr = 1/182 days). a Dynamics when effective transmission contact rates are held constant since
September 13, 2020, for the low compliance group, and since June 29, 2020 for the compliant group.
This is obtained by setting q21 = q31 = 0.23 and q22 = q32 = 0.27 in Eq. 13. b Dynamics when
effective transmission contact rates are increased 5% from September 16 to November 9, 2020, that
is, 0.23 = q21 < q31 = 0.28, and 0.28 = q22 < q32 = 0.32
Note added in proof: By the middle of November, incidence data for Mexico City
shows a pattern of increasing infections. This is in line with the projection presented
in Fig. 15b, where 6 months of immunity were considered and the contact rates
increased 5%. This situation is updated in Fig. 17. Here, blue bars show confirmed
cases by symptoms onset, orange bars show suspected cases that will be probably
confirmed given the positivity rate of 36% that is being observed now in Mexico
City, and the yellow bars show the total suspected cases. It is clear that the scenarios
that include atypical superdispersion events occurring on September and November
(dashed and dotted black lines) provide a better description of the increase in the
number of cases than the scenario that does not consider superdispersion (solid
black line). We conclude that the superspreading events described above may have
indeed increased the average effective contact rate that, by the time this note is being
written, may be starting an epidemic rebound.
(a)
(b)
Fig. 16 Daily reported cases dynamics when considering temporal immunity equal to twenty four
months (χr = 1/730 days). a Dynamics when effective transmission contact rates are held constant
since September 13, 2020, for the low compliance group, and since June 29, 2020 for the compliant
group. This is obtained by setting q21 = q31 = 0.23 and q22 = q32 = 0.27 in Eq. 13. b Dynamics
when effective transmission contact rates are increased 5% from September 16 to November 9,
2020, that is, 0.23 = q21 < q31 = 0.28, and 0.28 = q22 < q32 = 0.32
7 Conclusions
In the absence of vaccines, the fight against COVID-19 has been driven by the imple-
mentation of non-pharmaceutical interventions. These mitigation measures need to
be constantly monitored and adjusted according to the evolution of the epidemic.
From this work we conclude that, when planning nonpharmaceutical interventions
to control an epidemic, it is not enough to focus solely on flattening the curve (reduce
the growth rate). It is of utter importance to evaluate the impact of those interventions
on the evolution of the epidemic curve since they can cause undesired side effects
such as extending the epidemic for too long.
As we have shown in this chapter, changes in mobility and superspreading events
result in important changes in the epidemic dynamics. For this reason, we consider
that monitoring and prediction of these high mobility events should continue to be a
priority.
The results in Sects. 5 and 6 show that, in order to provide better predictions,
modelers must anticipate possible changes in the epidemic dynamics. Anticipating
these changes is difficult, but it is necessary since fitting the current data and creating
projections without considering scenarios is not a good strategy. It is also important to
Fig. 17 Added in proof. Updated data for Fig. 15. Daily reported cases from February 22 to
November 17, 2020 and predicted dynamics according to the scenarios created on September 5,
2020. Here, temporal immunity is equal to six months (χr = 1/182 days) and effective transmission
contact rates are increased 5% from September 16 to November 9, 2020, that is, 0.23 = q21 < q31 =
0.28, and 0.28 = q22 < q32 = 0.32. Blue bars show confirmed cases by symptoms onset, orange
bars show suspect cases that will be probably confirmed given the positivity rate of 36% that is being
observed now in Mexico City, and the yellow bars show the total suspect cases. Scenarios that include
atypical superdispersion events occurring on September and November are depicted by dashed and
dotted black lines respectively, and the baseline scenario that that does not consider superdispersion
is shown by the solid black line. Note the data roughly following the pattern projected in this scenario
mention that the same basic model was able to reproduce the observed data at different
periods by including minor modifications that can be justified by knowledge of the
local current situation of the region of interest.
There are several natural extensions of our work. We are already working on the
effect of vaccines with different characteristics, namely, efficacy, coverage, number
of doses, waning time. At the moment there is an important number of candidate
vaccines [20], each with its own properties, some of which will become available
in a few months. Another research line is to study the dynamics of syndemics with
acute respiratory infections such as influenza or RSV, for example, or with viruses that
have different ecological niche within the human host like dengue, zika, chikungunya
or measles. The coronavirus epidemic has caused the disruption of well-established
control strategies against arboviruses and childhood infectious diseases and outbreaks
of many of them may be expected in the coming months, some are expected to
generate coinfections with SARS-CoV-2.
Acknowledgements All authors acknowledge support from DGAPA-PAPIIT-UNAM grant IV100-

220 (convocatoria especial COVID-19), MAAZ acknowledges support from PRODEP Programme
(No. 511-6/2019-8291), MTA gratefully acknowledges the financial support from CONACyT
project A1-S-13909 and JXVH acknowledges support from DGAPA-PAPIIT-UNAM grant
IN115720.
Authors Contributions MAAZ, MSC, JXVH designed the study, all authors revised the manuscript
and discussed results and conclusions.
Competing Interests The authors declare no conflicts of interest.
References
1. Acuña-Zegarra, M.A., Santana-Cibrian, M., Velasco-Hernandez, J.X.: Modeling behavioral

change and COVID-19 containment in Mexico: A trade-off between lockdown and compliance.
Math. Biosci. 325, (2020). https://doi.org/10.1016/j.mbs.2020.108370
2. Adam, D.C., Wu, P., Wong, J.Y., Lau, E.H.Y., Tsang, T.K., Cauchemez, S.L., Leung, G.M.,
Cowling, B.J.: Clustering and superspreading potential of SARS-CoV-2 infections in Hong
Kong. Nat. Med. 26(11), 1717–1719 (2020). https://doi.org/10.1038/s41591-020-1092-0
3. Angulo, M.T., Castaños, F., Moreno-Morton, R., Velasco-Hernández, J.X., Moreno, J.A.: A
simple criterion to design optimal non-pharmaceutical interventions for mitigating epidemic
outbreaks. J. R. Soc. Interface 18(178), 20200803 (2021). https://doi.org/10.1098/rsif.2020.
0803
4. Azanza Ricardo, C., Hernandez Vargas, E.A.: The risk of lifting COVID-19 confinement in
Mexico (2020). https://doi.org/10.1101/2020.05.28.20115063
5. Bertozzi, A.L., Franco, E., Mohler, G., Short, M.B., Sledge, D.: The challenges of modeling
and forecasting the spread of COVID-19. Proc. Natl. Acad. Sci. 117(29), 16732–16738 (2020).
https://doi.org/10.1073/pnas.2006520117
6. Chen, T.-M., Rui, J., Wang, Q.-P., Zhao, Z.-Y., Cui, J.-A., Yin, L.: A mathematical model for
simulating the phase-based transmissibility of a novel coronavirus. Infect. Diseases Poverty
9(1), 1–8 (2020). https://doi.org/10.1186/s40249-020-00640-3
7. Chowdhury, R., Heng, K., Shawon, M.S.R., Goh, G., Okonofua, D., Ochoa-Rosales, C.,
Gonzalez-Jaramillo, V., Bhuiya, A., Reidpath, D., Prathapan, S., et al.: Dynamic interven-
tions to control COVID-19 pandemic: a multivariate prediction modelling study comparing
16 worldwide countries. Eur. J. Epidemiol. 35(5), 389–399 (2020). https://doi.org/10.1007/
s10654-020-00649-w
8. Chowell, G.: Fitting dynamic models to epidemic outbreaks with quantified uncertainty: a
primer for parameter uncertainty, identifiability, and forecasts. Infect. Disease Model. 2(3),
379–398 (2017). https://doi.org/10.1016/j.idm.2017.08.001
9. Christen, J.A., Fox, C.: A general purpose sampling algorithm for continuous distributions
(the t-walk). Bayesian Anal. 5(2), 263–281 (Jun, 2010). International Society for Bayesian
Analysis. https://projecteuclid.org/euclid.ba/1340218339
10. Cori, A., Ferguson, N.M., Fraser, C., Cauchemez, S.: A new framework and software to estimate
time-varying reproduction numbers during epidemics. Am. J. Epidemiol. 178(9), 1505–1512
(2013). https://doi.org/10.1093/aje/kwt133
11. Eikenberry, S.E., Mancuso, M., Iboi, E., Phan, T., Eikenberry, K., Kuang, Y., Kostelich, E.,
Gumel, A.B.: To mask or not to mask: modeling the potential for face mask use by the general
public to curtail the COVID-19 pandemic. Infect. Disease Model. 5, 293–308 (2020). https://
doi.org/10.1016/j.idm.2020.04.001
12. Estrada, E.: COVID-19 and SARS-CoV-2 modeling the present, looking at the future. Phys.
Rep. 869, 1–51 (2020). https://doi.org/10.1016/j.physrep.2020.07.005
13. Giordano, G., Blanchini, F., Bruno, R., Colaneri, P., Di Filippo, A., Di Matteo, A., Colaneri,
M.: Modelling the COVID-19 epidemic and implementation of population-wide interventions
in Italy. Nat. Med. 26, 855–860 (2020). https://doi.org/10.1038/s41591-020-0883-7
14. Gobierno de la Ciudad de México 2020. Información laboral. http://www.stps.gob.mx/gobmx/

estadisticas/pdf/perfiles/perfil%20distrito%20federal.pdf. Accessed 27 Sept 2020
15. Hernandez-Vargas, E.A., Velasco-Hernandez, J.X.: In-host mathematical modelling of COVID-
19 in humans. Annu. Revi. Control (2020). https://doi.org/10.1016/j.arcontrol.2020.09.006
16. Ivorra, B., Ferrández, M.R., Vela-Pérez, M., Ramos, A.: Mathematical modeling of the spread
of the coronavirus disease 2019 (COVID-19) taking into account the undetected infections. The
case of China. Commun. Nonlinear Sci. Numer. Simul. 88, (2020). https://doi.org/10.1016/j.
cnsns.2020.105303
17. Kaipio, J.P., Somersalo, E.: Statistical and Computational Inverse Problems, vol. 160 of Applied
Mathematical Sciences, Springer, New York. http://link.springer.com/10.1007/b138659 (2005)
18. Kermack, W.O., McKendrick, A.G., Walker, G.T.: A contribution to the mathematical theory
of epidemics. In: Proceedings of the Royal Society of London. Series A, Containing Papers of
a Mathematical and Physical Character, vol. 115, issue 772, pp. 700–721 (1927). https://doi.
org/10.1098/rspa.1927.0118
19. Komarova, N.L., Schang, L.M., Wodarz, D.: Patterns of the covid-19 pandemic spread around
the world: exponential versus power laws. J. R. Soc. Interface 17(170), 20200518 (2020).
https://doi.org/10.1098/rsif.2020.0518
20. Krammer, F.: SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020). https://doi.
org/10.1038/s41586-020-2798-3
21. Lee, S., Kim, T., Lee, E., Lee, C., Kim, H., Rhee, H., Park, S.Y., Son, H.-J., Yu, S., Park,
J.W., Choo, E.J., Park, S., Loeb, M., Kim, T.H.: Clinical course and molecular viral shedding
among asymptomatic and symptomatic patients with SARS-CoV-2 infection in a Community
Treatment Center in the Republic of Korea. JAMA Internal Med. 180(11), 1447–1452 (2020).
https://doi.org/10.1001/jamainternmed.2020.3862
22. Liu, Y., Eggo, R.M., Kucharski, A.J.: Secondary attack rate and superspreading events for
SARS-CoV-2. Lancet 395(10227) (2020). https://doi.org/10.1016/S0140-6736(20)30462-1
23. Lu, J., Peng, J., Xiong, Q., Liu, Z., Lin, H., Tan, X., Kang, M., Yuan, R., Zeng, L., Zhou,
P., Liang, C., Yi, L., du Plessis, L., Song, T., Ma, W., Sun, J., Pybus, O.G., Ke, C.: Clinical,
immunological and virological characterization of COVID-19 patients that test re-positive for
SARS-CoV-2 by RT-PCR. EBioMedicine 59 (2020). https://doi.org/10.1016/j.ebiom.2020.
102960
24. Ma, J.: Estimating epidemic exponential growth rate and basic reproduction number. Infect.
Disease Model. 5, 129–141 (2020). https://doi.org/10.1016/j.idm.2019.12.009
25. Ma, J., Dushoff, J., Bolker, B.M., Earn, D.J.: Estimating initial epidemic growth rates. Bull.
Math. Biol. 76, 245–260 (2014). https://doi.org/10.1007/s11538-013-9918-2
26. Mena, R.H., Velasco-Hernandez, J.X., Mantilla-Beniers, N.B., Carranco-Sapiéns, G.A., Benet,
L., Boyer, D., Castillo, I.P.: Using posterior predictive distributions to analyse epidemic mod-
els: COVID-19 in Mexico City. Phys. Biol. 17(6), (2020). https://doi.org/10.1088/1478-3975/
abb115
27. Munster, V., Koopmans, M., VanDorelmalen, N., VanRiel, D., DeWit, E.: A novel coronavirus
emerging in China—Key questions for impact assessment. New England J. Med. 382(8), 692–
694 (2020). https://doi.org/10.1056/NEJMp2000929
the 2019 novel Coronavirus. Math. Biosci. 325, (2020). https://doi.org/10.1016/j.mbs.2020.
108364
29. Nishiura, H., Linton, N.M., Akhmetzhanov, A.R.: Serial interval of novel coronavirus (COVID-
19) infections. Int. J. Infect. Diseases 93, 284–286 (2020). https://doi.org/10.1016/j.ijid.2020.
02.060
30. Obadia, T., Haneef, R., Boëlle, P.: The R0 package: a toolbox to estimate reproduction numbers
for epidemic outbreaks. BMC Med. Inf. Decis. Making 12, 147 (2012). https://doi.org/10.1186/
1472-6947-12-147
31. Ohnishi, A., Namekawa, Y., Fukui, T.: Universality in COVID-19 spread in view of the Gom-
pertz function. Progr. Theor. Exp. Phys. (2020). https://doi.org/10.1093/ptep/ptaa148
32. OurWorldInData.org: Total confirmed COVID-19 cases per million versus doubling
time of total confirmed cases. https://ourworldindata.org/grapher/covid-cases-per-capita-vs-
doubling-time. Accessed 15 Sept 2020
33. Paules, C.I., Marston, H.D., Fauci, A.S.: Coronavirus infections-more than just the common
cold. JAMA 323(8), 707–708 (2020). https://doi.org/10.1001/jama.2020.0757
34. Richards, F.J.: A flexible growth function for empirical use. J. Exp. Botany 10(2), 290–301
(1959). https://doi.org/10.1093/jxb/10.2.290
35. Robert, C.P., Casella, G.: Monte Carlo Statistical Methods, Springer Texts in Statistics, 2nd
edn. Springer, New York (2004). https://doi.org/10.1007/978-1-4757-4145-2
36. Roosa, K., Lee, Y., Luo, R., Kirpich, A., Rothenberg, R., Hyman, J., Yan, P., Chowell, G.:
Real-time forecasts of the COVID-19 epidemic in China from February 5th to February 24th,
2020. Infect. Disease Model. 5, 256–263 (2020). https://doi.org/10.1016/j.idm.2020.02.002
37. Sanche, S., Lin, Y.T., Xu, C., Romero-Severson, E., Hengartner, N., Ke, R.: High contagiousness
and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerging Infect. Diseases
26(7), 1470–1477 (2020). https://doi.org/10.3201/eid2607.200282
38. Santamaría-Holek, I., Castaño, V.: Possible fates of the spread of SARS-CoV-2 in the Mexican
context. R. Soc. Open Sci. 7(9), (2020). https://doi.org/10.1098/rsos.200886
39. Santana-Cibrian, M., Acuña-Zegarra, M.A., Velasco-Hernandez, J.X.: Lifting mobility restric-
tions and the effect of superspreading events on the short-term dynamics of COVID-19. Math.
Biosci. Eng. 17(5), 6240–6258 (2020). https://doi.org/10.3934/mbe.2020330
40. Secretaría de Movilidad de Ciudad de México: Diferencia porcentual en el tránsito vehicular
de la ciudad de méxico. https://semovi.cdmx.gob.mx/storage/app/media/Vialidad%20200826/
200826%20Vialidad.pdf. Accessed 30 August 2020
41. Singer, H.M.: The COVID-19 pandemic: growth patterns, power law scaling, and saturation.
Phys. Biol. 17(5), (2020). https://doi.org/10.1088/1478-3975/ab9bf5
42. Sánchez-Villegas, P., Codina, A.D.: Modelos predictivos de la epidemia de covid-19 en españa
con curvas de gompertz. Gaceta Sanitaria (2020). https://doi.org/10.1016/j.gaceta.2020.05.005
43. Stehlik, M., Kisel’ak, J., Dinamarca, M.A., Li, Y., Ying, Y.: On COVID-19 outbreaks predic-
tions: issues on stability, parameter sensitivity, and precision. Stoch. Anal. Appl. 1–22 (2020).
https://doi.org/10.1080/07362994.2020.1802291
44. Thompson, R., Stockwin, J., van Gaalen, R., Polonsky, J., Kamvar, Z., Demarsh, P., Dahlqwist,
E., Li, S., Miguel, E., Jombart, T., Lessler, J., Cauchemez, S., Cori, A.: Improved inference of
time-varying reproduction numbers during infectious disease outbreaks. Epidemics 29 (2019).
https://doi.org/10.1016/j.epidem.2019.100356
45. Thurner, S., Klimek, P., Hanel, R.: A network-based explanation of why most covid-19 infection
curves are linear. Proc. Natl. Acad. Sci. 117(37), 22684–22689 (2020). https://doi.org/10.1073/
pnas.2010398117
46. Tsallis, C., Tirnakli, U.: Predicting COVID-19 peaks around the world. Front. Phys. 8, 217
(2020). https://doi.org/10.3389/fphy.2020.00217
47. Utsunomiya, Y.T., Utsunomiya, A.T.H., Torrecilha, R.B.P., Paulan, S.D.C., Milanesi, M., Gar-
cia, J.F., : Growth rate and acceleration analysis of the COVID-19 pandemic reveals the effect
of public health measures in real time. Front. Med. 7, 247 (2020). https://doi.org/10.3389/
fmed.2020.00247
48. Vinceti, M., Filippini, T., Rothman, K.J., Ferrari, F., Goffi, A., Maffeis, G., Orsini, N.: Lockdown
timing and efficacy in controlling COVID-19 using mobile phone tracking. EClinicalMedicine
25 (2020). https://doi.org/10.1016/j.eclinm.2020.100457
49. Wallinga, J., Lipsitch, M.: How generation intervals shape the relationship between growth rates
and reproductive numbers. Proc. R. Soc. B: Biol. Sci. 274(1609), 599–604 (2007). https://doi.
org/10.1098/rspb.2006.3754
50. Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., Wang, B., Xiang, H., Cheng, Z., Xiong, Y.,
Zhao, Y., Li, Y., Wang, X., Peng, Z.: Clinical characteristics of 138 hospitalized patients with
2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323(11), 1061–1069
(2020). https://doi.org/10.1001/jama.2020.1585
51. Wang, L., Wang, J., Zhao, H., Shi, Y., Wang, K., Wu, P., Shi, L.: Modelling and assessing
the effects of medical resources on transmission of novel coronavirus (COVID-19) in Wuhan,
China. Aims Press 17(4), 2936–2949 (2020). https://doi.org/10.3934/mbe.2020165
52. Wang, X.-S., Wu, J., Yang, Y.: Richards model revisited: validation by and application to
infection dynamics. J. Theor. Biol. 313, 12–19 (2012). https://doi.org/10.1016/j.jtbi.2012.07.
024
international spread of the 2019-nCoV outbreak originating in Wuhan, China?: a modelling
study. Lancet 395(10225), 689–697 (2020). https://doi.org/10.1016/S0140-6736(20)30260-9
54. Zhao, H., Feng, Z.: Staggered release policies for COVID-19 control: costs and benefits of
relaxing restrictions by age and risk. Math. Biosci. 326, (2020). https://doi.org/10.1016/j.mbs.
2020.108405
55. Zhou, W., Xu, X., Chang, Z., Wang, H., Zhong, X., Tong, X., Liu, T. Li, Y.: The dynamic
changes of serum IgM and IgG against SARS-CoV-2 in patients with COVID-19. J. Med.
Virol. 1–10 (2020). https://doi.org/10.1002/jmv.26353
56. Zou, L., Ruan, F., Huang, M., Liang, L., Huang, H., Hong, Z., Yu, J., Kang, M., Song, Y., Xia,
J., Guo, Q., Song, T., He, J., Yen, H.-L., Peiris, M., Wu, J.: SARS-CoV-2 viral load in upper
respiratory specimens of infected patients. New England J. Med. 382(12), 1177–1179 (2020).
https://doi.org/10.1056/NEJMc2001737
Assessing the Impact of Public
Compliance on the Use of
Non-pharmaceutical Intervention with
Cost-Effectiveness Analysis on the
Transmission Dynamics of COVID-19:
Insight from Mathematical Modeling
Michael O. Adeniyi, Segun I. Oke, Matthew I. Ekum, Temitope Benson,

and Matthew O. Adewole
Abstract COVID-19, caused by a lately discovered coronavirus in Wuhan, China,

is a respiratory ailment. Since the manifestation in 2019, there are already over 56
million cases of COVID-19 worldwide, with over 1.3 million mortality cases in vul-
nerable countries with inadequate healthcare infrastructures. The interaction between
susceptible humans, infected individuals, and the coronavirus shed in the environ-
ment are investigated. A proper insight on the interaction between humans and coro-
navirus population will provide a comprehensive interplay between susceptible and
infected humans, and the virus. The main goal of this chapter is to conduct a rigorous
mathematical and statistical analysis of compartmentalized COVID-19 model that
takes into consideration public compliance to COVID-19 rules and sanitation, and the
interaction of human and the virus population in the environment, for the purpose of
obtaining the effective reproduction number R0 , at the coronavirus-free equilibrium,
and in the presence of compliance. A quality analysis is performed to determine the
stability of the system equilibrium point. To curtail the spread of the virus, a non-
pharmaceutical intervention, such as public adherence and sanitation, is adopted,
taking into account the cost effectiveness of the intervention. Our results show that
S. I. Oke (B)
Department of Mathematical and Applied Mathematics,
University of Pretoria, Pretoria, South Africa
e-mail: segunoke2016@gmail.com
M. O. Adeniyi · M. I. Ekum
Department of Mathematics and Statistics, Lagos State Polytechnic,
Ikorodu, Lagos, Nigeria
T. Benson
Department of Mathematics, College of Art and Sciences, Oklahoma State University,
Stillwater, OK, USA
M. O. Adewole
Department of Computer Science and Mathematics,
Mountain Top University, Prayer City, Nigeria
580 M. O. Adeniyi et al.
COVID-19 is locally and asymptomatically stable if R0 < 1 and globally stable if

R0 ≤ 1. Further results show that the control involving both adherence and compli-
ance to COVID-19 rules and sanitation prove to be the most cost-effective strategies.
Keywords COVID-19 · non-pharmaceutical · time series data · cost-effectiveness

analysis · Lyapunov function · public compliance
1 Introduction
Scientists discovered the first human coronavirus in the mid-sixties. This virus was
discovered by a scientist named June Almeida [1]. She was working at the Ontario
Cancer Institute in Toronto, Canada. She performed a virology experiment at the
time under the electron micro-scope with her group of collaborators. Coronaviruses
are a group of viruses known to be enveloped, non-segmented, single-stranded, and
positive-sense ribonucleic acid (RNA) viruses with a halo or crown-like (corona)
presence, when viewed under the microscope [1]. They are known to bring about
symptoms like common cold, sore throat, cough, suffocating nose, fever, headache,
pneumonia, respiratory problem, and in some cases, they lead to very severe ailments
and eventual death [2]. In the decade following the sixties, scientists formed a group
of comparable human and animal coronaviruses and named them based on their
appearance, which is crown-like. Some of these viruses are known to be found in
animals like bats, camels, and cattle, to mention a few. Six (HCoV-229E, HCoV-
OC43, SARS-CoV, HCoVNL63, HCoV-HKU1 and MERS-CoV) of these identified
viruses are attested to infect humans [1, 2]. All these viruses, with the exception of
SARS-CoV, and MERS-CoV, were never recorded to be highly pathogenic, and were
not taken very seriously until the emergence of SARS-CoV in the year 2002–2003.
HCoV-229E was one of the first coronavirus strains to be named. Its symptom is
known to get to the peak on day three (3) or four (4) of the illness and are self-
limited [3]. It is also associated with common cold symptoms, and no serious or
adverse effect was recorded to our knowledge until 2018, when it was reported
by Vassilara et al. [3] to have a severe and life threatening lower respiratory tract
infection. However, early treatment and administration of systemic corticosteroids
led to gradual clinical improvement with no co-morbidity. HCoV-229E is common
in early childhood, particularly in temperate climates, where it causes infections
during winter and spring seasons. Lack of controlled trials makes it difficult to have
a recommended treatment for both SARS CoV and MERS CoV infections.
The coronavirus responsible for the SARS outbreak emerged in southern China,
in the year 2002, and quickly dispersed to over twenty-eight nations in Asia,
Europe, North America, and South America. By July 2003, over 8000 people were
infected, with 774 dead, according to the United Kingdom National Health Service.
A small outbreak in 2004 involved only four more cases. With renewed interest
in CoV research, scientists discovered two new coronaviruses known as HCoV-
Assessing the Impact of Public Compliance on the Use of Non-pharmaceutical 581
HKU1 and HCoVNL63. Infection with HCoV-229E, HCoV-OC43, HCoV-HKU1

and HCoVNL63 requires supportive care [4, 5].
In the Saudi Arabian MERS coronavirus outbreak in 2012, nearly all of the roughly
2500 recorded cases were reported to have been in people who had either lived in,
or travelled to and from the Middle East. The MERS coronavirus is less communi-
cable, but more deadly than SARS, killing about 858 people, according to the World
Health Organization. It shared the same respiratory symptoms with SARS; that is,
headache, fever, and respiratory problems, such as cough and shortness of breath, and
sometimes, kidney failure. MERS coronavirus is easily transmitted through droplets
and contact, direct or indirect. The risk factors include, among others, contact with
camels, camel products, and infected persons [4, 6]. The novel coronavirus disease,
COVID-19, was first declared in Wuhan city, China, in December 2019, and is caused
by the virus SARS-CoV-2, also known as Severe Acute Respiratory Syndrome Coro-
navirus. By March 11, 2020, COVID-19 has been affirmed to be a pandemic by the
World Health Organization, and by March 13, 2020, a national state of emergency
was declared across the globe. From there onward, the whole world went into a
nation-wide state of emergency, prompting the government of almost every coun-
try on the planet, policy and decision- makers to announce lockdowns, which may
be partial shutdown of schools (going online in developed nations) or permanent
shutdown of schools in developing countries; lockdown of places of religious ser-
vices and worship centers; close of each country’s respective borders; travel bans or
travel restrictions, except for essential services; all of which led to global economic
damages, crash of stock markets, drops in oil prices, very high inflation rates, and
unemployment in many countries, including the United States. The novel coronavirus
can cause mild to moderate respiratory illnesses and infected persons can recover
without special treatment. It is attested to be more deadly than former existing coro-
naviruses, and has a higher transmission rate as well. Older people, and those with
underlying medical problems, such as chronic respiratory illnesses, diabetes, and
cancer, are more likely to develop serious and severe illnesses that may lead to death.
As of 28th of August, 2020, the period of this write-up, the Johns Hopkins Uni-
versity of medicine reported a worldwide total confirmed cases of 24,812,440; with
838,704 global death (182,217 deaths in the United States; 119,504 in Brazil; 41,585
in the United Kingdom; 63,146 in Mexico; 35,473 in Italy; 62,550 in India; 30,601
in France; 29,011 in Spain; 16,977 in Russia; 9299 in Germany; 9156 in Canada;
13,743 in South Africa; 4721 in China; 5362 in Egypt; 3840 in Saudi Arabia; and
1011 in Nigeria, to mention a few [7, 8].
1.1 Related Works
Despite all global public health care and medical practitioners’ efforts to develop
a vaccine or antiviral and drug treatments, there has not been any known vaccine
or cure, till the time of writing of this article, that can treat or prevent the novel
coronavirus disease (nicknamed COVID-19); although there has been some positive
responses to clinical trials. This has led the global population, governments, deci-
sion and policy makers, and researchers, to seek non-pharmaceutical approaches to
mitigate and curb the global impact and dynamic spread of the novel virus [9, 10].
Non-pharmaceutical approaches, such as total lockdown, social and self- isolation,
use of face mask, contact tracing, personal hygiene (hand washing with soap and
uses of hand sanitizers), and avoiding the touching of faces [11]. As a result of these
shortcomings in developing a cure or vaccine, mathematicians, biologist, modelers
and other scientists around the world have come together to perform experiments to
develop novel mathematical, computational and statistical models to forecast and to
curb the novel coronavirus disease pandemic [11]. Such forecasts have far-reaching
effects on how rapidly and vigorously policy makers are working to curb the coro-
navirus by implementing non-pharmaceuticals measures. This non-pharmaceutical
measures: total lockdowns; social distancing; self-isolation; quarantine; wearing of
different types of face masks; using hand sanitizers; wearing protective hand gears
like glove; and travel restrictions, have become necessities, because the novel coro-
navirus was discovered to have different and multiple transmission pathways that
include animals-to-human, environment-to-human, and human-to-human transmis-
sion pathways. The endemic new human coronavirus can persist on inanimate sur-
faces like metal, glass or plastic, for up to 9 days and an infected individual might
not be aware of infection as the incubation period takes about 14days for symptoms
to show and it can jump from animals to humans [12]. Hence, [11, 13] develop a
compartmental model for investigating the community-wide impact of face mask use
by the general, asymptomatic public, a portion of which may be asymptomatically
infectious. Their results show that wearing face mask, either the cloth or surgical
mask, as a non- pharmaceutical intervention, limit the spread of the COVID-19 pan-
demic by reducing the transmission rate. These have been evidenced in the policy
implementation for reducing the spread of the virus. A mathematical assessment
for studying the transmission dynamics and control of the COVID-19 pandemic in
the United States, and several other epicenter locations around the world, was per-
formed by Ngonghala et al. [8]. Their model is in the form of a Kermack-McKendrick
compartmental, deterministic system of nonlinear differential equations. They incor-
porated features pertinent to COVID-19 transmission dynamics and control, such as
the quarantine of suspected cases, isolation/hospitalization of confirmed COVID-19
cases, the implementation of self-quarantine, self-isolation, contact-tracing, social-
distancing, and the use of face-masks in public. Liu et al. [14] estimated the role
of the exposed classes (people who are not yet infectious) or in the latency period
(that is, the period of time in which newly infected individuals are asymptomatic and
non-infectious) in the dynamics of a COVID-19 epidemic
Stutt et al. [15] presented a simple agent-based modeling and SIR compartment
model framework to observe the effect of wearing face-mask on the dynamics of
COVID-19 epidemic during the lockdown. Their model involved scaling from indi-
vidual behavior to the level of populations to enable conclusions to be drawn about
the effectiveness of wearing face-masks to reduce the spread of SARS-CoV-2. Their
results show that strict compliance to using face mask in public, combined with lock-
down, will reduce and possibly eliminate the coronavirus disease. This is evident in
the reduction of coronavirus cases in some countries in Europe and Asia, where strict
laws and punishment are put in place for violators. Ndaïrou et al. [12] considered
the effect of super-spreader or asymptomatic individuals in the human-to-human
transmission of the dynamics of the novel virus. They also made known the fact
that different mathematical models and computer simulations have been developed
that have aided the planning and mobilization of huge resources to curb the impact
of COVID-19 in some countries. Their study reported that the early detection of
asymptomatic individuals and super-spreaders (mostly the young and vibrant youth,
who love to party, and who go all the way out to have fun in places like beaches),
their self-isolation, and social distancing would reduce the spread of the virus. How-
ever, these individuals need to be aware of their roles in the spread of the disease,
so that they can take necessary preventive measures to protect not only themselves,
but others around them. Adeniyi et al. [2], discussed personal hygiene and educa-
tional program as effective public health intervention. Scholars, in response to the
speedy spread of COVID-19 and the effects on humans, suggest awareness creation
as the most effective and efficient way to avert and reduce the transmission of the
COVID-19 virus. That is, getting people informed about how it spreads and how to
protect themselves and others from getting infected, such as by washing their hands
frequently, using alcohol-based sanitizer, and ensuring both environmental and per-
sonal hygiene. It is essential to reduce the spread of COVID-19, and this can be
done by advising patients with mild symptoms to stay back home, and that workers,
where possible,should telecommute, rather than being mandated to be physically
present at work or be laid off. People who have been exposed should get tested
and stay in quarantine for about two weeks. Given the wide spread of COVID-19,
governments have had to impose quarantines and travel bans. For instance, China
locked down whole cities, Italy imposed draconian restrictions, and in the United
States, thousands of people have been subjected to legally enforced quarantines,
or are in self-quarantine [7, 8]. Several published peer-reviewed articles have dis-
cussed the importance of optimal control strategies, using Pontryagin’s Maximum
principle of variants SIR models and various control variables, such as quarantine,
isolation [16], social distancing [17], contact rate, transmission rate of symptomatic
infected individuals [18], minimizing the number of exposed and infected individu-
als, and considering the cost of implementation [19], through a genetic algorithm (or
a multi-objective evolutionary algorithm). Early implementations of these optimal
and suboptimal control strategies have been proven to mitigate the dynamic spread
of the pandemic and could possibly lead to elimination, if there is strict compliance
to the aforementioned controls [20, 21].
Zamir et al. [22] also considered the non-pharmaceutical interventions for optimal
control of COVID-19, using four control variables in the transmission parameters,
which are the transmission probability of the infection from the infected human to
the susceptible human, case detection period, the life span of the virus, and con-
tact with non-living contaminated items. Their sensitivity test of the reproduction
number shows that none of the parameters have got the dominant role in the disease
transmission [23, 24]. However, the efforts to abate the spread and transmission of
COVID-19 did not reduce the number of infected cases and deaths. This implies that
travel bans and restriction, (self) isolation, social distancing, sanitizing, nose mask
and mandatory quarantine are not enough. This leads to the questions: what will be
the impact of school reopening? Should we return to work or not? What will be the
cost incurred and its effectiveness? Will our big meetings be free again? Are things
going back to normal soon? What will be the impact of a possible second wave when
schools finally reopen and there are spikes? Will social gathering become impossible
should spike and surge go beyond measure? Will the government impose strict rules
and regulations, such as a second lockdown? Will cameras be installed everywhere
to ensure strict law abiding? And where do we go from here? These are the questions
we hope to investigate in this chapter, by accessing the impact of public compliance
on the use of non-pharmaceutical intervention with cost-effectiveness analysis on the
transmission dynamics of Coronavirus, using insights from mathematical modeling
[5, 7, 24, 25].
In existing literature, the interaction between humans and the coronavirus has not
been fully studied. Most works on COVID-19 have focused on the heterogeneity of
human population. The cost of controlling the current pandemic is overwhelming,
especially in poor nations; thus, it is important to carry out epidemiological studies on
the dynamics of human-coronavirus, with a view to suggesting possible cost-effective
controls.
The review of literature has established that COVID-19 is a transmission disease
caused by a novel coronavirus. The virus can be transmitted from virus to human
and from human to human, and the rate of transmission of the virus can be reduced
if humans comply to Center for Disease Control (CDC) and WHO regulations. It
can be deduced that the higher the rate of compliance by humans, the lower the
transmission rate and the higher the mortality rate of the virus. We note that the
major concern about the pandemic is the rate at which it is transmitted from one
person to another and that there are no pharmaceutical interventions for the cure
of the disease as at the time of writing this chapter. However, the CDC and WHO
have identified the modes of transmission and have recommended different control
strategies, in order to reduce the virus population and transmission rate. Thus, our
main research question is “What rate of compliance can reduce the virus population
and transmission rate to zero?” Expectedly, this will attract some costs. So, we opined
that the cost effectiveness of the process will need to be modeled.
We acknowledge that many scholars have tried to contribute to this subject in
diverse ways, leading to the development of different mathematical and statistical
models on how the spread of COVID-19 can be contained, and/or eliminated. Dif-
ferent control strategies have also been identified by various researchers, and early
detection and implementation of these control strategies have been reported to have
very significant effects in curbing and mitigating the spread of COVID-19 pandemic
[14]. Stutt et al. [15] revealed that strict compliance to the use of face mask in public,
combined with lockdown, will reduce the number of cases and possibly eliminate the
coronavirus disease. However, none of these authors have actually considered com-
pliance combined with cost effectiveness as means of reducing the virus population
and transmission rate. This is the gap our study sought to fill.
Premised on the submissions above, in this chapter, we developed a mathemat-

ical model with both human and virus populations to access the impact of public
compliance on the use of non-pharmaceutical Intervention, with cost-effectiveness
analysis on the transmission dynamics of COVID-19. Also modeled was compliance
parameter to control the mortality and transmission rates of the virus. Real life data
were collected from the CDC of selected countries on COVID-19 pandemic. The
parameters of the models were estimated using the least square estimation method,
a statistical technique. The necessary tests, such as positivity of solutions, bound-
edness, equilibrium analysis, stability analysis, global sensitivity analysis, optimal
control theory, and cost-effectiveness were carried out on the formulated model. Dif-
ferent plots of the real data and simulated data are displayed to aid the understanding
of the model.
The rest of the chapter is organized as follows: Sect. 2 contains the mathemati-
cal formulation; Sect. 3 positivity of solutions, boundedness, equilibrium analysis,
stability analysis, statistical parameter estimation from COVID-19 data, and global
sensitivity analysis; Sect. 4 contains optimal control theory and cost-effectiveness
analysis; and in Sect. 5, we present the numerical simulation, model fitting, and dis-
cussions. The conclusion of the study is discussed in Sect. 6, while Sect. 7 contains
the appendix.
2 Mathematical Formulation
We assume that the population of interest is homogeneously mixed and that the
spread of coronavirus disease can be acquired through
1. direct contact between susceptible human and infected individual
2. indirect contact between susceptible individual and coronavirus in the environ-
ment.
Let us denote the total human population at a given time t by N (t) which is further sub-
divided into susceptible population S(t), infected population I (t) while the density
of the virus population at time t is C(t). For clarity, we shall drop the t dependency
from this point on. For example, when we write S, it is taken to be a function and
not a class, in general.
Further assumption is that all susceptible humans S in the environment can be
infected by virus population with no permanent immunity to the virus infection.
Susceptible individuals are recruited into the population at the rate and humans
die naturally at the rate μ. Since there is no permanent immunity conferred on humans
due to the virus infections, recovered infected individual progress to the susceptible
class at the rate γ while death due to the disease occur at a rate σ. Direct or indirect
contact between susceptible individual with an infected human or virus is assumed
to decrease at a factor
βh (α) = βmax − α(βmax − βmin ), βc (α) = ηmax − α(ηmax − ηmin )

for humans and virus respectively, where α, (0 < α < 1) is the parameter accounting
for the compliance rate on polices to control the disease, βmax and βmin are the
maximum and minimum transmission rate from an infected person to a susceptible
human respectively, while the maximum and minimum rate of transmission of the
disease from cirus to humans are ηmax and ηmin respectively. The force of infection
due to the interaction of susceptible with infected human directed by λ(α) = βh (α)I
while the force of infection as a result of the contact between the susceptible and
virus shed in the environment is η(α) = βc (α)C. The natural death rate of the virus
is assumed to be δ1 . The mortality rate of the virus is further increased through
sanitation (i.e cleaning of surfaces with sanitizers, fumigation of mall, public places
et cetra. with chemicals lethal to the virus) at a rate δ2 , so that the total death rate
of the virus is φ3 = δ1 + δ2 . The virus self growth rate is assumed to be φ2 . Further,
we assume that φ3 > φ2 . The virus growth rate due to increase in infected individual
is given as φ1 . In view of the foregoing, the dynamics of the model is driven by a
system of non-linear differential equations.
⎧
⎪
⎨S (t) = − λ(α)S − η(α)S − μS + γI ,
I (t) = λ(α)S + η(α)S − (μ + σ + γ) I , (2.1)
⎪
⎩
C (t) = φ1 I + φ2 C − φ3 C
where ⎧
⎪
⎪ λ(α) = βh (α)I ,
⎪
⎨η(α) = β (α)C,
c
(2.2)
⎪
⎪ β (α) = β max − (α)(βmax − βmin ),
⎪
⎩
h
βc (α) = ηmax − (α)(ηmax − ηmin )
and 0 ≤ α ≤ 1 (Table 1).
Table 1 Symbols and parameters used in model

Parameter Symbol
Recruitment rate
Parameter accounting for compliance α
Natural death rate of humans μ
Recovery rate γ
Covid-19 induce death rate σ
Growth rate of virus due to increase in infected φ1
individuals
Self growth rate of the virus φ2
Total death rate of virus φ3
3 Positivity of Solutions and Boundedness
Model System (2.1) is epidemiological meaningful and feasible if all the variables of
the model system are non-negative for all time t. We show this through the following
lemma:
Lemma 1 The solution of the model system (2.1), S(t), I (t), and C(t) with initial
conditions S(0) = S0 > 0, I (0) = I0 ≥ 0 and C(0) = C0 ≥ 0 are positive for all
time t > 0.
Now, it is sufficient to consider model system (2.1) in detail in the region of the
attraction [7] given by

= {(S, I , C) ∈ R3+ : S + I ≤ , C ≤ Cm } (3.1)
μ
where Cm = μ(φφ31−φ

2)
and its attracts all solutions originating in the interior of positive
invariant. The proof of the positivity of the solutions and boundedness is provided
in the Appendix (7.1 and 7.2).
3.1 Equilibrium Analysis
We next discuss the qualitative behavior of the equilibrium points of the model
system (2.1) using stability theory of differential equations to study in detail the long
term of Covid-19 disease dynamics and possible control strategies [26, 27]. Suppose
the model system is at equilibrium, three feasible equilibrium points are obtained
namely:
1. The compliance-free endemic equilibrium P1 = (S1∗ , I1∗ , C1∗ ). This equilibrium
exists for R0 > 1
2. The disease- free equilibrium P0 = ( μ , 0, 0)
3. The endemic equilibrium P ∗ = (S ∗ , I ∗ , C ∗ ) This equilibrium is feasible if Rα >
1
where
R0 = R0d + R0c
βmax φ1 ηmax
= +
μ(γ + σ + μ) μ(φ3 − φ2 )(γ + σ + μ)
Rα = Rαd + Rαc
βh (α) φ1 βc (α)
= +
μ(γ + σ + μ) μ(φ3 − φ2 )(γ + σ + μ)
Remark 1 R0 is a quantity called the basic reproduction number in the absence of

compliance. It is defined as the average number of secondary infected persons pro-
duced by a single infected individual due to direct contact as well as indirectly through
COVID-19 virus during his/her entire period of infection in a population containing
only susceptible individuals [9, 10]. In epidemiology, the basic reproduction number
R0 is an important threshold to predict whether a disease dies out or persist in the
population. Further, if R0 < 1 (or R0 > 1), then on average an infected individual will
produce less than ( or more than) one secondary infected persons during his or her
entire infections period in a wholly susceptible population and thus the disease will be
eradicated (or persist ) in the population respectively. R0 = R0d + R0c represent the
dynamic of the model with immigration when COVID-19 disease is transmitted in the
population through direct contact or indirect contact in the absence of compliance. In
the presence of compliance, the basic reproduction number R0 = R0d + R0c is mod-
ified to effective basic reproduction number. Rα = Rαd + Rαc such that Rα < R0 ,
which implies that the presence of compliance in the population lowers the covid-19
pandemic threshold and reduces the infection risk by susceptible individuals . We
state here that the effective basic reproduction number Rα is obtained by using the
next generation matrix method [9, 26]. The detail of the derivations is provided in
the Appendix (7.3).
3.2 Feasibility of Equilibrium Points
Without loss of generality, the feasibility of any equilibrium P = (S, I , C) of model

system (2.1) is considered by setting the derivatives of (2.1) to zero at equilibrium
to obtain the sets of algebraic equations:
⎧
⎪
⎨ − βh (α)IS − βc (α)CS − μS + γI = 0,
βh IS + βc (α)CS − (μ + σ + γ) I = 0, (3.2)
⎪
⎩
φ1 I + φ 2 C − φ 3 C = 0
from the third equation of (3.2), we have
φ1 I
C= , φ3 > φ2 (3.3)
φ3 − φ2
using (3.3) in the first equation of (3.2), and making S the subject, we obtain
φ3 − φ2 ( + γI )
S= (3.4)
[(φ3 − φ2 )βh (α) + φ1 βc (α)]I + μ(φ3 − φ2 )
taking into account (3.3) and (3.4) in second equation of (3.2), we have

G(I ) = (φ3 − φ2 )βh (α) + φ1 βc (α) − μ(γ + σ + μ)(φ3 − φ2 )

− (σ + μ) (φ3 − φ2 )βh (α) + φ1 βc (α) I = 0 (3.5)
It is easy to verify from (3.5) that
1.
G(0) = [(φ3 − φ2 )βh (α) + φ1 βc (α)] − μ(γ + σ + μ)(φ3 − φ2 ),

G(0) = μ(γ + σ + μ)(φ3 − φ2 ) +
μ(γ + σ + μ) μ(γ + σ + μ)(φ3 − φ2 )
G(0) = μ(γ + σ + μ)(φ3 − φ2 )(Rα − 1)
if Rα > 1
2.

G = −μ(γ + σ + μ)(φ3 − φ2 ) < 0
σ+μ
3.

G (I ) = (σ + μ) (φ3 − φ2 )βh (α) + φ1 βc (α) < 0

Thus, G(I ) = 0 in (3.5) has a unique positive root in (0, σ+μ ) i.e
μ(γ + σ + μ)(φ3 − φ2 )(Rα − 1) (Rα − 1)

I = I∗ = = (3.6)
(σ + μ)[(φ3 − φ2 )βh (α) + φ1 βc (α)] (σ + μ)Rα
Thus from (3.4) and (3.3), we have
(φ3 − φ2 )( + γI ∗ )
S = S∗ = ∗
= (3.7)
[(φ3 − φ2 )βh (α) + φ1 βc (α)]I + μ(φ3 − φ2 ) μRα
φ1 I ∗ φα (Rα − 1)
C= = (3.8)
φ3 − φ2 (σ + μ)(φ3 − φ2 )Rα
If R1 = 1, yield the disease-free equilibrium, P0 . It

is important to note that if

Rα < 1, Eq. (3.5) has no positive solution in 0, σ+μ . Therefore, the equilibrium
P = (S, I , C) = (S ∗ , I ∗ , C ∗ ) is feasible if Rα > 1.
Remark 2 From the third equation of (2.2) and Eq. (3.6), clearly d βdhα(α) < 0 and
dI ∗
βh (α)
< 0. This implies that the equilibrium number of infected individuals decreases
as the rate of contact with uninfected individuals decreases due to increase in public
compliance to rules put in place by government and bodies in-charge of health. Fur-
∗
ther, it is also observed that d βdcα(α) < 0 and βdI
c (α)
< 0 indicating that the equilibrium
number of infected individual via contact with the virus decreases as the contact rate
between humans and virus decreases due to increase in general public compliance
(α).
3.3 Stability Analysis
In this section, the local stability of equilibrium P0 , P1 , and P ∗ are considered by

determining the sign of real part of the eigenvalues of the Jacobian matrix of system
(2.1) evaluated at P0 , P1 , and P ∗ respectively. In the following, the local stability
conditions for equilibrium point Pi ; (i = 0, 1) and P ∗ are presented. First, we obtain
the Jacobian matrix of the system (2.1) at any equilibrium P ∗ = (S ∗ , I ∗ , C ∗ ) as
follows ⎛ ⎞
ρ11 ρ12 ρ13
J (P) = ⎝ ρ21 ρ22 ρ23 ⎠ (3.9)
0 φ1 −(φ3 − φ2 )
where:
ρ11 = −βh (α)I − βc (α) − μ

ρ12 = γ − βh (α)S
ρ13 = −βc (α)S
ρ21 = βh (α)I + βc (α)
ρ22 = βh (α)S − (γ + σ + μ)
ρ23 = βc (α)S
3.4 Local Stability of P0
It is easy to convert the matrix in (3.9) at P0 to an upper triangular matrix to get

⎛ ⎞
−μ γ − β(α)
μ − βμc (α)
⎜ φ1 βc (α) β(α) ⎟
J (P0 ) = ⎝ 0 (γ + σ + μ)[Rα − 1 − μ(φ −φ ] ⎠
3 2 )(γ+σ+μ) μ
0 0 (φ3 − φ2 )(γ + σ + μ)(Rα − 1)
(3.10)

Then, the eigenvalues of (3.10) are λ1 = −μ, λ2 = (γ + σ + μ) Rα − 1 −

φ1 βc (α)
μ(φ3 −φ2 )(γ+σ+μ)
= Rα − 1 − Rαc , λ3 = (φ3 − φ2 )(γ + σ + μ)(Rα − 1). In par-
ticular, λ1 and λ2 are real and negative if Rα < 1. Thus, the disease-free equilibrium
P0 of the model system (2.1) is feasible and locally asymptotically stable if Rα < 1.
Further, P0 is locally unstable if Rα > 1 whenever the equilibrium P ∗ is feasible.
3.5 Local Stability of P1
It is easy to write the matrix in (3.9) evaluated at P1 as an upper triangular matrix as

follows:
⎛ ⎞
p11 p12 p13
J (P1 ) = ⎝ 0 p22 p11 − p12 p21 p23 p11 − p13 p21 ⎠
0 0 −[(φ3 − φ2 )(p22 p11 − p12 p21 + φ1 p23 p11 − p13 p21 )]
(3.11)
where:
−μ(γ + σ + μ)(R0 − 1)
p11 = −μ
σ+μ
βmaxc
p12 =γ−
μR0
μ(γ + σ + μ)(R0 − 1)
p13 =
σ+μ
p21 = βh (α)I + βc (α)
βmaxc
p22 = − (γ + σ + μ)
μR0
ηmaxc
p23 =
μR0
It is straight forward to see that the eigenvalues of (3.11) are λ1 = p11 < 0 if
R0 > 1, λ2 = p22 p11 − p12 p21 and λ3 = −[(φ3 − φ2 )(p22 p11 − p12 p21 + φ1 p23 p11 −
p13 p21 )].

Now, λ2 = −μ(γ+σ+μ)
(σ+μ)
R0d
R0
− 1 (γ + σ + μ)R0 − γ − μ(γ+σ+μ)γ(R0 −1)
(σ+μ)
1−

(γ+σ+μ)R0d
γR0
= μ(γ + σ + μ) R0d
R0
− R 0 > 0 if R0 > 1. Further, λ3 = −(φ3 − φ2 )
φ1 ηmaxc (φ3 −φ2 )μ(γ+σ+μ)R0d
μ(γ + σ + μ)( RR0d0 − R0 ) + R0
= R0
> 0.
Thus two eigenvalues of J (P1 ) are positive if R0 > 1 and the remaining one
eigenvalue is negative for R0 > 1. Thus, the compliance-free endemic equilibrium
P1 is locally unstable with unstable manifold locally in I − C space and locally stable
manifold in S direction.
3.6 Local Stability of P ∗
In other to investigate the local stability analysis of the model endemic equilibrium
P ∗ , we consider the following Jacobian matrix of model system (2.1) written as
⎛
⎞
p11 p12 p13
J (P ) = ⎝ 0 p22

p23 ⎠ (3.12)
0 0 −(φ3 − φ2 )
where:
μ(γ + σ + μ)(R1 − 1)
p11 =− −μ
(σ + μ)
βh (α)
p12 =γ−
μR1
βc (α)
p13 =−
μR1
βh (α)
p22 = − (γ + σ + μ)
μR1
βc (α)
p23 =
μR1
so that the eigenvalues λ∗1 = P11

∗
, λ∗2 = P22
∗
and λ∗3 = −(φ3 − φ2 ) are all real and
negative if Rα > 1. Thus, the endemic equilibrium P ∗ is locally asymptotically stable
if Rα > 1 otherwise unstable.
3.7 Global Stability of P0 and P ∗
In the following section, the global stability analysis of the disease-free equilib-
rium P0 and Covid-19 endemic equilibrium P ∗ are considered using Lyapunov’s
direct method by constructing a suitable scalar-valued function called the Lyapunov
function.
3.8 Global Stability of P0
From the model system (2.1), we have

I = βh (α)IS + βc (α)CS + (γ + σ + μ)I = f1 ,
(3.13)
C = φ1 I − (φ3 − φ2 )C = f2 ,
considering a Lyapunov function defined as follows:
βc (α)C
L(I , C) = I + (3.14)
μ(φ3 − φ2 )
since L(I , C) > 0 for all I , C > 0 and so we obtain using (3.13)
βc (α)f2
L (I , C) = f1 + (3.15)
μ(φ3 − φ2 )
φ1 βc (α) (φ3 − φ2 )βc (α)

= βh (α)S + − (γ + σ + μ) I + βc (α)S − C
μ(φ3 − φ2 ) μ(φ3 − φ2 )
(3.16)
so that at disease free equilibrium S = μ , then

L (I , C) = (γ + σ + μ) + −1 I
μ(γ + σ + μ) μ(φ3 − φ2 )(γ + σ + μ)
(3.17)

L (I , C) = (γ + σ + μ)(Rα − 1)I ≤ 0 if R1 ≤ 1 (3.18)
3.9 Global Stability of P ∗
Consider a suitable scalar-valued positive definite function of system (2.1) about the
endemic equilibrium P ∗ .
S I
G(S, I , C) = S − S ∗ − S ∗ ln + I − I ∗
− I ∗
ln
S∗ I∗
C
+ m(C − C ∗ − C ∗ ln ) (3.19)
C∗
where m is to be carefully chosen. The time derivative of (3.19) yields

S I C∗
G(S, I , C) = S − S ∗ − I − I ∗ + mC − m C (3.20)
S I C
making use of (2.1) in (3.20), we obtain

G = − βh IS − βc CS − μS + μS + γI
S∗
− [ − βh IS − βc CS − μS + μS + γI ]
S
+ βh IS + βc CS − (γ + σ + μ)I
I∗
− [βh IS + βc CS − (γ + σ + μ)I ]
I
mC ∗
+ m[φ1 I − (φ3 − φ2 )C] − [φ1 I − (φ3 − φ2 )C] (3.21)
C
If we choose at equilibrium,
⎧ ∗ ∗
⎪
⎪m = βcφC1 I ∗S ,
⎪
⎨ + γI = β I ∗ S ∗ + β C ∗ S ∗ + μS ∗ ,
h c
βc C ∗ S ∗ (3.22)
⎪
⎪(γ + σ + μ) = β S ∗
+
⎪
⎩ ∗
h I∗
(φ3 − φ2 ) = φC1 I∗
By substituting (3.22) into (3.21) and rearranging the terms, we obtain
βh I ∗ S ∗2 βc C ∗ S ∗2 μS ∗2
G = 2βh I ∗ S ∗ + 3βc C ∗ S ∗ + 2μS ∗ − μS − − −
S S S
βc I ∗ CS βC IC ∗2 S ∗
− βh I ∗ S − − (3.23)
I I ∗C
Therefore,

∗ ∗S∗ S ∗ ∗ S∗ I∗ C S C∗ I ∗
G = βh I S 2 − − ∗ + βc C S 3 − − −
S S S I C∗ S∗ C I

∗
S S
+ μS ∗ 2 − ∗ − (3.24)
S S
By applying the arithmetic mean-geometric mean (AM-GM) relationship namely:

AM ≥ GM i.e
a1 + a2 + · · · + an √
AM = ≥ n a1 a2 . . . an = GM (3.25)
n
if (3.25) holds, we can have
⎧
∗ ∗ S∗
⎪
⎨βh (α)I S (2 − S − S ∗ ) ≤ 0
S
∗ ∗ S∗ ∗
C∗ I
βc (α)C S (3 − S − II ) CC∗ SS∗ − ≤0 (3.26)
⎪
⎩ ∗ ∗
C I∗
μS (2 − SS∗ − SS ) ≤ 0

In view of (3.26), we have that G (S, I , C) ≤ 0,
3.10 Statistical Parameter Estimation from COVID-19 Data
All the parameters are estimated from COVID-19 data and online demographic data.
3.11 Global Sensitivity Analysis
Global sensitivity analysis allows other parameters to vary as the effect of a certain
parameter is estimated, unlike local sensitivity analysis, applying ranges and baseline
values in Table 2 (confidence interval), the partial rank correlation coefficient (PRCC)
of the model parameters were computed and presented in Fig. 1a. Parameters were
sampled and input using Latin Hypercube Sampling (LHS) method [26, 28] (a valid
Table 2 Parameter estimates

Parameter Symbol Estimate Range Ref.
Recruitment rate 6799 (500, 19700) Demographic data
Parameter accounting for α 0.6496 (0.3969, 0.9022) Estimated from COVID-19
compliance data
Natural death rate of μ 0.0163 (0.0135, 0.0191) Demographic data
humans
Recovery rate γ 0.6754 (0.3137, 0.9371) Estimated from COVID-19
data
Covid-19 induce death rate σ 0.0252 (0.0026, 0.0578) Estimated from COVID-19
data
Growth rate of virus due to φ1 0.2994 (0.0281, 0.6707) Estimated from COVID-19
increase in infected data
individuals
Self growth rate of the φ2 0.6969 (0.2924, 0.9400) Estimated from COVID-19
virus data
Total death rate of virus φ3 0.7468 (0.4851, 0.9600) Estimated from COVID-19
data
Minimum rate of ηmin 0.00000005 (0, 0.00000014) Estimated from human
transmission of the disease population
from virus to humans
Maximum rate of ηmax 0.00000456 (0, 0.00001423) Estimated from human
transmission of the disease population
from virus to humans
Minimum transmission βmin 0.00000005 (0, 0.00000014) Estimated from human
rate from an infected population
person to a susceptible
human
Maximum transmission βmax 0.00000456 (0, 0.00001423) Estimated from human
rate from an infected population
person to a susceptible
human
1.0
0.5
PRCC
0.0
−0.5
−1.0 γ
Λ beta_Max μ σ eta_Max phi_1 phi_2 phi_3
Parameters
Fig. 1 Partial Rank Correlation Coefficient (PRCC) plots of the various parameters of the COVID-
19 model (2.1), using R0 as the output function with value in Table 2, see Appendix 7.4 for the
analysis
statistical method for generating a sample of collections of parameter values from a

multidimensional distribution), and a total of 1000 simulations were ran.
The parameter baseline values in Table 2 were varied in the range of 25%.
Figure 1a, displays a tornado plot of PRCCs plotted against the homogeneous param-
eter value with R0 as the baseline dependent variable. The parameter which are sig-
nificantly positively correlated with COVID-19, at p < 0.05 level of significance,
are , βmax , ηmax , φ1 and φ2 while μ, γ, σ, and φ3 are significantly negatively corre-
lated. The effective contact rate β, progression rates to infected class θ, probability
of getting infected from susceptible must be reduce and enforcement of compliance
to the social-distancing ( wearing of face-mask, through hand-washing, etc)
The recruitment rate is estimated from birth rate per day of each country,
collected from demographic online resources. The parameter accounting for compli-
ance, α is directly proportional to the difference between recovery rate and mortality
rate. The wider the difference, the greater the rate of compliance. Natural death rate of
humans, μ is the multiplicative inverse of life expectancy, which can be gotten from
demographic data. COVID-19 recovery rate, γ is the ratio of COVID-19 recovery
to COVID-19 laboratory confirmed cases. COVID-19 induced death rate, σ is is the
ratio of COVID-19 induced deaths to COVID-19 laboratory confirmed cases. The
growth rate of virus due to increase in infected individuals, φ1 is directly proportional
to COVID-19 active cases and varies from country to country. Self growth rate of the
virus, φ2 is estimated from the relationship between φ1 and φ3 , where φ3 is the total
death rate of the virus. It is assumed that virus dies naturally after 14 days and dies
when individuals recovered from COVID-19. So, φ1 , φ2 and φ3 vary from country
to country. The virus population is more than infected human population. The virus
can be found on infected humans and in the environment/infected surfaces. Thus, the
population of the virus in any geographical location is greater than the population of
infected humans in that location.
Fig. 2 Partial Rank Correlation Coefficient (PRCC) plots of the various parameters of the COVID-
19 model (2.1), using effective reproduction R0 as the output function with value in Table 2
The effective reproduction number shows the effect of control parameters on the
basic reproduction number. The partial rank correlation coefficient (PRCC) plot in
Fig. 2b shows that the effective reproduction number, R0 , is positively correlated
to recruitment rate (), maximum transmission rate from an infected person to a
susceptible human (βmax ), maximum rate of transmission of the disease from virus
to humans (ηmax ), growth rate of virus due to increase in infected individuals (φ1 ),
self growth rate of the virus (φ2 ), while R0 is negatively correlated with minimum
transmission rate from an infected person to a susceptible human (βmin ), natural death
rate of humans (μ), recovery rate (γ), Covid-19 induce death rate (σ), minimum rate
of transmission of the disease from virus to humans (ηmin ), natural death rate of virus
φ3 and parameter accounting for compliance (α).
This implies that the higher the recruitment rate (), maximum transmission rate
from an infected person to a susceptible human (βmax ), maximum rate of transmission
of the disease from virus to humans (ηmax ), growth rate of virus due to increase in
infected individuals (φ1 ), self growth rate of the virus (φ2 ), the higher the effective
reproduction number, and the more possibility of spreading the virus. So, for the
spread of the virus to reduce effectively and drastically, then all hands must be on
deck to increase recovery rate (γ), natural death rate of virus φ3 and parameter
accounting for compliance (α). When individuals comply, COVID-19 population
will reduce asymptotically. Also, we have to minimize transmission rate from an
infected person to a susceptible human (βmin ), make sure that death of human is not
dependent on COVID-19, minimize rate of transmission of the disease from virus to
humans (ηmin ).
4 Optimal Control Theory and Cost-Effectiveness Analysis
This section employs the Pontryagin’s Maximum Principle to define the essential
conditions for the optimal control of the Covid-19 model. We include time-dependent
controls into the model to find out the optimal strategy to curtail the spread of the
virus [21, 26, 29]. Thus, we have
⎧
⎪
⎪
dS
= − (βmax − u1 (t)(βmax − βmin )SI − CS(ηmax − u1 (t)(ηmax − ηmin )
⎪
⎪ dt
⎪
⎪ −μS + γIu1 (t)),
⎨
dI
= (βmax − u1 (t)(βmax − βmin )SI + CS(ηmax − u1 (t)(ηmax − ηmin )
⎪
⎪
dt
⎪
⎪ −(γ + σ + μ)I ,
⎪
⎪
⎩ dC = φ I + φ C − (δ + u (t))C
dt 1 2 1 2
(4.1)
with
⎧
⎪
⎪ λ(α) = βh (α)I ,
⎪
⎨η(α) = β (α)C,
c
(4.2)
⎪
⎪ β (α) = β max − (α)(βmax − βmin ),
⎪
⎩
h
βc (α) = ηmax − (α)(ηmax − ηmin )
and 0 ≤ α ≤ 1.
The control functions, u1 (t) and u2 (t) are bounded, Lebesgue integrable func-
tions. The control u1 (t) represents the compliance to non-pharmaceutical therapy
such as: effective use of face mask, hand-sanitizer, physical distancing etc to pre-
vent Covid-19. Fumigation of the environment against Covid-19 is denoted by u2 (t).
The controls u1 (t),and u2 (t) satisfies 0 ≤ u1 , u2 ≤ 1. Our optimal control problem
involves a scenario where the number of infected, coronavirus, and the cost of imple-
menting preventive and non-pharmaceuticals treatment controls u1 (t) and u2 (t) are
minimized subject to the state system (4.1). For this, we consider the objective func-
tional
Tf
∗ ∗ b1 b2
J (u1 , u2 ) = [I (t)A1 + C(t)A2 + u12 + u22 ]dt (4.3)
2 2
0
where Tf is the final time. We seek to find an optimal control, u1∗ (t) and u2∗ (t) such
that
J (u1∗ , u2∗ ) = min{J (u1∗ , u2∗ )|u1∗ , u2∗ ∈ U } (4.4)
where U = {(u1∗ , u2∗ )} such that u1∗ , u2∗ are measurable with 0 ≤ u1∗ , u2∗ ≤ 1 for t ∈
[0, Tf ] is the control set. The Pontryagin’s Maximum Principle [27, 30, 31]gives
the necessary conditions which an optimal control pair must satisfy. This principle
Table 3 Parameter estimated by country

Parameter Nigeria South Egypt Kenya CAR Estimate Stdev. Max. Min.
Africa
19607 3017 7839 2995 535 6799 7635 19700 500
α 0.7611 0.8546 0.6914 0.5741 0.3668 0.6496 0.1883 0.9022 0.3969
μ 0.0182 0.0156 0.0139 0.0150 0.0187 0.0163 0.0021 0.0191 0.0135
δ 0.7799 0.8799 0.7461 0.5909 0.3800 0.6754 0.1950 0.9371 0.3137
σ 0.0188 0.0224 0.0548 0.0169 0.0132 0.0252 0.0169 0.0578 0.0026
φ1 0.2013 0.0976 0.1991 0.3922 0.6069 0.2994 0.2022 0.6707 0.0281
φ2 0.8178 0.9351 0.7844 0.5970 0.3502 0.6969 0.2287 0.9400 0.2924
φ3 0.8513 0.9513 0.8176 0.6624 0.4514 0.7468 0.1950 0. 9600 0.4851
transforms(the last three equations) into a problem of minimizing a Hamiltonian, H,

point-wisely with regards to the control functions u1 (t) and u2 (t) .

H (S, I , C, u1 , u2 , θi ) = L(S, I , C, u1 , u2 ) + θ1 S + θ2 I + θ3 C
⎧
⎪
⎪ H (S, I , C, u1 , u2 , θi ) = I (t)A1 + C(t)A2 + b21 u12 + b2 2
u
⎪
⎪
2 2
⎪
⎪ +θ1 [ − (βmax − u1 (t)(βmax − βmin )SI
⎪
⎪
⎨−CS(η − u (t)(η − η ) − μS + γIu (t))]
max 1 max min 1
(4.5)
⎪
⎪ +θ [(β − u (t)(β − β )SI
⎪
⎪
2 max 1 max min
⎪
⎪ +CS(η − (t)(η − η )) − (γ + σ + μ)I ]
⎪
⎪ max u 1 max min
⎩
+θ3 [φ1 I + φ2 C − (δ1 + u2 )C]
Theorem 1 For an Optimal control set u1 , u2 that minimizes J over U , there are
adjoint variables θ1 , θ2 , θ3 satisfying
∂θi ∂H
− = (4.6)
∂t ∂ui
and with transversality conditions θi (tf ) = 0 where i = 1, 2, 3. Furthermore,

u1∗ = max{0, min(1, θ2b−θ 1
(2k1 SI − 2CSk2 )
∗ θ3 C
1
(4.7)
u2 = max{0, min(1, b2 )}
where:
k1 = βmax − βmin and k2 = ηmax − ηmin
Proof of Theorem Suppose U ∗ = (u1∗ , u2∗ ) is an optimal control and S ∗ , I ∗ , C ∗ are

the corresponding state solutions. Applying the Pontraygin’s Maximum Principle
[27], there exists adjoint variables satisfying:
Cumulative COVID−19 Cases Daily COVID−19 Cases

50000 Nigeria Nigeria
No. of Persons
South Africa South Africa

Egypt Egypt
No. of Persons
600
Kenya Kenya
CAR CAR
20000
0 200
0
0 50 100 150 0 50 100 150

Time (in days) Time (in days)
Cumulative COVID−19 Mortality Daily COVID−19 Mortality

Nigeria Nigeria
10 20 30 40
South Africa South Africa
800
No. of Persons
No. of Persons
Egypt Egypt
Kenya Kenya
CAR CAR
400
0
0 50 100 150 0 50 100 150

Time (in days) Time (in days)
Fig. 3 COVID-19 cases and mortality for selected countries using the data in the following Tables 2,
3 and 4
⎧
d θ1 ∂H
⎪
⎨ dt = − ∂S , θ1 (tf ) = 0
d θ2
= − ∂H , θ2 (tf ) = 0 (4.8)
⎪ dt
⎩ d θ3
∂I
∂H
dt
= − ∂C , θ3 (tf ) = 0
with transversality conditions; θ1 (tf ) = θ2 (tf ) = θ3 (tf ) = 0. We can determine the

behavior of the control by differentiating the Hamiltonian, H with respect to the
controls (u1 , u2 ) at t. On the interior of the control set, where 0 < ui < 1 for all
(i = 1, 2), we obtain

∂H
0= ∂u1
= b1 u1 + θ1 (k1 SI + CSk2 ) − θ2 (SIk1 + CSk2 )
∂H
(4.9)
0= ∂u2
= b2 u2 − θ3 C
Therefore, we have that,

θ2 −θ1
u1∗ = b1
(2k1 SI − 2CSk2 )
θ3 C (4.10)
u2∗ = b2
so, we have
u1∗ = max{0, min(1, θ2b−θ 1
(2k1 SI − 2CSk2 )}
∗ θ3 C
1
(4.11)
u2 = max{0, min(1, b2 )}
Coronavirus Susceptible Humans

3500000
8e+05
2500000
6e+05
Number of Persons
Virus
1500000
4e+05
2e+05
500000
0e+00
0
Nigeria SA Egypt Kenya CAR Nigeria SA Egypt Kenya CAR
Countries Countries
(a) (b)
Fig. 4 a Susceptible humans by country, b coronavirus abundance by country using the data in the
following Tables 2, 3 and 4
Cum. Cases Daily Cases

6e+05
No. of persons
No. of persons
2500
3e+05
1000
0e+00
Ng SA Eg Ke car Ng SA Eg Ke car
Countries Countries
Cum. Mortality Daily Mortality

10000
120
No. of persons
No. of persons
80
4000
40
0
Ng SA Eg Ke car Ng SA Eg Ke car
Countries Countries
Fig. 5 COVID-19 Cases and Mortality by Country using the data in the following Tables 2, 3 and 4
5 Numerical Simulations and Discussion
5.1 Average cost-Effectiveness Ratio (ACER)
The cost-effectiveness technique reveals that strategy B is more cost-effective than

Strategy A and Strategy A is more cost-effective than strategy C (see Table 6). The
Table 4 Expected susceptible humans and coronavirus estimated by country

Parameter Nigeria South Africa Egypt Kenya CAR
ηmin 0.0000000049 0.0000000181 0.0000000101 0.0000000207 0.0000001741
ηmax 0.0000004915 0.0000018057 0.0000010059 0.0000020662 0.0000174063
βmin 0.0000000049 0.0000000181 0.0000000101 0.0000000207 0.0000001741
βmax 0.0000004915 0.0000018057 0.0000010059 0.0000020662 0.0000174063
Susceptible 93,836 457,244 349,409 101,546 6,049
Coronavirus 323,190 3,750,336 593,634 205,206 28,266
incremental cost-effectiveness ratio (ICER) was evaluated in order to investigate the

cost-effectiveness of the distinct control strategies.
Difference in infection averted cost in strategies i and j

ICER =
Difference in total number of infection averted in strategies i and j
Total cost of C
ICER(C) =
Total infection Averted
4.499451 × 102
ICER(C) = = 2.5287532 × 10−7
1.779316 × 109
Total cost of B − Total cost C

ICER(B) =
Total inf Averted B − Total inf Averted C
4.499966 × 102 − 4.499451 × 102

ICER(B) = = 1.95883033 × 10−10
2.042228 × 109 − 1.779316 × 109
Total cost of A − Total cost B

ICER(A) =
Total inf Averted A − Total inf Averted B
7.440212 × 102 − 4.499966 × 102

ICER(A) = = 2.7731629 × 10−6
2.148253 × 109 − 2.042228 × 109
The computational shows a cost saving of 2.5288 × 10−7 for Strategy C, which
is obtained by comparing ICER(B) and ICER (C). The ICER for Strategy B is lower
than that of Strategy C, indicating that the latter strongly dominated, and is, thus,
less cost-effective than Strategy B. Hence, Strategy C is better excluded from the set
of control strategies, so that resources and energy can be saved. Strategy A is further
compared with Strategy B. Thus, we obtain the following numerical results:
Table 5 Total infection averted, total cost, and ACER for the intervention strategies A, B, and C
Strategies Total infection averted Total cost ACER
A (u1 & u2 ) 2.148253 × 109 7.440212 × 102 2.151593 × 10−3
B (u1 ) 2.042228 × 109 4.499966 × 102 5.417977 × 10−2
C (u2 ) 1.779316 × 109 4.499451 × 102 2.099451 × 10−1
Table 6 Total infection averted, total cost and ICER (Ranking is the increasing order of the total
infection averted)
Strategies Total infection averted Total cost ICER
C (u2 ) 1.779316 × 109 4.499451 × 102 2.5288 × 10−7
B (u1 ) 2.042228 × 109 4.499966 × 102 1.9588 × 10−10
A (u1 & u2 ) 2.148253 × 109 7.440212 × 102 2.7732 × 10−6
Total cost of B 4.499966 × 102

ICER(B) = = = 2.20346 × 10−7
Total infection Averted of B 2.042228 × 109
Therefore, it is better to exclude Strategy C from the set of control strategies and
consider alternative interventions to implement in order to preserve limited resources.
Therefore,Strategy C is left out, and A is further compared with Strategy B. Hence,
we obtain the following numerical results (Table 5).
Total cost of A − Total cost B

ICER(A) =
Total inf Averted A − Total inf Averted B
7.440212 × 102 − 4.499966 × 102

ICER(A) = = 2.7731629 × 10−6
2.148253 × 109 − 2.042228 × 109
We compare the effect of varying the weights b1 ; b2 on the average cost-

effectiveness ratio (ACER), infection averted, total cost, and control profiles, using
control weights b1 = 0.1, b1 = 10.0, and b1 = 100 when b2 = 1.0, the baseline
value. Likewise, using b2 = 0.1, b2 = 10.0, and b2 = 100, at the baseline value of
b1 = 1. The results of the simulations are in Fig.5.1, where the bar graphs of the
two weights: b1 and b2 , for the different cost-effectiveness metrics are plotted. When
the weights are high, the two controls forestall more infections (see Fig. 6b, the
blue bar in the first column of Fig. 6b corresponds to b2 = 100, while the magenta
bar is b2 = 100), but with compliance to non-pharmaceutical measures: wearing
face-mask, ensuring physical distancing, etc. more infections are curbed than with
fumigation. The results illustrated in Fig. 6a, c are anticipated, as lower weights are
more cost-effective than higher weights. Remarkably, with low compliance level,
higher weights led to lower cost. This can be due to the fact that compliance to non-
pharmaceutical measures- physical distancing and using face-mask, among others,
ensures fewer infection after the numerical simulation.
Average Cost-Effectiveness Ratio

10 9 b1
0.09 2.5
b1 b2
0.08 b2
Infection Averted
0.07
0.06
(ACER)
1.5
0.05
0.04
1
0.03
0.02 0.5
0.01
0 0
0.10 1.00 10.0 100 0.10 1.00 10.0 100
Weights Weights
(a) (b)
10 4
3.5 1
b1
3 b2
0.8
Control Profiles
u1
2.5 u2
Total Cost
0.6
2
1.5 0.4
1
0.2
0.5
0
0 0 20 40 60 80 100
0.10 1.00 10.0 100
Weights Time (days)
(c) (d)
Fig. 6 Simulation results of model (2.7) using control weights b1 = 0.1, b1 = 10.0,and b1 = 100
when b2 = 1.0 1, the baseline value (the turquoise coloured bars). Similarly, using b2 = 0.1, b2 =
10.0, and b2 = 100, at the baseline value of b1 = 1 (the magenta coloured bars). a Average cost-
effective ratio (ACER); b Infection averted; c Total cost; and d control profiles
Table 7 Total infection averted, total cost and ICER

Strategies Total infection averted Total cost ICER
B (u1 ) 2.042228 × 109 4.499451 × 102 2.203459 × 10−7
A (u1 & u2 ) 2.148253 × 109 7.440212 × 102 2.773163 × 10−6
From Table 7, Strategy B is seen to strongly dominates Strategy A, making it

costlier than strategy A. Here also, Strategy B is left out. We then conclude that Strat-
egy A(u1 & u2 ) is the most cost-effective Strategy, followed by Strategy B, u1 -only.
Strategy C (u2 )-only is the least cost-effective strategy and should not be considered
for use where there are limited resources, as is the case in many countries affected
by the COVID-19.
The partial rank correlation coefficient plot in Fig. 1 shows that the basic repro-
duction number, R0 , is positively correlated to recruitment rate , maximum trans-
mission rate from an infected person to a susceptible human βmax , maximum rate
of transmission of the disease from virus to humans ηmax , growth rate of virus due
to increase in infected individuals φ1 , self-growth rate of the virus φ2 , while R0 is
negatively correlated with natural death rate of humans μ, recovery rate γ, Covid-19
induce death rate σ and growth rate of virus due to increase in infected individuals φ.
This implies that the higher the recruitment rate , maximum transmission rate from
an infected person to a susceptible human βmax , maximum rate of transmission of the

disease from virus to humans ηmax , self-growth rate of the virus φ2 and growth rate
of virus due to increase in infected individuals φ1 in that order, the higher the basic
reproduction number, and the more possibility of spreading the virus. So, for the
spread of the virus to reduce drastically, then all hands must be on deck to increase
recovery rate γ and decrease maximum rate of transmission of the disease from virus
to humans ηmax by complying to WHO and CDC regulations of not touching sur-
faces, washing of hands regularly with soap, using of hand sanitizers and cleaning
of surfaces, which will help to increase the natural death rate of virus.
Figure 3 shows that South Africa has the highest COVID-19 laboratory confirmed
cases among the 5 selected countries in Africa and also has the highest mortality
rate. However, the daily cases and daily deaths is decreasing with time, meaning the
cumulative curves would flatten in the nearest future if compliance rate is high. The
second highest cases of Covid-19 and mortality is Egypt. This is followed by Nigeria,
then Kenya and the least affected country is Central Africa Republic (CAR). The
cumulative and daily curves of both infected cases and mortality over the period under
review show these trends. Figure 4a shows that Nigeria has the highest susceptible
humans compared to the four other countries, which can be due to her population and
recruitment rate. The second is South Africa, then Egypt, Kenya and Central African
Republic in that order. This implies that Nigeria has capacity of humans who can
be easily infected with the virus more than the remaining four countries if not for
government regulations and individual compliance to these regulations. Figure 4b
shows that South Africa has the highest virus population compared to the four other
selected countries, which can be due to high number of infected individuals with
high contact with surfaces. The second is Egypt, Nigeria, Kenya and Central African
Republic in that order. This implies that South Africa breeds the virus more than
the remaining four countries. This virus population can be reduced by increasing
recovery rate of infected individuals and by maintaining physical distance, wearing
of face masks and by killing the virus population on surfaces that are in form of
droplets. Figure 5 is to buttress the time plots in Fig. 3. Figure 3 shows a trend over
time while Fig. 5 shows the average over the period under review. This shows that
on the average South Africa has the highest cases followed by Nigeria, then Egypt,
Kenya and CAR in that order. For the mortality rate, on the average, South Africa is
the highest, followed by Egypt, then Kenya, before Nigeria and CAR. This implies
that Nigeria may have higher daily cases than Egypt and Kenya but lower mortality
rate, which could be due to many factors not considered in this work. Figure 7 shows
curve fitting plots for the selected countries using optimal control. The figure shows
that Kenya and Nigeria cumulative infected curves are not yet flatten, while that of
Egypt and CAR are already flattened. Figure 8a shows that without control, the virus
population will increase significantly before gradually reducing and might not touch
the asymptote over time, while the virus population would be kept significantly
low with both controls (u1 , u2 ) implemented over the same period. The infected
human population as shown in Fig. 8b increased sharply before steadily settling
down to a stable level around 80 days when no control is implemented, while there
is a sharp decline in the number of infected individuals as both controls are fully
implemented. Figure 8c, d display the control profiles for u1 and u2 respectively.
Control u1 can be seen to be effective for about 38 days before reducing to 80%
effectiveness for another 50 days, while control u2 is fully effective for the first 20
days before reducing to 80% effectiveness over the next 60 days. In Fig. 9, the control
profile of only u1 is considered. It can be observed for the coronavirus population,
the effect of control u1 can be seen around 40 days while the effect of u1 on the
infected population is the same as using both controls u1 and u2 . The control profile
for u1 in Fig. 9c shows that the control is effective over 80 days before dropping
around 90 days. With just control u2 , the coronavirus population is expected to
reduce to its barest minimum at about 40 days before attaining a constant level
as shown in Fig. 10a. The control u2 has significantly small effect on the infected
population when compared to control u1 and the combination of both controls as
depicted in Fig. 10b. Control is potent for about 90 days before declining after 90
days. The effect of varying the weights, b1 , corresponding to compliance levels
when b2 is fixed are considered in Figs. 11, 12 and 13, where b1 = 0.1, 10 and 100
represent relative, high and extreme compliance respectively. The simulation result
for coronavirus population reduce significantly for about 60 days before witnessing
a sudden spike in the virus population and then maintain a constant level after 80
days. The sudden rise may be largely due to the low compliance level when b1 = 0.1.
For high and extreme level of compliance corresponding to b1 = 10 and b1 = 100,
we observed in Figs. 12 and 13 that the coronavirus and infected human population
decline significantly over the same time. Further, the performance profile of both
controls u1 and u2 are approximately the same over the same period. The effect of
varying the weights, b2 , corresponding to cost levels when b1 is fixed are considered
in Figs. 14, 15, and 16 for b2 = 0.1, 10 and 100 respectively. Notably, when b1 is
fixed and b2 = 0.1 represent cheap cost, Fig. 14 shows that the combination of the
two controls reduced the coronavirus population significantly over time. Initially,
the infected human population reduced drastically for about 59 days before a sudden
spike in the number of infected individual after 59 days. The sudden increase in the
number of infected humans with coronavirus may be due to the unsustainable costs
of implementing the controls. Consequently, in Figs. 15 and 16, when the weight is
increased from b2 = 0.1 to b2 = 10 and b2 = 100, we can see that both coronavirus
and infected human population reduced significantly over the same course of time
with both controls implemented fully. This shows that the costs associated with the
controls should be sustained for at least 90 days.
6 Conclusion
In this work, we present a mathematical model to analyze the interaction between

humans and coronavirus population which take into account public compliance and
sanitation on the transmission dynamics of COVID-19. Three feasible solutions of
the model were obtained. Firstly, the compliance-free equilibrium which is feasible if
the basic reproduction number R0 > 1. Secondly, the disease-free (COVID-19 free)
10 4 10 4
4 6
Cumulative number of reported

Model Model
Kenya COVID-19 Data Nigeria COVID-19 Data
5
3
4
cases
cases
2 3
2
1
1
0 0
0 50 100 150 200 0 50 100 150 200
Time (days) Time (days)
(a) (b)
10 4
5000 10

Model
Model
CAR COVID-19 Data
Egypt COVID-19 Data
4000 8
3000 6
cases
cases
2000 4
1000 2
0 0
0 50 100 150 200 0 50 100 150 200 250
(c) (d)
Fig. 7 Fitting the data of the selected countries to system (2.1)
10 5
10 6
without control
2.5 without control 8
optimal control
optimal control
7
2
Coronavirus
6
Infected
5
1.5
4
1 3
2
0.5
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1
1
u1
u2
0.8 0.8
Control(u 1)
Control(u2 )
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 8 Simulations of system (2.1) u1 & u2

106 105
2.5 without control without control

8
optimal control optimal control
7
2
6
Coronavirus
Infected
1.5 5
4
1 3
2
0.5
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8
0.5
Control (u1)
Control(u2)
0.6
0
0.4
-0.5
0.2
0 -1
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 9 Simulations of system (2.1) u1 -only
106 105

8
7
2
Coronavirus
6
Infected
1.5 5
4
1
3
0.5 2
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1
1
u1 u2
0.8
0.5
Control(u2)
Control(u1)
0.6
0
0.4
-0.5
0.2
-1 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 10 Simulations of system (2.1) u2 -only

106 105

8
7
2
6
Coronavirus
Infected
1.5 5
4
1
3
2
0.5
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u1)
Control(u2)
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 11 Effect of weight on the compartments of system (2.1) when b1 = 0.1 i.e. relatively com-
pliance simulations of system (2.1)
106 105

8
2
6
Coronavirus
Infected
1.5
4
1
2
0.5
0 0
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u1)
control(u2)
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 12 Effect of weight on the compartments of system (2.1) when b1 = 10 i.e. highly compliance
106 105

8
7
2
6
Coronavirus
Infected
1.5 5
4
1
3
2
0.5
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u1)
control(u2)
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 13 Effect of weight on the compartments of system (2.1) when b1 = 100 i.e. extremely
compliance
106 105

8
7
2
6
Coronavirus
Infected
1.5 5
4
1 3
2
0.5
1
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u1)
control(u2)
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 14 Effect of weight on the compartments of system (2.1) when b2 = 0.1 ie CHEAP
106 105
2.5 without control 8 without control
Coronavirus
Infected
6
1.5
4
1
2
0.5
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u1 )
control(u2 )
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 15 Effect of weight on the compartments of system (2.1) when b2 = 10 i.e. expensive
106 105
2.5 without control 8 without control
Coronavirus
2
Infected
6
1.5
4
1
2
0.5
0 20 40 60 80 0 20 40 60 80
(a) (b)
1 1
u1 u2
0.8 0.8
control (u 1 )
control (u 2 )
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 20 40 60 80 100 0 20 40 60 80 100
(c) (d)
Fig. 16 Effect of weight on the compartments of system (2.1) when b2 = 100 i.e. very expensive
equilibrium is feasible if the effective reproduction number Rα < 1 while the endemic
equilibrium is feasible whenever Rα > 1. Stability theory were used to analyze the the
local stability of the model equilibrium points while the method of Lyapunov function
construction were used to study the global stability of the disease-free and endemic
equilibrium. The analyses revealed that both disease-free and endemic equilibrium
are locally asymptotically stable if Rα < 1 and Rα > 1 respectively. The disease-free
equilibrium of the model is globally asymptotically stable if Rα ≤ 1 . Consequently,
the global sensitivity analysis was performed using Partial Rank Correlation Coeffi-
cient (PRCC) to determine parameters that are globally sensitive to the reproduction
number R0 at 95% confidence level. The analyses revealed that , βmax , ηmax , φ1 , φ2
are all positively correlated while μ, γ, σ and φ3 are negatively correlated. In a bid
to reduce the virus spread, an optimal control problem with dependent controls u1 (t)
representing public compliance level to policies put in place to reduce the spread
of the disease and u2 (t) denoting sanitation efforts put in place to reduce the virus
population. The study revealed that the combination of both controls proved to be
most effective in controlling the virus spread depending on the level of compliance
and cost of implementing effective sanitation. Further, the cost effectiveness of all
the possible combinations of the controls was considered through cost effectiveness
analyses. The result of the analyses indicates that strategy A which involve using
both controls u1 and u2 proved to be most cost-effective strategy, this is followed
by strategy B in which u2 is the only control while the implementation of strategy
C which involve u1 only is the least cost-effective strategy. Strategy C, if adopted,
should be carefully implemented particularly in a setting like the COVID-19 selected
countries in this study where resources are limited in controlling the virus spread.
Lastly, further research work is needed on the subject to look into the heterogene-
ity in the population, model extension by incorporating other compartments such
as recovery, hospitalization, death etc. This will form the foundation of a separate
research.
7 Appendix
7.1 Positivity of Solutions
In this section, we established that all the dynamical variables of the model system
(2.1) are non-negative for all time t. Note that the positivity of S(t) and C(t) depends
on the positivity of I (t), we shall start by proving the positivity of I (t). Thus, from
the second equation of the model system (2.1), we have
dI
I = = [βh S + βc CS − (γ + σ + μ)]I + βc CS (7.1)
dt
and dI
dt
− f (S)I (t) = βc CS where f (S) = βh S − (γ + σ + μ). This can be sup-
pressed as
⎧ t t
⎪ dI − 0t f (S)dS
⎪ e − f (S)e− 0 f (S)dS I (t) = e− 0 f (S)dS βc CS
⎪
⎪ dt
⎪
⎪
t
− 0 f (S)dS
t
) = e− 0 f (S)dS βc CS
⎨ dt (I (t)e
d
t t
I (t)e− 0 f (S)dS = 0 e− 0 f (S)dS βc CSdS + I0
t
(7.2)
⎪
⎪ t − t f (S)dS t
⎪ − (S)dS
⎪I (t) = [I0 + t 0 e 0
⎪ βc CSdS]e 0 f
⎩I (t) = I e− 0 f (S)dS + e− 0t f (S)dS t e− 0t f (S)dS β CSdS ≥ 0
⎪
0 0 c
for all t ≥ 0. Other, from the first equation of system (2.1), we have
dS
= + γI − [βh (α)I (t) + βc C(t) + μ] S(t) (7.3)
dt
(34) can be expressed as
t t t
dS 0 f2 (S)dS
e + f2 (S)e 0 f2 (S)dS = ( + γI (t))e 0 f2 (S)dS
dt t t (7.4)
d
dt
(S(t)e 0 f2 (S)dS ) = ( + γI (t))e 0 f2 (S)dS
Thus, we obtain
t t t
S(t)e 0 f2 (S)dS = 0 ( + γI (t))e 0 f2 (S)dS + S0
t t t t (7.5)
S(t) = e− 0 f2 (S)dS 0 ( + γI (t))e 0 f2 (S)dS + S0 e− 0 f2 (S)dS
Hence, S(t) > 0 for all t > 0, f2 = βh I (t) + βc C(t) + μ. Also, from the third
equation of the model system (2.1), we have
⎧ dC
⎪
⎪ + (φ3 − φ2 )C(t) = φ1 I (t)
⎪
⎨ d (C(t)e0t (φ3 −φ2 )du ) = φ I (t)e0t (φ3 −φ2 )du
dt
1
dt t t u (7.6)
⎪
⎪ C(t)e 0 (φ3 −φ2 du = φ I (t)e 0 (φ3 −φ2 )dp du + C0
⎪
⎩ t t
0 1
u t
C(t) = e 0 (φ3 −φ2 du 0 φ1 I (t)e 0 (φ3 −φ2 )dp du + C0 e− 0 (φ3 −φ2 du
for all t > 0. Thus, the solutions S(t), I (t) and C(t) of model system (2.1) with the
initial conditions S(0) = S0 > 0, I (0) = I0 ≥ 0 and C(0) = C0 ≥ 0 are non-negative
for all t > 0. Hence, the proof.
7.2 Boundedness of Solution
The total human population of the model denoted by N (t) at time t is given as
N (t) = S(t) + I (t) (7.7)

so that
dN (t)
= − μN (t) − σI (t) (7.8)
dt
since CI (t) is non-negative, then (A2.2) reduces to
dN (t)
≤ − μN (t) (7.9)
dt
The above equation can be written as
d
≤ − μN (t) (7.10)
dt
Integrating the above equation, we have
⎧
μt μt
⎨N (t)e ≤ e dt + N0
⎪
N (t)eμt ≤ μ eμt e−μt + N0 e−μt (7.11)
⎪
⎩
N (t) ≤ μ e + N0 e−μt
By applying theory of differential inequality (17), we have

lim sup N (t) ≤ (7.12)
t→0 μ
thus 0 ≤ N (t) ≤ μ as t → ∞. Now, I (t) = N (t) − S(t) ≥ 0 =⇒ 0 ≤ I (t) ≤ N (t)

≤ μ as t → ∞.
From the third equation of the model system (2.1), and observing the fact that
I (t) ≤ μ for t → ∞, we have
⎧
⎪
⎪
⎪
dC(t)
+ (φ3 − φ2 )C(t) ≤ φ1μ
⎪ dt
⎨ d (C(t)e(φ3 −φ2 )t ) ≤ φ1 e(φ3 −φ2 )t )
dt μ
φ1 (7.13)
⎪
⎪ C(t)e (φ3 −φ2 )t
≤ e(φ3 −φ2 )t ) + C1
⎪
⎪ μ(φ 3 −φ 2)
⎩C(t) ≤ φ1 + C e−(φ3 −φ2 )t
μ(φ3 −φ2 ) 1
φ1
using theory of differential inequality, we obtain lim sup C(t) ≤ μ(φ3 −φ2 )
and 0 ≤
t→∞
φ1
C(t) ≤ μ(φ3 −φ2 )
7.3 Basic Reproduction Number (Rα )
The next equilibrium matrix method is used to obtain the basic reproduction (Rα )
of model system (2.1). This method is well documented in [2, 26] and has been
implemented by several researchers [9, 10]. First, we obtain the transmission matrix
of new infections F(x) and the transition matrix V (x) as follows: Consider the model
system (2.1) expressed as
dx
= F(x) − V (x) (7.14)
dt
where x = (S, I , C)T

βh (α)IS + βc (α)CS
F(x) = (7.15)
0
and

(γ + σ + μ)I
V (x) = (7.16)
(φ3 − φ2 )C − φ1 I
and the Jacobian matrix of F(x) and V (x) calculated at Covid-19 disease free
equilibrium P0 = ( μ , 0, 0) are

βh (α) βc (α)
J (F(x)P0 ) = μ μ (7.17)
0 0
and

(γ + σ + μ) 0
J (V (x)P0 ) = (7.18)
−φ1 (φ3 − φ2 )
The next generation matrix K = J (F(x), P0 )(J (V (x)P0 ))−1 is given by

βh (α) βc (α) 1

(γ+σ+μ)
0
K= μ μ
φ1 1 (7.19)
0 0 (γ+σ+μ)(φ3 −φ2 ) (φ3 −φ2 )

βh (α) βc (α) βc (α)
+
K= μ(γ+σ+μ) μ(γ+σ+μ)(φ3 −φ2 ) μ(φ3 −φ2 ) (7.20)
0 0
7.4 Model Parameters Estimation
The model parameters were estimated from real life data using statistical techniques.
Some of the parameters were assumed based on real life situations and data available
for the countries selected for consideration, while some others were extracted from
demographic data of the countries considered.
All the parameters are positive numbers, that is, > 0, where is the parameter
space. The natural death rate for human, μ is directly obtained from demographic
data, and it is estimated by
1
μ̂ = (7.21)
μ0
where μ0 is the average life expectancy obtained from demographic data.

Without loss of generality, we can denote S(t), I (t) and C(t) as St , It and Ct
respectively. The recovery rate of infected individuals, γ is estimated by
n
Rt
γ̂ = t=1
n (7.22)
t=1 It
where t, t = 1, 2, ..., n is time measured in days and n is the number of days covered.
The variables Rt and It are the number of recovered individuals at time t and number
of infected individuals at time t respectively.
COVID-19 induced death rate of infected individuals, σI is estimated by
n
Dt
σ̂ = t=1
n (7.23)
t=1 It
The variable Dt is the number of COVID-19 induced deaths at time t.

The parameter accounting for compliance, α is assumed to lie be between 0 and
1 and it is assume that the more the compliance level, the more the recovery rate and
the less the mortality rate. Thus, α is estimated by
n n
Rt − Dt
α̂ = t=1
n t=1
(7.24)
t=1 It
The growth rate of virus due to increase in infected individuals of COVID-19, φ1 is

estimated by n n
t=1 It − sumt=1 Rt −
n
t=1 Dt
φ̂1 = n (7.25)
I
t=1 t
This is because the growth rate of virus is assumed to be the additive inverse of
compliance level. If the compliance rate of individuals increases, the growth rate of
virus reduces and vice versa.
Natural death rate of virus, φ3 is estimated by adding a fraction constant to recovery
rate. The natural death rate of virus is partly constant and partly varies directly as
recovery rate. Thus, φ3 is estimated by
n
Rt
φ̂3 = κ + t=1
n (7.26)
t=1 It
where κ is the fraction constant selected for all countries, so that φ̂3 > 0. Self growth
rate of the virus, φ2 is estimated by subtracting a fraction of φ1 from φ3 and it is
given by
1
φ̂2 = φ̂3 − φ̂1 , φ̂3 > φ̂2 (7.27)
q
where q > 0 is a real number, which is constant for all countries considered. It is
also chosen so that φ̂2 > 0.
The density of the virus population at time t is Ct and it is estimated by
φ1 I t
Ĉt = , φ̂3 > φ̂2 . (7.28)
φ̂3 − φ̂2
But it is restricted by an upper bound given by
ˆ
φ̂1
Ĉm = , φ̂3 > φ̂2 (7.29)
μ(φ̂3 − φ̂2 )
where ˆ is the recruitment rate gotten from demographic data of birth of each country
considered, and may be restricted below by a lower bound St + It .
Minimum rate of transmission of the disease from virus to humans (ηmin ) is esti-
mated by 1/N where N is the population of each country considered. And it is also
assumed to be directly proportional to minimum transmission rate from an infected
person to a susceptible human (βmin ). So, ηmin and βmin can be varied but must always
be less than ηmax and βmax respectively. Note that ηmax and βmax are fixed as a supre-
mum. This implies that ηmax = ηmin ∗ w and βmax = βmin ∗ w, where w is a positive
constant and a multiple of 10.
References
1. Poutanen, S.M.: Human coronaviruses. In: Principles and Practice of Pediatric Infectious Dis-
eases, p. 1148 (2018)
2. Adeniyi, M.O., Ekum, M.I., Iluno, C., Oke, S.I., et al.: Dynamic model of COVID-19 disease
with exploratory data analysis. Sci. Afr. 9 (2020)
3. Vassilara, F., Spyridaki, A., Pothitos, G., Deliveliotou, A., Papadopoulos, A.: A rare case of
human coronavirus 229e associated with acute respiratory distress syndrome in a healthy adult.
Case Rep. Infect. Diseases, vol. 2018 (2018)
4. Zhong, N., Zeng, G.: What we have learnt from SARS epidemics in China. BMJ 333(7564),
389–391 (2006)
5. Ekum, M., Ogunsanya, A.: Application of hierarchical polynomial regression models to predict
transmission of COVID-19 at global level. Int. J. Clin. Biostat. Biom 6, 027 (2020)
6. Maunder, R., Hunter, J., Vincent, L., Bennett, J., Peladeau, N., Leszcz, M., Sadavoy, J., Ver-
haeghe, L.M., Steinberg, R., Mazzulli, T.: The immediate psychological and occupational
impact of the 2003 SARS outbreak in a teaching hospital. CMAJ 168(10), 1245–1251 (2003)
7. World Health Organization: Coronavirus disease 2020 (COVID-19) situation report-1 (2020)
the 2019 novel coronavirus. Math. Biosci.108364 (2020)
9. Okuonghae, D., Omame, A.: Analysis of a mathematical model for COVID-19 population
dynamics in Lagos, Nigeria. Chaos Solit. Fract. 139 (2020)
10. Jewell, N.P., Lewnard, J.A., Jewell, B.L.: Predictive mathematical models of the COVID-19
pandemic: underlying principles and value of projections. JAMA 323(19), 1893–1894 (2020)
11. Eikenberry, S.E., Mancuso, M., Iboi, E., Phan, T., Eikenberry, K., Kuang, Y., Kostelich, E.,
Gumel, A.B.: To mask or not to mask: Modeling the potential for face mask use by the general
public to curtail the COVID-19 pandemic. Infect. Disease Modell. (2020)
12. Ndairou, F., Area, I., Nieto, J.J., Torres, D.F.: Mathematical modeling of COVID-19 transmis-
sion dynamics with a case study of Wuhan. Chaos Solit. Fract. 109846 (2020)
13. Owusu-Mensah, I., Akinyemi, L., Oduro, B., Iyiola, O.S.: A fractional order approach to
modeling and simulations of the novel COVID-19 (2020)
14. Liu, Z., Magal, P., Seydi, O., Webb, G.: A COVID-19 epidemic model with latency period.
Infect. Disease Model. 5, 323–337 (2020)
15. Stutt, R.O., Retkute, R., Bradley, M., Gilligan, C.A., Colvin, J.: A modelling framework to
assess the likely effectiveness of facemasks in combination with ‘lock-down’ in managing the
COVID-19 pandemic. Proc. R. Soc. A 476(2238), 20200376 (2020)
16. Yang, C., Wang, J.: A mathematical model for the novel coronavirus epidemic in Wuhan, China.
Math. Biosci. Eng. 17(3), 2708–2724 (2020)
17. Kruse, T., Strack, P.: Optimal control of an epidemic through social distancing (2020)
18. Yousefpour, A., Jahanshahi, H., Bekiros, S., Optimal policies for control of the novel coron-
avirus (COVID-19). Chaos Solit. Fract. 109883 (2020)
19. Lemecha Obsu, L., Feyissa Balcha, S.: Optimal control strategies for the transmission risk of
COVID-19. J. Biol. Dyn. 14(1), 590–607 (2020)
20. Okedoye, A., Salawu, S., Oke, S., Oladejo, N.: Mathematical analysis of affinity hemodialysis
on T-cell depletion. Sci. Afri. e00427 (2020)
21. Oke, S., Matadi, M., Xulu, S.: Cost-effectiveness analysis of optimal control strategies for
breast cancer treatment with ketogenic diet. Far. East J. Math. Sci. 109(2), 303–342 (2018)
22. Zamir, M., Shah, Z., Nadeem, F., Memood, A., Alrabaiah, H., Kumam, P.: Non pharmaceutical
interventions for optimal control of COVID-19. Comput. Methods Programs Biomed. 196
(2020)
23. Anirudh, A.: Mathematical modeling and the transmission dynamics in predicting the COVID-
19-what next in combating the pandemic. Infect. Disease Model. 5, 366–374 (2020)
24. Are, S.O., Ekum, M.I.: COVID-19 pandemic data visualization with moment about midpoint
exploratory and expository analyses. Asian J. Prob. Stat. 15–37 (2020)
25. Ngonghala, V., Iboi, E., Gumel, A.B.: Could masks curtail the post-lockdown resurgence of
COVID-19 in the us? Math. Biosci. 108452 (2020)
26. Oke, S.I., Ojo, M.M., Adeniyi, M.O., Matadi, M.B.: Mathematical modeling of malaria disease
with control strategy. Commun. Math. Biol. Neurosci. 2020(Article-ID) (2020)
27. Pontryagin, L.S.: Mathematical Theory of Optimal Processes. Routledge (2018)
28. Oke, S.I., Matadi, M.B., Xulu, S.S.: Optimal control analysis of a mathematical model for
breast cancer. Math. Comput. Appl. 23(2), 21 (2018)
29. Oke, S., Matadi, M., Xulu, S.: Optimal control of breast cancer: Investigating estrogen as a risk
factor. In: International Conference on Applied Mathematics, Modeling and Computational
Science, pp. 451–463. Springer (2017)
30. Asamoah, J.K.K., Owusu, M.A., Jin, Z., Oduro, F., Abidemi, A., Gyasi, E.O.: Global stability
and cost-effectiveness analysis of COVID-19 considering the impact of the environment: using
data from Ghana. Chaos Solit. Fract. 140 (2020)
31. Agusto, F., Leite, M.: Optimal control and cost-effective analysis of the 2017 meningitis out-
break in Nigeria. Infect. Disease Model. 4, 161–187 (2019)
A Comparative Study of Amino Acid
Encoding Methods for Predicting
Drug-Target Interactions in COVID-19
Disease
Talha Burak Alakus and Ibrahim Turkoglu
Abstract Identifying drug-target interactions plays an important role in discovering

drugs. Identifying, finding, and preparing drug molecule targets is the key for modern
drug discovery. However, potential drug-target interactions are usually determined
experimental approaches (in vivo and in vitro). Experimental approaches are expen-
sive, require a lot of manpower, and the data are complex, making it difficult to
use these methods effectively. For these reasons, the importance of simulation-based
methods (in-silico) has increased and computational methods have started to be used
more actively. In addition, more computational methods need to be developed to
validate the interactions between drugs and their targets. In order to predict and vali-
date the interactions between drugs and their targets by computational methods, both
drugs and targets need to be mapped and to be classified with artificial intelligence
techniques. As it is known, targets consist of proteins and protein sequences consist
of letters. Furthermore, drug compounds are expressed in molecular codes. It is not
possible to determine the interactions between drugs and their targets by computa-
tional methods without any pre-processing (mapping). The performance of the DTI
(Drug-Target Interaction) prediction process varies according to the protein mapping
and artificial intelligence approaches selected thus, it is important to choose the right
methods in such applications. There are a number of protein mapping techniques and
artificial intelligence algorithms in the literature. In this study, prediction of drug-
target interactions carried out for COVID-19 disease by using certain protein mapping
techniques and a deep learning. The proposed method consists of 5 stages. In the
first stage, drug-target interactions were obtained from the DrugBank database. In
the second stage, mapping of drug compounds and target proteins was made. While
PubChem fingerprinting method was used for the mapping of drug compounds,
target proteins were mapped with 6 different methods; Meiler parameters, Atchley
T. B. Alakus (B)
Department of Software Engineering, Faculty of Engineering, Kirklareli University, Kirklareli,
Turkey
e-mail: talhaburakalakus@klu.edu.tr
I. Turkoglu
Department of Software Engineering, Faculty of Technology, Firat University, Elazig, Turkey
e-mail: iturkoglu@firat.edu.tr
620 T. B. Alakus and I. Turkoglu
factors, PAM250, BLOSUM62, Miyazawa energies and Micheletti potentials. In

the third stage, the mapped drug compounds and the mapped target proteins were
combined and a one-dimensional feature space was obtained. In the fourth stage, the
one-dimensional feature that was generated before was classified with the LSTM
(Long-Short Term Memory) deep learning model and the prediction was performed.
In the last stage, the performance of the protein mapping methods was determined and
compared with accuracy, precision, recall, f1-score, and ROC (Receiver Operating
Characteristic) evaluation matrices. When the application results were examined, it
was seen that all protein mapping techniques performed above 85%. The best accu-
racy and ROC scores were obtained from Atchley factors and Meiler parameters.
With Atchley factors, an average of 92% accuracy and 98% ROC were obtained.
With the Meiler parameters, the ROC value did not change, but the accuracy value
was measured as 91%. Afterwards, it was observed that Micheletti potentials and
Miyazawa energies showed the second best performance. On average, 90 and 91%
accuracy values were obtained, respectively. ROC values were calculated to be close
to each other and 98% ROC value was obtained for Micheletti potentials, while this
ratio decreased to 96% with Miyazawa energies. BLOSUM62 and PAM250 protein
mapping methods were more ineffective than other methods. While BLOSM62
showed an average accuracy of 87%, PAM250 predicted drug-target interactions
an average of 91% accuracy. While the ROC value of the BLOSUM62 method was
89%, this rate increased in PAM250 and a ROC value of 92% was obtained. Contri-
butions obtained by the end of the study can be expressed as follows; with this study
for the first time, drug-target interactions of COVID-19 were predicted by protein
mapping techniques. In addition, the most effective protein mapping method among
protein mapping techniques was determined. It was demonstrated that the selected
protein mapping techniques are important in determining drug-target interactions.
Additionally, it has been observed that computational-based methods can be at least
as effective as experimental approaches.
Keywords COVID-19 disease · Drug-target interactions · Deep learning · Protein

mapping
1 Introduction
The new type of corona virus also called COVID-19 first appeared in Wuhan, China
in December 2019 and spread rapidly and became a pandemic [49, 58]. COVID-
19 affects the immune system, causing disorders such as fever, cough, shortness of
breath and pneumonia [17]. Although 80% of infected patients survive this condi-
tion moderately, COVID-19 can be fatal for people with cancer, asthma and chronic
diseases [3]. Corona viruses, which generally affect animals, can also infect humans
due to their genomics structure. The SARS-COV virus, which emerged in the 2000s,
infected approximately 8000 people and reached a mortality rate of 10% [57]. Simi-
larly, the MERS-COV virus, which occurred in 2012, reached a mortality rate of 36%
A Comparative Study of Amino Acid Encoding Methods … 621
and was described as a dangerous disease [15]. It has been observed that the new
type of corona virus (SARS-COV-2) spreads faster than MERS-COV and SARS-
COV viruses and is more difficult to control [4]. People suffering from COVID-19
disease are evaluated based on symptoms. In some cases, people are hospitalized,
and in very serious cases, infected people are taken to intensive care. The new type
of corona virus significantly affects the health system due to reasons such as high
spreading rate, lack of specific treatment, and insufficient hospital resources in case
of high number of people in intensive care unit [16, 25]. For these reasons, it is
important to start treatment at an early stage, to have information about how the
virus infects the host, to develop new drugs or to use existing drugs.
No specific treatment has been found for the new type of corona virus so far.
Clinical trials are being conducted for treatment, and RNA and protein sequences
are used effectively in these studies [50, 64]. One of these methods is drug-target
interactions. Drug-target interactions play a vital role in the discovery of drugs at
an early stage. Drug targets form the basis of drug research and drug development
studies. Recently, researchers have been able to identify potential drugs using known
drug targets [30]. The development of new drugs is possible by determining the
interactions between drugs and their targets [54]. However, determining drug-target
interactions experimentally (in-vivo and in-vitro) is both time consuming and costly.
This period varies between 2–3 years, mostly due to biological and chemical reasons,
and a large number of resources and budgets are needed [28, 29, 38]. Therefore,
drugs, targets and drug-target interactions can be determined more quickly with
computational methods and possible drug-target interactions can be predicted.
Computational methods can be evaluated in three different categories: docking
approach, similarity-based approach and feature-based approach. In the similarity-
based approach, the chemical structural similarity of known targets of a particular
drug or compound is calculated and potential targets are determined. Yamanashi
et al. [61] evaluated known drug interactions using the kernel regression method and
predicted new drug-target interactions. In another study, Keiser et al. [29] predicted
drug-target interactions by measuring the chemical similarity of targets. Similarity-
based approaches are effective and easy to apply when chemical structure similarity
is high. Yet, when the data are abundant, their accuracy decreases [54]. In addition,
similarity-based approaches are effective in determining drug-target interactions for
a particular protein family, but not in interactions with other protein families [55].
For these reasons, this approach has not been preferred by researchers recently.
In the docking approach, the structure and electrical compatibility of drugs and
potential targets are calculated on the three-dimensional structure and possible targets
are determined. Li et al. [36] developed an application running on the web and
predicted drug-target interactions with docking approach. The docking approach
requires 3-dimensional structure information of the target protein. Therefore, the
prediction accuracy of this approach is low [54]. Another problem with this approach
is that it cannot be applied to proteins whose 3-dimensional structure is unknown.
Nowadays, there are very few proteins whose 3-dimensional structure is known,
which causes this approach to be limited and not be used actively. The limitations
of similarity-based and docking-based approaches have increased the popularity of
the feature-based approach [11, 19]. In the feature-based approach, there are two
scenarios for drug-target interactions, interaction either exists or does not exist.
In this approach, patterns of known interactions are used and a prediction model
is developed with the machine learning method to determine potential drug-target
interactions. Pliakos and Vens [46] determined drug-target interactions using the tree-
ensemble learning method. Chen et al. [9, 10] conducted a study comparing machine
learning algorithms used to predict drug-target interactions. Similarly, Bagherian
et al. [7] evaluated the machine learning algorithms used in the study of drug-
target interactions and additionally provided information about the data sets used.
However, in studies conducted with machine learning, there is a loss of information
[35]. Retrieving this information is very difficult with traditional machine learning
methods. In order to avoid the problem caused by machine learning, deep learning
has been used. Lee et al. [35] determined drug-target interactions using convolutional
neural networks. Hinton et al. [21] used deep belief networks to identify drug-target
interactions. For these reasons, feature-based approach was preferred in this study,
and deep learning was used for this. In order to predict drug-target interactions by
artificial intelligence approaches, drug and target sequences need to be expressed
numerically. There are a number of protein mapping methods in the literature, and
in this study, some of these methods are emphasized and their performances are
compared.
In this study, drug-target interactions determined for COVID-19 disease were
predicted with specific protein mapping methods and LSTM deep learning model
and the performances of these mapping methods were compared. The study consists
of five stages; in the first stage, the drug-target interactions determined for COVID-
19 disease were obtained from the DrugBank data set. In the second stage, drug
compounds were characterized with PubChem fingerprint method and target proteins
were mapped with various protein mapping methods. In the third stage, both the char-
acterized drug compounds and the mapped target protein sequences were combined
and made into a one-dimensional vector. In the fourth stage, this data, which became
a one-dimensional vector, was classified with LSTM and the prediction process
was carried out. In the last stage, the performance of all protein mapping methods
was compared with respect to accuracy, precision, recall, f1-score, and ROC score.
Figure 1 contains a graphical abstract of this study. In general, we can express
the contributions of the chapter as follows; drug-target interactions determined for
COVID-19 disease were predicted by protein mapping methods. To the best of our
knowledge, there is no previous study in the literature that predicts drug-target inter-
actions of COVID-19 with protein mapping techniques. In this sense, this study can
be a reference to drug-target interaction studies of COVID-19. Another contribution
of the chapter is to determine which protein mapping method is more successful. In
this way, when determining drug-target interactions of COVID-19, inferences can be
made based on these achievements, and in future studies, researchers can use certain
protein mapping techniques, considering the results of this study. Thus, there will
be no waste of time in future studies and studies can be carried out faster. The final
contribution of this chapter is that it has been observed that simulation-based interac-
tion prediction processes can be as successful as experimental and chemical methods.
Fig. 1 Workflow of the study
Thus, the importance of simulation-based approaches may increase and drug studies
against this new coronavirus may gain momentum. The motivations of this study can
be summarized as follows; since COVID-19 is a new disease, no vaccine or drug has
not been developed. For the development of drugs, it is necessary to determine drug-
target interactions. One of our aims in this study is to validate experimentally deter-
mined drug-target interactions of COVID-19 disease with computational methods, to
lay the groundwork for potential drug studies of these interactions. Another aim is to
show that computational methods can be as successful as experimental methods. In
this way, fast and effective computational-based methods can be developed that will
validate the drug-target interactions determined not only for COVID-19 disease but
also for other diseases. These developments will assist in the development of potential
drugs. Another aim of ours is to determine effective mapping methods by comparing
protein mapping techniques. In this way, researchers can examine effective protein
mapping methods and suggest new protein mapping methods. This will accelerate
the studies performed with proteins (prediction drug-target interactions, prediction

of protein–protein interactions, determination of protein families, classification of
protein functions, determination of host-cell interactions, etc.).
The remainder of the chapter is organized as follows: Sect. 2 mentions drug-
target interaction studies carried out with deep learning algorithms. Section 3 gives
information about the data set used. In addition, in this section, the protein mapping
methods used in the study are explained. In Sect. 4, information is given about the
parameters of the deep learning model used by including application results. By
determining the performances of protein mapping methods, the comparison process
is also performed. In Sect. 5, the results are evaluated and the performances of the
methods are discussed. In the Conclusion section, the common effect of the study
and the importance of drug-target interactions are emphasized. In addition to these,
applications that can be done in future studies are mentioned.
2 Related Works
In this section, drug-target interaction studies carried out with deep learning are
mentioned. Wen et al. [55] proposed a deep learning model to predict drug-target
interactions. In the study, data were obtained from the DrugBank data set and a
total of 1412 drugs and 1520 targets were evaluated. DBN (Deep Belief Network)
were used as a deep learning model in the study and the performance of this clas-
sifier was compared with NB (Naive Bayes) and RF (Random Forest) classifiers.
The performance of the proposed classifier was determined by true-positive rate,
true-negative rate, accuracy, and ROC scores. An accuracy of 85.88% and ROC
score of 91.58% was achieved with DBN. In another study, the authors predicted the
drug-target interaction network using the deep learning model [63]. Interaction data
were obtained from the DrugBank data set, while protein information was collected
from the NCBI data set. In the study, LASSO (Least Absolute Shrinkage and Selec-
tion Operator) based deep neural network was proposed as a deep learning model.
The performance of the proposed method was evaluated only with accuracy and
ROC scores and these results were compared with SLG (Standard Logistic Regres-
sion), SVM (Support Vector Machines), and Standard DNN (Deep Neural Network)
models. The best values were obtained with the proposed method and the accu-
racy and ROC scores of 0.81 and 0.89 were achieved, respectively. Similarly, in
study of Xie et al. [59] drug-target interaction was predicted with deep learning. The
interactions were collected from the DrugBank data set. The study was carried out
using 415 drugs and 350 targets. Furthermore, drug-target interactions were vali-
dated using 4 different data sets; TTD, MATADOR, IUPHAR and STITCH. For 632
drugs, 2529 interactions from the TTD data set, 15,483 from the MATADOR data
set, 13,679 from the IUPHAR/BPS data set and 3424 from the STITCH data set
were obtained. DNNs were used as a deep learning model and it was compared with
LR (Linear Regression), RF, VC (Voting Classifier), and GBDT (Gradient Boosting
Decision Tree) classifiers. The performance of the models was determined by accu-
racy and F-score, and the best performance was obtained with DNNs. In study of
Wang et al. [54], drug-target interactions prediction was performed with the LSTM
model. The data were obtained from 3 different data sets including, KEGG, Drug-
Bank and SuperTarget. Drug molecules have been characterized using PubChem
fingerprint. Target proteins were mapped with the PSSM (Position-Specific Score
Matrices) matrix. Subsequently, drug molecules and target proteins were combined
to form a vector space. However, due to the large size of the vector space, SPC (Sparse
Principal Component) analysis was used and the feature space was reduced. Later,
these reduced features were classified with the deep LSTM model. The performance
of the proposed method was determined by accuracy, true-positive rate, specificity,
positive-predictive value, and MCC (Matthews Correlation Coefficient). In addition,
the classification results of deep LSTM model was compared with SVM, and MLP
(Multi-Layer Perceptron). It was observed that the best results were obtained with the
proposed deep LSTM model. Hu et al. [22] performed large-scale prediction to deter-
mine drug-target interactions. In the study, authors firstly applied data extraction. In
data extraction phase, drug compounds were analyzed with molecular fingerprints
and protein sequences were analyzed with protein descriptors. Later, they applied
SAE (Stacked Auto-Encoder) to generate representations for both drugs and protein
sequences. By applying SAE, researchers obtained deep representations and they
classified the representations with SVM classifier. After the classification, the inter-
actions between drugs and targets were determined. The performance of the classifier
was determined by the AUC (Area Under Curve) score, and at the end of the study,
researchers achieved AUC scores of 0.886 for nuclear receptors, 0.904 for GPCRs
(G-Protein Coupled Receptors), 0.933 for Ion channels, and 0.969 for enzymes. In
study of Xie et al. [60], drug-target interaction prediction was carried out by classi-
fying transcriptome data with deep learning. In the study, data were obtained from
L1000 and DrugBank data sets. Firstly, researchers computed Pearson correlation
coefficient values for certain drugs. Then, they applied k-means clustering algorithm
to cluster the drugs. Later, researchers formed sets for drugs to determine the drug-
target interactions. In the study, the interactions between drugs and targets were
determined several machine learning algorithms and one deep learning algorithm.
They can be expressed as follows; LR, RF, VC, GBDT, and DNN. The performance
of classifiers was determined with validation accuracy, and F-score matrices. With the
proposed deep learning model (DNN), the researchers achieved a validation accuracy
of 90.53% and an F-score of 86.38. Mahmud et al. [37] proposed a deep learning-
based model called DeepACTION to predict novel drug-target interactions. Drugs
and targets were obtained from the DrugBank data set and a total of 5877 drugs and
3348 targets were used. Study consisted of three stages; feature extraction, feature
selection, and classification. While protein sequences were analyzed by PROFEAT
web server, chemical structures of drugs were analyzed with Rcpi toolkit. Then, 193
and 1290 features were obtained for drugs and protein sequences, respectively. After
the feature extraction process, feature selection was made using the LASSO regres-
sion analysis method. In the last stage, the classification was made and drug-target
interactions were predicted. CNN-based deep learning model was developed for clas-
sification and the performance of this developed method was compared with KNN,
XGBoost and GBN (Gaussian Naïve Bayesian) algorithms. The performances of
the classifiers were determined by AUC, accuracy, sensitivity, precision, F1-score,
and PR (Positive Rate). The best performance was achieved with the developed
classifier and an accuracy of 0.9744 was obtained. Ozturk et al. [44] proposed a
deep learning method to predict drug-target binding affinity. In the study, authors
evaluated their deep learning model on two various datasets, including Kinase, and
KIBA. A total of 442 protein sequences, 68 drug compounds and 30,056 interactions
were obtained from the Kinase data set. In addition, a total of 229 protein inter-
actions, 2111 drug compounds and 118,254 interactions were evaluated from the
KIBA data set. Drug compounds were expressed with SMILES (Simplified Molec-
ular Input Line Entry System) codes and mapped with label encoding method. Simi-
larly, protein sequences were mapped by label encoding method. Subsequently, the
mapped drug compounds and protein sequences were classified using convolutional
neural networks and feature extraction was performed. Finally, the features were
combined and the classification process was carried out. The performance of the clas-
sifier has been determined by the CI (Concordance Index) and AUPR (Area Under
Precision Recall). In study of Wang et al. [53], authors predicted drug-target inter-
actions by applying deep neural network. As data sets, authors obtained interactions
between drugs and target proteins from SuperTarget, DrugBank, KEGG BRITE,
and BRENDA. The data in the data set were evaluated in 4 different categories;
enzymes, ion channels, GPCRs and nuclear receptors. A total of 932 drugs, 989
target proteins and 5118 interactions were evaluated in the study. In the study, while
protein sequences were mapped by the PSSM method, drug compounds were mapped
by molecular fingerprint method. Later, PCA (Principal Component Analysis) was
applied to reduce the features. In order to determine the drug-target interactions,
RFC (Rotation Forest Classifier) was employed. The performance of the classifier
was determined with accuracy, sensitivity, precision, MCC, and AUC scores. At the
end of the study, an average performance of 94.14% accuracy, 95.55% sensitivity,
92.93% precision, 88.32% MCC and 94.25% AUC values were obtained.
3 Proposed Method
3.1 COVID-19 Drug-Target Interactions
In this study, the known drug-target interactions of COVID-19 were obtained from the
DrugBank data set. DrugBank data set [31, 34, 56] is one of the most used data sets in
this field. The DrugBank data set contains comprehensive and detailed information
on drug-target interactions. Interactions in this data set have been obtained from
published articles and other electronic data sets. Researchers can access the data
free of charge via the given link (https://www.drugbank.ca/). When the study was
Table 1 Some of the

Drug Target
drug-target interactions
identified for COVID-19 Ritonavir Human immunodeficiency virus type 1
disease Darunavir Human immunodeficiency virus type 1
Lopinavir Human immunodeficiency virus type 1
Methylprednisolone Glucocorticoid receptor
Leronlimab C–C chemokine receptor type 5
Tocilizumab Interleukin-6 receptor subunit alpha
Colchicine Tubulin beta chain
Remdesivir Replicase polyprotein 1ab
Galidesivir RNA-directed RNA polymerase L
Favipiravir RNA-directed RNA polymerase catalytic
subunit
conducted, a total of 58 drug-target interactions were identified for COVID-19. These

interactions may have increased for now, but in this study, we predicted over 58
interactions. Table 1 shows some of the drug-target interactions specified for the new
type of corona virus. Researchers can access all targets from the DrugBank data set.
A total of 8050 proteins were used in the study and 58 drug-target interactions
were employed. Drug-target interactions were collected from the DrugBank data set,
while protein sequences were obtained from the UniProt data set. This data set of
known drug-target interactions are considered to be the gold standard for evaluating
the performance of the proposed model. Target proteins bind to drug molecules and
form an interaction network. In order to obtain positive data from the interaction
network, all known drug-target pairs in gold standard data set were regarded as
positive samples. The remaining drug-target pairs in the interaction network formed
negative samples. Since the number of non-interacting pairs is higher than the number
of interacting pairs, the generated data sets were imbalanced. To solve this problem,
we randomly selected negative samples (non-interacting drug-target pairs) from the
remaining interaction network, until the number of negative samples is the same as
that of positive samples (interacting drug-target pairs). In this case, half of the 8050
proteins formed positive samples, while the other half constituted negative samples.
3.2 Characterization of Drug Compounds
In the study, drug compounds were mapped with PubChem fingerprint method.
Fingerprints were originally introduced to help researches to describe the chemical
sub-structures of drugs. The fingerprints in this study were generated by the PubChem
in order to encode 3D structures of drug compounds to simulation-based method. In
general, these fingerprints are employed to generate the ideal 3D chemical structure
of a drug compound by similarity searching and similarity neighboring. The main
O OH Bit Position Bit Substructure
0 >= 4 H
1 >= 8 H
2 >= 16 H
O 3 >= 32 H
4 >= 1 Li
5 >= 2 Li
6 >= 1 B
7 >= 2 B
O 8 >= 4 B
... ...
Aspirin Structure PubChem Molecular Fingerprint
Fig. 2 Drug structure of aspirin and its PubChem fingerprint
reason we used this method is, in some studies, it has been confirmed that substructure
fingerprints has an ability to characterize drug molecules. Drugs were characterized
with Boolean substructure vector which represents the presence or absence of corre-
sponding substructures in a drug molecule. According to the PubChem data set, there
are 881 chemical substructures in which each substructure is assigned to a particular
location. In this method, each drug compound is represented with a chemical feature
vector DC (chem) = (dc1 , dc2 , dc3 , . . . , dcx )T , where each element encodes for
the presence or absence of each substructure by 1 or 0, respectively and x repre-
sents the fingerprints. In short, when a substructure appears in the drug compound,
the position in the fingerprint vector corresponding to the substructure is set to 1,
otherwise is set to 0. Figure 2 gives the structure of aspirin and the corresponding
PubChem molecular fingerprint.
3.3 Mapping of Target Protein Sequences
Protein sequences are usually expressed in letters. Each amino acid has a specific
letter equivalent. However, protein sequences expressed in this way cannot be evalu-
ated by computational methods. These sequences must be converted to the numerical
representations in order to be processed by artificial intelligence. Selected numerical
mapping methods also significantly affect the success of studies based on artificial
intelligence [6]. When predicting drug-target interactions, target proteins are usually
mapped by methods such as PSSM and embedding. In this study, protein mapping
methods were used rather than these methods to convert target proteins to their numer-
ical representations. Protein mapping methods are evaluated in different categories
according to information acquisition and information sources [26]. In this study, 6
protein mapping techniques belonging to 3 different categories were examined. In
Table 2, protein mapping techniques and their categories are given.
Table 2 Protein mapping

Category Protein mapping technique
methods and their categories
used in the study Physicochemical-based Meiler parameters
Atchley factors
Evolution-based PAM250
BLOSUM62
Structure-based Miyazawa energies
Micheletti potentials
3.3.1 Physicochemical-Based Protein Mapping Methods
Generally, an amino acid consists of carbon, hydrogen, carboxyl group, side chain
and an amino group. The physicochemical properties of these components play a
key role in the formation of the protein’s structure and functions. In similarity-
based approach, chemical structure similarity is very important when determining
drug-target interactions. Therefore, in this study, we examined two different protein
mapping techniques from the physicochemical-based category to predict drug-target
interactions. Additionally, we thought that physicochemical-based approaches could
be an alternative to similarity-based approaches since, both contain chemical struc-
ture information of drug and target proteins. Meiler parameters [39, 40] have been
presented to determine reduced representations of amino acids. The main idea of
reduction and extraction of relevant information from amino acid sequences is to
provide a fast and efficient protein mapping to process protein data. Meiler parame-
ters includes seven parameters and can be indicated as follows; steric parameter (s),
polarizability (p), volume (v), hydrophobicity (h), isoelectric point (i), helix proba-
bility (h), and sheet probability (sp). Meiler parameters used in the study are given
in Table 3.
Steric parameter represents the graph shape index. Polarity or polarizability is
the property of a molecule to be induced by a dipole. Polarization increases with
the number of electrons. Volume value refers to the van der Waals volume values
of the proteins. Hydrophobicity, can be represented as a free energy change for the
exchange of an amino acid from an apolar solvent. Isoelectric point is the pH point
at which the net charge of a molecule is zero (0). Helix and sheet are concepts
related to protein structures. Atchley factors have been proposed to eliminate metric
problems in protein sequences [6]. In recent studies, alphabetical ordering and infor-
mation theory are used to map protein sequences to determine variability, and covari-
ability within protein sequences. Some of the authors, applied multivariate analyses
to better comprehend the dimensionality and patterns of multidimensional sequence
data [12, 27]. Yet, with these methods, it is difficult to define negative relationships
between protein sequence sites [5]. In addition, it provides little information about
the observed covariations. Because of such disadvantages and metric problems, the
authors proposed a novel protein mapping technique. There are 5 factors in total
and these factors express the polarity value, secondary structure, molecular volume,
codon density and electrostatic charge of the protein, respectively. The first factor was
Table 3 Meiler parameters of amino acid codes

Amino acid s p v h i h sp
A 1.28 0.05 1.00 0.31 6.11 0.42 0.23
R 2.34 0.29 6.13 −1.01 10.74 0.36 0.25
N 1.60 0.13 2.95 −0.60 6.52 0.21 0.22
D 1.60 0.11 2.78 −0.77 2.95 0.25 0.20
C 1.77 0.13 2.43 1.54 6.35 0.17 0.41
E 1.56 0.15 3.78 −0.64 3.09 0.42 0.21
Q 1.56 0.18 3.95 −0.22 5.65 0.36 0.25
G 0.00 0.00 0.00 0.00 6.07 0.13 0.15
H 2.99 0.23 4.66 0.13 7.69 0.27 0.30
I 4.19 0.19 4.00 1.80 6.04 0.30 0.45
L 2.59 0.19 4.00 1.70 6.04 0.39 0.31
K 1.89 0.22 4.77 −0.99 9.99 0.32 0.27
M 2.35 0.22 4.43 1.23 5.71 0.38 0.32
F 2.94 0.29 5.89 1.79 5.67 0.30 0.38
P 2.67 0.00 2.72 0.72 6.80 0.13 0.34
S 1.31 0.06 1.60 -0.04 5.70 0.20 0.28
T 3.03 0.11 2.60 0.26 5.60 0.21 0.36
W 3.21 0.41 8.08 2.25 5.94 0.32 0.42
Y 2.94 0.30 6.47 0.96 5.66 0.25 0.41
V 3.67 0.14 3.00 1.22 6.02 0.27 0.49
evaluated in this study since chemical values are prominent in the physicochemical-
based approach. Table 4 represents the Atchley factors which have been applied in
this study.
Table 4 Atchley factors of

Amino acid Factor 1 Amino acid Factor 1
amino acid codes
A −0.591 L −1.019
R 1.538 K 1.831
N 0.945 M −0.663
D 1.050 F −1.006
C −1.343 P 0.189
E 1.357 S −0.228
Q 0.931 T −0.032
G −0.384 W −0.595
H 0.336 Y 0.260
I −1.239 V −1.337
3.3.2 Evolution-Based Protein Mapping Methods
In evolution-based approaches, evolutionary information of sequences is obtained.

This information is often gathered from phylogenetic trees or sequence alignment
processes. The evolution-based approach falls into two separate categories: position-
dependent and position-independent. In this study, we considered two of the position-
independent methods, PAM250 and BLOSUM62 matrices. The main reason we
chose position-independent mapping methods is that amino acid sequences are
encoded in these methods regardless of the location and composition of amino
acids. PSSM, one of the evolution-based methods, is generally preferred in drug-
target interaction studies. Yet, this method was not evaluated in this study as it
is position-dependent. The PAM250 scoring matrix is often used to score aligned
peptide sequences to determine similarity in these sequences [45]. The matrix scores
are derived from comparing aligned sequences of proteins with known homology
[13]. In the matrix, each column and each row represents the standard twenty amino
acids. Each input in a PAM250 matrix shows that the amino acid of that row will be
replaced with the amino acid of that column based on likelihood through a series of
one or more point accepted mutations. In Table 5, we provided the PAM250 scoring
matrix.
Similarly, the BLOSUM62 matrix is a scoring matrix and it is often used to score
alignments between different protein sequences [20]. The process is based on local
alignments. The BLOSUM62 matrix was formed from the relative frequencies of
amino acid sequences and their substitution probabilities. Later log-odds scores of
each of the 210 possible substitution pairs of the 20 amino acid sequences. All of
the BLOSUM matrices were generated based on observed alignments. In Table 6,
BLOSUM62 scoring matrix is given.
3.3.3 Structure-Based Protein Mapping Methods
Structure-based mapping methods encode amino acid sequences using statistical

potentials linked to the structure [51]. In this study, Miyazawa energies and
Micheletti potentials were considered from this category. Miyazawa energies have
been proposed to determine energies between residues in protein sequences [42].
Since protein structures are also used in the docking-approach, we have used protein
mapping techniques from the structure-based category. The contact energies of
protein sequences were obtained with regression coefficients in Miyazawa ener-
gies. After the calculation of contact energies, the conformational energy values of
protein sequences were considered. In Miyazawa energies, conformational energies
were categorized into two terms; secondary structure energies and tertiary structure
energies. Tertiary structure energies are obtained by summing the residue-residue
contact energies of the proteins. The secondary structure energies are calculated
based on backbone-backbone interactions and backbone-side chain interactions. All
these calculations are based on the structure information of proteins, and hence
Table 5 PAM250 scoring matrix

A R N D C Q E G H I L K M F P S T W Y V B Z X *
A 2 -2 0 0 -2 0 0 1 -1 -1 -2 -1 -1 3 1 1 1 -6 -3 0 0 0 0 -8
R -2 6 0 -1 -4 1 -1 -3 2 -2 -3 3 0 -4 0 0 -1 2 -4 -2 -1 0 -1 -8
N 0 0 2 2 -4 1 1 0 2 -2 -3 1 -2 -3 0 1 0 -4 -2 -2 2 1 0 -8
D 0 -1 2 4 -5 2 3 1 1 -2 4 0 -3 -6 -1 0 0 -7 -4 -2 3 3 -1 -8
C -2 -4 -4 -5 12 -5 -5 -3 -3 -2 -6 -5 -5 -4 -3 0 -2 -8 0 -2 -4 -5 -3 -8
Q 0 1 1 2 -5 4 2 -1 3 -2 -2 1 -1 -5 0 -1 -1 -5 -4 -2 1 3 -1 -8
E 0 -1 1 3 -5 2 4 0 1 -2 -3 0 -2 -5 -1 0 0 -7 -4 -2 3 3 -1 -8
G 1 -3 0 1 -3 -1 0 5 -2 -3 -4 -2 -3 -5 0 1 0 -7 -5 -1 0 0 -1 -8
H -1 2 2 1 -3 3 1 -2 6 -2 -2 0 -2 -2 0 -1 -1 -3 0 -2 1 2 -1 -8
I -1 -2 -2 -2 -2 -2 -2 -3 -2 5 2 -2 2 1 -2 -1 0 -5 -1 4 -2 -2 -1 -8
L -2 -3 -3 -4 -6 -2 -3 -4 -2 2 6 -3 4 2 -3 -3 -2 -2 -1 2 -3 -3 -1 -8
K -1 3 1 0 -5 1 0 -2 0 -2 -3 5 0 -5 -1 0 0 -3 -4 -2 1 0 -1 -8
M -1 0 -2 -3 -5 -1 -2 -3 -2 2 4 0 6 0 -2 -2 -1 -4 -2 2 -2 -2 -1 -8
F -3 -4 -3 -6 -4 -5 -5 -5 -2 1 2 -5 0 9 -5 -3 -3 0 7 -1 -4 -5 -2 -8
P 1 0 0 -1 -3 0 -1 0 0 -2 -3 -1 -2 -5 6 1 0 -6 -5 -1 -1 0 -1 -8
S 1 0 1 0 0 -1 0 1 -1 -1 -3 0 -2 -3 1 2 1 -2 -3 -1 0 0 0 -8
T 1 -1 0 0 -2 -1 0 0 -1 0 -2 0 -1 -3 0 1 3 -5 -3 0 0 -1 0 -8
W -6 2 -4 -7 -8 -5 -7 -7 -3 -5 -2 -3 -4 0 -6 -2 -5 17 0 -6 -5 -6 -4 -8
Y -3 -4 -2 -4 0 -4 -4 -5 0 -1 -1 -4 -2 7 -5 -3 -3 0 10 -2 -3 -4 -2 -8
V 0 -2 -2 -2 -2 -2 -2 -1 -2 4 2 -2 2 -1 -1 -1 0 -6 -2 4 -2 -2 -1 -8
B 0 -1 2 3 -4 1 3 0 1 -2 -3 1 -2 -4 -1 0 0 -5 -3 -2 3 2 -1 -8
Z 0 0 1 3 -5 3 3 0 2 -2 -3 0 -2 -5 0 0 -1 -6 -4 -2 2 3 -1 -8
X 0 -1 0 -1 -3 -1 -1 -1 -1 -1 -1 -1 -2 -2 -1 0 0 -4 -2 -1 -1 -1 -1 -8
* -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8
Miyazawa energies are evaluated in structure-based mapping techniques. Miyazawa

energy values of amino acids are given in Table 7.
Micheletti potentials, one of the structure-based mapping methods, are based on
the potential energy in the interaction between proteins [41]. The main idea of the
Micheletti potentials was to determine the optimal interactions. In order to find the
optimal interactions between proteins, they used the perceptron algorithm defined
by Krauth and Mezard [32]. In Table 8, Micheletti potentials of each amino acids
have been given.
Table 6 BLOSUM62 scoring matrix

A 4
R -1 5
N -2 0 6
D -2 -2 1 6
C 0 -3 -3 -3 9
Q -1 1 0 0 -3 5
E -1 0 0 2 2 2 5
G 0 -2 0 -1 -3 -2 -2 6
H -2 0 1 -1 -3 0 0 -2 8
I -1 -3 -3 -3 -1 -3 -3 -4 -3 4
L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4
K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5
M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5
F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6
P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7
S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4
T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5
W -3 -3 -4 4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -2 11
Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7
V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4
A R N D C Q E G H I L K M F P S T W Y V
Table 7 Miyazawa energies

Amino acid Miyazawa Amino acid Miyazawa
of amino acid codes
energies energies
A −0.02 L −0.32
R 0.08 K 0.30
N 0.10 M −0.25
D 0.19 F −0.33
C −0.32 P 0.11
E 0.21 S 0.11
Q 0.15 T 0.05
G −0.02 W −0.27
H −0.02 Y −0.23
I −0.28 V −0.23
Table 8 Micheletti potentials

Amino acid Micheletti Amino acid Micheletti
of amino acid codes
potentials potentials
A −0.001461 L −0.000782
R 0.009875 K 0.005109
N −0.001962 M 0.031655
D −0.000531 F −0.013128
C −0.002544 P −0.003621
E 0.006456 S −0.000802
Q 0.008438 T 0.003269
G 0.000990 W 0.131813
H 0.001314 Y −0.007699
I 0.006801 V 0.001445
4 Application Results and Discussion
Deep learning is used actively in almost every field today. There are studies in the
biomedical field such as diagnosis of cardiac arrhythmia [24, 52], detection of brain
injuries [43, 48], prediction of breast and skin cancer [8, 18, 62], and prediction of
epilepsy [1, 23]. In addition to biomedical studies, bioinformatics studies are also
observed. Some of these studies include prediction of interactions between proteins
[2], classification of protein families [65], determination of protein functions [33],
prediction of drug-target interactions [47]. When these studies were examined in
detail, it was observed that the LSTM deep learning model was efficient. One of the
biggest reasons for this situation is that the LSTM deep learning model is effective
on time series data. Therefore, in this study, the LSTM deep learning model was
employed and drug-target interactions of COVID-19 were predicted. LSTM is a
type of recurrent neural network and generally produces more successful results than
traditional RNN (Recurrent Neural Network) architectures [9]. The main difference
of LSTM model from standard RNN model is that there are memory blocks in LSTM
model. In memory blocks, self-connection memory cells are responsible for swaying
the information flow by storing input gate, output gate, forget gate, and temporal state.
Forget gate removes information from the cell state. Information that LSTM won’t
use or that is of low importance is removed through certain filters. This is an essential
process for optimizing the performance of the LSTM network. The input gate, as the
name suggests, adds inputs that enter the network. The output gate gives the output
of the network. The gates in the LSTM model allow LSTM to store information and
access this information over time. In this way, the effect of the vanishing gradient
problem that occurs in the RNN architecture significantly decreases. Recurrent neural
networks are effective in analyzing short-term dependencies. In RNN architectures,
it doesn’t matter what previous information is or what this information means. RNN
architectures only work with the information provided. However, RNN architectures
have difficulty understanding the context of an input. Something that was analyzed
Fig. 3 Structure of designed LSTM model
long before, cannot be recalled when making predictions in the present. The related
information may be dispersed from the point where it is needed, by a huge load of
irrelevant data. When this is the case, the gradient vanishing problem arises. In order
to make a good prediction and classification, RNN should remember the context
of the information. In summary, RNN architectures can be effective if there is a
short-term flow of information. However, it has been observed that the LSTM model
is more successful if long-term information is required to perform the prediction
process. In this study, vanilla LSTM was used and the flow chart of the developed
deep learning model is given in Fig. 3.
As seen in Fig. 3, in the first step, the characterized drug compounds and mapped
protein sequences were combined and formed an array. Then this array was selected
as an input to be classified in the LSTM model. The parameters of the developed
LSTM model were determined by trial and error approach and the parameters that
gave the best result were used in the study. These parameters can be expressed as
follows:
• Single layer LSTM with 512 units was applied.
• Then, the flatten process was employed and the data were transformed into a
1-dimensional array and prepared for the next layer.
• After, batch normalization was performed to make the model work faster and
more stable, and the values were scaled and re-centered again.
• Later, two fully-connected layers were used and the number of neurons in these
layers was determined as 2048 and 1024, respectively.
• Finally, two neurons were used in the output layer and the prediction was
performed.
• To determine the loss of the network, binary cross-entropy was considered.
• As an optimizer, SGD (Stochastic Gradient Descent) optimization was used with
default parameters.
• In order to train and validate the data, tenfold cross-validation approach was
considered with number of 250 epochs.
• We split the original dataset for training, validation and testing to evaluate the
performance off the protein mapping methods. 70% of the data was used for
training, 15% was evaluated for validation, and the remaining 15% was employed
for testing (blind dataset). In Fig. 4, we provided the diagrammatic scheme of the
validation phase of the drug-target interaction used in this study.
• This process was carried out one by one for 6 protein mapping techniques and
their performances were compared. The efficiency of protein mapping methods
was determined with accuracy (ACC), precision (PREC), recall (REC), f1-score
(F1SC), and receiver operating characteristic (ROC). Table 9 shows the evaluation
results of protein mapping techniques.
Original Dataset
Training/Validation Dataset Blind Dataset (Test Dataset)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Iteration # Iteration # Test Set

Iteration 1 F1...F9 F10
Iteration 2 F1...F8, F10 F9
Iteration 3 F1...F7, F9, F10 F8
Iteration 4 F1...F6, F8...F10 F7
Iteration 8 F1, F2, F4...F10 F3
Iteration 9 F1, F3...F10 F2
Iteration 10 F2...F10 F1
Fig. 4 Validation process of the drug-target interaction. While 85% of the original dataset includes
of training and validation data, the remaining 15% is the blind dataset
Table 9 Comparison results of protein mapping methods

Protein mapping Category ACC REC PREC F1SC ROC
BLOSUM62 Evolution 0.8735 0.8770 0.8756 0.8762 0.89
PAM250 Evolution 0.9138 0.9145 0.9138 0.9141 0.92
Atchley factors Physiochemical 0.9211 0.9179 0.9171 0.9174 0.98
Meiler parameters Physiochemical 0.9106 0.9126 0.9130 0.9127 0.98
Micheletti potentials Structure 0.9042 0.9065 0.9069 0.9067 0.98
Miyazawa energies Structure 0.9181 0.9203 0.9203 0.9203 0.96
When the results in Table 9 are evaluated, it is seen that all methods successfully
predicted DTIs of COVID-19. Evolution-based approaches have been observed to
be the most unsuccessful of the three categories. Accuracy, precision, recall and f1-
score results were as effective as other methods, while ROC scores did not produce
as successful results as other methods. While the PAM250 scoring matrix predicted
drug-target interactions with an accuracy of 0.9138, this rate decreased to 0.8735 with
BLOSUM62. Similar inferences can be made for other evaluation criteria. Overall,
the main reason why evolution-based approaches perform poorly may be that distant
homologous protein sequences provide only limited evaluation information for the
target residue [14]. The reason for this may be that the disease is a new disease
and the target proteins are not known clearly. Thus, knowledge of evolution in this
disease is limited. It was determined that the second best results were obtained from
structure-based approaches. The average accuracy, precision, sensitivity, f1-score and
ROC values of these structure-based approaches were calculated as 0.9112, 0.9136,
0.9134, 0.9135, and 0.97, respectively. When the mapping methods in this category
were examined, it was seen that both methods produced similar results. The difference
between the two methods is calculated as approximately 2 in all evaluation criteria.
This situation shows that although the two methods perform different mapping, they
reveal similar structural features. This may be because the structure of the proteins
belonging to COVID-19 has not been clearly determined. In contrast to these two
categories, it has been observed that the best interaction prediction results are obtained
from physicochemical-based approaches. Average accuracy, precision, recall, f1-
score and ROC values were calculated as 0.9159, 0.9153, 0.9151, 0.9151 and 0.98,
respectively. Atchley factors and Meiler parameters produced very similar results.
The main reason why the most successful category is this category may be that the
mapping methods in this category obtain various numbers of features. The presence
of five factors in Atchley factors and seven parameters in Meiler parameters increase
the number of features obtained from proteins. In this way, a lot of information can
be obtained from a protein. Looking at the comparison results, it was observed that
mapping techniques belonging to all categories were successful. ROC curves of all
protein mapping methods are given in Fig. 5.
As in every study, there are some advantages and disadvantages in this study.
The advantages can be listed as follows; with this study, it was determined that the
deep learning method is at least as effective as the existing methods. Furthermore, it
has been observed that the deep learning algorithm is successful for the prediction
process. To the best of our knowledge, for the first time in this study, drug-target inter-
actions of COVID-19 disease were predicted by deep learning method and protein
mapping methods. The disadvantages can be expressed as follows; the performance
of deep learning algorithms generally varies according to the number of data. In order
for deep learning algorithms to be applied, the number of data should be sufficient.
In this study, a total of 8050 protein sequences and 58 drug-target interactions were
used. These data may not be sufficient to determine the reliability of the system.
While this study was being carried out, there were 58 drug-target interactions in
total for COVID-19 disease. The number of these interactions may change in the
Fig. 5 ROC curve of all protein mapping methods. (Orange ones refer to evolution-based methods,
blue ones to physicochemical-based, and pink ones to structure-based protein mapping methods)
future. This may cause the data used to be too little or too much. Researchers need
to consider these situations.
5 Conclusion
In this study, the prediction of drug-target interactions for COVID-19 disease

was performed. The study consisted of five stages. In the first stage, drug-target
interactions of COVID-19 were obtained from the DrugBank data set and the
target proteins were collected from the UniProt data set. In the second stage, the
drug compounds were characterized by PubChem fingerprint method while target
proteins were converted to the numerical representations by certain protein mapping

methods. In the third stage, the characterized drug compounds and mapped target
proteins were combined. Thus, a one-dimensional space vector has been obtained
for each interaction. In the fourth stage, all interactions were brought together and
classified using the LSTM model. In the last stage, the performances of protein
mapping methods were compared. Protein mapping techniques were divided into
three different categories; Evolution-based, structure-based and physicochemical-
based. PAM250 and BLOSUM62 scoring matrices were used for the evolution-
based approach. Micheletti potentials and Miyazawa energies were employed for the
structure-based approach. Finally, for the physicochemical-based approach, Atchley
factors and Meiler parameters were considered. The results of the application showed
that the protein mapping techniques were successful. The average accuracy and ROC
value were 0.8937 and 0.81 in the evolution-based approach, while this ratio increased
in the structure-based approach and was 0.9112 and 0.97, respectively. However,
the best results have been obtained from physicochemical-based approaches. These
results show that protein mapping techniques can be used successfully in this field.
Yet, the performance of the methods should also be determined in other drug-target
interaction studies. Therefore, these methods may be tested on different drug-target
interactions in the future. In this way, the performance of these approaches can be
observed in more detail. In addition, as with many other diseases, it may be neces-
sary to determine virus-host interactions in order to observe and understand infor-
mation about COVID-19 disease. For this reason, in the future, these methods may
be evaluated in studies to predict the interaction of the SARS-COV2 virus with host
cells.
Furthermore, protein functions play an important role to understand the structure
of amino acids and their behavior. In future studies, protein functions of the virus
belonging to COVID-19 can be predicted by protein mapping methods and more
detailed information about amino acids can be obtained. Determining the family
of the protein sequences is important to develop new types of drugs or the correct
use of existing drugs. Protein families contain information about the functions and
structures of proteins. In this context, the families of proteins belonging to COVID-19
can be examined with existing protein mapping methods and the GO terms to which
the proteins are bound can be determined in future studies. In addition, protein–
protein interactions play an important role in protein studies. Accurate prediction of
the interactions between protein pairs belonging to COVID-19 and the interactions
between proteins of the human genome can provide us with more detailed information
about the protein structure of this virus. Therefore, it is important to evaluate existing
protein mapping methods and to compare their results.
References
1. Alakus, T.B., Turkoglu, I.: Detection of pre-epileptic seizure by using wavelet packet decompo-
sition and artificial neural networks. In: Proceedings of International Conference on Electrical
and Electronics Engineering. IEEE (2017)
2. Alakus, T.B., Turkoglu, I.: Prediction of protein-protein interactions with LSTM deep learning
model. In: Proceedings of the International Symposium on Multidisciplinary Studies and
Innovative Technologies. IEEE (2019)
3. Alakus, T.B., Turkoglu, I.: Comparison of deep learning approaches to predict COVID-19.
Chaos, Solutions Fractals 140, 110120 (2020)
4. Anderson, R.M., Heesterbeek, H., Klinkenberg, D., Hollingsworth, T.D.: How will country-
based mitigation measures influence the course of the COVID-19 epidemic? Lancet
395(10228), 931–934 (2020)
5. Atchley, W.R., Terhalle, W., Dress, A.: Positional dependence, cliques, and predictive Motifs
in the bHLH protein domain. J. Mol. Evol. 48(5), 501–516 (1999)
6. Atchley, W.R., Zhao, J., Fernandes, A.D., Drüke, T.: Solving the protein sequence metric
problem. Proc. Nat. Acad. Sci. U.S.A. 102(18), 6395–6400 (2005)
7. Bagherian, M., Sabeti, E., Wang, K., Sartor, M.A., Nikolovsa-Coleska, Z., & Najarian, K.:
Machine learning approaches and databases for prediction of drug-target interaction: a survey
paper. Briefings Bioinf. bbz157 (2020)
8. Charan, S., Khan, M.J., Khurshid, K.: Breast cancer detection in mammograms using convolu-
tional neural network. In: Proceedings of International Conference on Computing, Mathematics
and Engineering Technologies. IEEE (2018)
9. Chen, H., Engkvist, O., Wang, Y., Olivecrona, M., Blaschke, T.: The rise of deep learning in
drug discovery. Drug Discov. Today 23(6), 1241–1250 (2018)
10. Chen, R., Liu, X., Jin, S., Lin, J., Liu, J.: Machine learning for drug-target interaction prediction.
Molecules 23(9), 2208 (2018)
11. Cheng, F., Zhou, Y., Li, J., Li, W., Liu, G., Tang, Y.: Prediction of chemical-protein interactions:
multitarget-QSAR versus computational chemogenomic methods. Mol. BioSyst. 8, 2373–2384
(2012)
12. Clementi, M., Clementi, S., Cruciani, G., Pastor, M., Davis, A.M., Flower, D.R.: Robust multi-
variate statistics and the prediction of protein secondary structure content. Protein Eng. Des.
Sel. 10(7), 747–749 (1997)
13. Dayhoff, M.O., Schwartz, R.M.: Chapter 22: A model of evolutionary change in proteins. In:
Atlas of Protein Sequence and Structure, vol. 5, pp. 89–99 (1978)
14. ElAbd, H., Bromberg, Y., Hoarfrost, A., Lenz, T., Franke, A., Wendorff, M.: Amino acid
encoding for deep learning applications. BMC Bioinf. 21, 235 (2020)
15. Gates, B.: Responding to Covid-19—a once-in-a-century pandemic? N. Engl. J. Med. 382,
1677–1679 (2020)
16. Grasselli, G., Pesenti, A., Cecconi, M.: Critical care utilization for the COVID-19 outbreak in
Lombardy, Italy: early experience and forecast during an emergency response. JAMA 323(16),
1545–1546 (2020)
17. Guan, W., Ni, Z., Hu, Y., Liang, W., Ou, C., He, J., Liu, L., Shan, H., Lei, C., Hui, D.S.C., Du,
B., Li, L., Zeng, G., Yuen, K.Y., Chen, R., Tang, C., Wan, T., Chen, P., Xiang, J., Li, S., Wang,
J., Liang, Z., Peng, Y., Wei, L., Liu, Y., Hu, Y., Peng, P., Wang, J., Liu, J., Chen, Z., Li, G.,
Zheng, Z., Qiu, S., Luo, J., Ye, C., Zhu, S., Zhong, N.: Clinical characteristics of coronavirus
disease 2019 in China. N. Engl. J. Med. 382(18), 1708–1720 (2020)
18. Hadush, S., Girmay, Y., Sinamo, A., Hagos, G.: Breast cancer detection using convolutional
neural networks. arXiv.2003.07911 (2020)
19. He, Z., Zhang, J., Shi, X.H., Hu, L.L., Kong, X., Cai, Y.D., Chou, K.C.: Predicting drug-target
interaction network based on functional groups and biological features. PLoS ONE 5(3), e9603
(2010)
20. Henikoff, S., Henikoff, J.G.: Amino acid substitution metrices from protein blocks. Proc. Nat.
Acad. Sci. U.S.A. 89(22), 10915–10919 (1992)
21. Hinton, G.E., Osindero, S., Teh, Y.W.: A fast learning algorithm for deep belief nets. Neural
Comput. 18(7), 1527–1554 (2006)
22. Hu, P.W., Chan, K.C.C., You, Z.H.: Large-scale prediction of drug-target interactions from
deep representations. In: Proceedings of International Joint Conference on Neural Networks.
IEEE (2016)
23. Ilakiyaselvan, N., Khan, A.N., Shahina, A.: Deep learning approach to detect seizure using
reconstructed phase space images. J. Biomed. Res. 34, 240–250 (2020)
24. Isin, A., Ozdalili, S.: Cardiac arrhythmia detection using deep learning. Procedia Comput. Sci.
120, 268–275 (2017)
25. Jiang, X., Coffee, M., Bari, A., Wang, J., Jiang, X., Huang, J., Shi, J., Dai, J., Cai, J., Zhang,
T., Wu, Z., He, G., Huang, Y.: Towards an artificial intelligence framework for data-driven
prediction of Coronavirus clinical severity. Comput. Mater. Continua 63(1), 537–551 (2020)
26. Jing, X., Dong, Q., Hong, D.C., Lu, R.: Amino acid encoding methods for protein sequences: a
comprehensive review and assessment. In: IEEE Transactions on Computational Biology and
Bioinformatics, 30998480 (2019)
27. Kanehisa, M.: A multivariate analysis method for discriminating protein secondary structural
segments. Protein Eng. 2(2), 87–92 (1988)
28. Kapetanovic, I.M.: Computer-aided drug discovery and development (CADDD): in Silico-
Chemico-Biological approach. Chem. Biol. Interact. 171(2), 165–176 (2008)
29. Keiser, M.J., Setola, V., Irwin, J., Laggner, C., Abbas, A.I., Hufeisen, S.J., Jensen, N.H., Kuijer,
M.B., Matos, R.C., Tran, T.B., Whaley, R., Glennon, R.A., Hert, J., Thomass, K.L.H., Edwards,
D.D., Shoichet, B.K., Roth, B.L.: Predicting new molecular targets for known drugs. Nature
462, 175–181 (2009)
30. Knowles, J., Gromo, G.: Target selection in drug discovery. Nat. Rev. Drug Discov. 2, 63–69
(2003)
31. Knox, C., Law, W., Jewison, T., Liu, P., Ly, S., Frolkis, A., Pon, A., Banco, K., Mak, C.,
Neveu, V., Djoumbou, Y., Eisner, R., Guo, A.C., Wishart, D.S.: DrugBank 3.0: a comprehensive
resource for ‘Omics’ research on drugs. Nucleic Acid Res. 39, 1035–1041 (2011)
32. Krauth, W., Mezard, M.: Learning algorithms with optimal stability in neural networks. J. Phys.
A: Math. Gen. 20(11), 745–752 (1999)
33. Kulmanov, M., Khan, M.A., Hoehndorf, R., Wren, J.: DeepGo: predicting protein functions
from sequence and interactions using a deep ontology-aware classifier. Bioinformatics 34(4),
660–668 (2018)
34. Law, V., Knox, C., Djoumbou, Y., Jewison, T., Guo, A.C., Liu, Y., Maciejewski, A., Arndt, D.,
Wilson, M., Neveu, V., Tang, A., Gabriel, G., Ly, C., Adamjee, S., Dame, Z.T., Han, B., Zhou,
Y., Wishart, D.S.: Nucleic Acid Res. 42, 1091–1097 (2014)
35. Lee, I., Keum, J., Nam, H.: DeepConv-DTI: prediction of drug-target interactions via deep
learning with convolution on protein sequences. PLoS Comput. Biol. 15, 6 (2019)
36. Li, H., Zhenting, G., Kang, L., Zhang, H., Yang, K., Yu, K., Luo, X., Zhu, W., Chen, K., Shen,
J., Wang, X., Jiang, H.: TarFisDock: a web server for identifying drug targets with docking
approach. Nucleic Acid Res. 34(2), 219–224 (2006)
37. Mahmud, S.M.H., Chen, W., Jahan, H., Dai, B., Din, S.U., Dzisoo, A.M.: DeepACTION: a
deep learning-based method for predicting novel drug-target interactions. Anal. Biochem. 610,
113978 (2020)
38. Marcucci, F., Stassi, G., De Maria, R.: Epithelial-Mesenchymal transition: a new target in
anticancer drug discovery. Nat. Rev. Drug Discov. 15, 311–325 (2016)
39. Meiler, J.: PROSHIFT: protein chemical shift prediction using artificial neural networks. J.
Biomol. NMR 26, 25–37 (2003)
40. Meiler, J., Müller, M., Zeidler, A., Xhmaschke, F.: Generation and evaluation of dimension-
reduced amino acid parameter representations by artificial neural networks. Mol. Model. Annu.
7, 360–369 (2001)
41. Micheletti, C., Seno, F., Banavar, J.R., Maritan, A.: Learning effective amino acid interactions
through iterative stochastic techniques. Proteins 42(3), 422–431 (2001)
42. Miyazawa, S., Jernigan, R.L.: Self-consistent estimation of inter-residue protein contact
energies based on an equilibrium mixture approximation of residues. Proteins 34, 49–68 (1999)
43. Monteiro, M., Newcombe, V.F.J., Mathieu, F., Adatia, K., Kamnitsas, K., Ferrante, E., Das, T.,
Whitehouse, D., Rueckert, D., Menon, D.K., Glocker, B.: Multiclass semantic segmentation and
quantification of traumatic brain injury lesions on head CT using deep learning: an algorithm
development and multicentre validation study. Lancet 2(6), 314–322 (2020)
44. Ozturk, H., Ozgur, A., Ozkirimli, E.: DeepDTA: deep drug-target binding affinity prediction.
Bioinformatics 34(17), 821–829 (2018)
45. Pearson, W.R.: Rapid and sensitive sequence comparison with FASTP an FASTA. Methods
Enzymol. 183, 63–68 (1990)
46. Pliakos, K., Vens, C.: Drug-target interaction prediction with tree-ensemble learning and output
space reconstruction. BMC Bioinf. 21, 49 (2020)
47. Rifaioglu, A.S., Nalbat, E., Atalay, V., Martin, M.J., Atalay, R.C., Dogan, T.: DEEPScreen:
high performance drug-target interaction prediction with convolutional neural networks using
2-D structural compound representations. Chem. Sci. 11, 2531–2557 (2020)
48. Roy, S., Knutsen, A., Korotcov, A., Bosomtwi, A., Dardzinski, B., Butman, J.A., Pham, D.L.:
A deep learning framework for brain extraction in humans and animals with traumatic brain
injury. In: Proceedings of the International Symposium on Biomedical Imaging. IEEE (2018)
49. Sahin, A.R., Erdogan, A., Agaoglu, P.M., Dineri, Y., Cakırcı, A.Y., Senel, M.E., Okyay, R.A.,
Tasdogan, A.M.: 2019 Novel Coronavirus (COVID-19) outbreak: a review of the current
literature. Euras. J. Med. Oncol. 4(1), 1–7 (2020)
50. Sheahan, T.P., Sims, A.C., Leist, S.R., Schafer, A., Won, J., Brown, A.J., Montgomery, S.A.,
Hogg, A., Babusis, D., Clarke, M.O., Spahn, J.E., Bauer, L., Sellers, S., Porter, D., Feng,
J.Y., Cihlar, T., Jordan, R., Denison, M.R., Baric, R.S.: Comparative therapeutic efficacy of
remdesivir and combination iopinavir, ritonavir, and interferon beta against MERS-CoV. Nat.
Commun. 11(1), 222 (2020)
51. Tanaka, S., Scheraga, H.A.: Medium-and long-range interaction parameters between amino
acids for predicting three-dimensional structures of proteins. Macromolecules 9(6), 945–950
(1976)
52. Ulah, A., Anwar, S.M., Bilal, M., Mehmood, R.M.: Classification of arrhythmia by using deep
learning with 2-D ECG spectral image representation. Remote Sens. 20, 1685 (2020)
53. Wang, L., You, Z.H., Chen, X., Xia, S.X., Liu, F., Yan, X., Zhou, Y., Song, K.J.: A
computational-based method for predicting drug-target interactions by using stacked autoen-
coder deep neural network. J. Comput. Biol. 24, 1–13 (2017)
54. Wang, Y., You, Z., Yang, S., Yi, H., Chen, Z., Zheng, K.: A deep learning-based method for
drug-target interactions prediction based on long short term-memory neural network. BMC
Med. Inform. Decis. Mak. 20, 49 (2020)
55. Wen, M., Zhang, Z., Niu, S., Sha, H., Yang, R., Yun, Y., Lu, H.: Deep-learning-based drug-target
interaction prediction. J. Proteome Res. 16(4), 1401–1409 (2017)
56. Wishart, D.S., Feunang, Y.D., Guo, A.C., Lo, E.J., Marcu, A., Grant, J.R., Sajed, T., Johnson,
D., Li, C., Sayeeda, Z., Assempour, N., Iynkkaran, I., Liu, Y., Maciejewskş, A., Gale, N.,
Wilson, A., Chin, L., Cummings, R., Le, D., Pon, A., Knox, C., Wilson, M.: Nucleic Acid Res.
46, 1074–1082 (2018)
57. Wit, E., Doremalen, N., Falzarano, D., Munster, V.: SARS and MERS: recent insights into
emerging Coronaviruses. Nat. Rev. Biol. 14, 523–534 (2016)
58. World Health Organization: Report of the WHO-China joint mission on coronavirus
disease (COVID-19). https://www.who.int/docs/default-source/coronaviruse/who-china-joint-
mission-on-covid-19-final-report.pdf (2020)
59. Xie, L., He, S., Song, X., Bo, X., Zhang, Z.: Deep learning-based transcriptome data
classification for drug-target interaction prediction. BMC Genomics 19 (2018)
60. Xie, L., Zhang, Z., He, S., Bo, X., Sung, X.: Drug-target interaction prediction with a deep-
learning-based model. In: Proceedings of International Conference on Bioinformatics and
Biomedicine. IEEE (2017)
61. Yamanishi, Y., Araki, M., Gutteridge, A., Honda, W., Kanehisa, M.: Prediction of drug-target
interaction networks from the integration of chemical and genomic spaces. Bioinformatics
24(13), 232–240 (2008)
62. Yildiz, O.: Melanoma detection from dermoscopy images with deep learning methods: a
comprehensive study. J. Fac. Eng. Archit. Gazi Univ. 34(4), 2241–2260 (2019)
63. You, J., McLeod, R.D., Hu, P.: Predicting drug-target interaction network using deep learning
model. Comput. Biol. Chem. 80, 90–101 (2019)
64. Zarin, D.A., Tse, T., Williams, R.J., Califf, R.M., Ide, N.C.: The ClinicalTrials.gov results
database—update and key issues. N. Engl. J. Med. 364(9), 852–860 (2011)
65. Zhang, D., Kabuka, M.: Protein family classification from scratch: a CNN based deep learning
approach. IEEE/ACM Trans. Comput. Biol. Bioinf. (2020)
COVID-19 Drug Repositioning: Present
Status and Prospects
Chandana Mohanty, Chiluka Vinod, Sarbari Acharya,

and Nikita Mahapatra
Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing

the COVID-19 disease has gained the status of a pandemic worldwide. Till now
no appropriate drug has been identified which can become the gold standard for
coronavirus-2 and drugs such as Favipiravir, Hydroxychloroquine and Remdesivir
used for the treatment of severe cases of COVID-19 have not yielded satisfactory
results owing to many side effects. Although the entire scientific fraternity of the
world is currently engaged to find a permanent cure for this deadly disease, clinical
development of a new drug or vaccine precisely for SARS-CoV-2 will normally take
time. Given the pressing need to quickly find effectual medications for COVID-19,
existing drugs are being repositioned. The term “repositioning” or “repurposing”
refers to the use of approved drugs originally used against other pathogens which
can also be used against SARS-CoV-2. These therapeutics can be chosen from a wide
spectrum of drugs used for cancer-induced inflammation, immune dysfunction, and
coagulopathy. As all these symptoms prevail in patients affected by COVID-19, it is
reasonable to consider testing above mentioned agents in a rational manner against
this viral illness. The main idea behind the repositioning of the drug is to lessen the
time and expenditure which is done to find a new drug and then ushering its transition
from bench to bedside. For narrowing down the search as to which therapeutics can
be considered for repositioning, Artificial Intelligence (AI) can be of great aid. AI
can quickly detect drugs that can fight against COVID-19 pandemic. Besides, it is a
cheaper, faster, and effective approach to find repurposed drugs from a vast array of
therapeutics thereby minimizing the failures in clinical trials. AI-based Deep learning
models can also predict drug structures that could potentially treat COVID -19 which
can be a step forward in finding appropriate drugs for COVID -19. The present book
chapter will comprehensively highlight all these points.
Keywords Drug repositioning · COVID-19 · Coronavirus · Artificial

intelligence · Machine learning · Deep learning
C. Mohanty (B) · C. Vinod · S. Acharya · N. Mahapatra

School of Applied Sciences, Kalinga Institute of Industrial Technology (Deemed to be
University), Bhubaneswar, Odisha 751024, India
646 C. Mohanty et al.
1 Introduction
Human coronaviruses, especially the 2019 novel coronavirus (SARS-CoV-2) is the

major cause of recent outbreaks of deadly COVID-19 pandemic in the world. The
last two decades have witnessed, two viruses from the same family, SARS-CoV from
2002 to 2003 and (Middle East Respiratory Syndrome coronavirus) MERS-CoV in
2012, which caused two out of four outbreaks in the twenty-first century and the other
two are influenza virus H1N1 in 2009 and Ebola in 2014. In mild cases, SARS-CoV-
2 infection can cause fever, fatigue and dry cough, while severe cases often drive
conditions like pneumonia, respiratory and kidney failure. Apart from respiratory and
flu-like symptoms, this infection may be complicated by lymphopenia and interstitial
pneumonia with cytokine storm. There are currently no effective drugs targeting
SARS-CoV-2, although there is plenty of euphoria regarding the identification of
potential drugs. Two drugs, Remdesvir and Chloroquine, formulated for the treatment
of Ebola virus and Malaria, respectively, have been approved by the FDA for COVID-
19 although no concrete clinical trial results have furnished this view [1]. However,
both the drugs have their long list of drawbacks which plagues their effective used
as gold standards for COVID-19 therapy. Hence the medical fraternity is restricting
the use of both these drugs until absolute results regarding the same do not surface.
As for several infectious diseases, vaccination is the only hope for generating long-
lasting protection against SARS-CoV-2 infection. Although till now no effective
vaccine has been developed each day the researchers are inching closer to finding
one as several vaccines are now in different stages of the clinical trial [2]. Besides this
antiviral drugs, or modulators of the host immune response which target virus or host
factors are also being investigated against SARS-CoV-2. However, synthesizing and
investigating about them from scratch i.e. from preclinical studies to phase III trials
is a time-consuming procedure, and is not feasible in a global emergency scenario
like this [2]. Moreover, after this pandemic, COVID-19 may still have a chance to
revert much stronger than the present, therefore, we need to come out with new
and absolute strategies of drug discovery for combating COVID-19 in the future.
The current COVID-19 epidemic demands an urgent investment in repurposed drugs
which can be an effective tool in the present arsenal for COVID-19 therapy.
Drug repositioning (also known as drug repurposing), which concerns the inves-
tigation of existing drugs for new therapeutic target indications, has emerged as a
successful strategy for drug discovery [3]. Drug repositioning involves identifying
new uses of previously approved drugs commonly used for other diseases. In simple
terms, it pertains to identifying existing compounds by in vitro, in vivo and in silico
studies; or serendipitous observance. It represents a befitting secondary means in the
current period, reducing drug development time and costs compared with de novo
new drug discovery. It is old wine in a new bottle as the process has been a common
occurrence for many years. Drug repositioning has achieved success in many clin-
ical settings. A noted example was the identification of sildenafil (Viagra; Pfizer),
originally used to relieve the symptoms of angina, as an effective drug for erectile
dysfunction [4]. Similarly, Nelfifinavir, initially used for the treatment of HIV, is now
COVID-19 Drug Repositioning: Present Status and Prospects 647
being used for cancer treatments. Again, amantadine designated for treatment of type
A influenza viral infection is being used for the Parkinson’s disease. Although the
idea of repositioning of the drug has been existing since ages, its importance has risen
many-fold now. Firstly, the exploration of existing drugs for new purposes reduces
drug development time as already concrete information regarding the pharmacoki-
netics, pharmacodynamics, toxicity profile, dosing schedule, and mode of action of
these drugs are available. This indicates that most steps of the pre-clinical and early
clinical development phases can be bypassed in case of repositioned drugs which
cannot be ignored in case of traditional drug discovery where the safety, dosing and
toxicity profile of new drugs are unknown [5]. As a result, the development-related
financial investment is considerably curtailed. Most drugs considered apt for repur-
posing/ repositioning for COVID-19 therapy are commercially available and their
dosage and toxicity in humans is already known owing to their use in clinics. This
can allow their faster and inexpensive use in phase II-III clinical trials. In particular,
a remarkable number of drugs considered for COVID-19 therapy have been used
in cancer therapy and it is observed that drugs meddling with specific cancer cell
signalling pathways may be effective against viral replication [6]. However, in-spite
of repositioning of drugs being a lucrative strategy for COVID-19, we must be careful
to prioritize proper distribution of resource. In other words, we must endeavour to
guarantee that medications that are already required by the patient for a particular
disease are not devoid from these patients. For example use of anti-HIV drugs in large
quantities by COVID-19 patients can deplete the supply of these drugs required by
HIV carriers. Another dearth in number was observed in Bacillus Calmette-Guérin
(BCG) vaccine, so the drugs which can be repurposed should be carefully selected.
To identify appropriate drugs which can be repurposed, the usual approach taken
is to analyse the molecular similarity between drugs and the diseases. To make these
correlations more effectual, the researchers use Artificial Intelligence (AI) more
precisely machine-learning (ML) approach known as network medicine to investigate
the molecular characteristics and mechanisms of action. These AI-based techniques
promise to speed up the process of drug discovery and reduce costs. AI-based deep
learning methods have shown promising results on protein–ligand binding predic-
tion. In this context, molecular dynamics simulations and molecular docking studies
are mostly implemented for the same In recent years, the speedy growth of drug-
related data sets, as well as open data initiatives, has led to new developments for
computational drug repositioning, particularly structural-based drug repositioning
[4]. Machine learning, network analysis, and text mining and semantic inference
are the pillars of computational conceptualization commonly used for drug repo-
sitioning. Fast-paced gathering of genetic and structural databases, development
of low-dimensional mathematical representations of complex biomolecular struc-
tures, and the availability of advanced deep learning algorithms have made AI-based
drug repositioning a promising avenue which can be explored maximum for finding
repurposed drugs for SARS-CoV-2 [7].
However, in-spite of repositioning of drugs being a lucrative strategy for COVID-
19, we must be careful to prioritize proper distribution of resource. In other words, we
must endeavour to guarantee that medications that are already required by the patient
for a particular disease are not devoid from these patients. For example use of anti-
HIV drugs in large quantities by COVID-19 patients can deplete the supply of these
drugs required by HIV carriers. Another dearth in number was observed in Bacillus
Calmette-Guérin (BCG) vaccine [8]. In this scenario, data on quantities of available
drugs and the number of patients who need them are paramount. Next, we must
ascertain the amount of repurposed drugs stored in various facilities which would
require the cooperation of pharmacists and distributors of medical goods. Finally,
we need to estimate the time required by a pharmaceutical company to produce
additional quantities of a given drug. If all this is taken into consideration drug re-
purposing would achieve its actual impact on COVID-19 care. In this book chapter,
all these aspects of drug repositioning would be discussed elaborately. The present
book chapter is a compilation of facts involving COVID-19 and how repurposed
drugs can be an alternative solution to meet the demands of the teeming millions
for an ideal medicine. The chapter first focusses about the COVID-19 disease, its
pathogenesis and how different drugs are being used to counteract this deadly disease.
Next, the chapter introduces the concept of “drug repositioning” why it is preferred
w.r.t finding entirely new drugs against any disease, its benefits and how this strategy
can be lucidly explored for COVID-19 therapy. The chapter also enumerates some
of the drugs which are being repurposed or can be considered for re-purposing in this
regards. The last section of the chapter explains elaborately how artificial intelligence
can be extensively used to zero down the drugs which can be repositioned from a vast
array of drugs which can not only reduce the economical burden on pharmaceutical
companies but also can be time-saving.
2 Brief on COVID-19
CoV’s are a group of RNA viruses that derive their name from the projections
they have on their surface that gives them a crown-like appearance. They are large,
enveloped, unsegmented, single-stranded, positive-sense RNA viruses that belong to
order Nidovirales, family Coronaviridae and genus Betacoronavirus [9]. They have
the capability of infecting different animals including humans and can cause a range
of diseases related to respiratory, digestive and nervous systems. SARS-CoV-2, the
causative agent of coronavirus disease 2019 (COVID-19) is a betacoronavirus [10].
Genome analysis suggests that it is a novel virus as it is different from the two
human infecting CoV’s that cause SARS and MERS and is more closely related to
two bat-derived SARS-like CoV [11].
CoV’s are spherical in shape with a diameter ranging from 80 to 120 nm. The
surface of the virus is covered with numerous club-like projections made up of spike
(S) protein that facilitates the entry of the virus into the cells. Besides S, the virus also
encodes membrane (M), envelope (E), and nucleocapsid (N) proteins. The M protein
is the most abundant in the virus that provides shape to the viral envelope and acts as
a centre for coronavirus assembly. The E protein is the smallest and basically helps in
the assembly and release of the virus. The N protein is bound to the RNA genome and
usually expedites M protein interaction needed for virus assembly. Besides the impor-
tant structural proteins, the SARS-CoV-2 genome also codes for 15 non-structural
proteins and 8 accessory proteins which play an important role in the replication of the
virus [12–14]. The virus gains access to a cell through the angiotensin-converting
enzyme 2 (ACE 2) receptor, predominantly expressed in heart, epithelial cells of
blood vessels, epithelium of the small intestine, kidney, testis, alveolar macrophage
and monocytes of the respiratory tract and epithelial cells of the trachea, bronchi,
and alveoli [9]. Attachment of the virus to the cell membrane receptor is followed by
endocytosis and subsequently endosomes aided membrane fusion releases the viral
genome to the cytoplasm. This genomic RNA serves as a template for translation
of polyproteins [15]. The polyproteins produced are then cleaved to form the non-
structural proteins that induce the formation of double-membrane vesicles, where the
viral replication transcription complexes are located. Replication of viral genomic
RNA occurs with the help of a negative-sense intermediate. Further, a nested set of
subgenomic RNAs responsible for encoding viral structural and accessory proteins
are synthesized by discontinuous transcription. Assembly of the virus occurs in the
ER-Golgi intermediate complex, and subsequently, mature viruses are released by
the secretory pathway into the host system [15].
After entering the host system, the virus comes across the innate immune response.
In order to effectively infect the new host, the virus must be able to inhibit or deceive
the host innate immune signalling. However, it is not known how SARS- CoV-2
manages to trick the body’s defence system and causes pathogenesis. It is suggested
that the virus might follow the same pattern as SARS-CoV to trick the immune
system [16]. Usually, viral replication is inhibited inside the body by type I interferon-
stimulated genes. SARS-CoV may inhibit type I interferon and infect cells of both
innate and adaptive immunity by deploying a cytopathic effect. The dysfunctional
immune cells and impaired antiviral effect of type I interferon would further favor
immune evasion by the virus, resulting in highly damaging pathological effects
like acute respiratory distress syndrome, cytokine release syndrome, secondary
hemophagocytic lymphohistiocytosis, and disseminated intravascular coagulation
leading to multiorgan failure and finally death.
2.1 Transmission
The transmission of the virus takes place mostly through direct contact with an
infected person and by respiratory droplets generated from an infected person while
talking, coughing and sneezing. But, there are other ways of transmission as well
like faecal-oral transmission, transfer of virus by an infected object i.e., fomite
transmission (as the virus is viable for days) and intrauterine transmission.
2.2 Risk Factors and Clinical Manifestations
Usually, the virus doesn’t discriminate much, but people who are old or have immun-
odeficiency or have underlying co-morbidities (e.g., hypertension, diabetes, cardio-
vascular disease, chronic respiratory disease, and cancer) are considered to be more
at risk of being infected and developing severe symptoms of COVID-19. Apart from
those, health-care workers involved in the care of COVID-19 patients are also at threat
as they are constantly exposed to higher viral loads. Co-infections of bacteria and
fungi may also add to the severity of the disease [1, 17]. The virus shows preference in
infecting adult males than women. Children, however, are less likely to be infected
or, if infected, present milder symptoms than adults [17]. The clinical features of
COVID-19 range from asymptomatic to acute respiratory distress syndrome (ARDS)
and multiorgan dysfunction and death in severe cases. Studies suggest that the virus
might have a greater preference for infecting the lower respiratory tract [13, 14].
The most common symptoms include fever, dry cough, dyspnoea, chest pain, fatigue
and myalgia. Less common symptoms include headache, dizziness, abdominal pain,
diarrhoea, nausea, and vomiting [14].
3 Drug Discovery Approaches to Target SARS-CoV2
Recently many approaches have been made to identify drugs to target SARS-COV2,
but so far no antiviral drug is significantly effective to combat COVID-19. Progress
in drug discovery and development solely relies on targeting SARS-CoV-2 through
different approaches. One approach is based on targeting virus-host interactions or
inhibiting viral assembly [3, 5]. The other approach comprises of drugs that modulate
broad-spectrum host innate immune responses or interfere with signaling pathways
involved in viral replication. To fight against COVID-19 infection, numerous molec-
ular drug target proteins which have a major role in the SARS-CoV-2 life cycle that
includes ACE2 receptor, viral proteins, various cysteine proteases such as papain-
like cysteine protease(PLpro ) or Chymotrypsin like protease (3CLpro ) helicases and
RNA-dependent RNA polymerase etc. (Fig. 1). The antiviral drugs mostly block
the host receptors or proteases that is used for entry of the virus into the host cell
through endocytosis pathway [1, 5]. Besides this, some immune boosters are also
used along with normal medications during COVID-19 therapy to elicit the synthesis
of antibodies in the body. Various approaches have been exploited and are underway
at a war footing to identify the best drug combination to address the disease by
targeting the above mentioned molecular targets. Owing to the huge financial infer-
ences and more time involved in new drugs discovery, the pharmaceutical companies
and researchers nowadays have oriented towards the strategy of drug repositioning
or drug repurposing by screening the potential molecular targets of existing drugs
[9, 10].
Spike glycoprotein(S) Envelope small membrane

protein (E)
IgM Antibody
Membrane Immunogenic
Protein (M) response
against
COVID-19
IgG Antibody
Nucleoprotein (N)
Genomic RNA Haemagglutinin-esterase (HE)
Fig. 1 Structure of SARS-CoV-2 and possible targets for drug development
4 Drug Repositioning
The drug development process can be implausibly costly and time consuming [18].
The bottlenecks, which stagnant development of any molecule as a potential drug
include initial research regarding drug synthesis, toxicity and efficacy. Delays in
translating any molecule from bench side to clinics can sometimes take more than
14 years. This is due to the fact that these drug molecules have to pass different stages
of clinical trials which have their own purpose and goals. For example, phase one
studies are by and large conducted with healthy volunteers which mostly focuses
on the safety of the products and determining any adverse effects in addition to its
metabolic pathway. Similarly, phase two studies are centred on the effectiveness of
the candidate drug w.r.t control group. Phase three trials deals on both safety and
efficacy, while experimenting with dosages and different patient populations [18].
Passing all these stages with flying colours is the major hurdle which most new drug
molecule encompasses. In order to modulate drug development time and supplement
the research and development work, drug repositioning has been introduced for
various diseases (Fig. 2).
The term “drug repositioning” has been synonymous with “drug repositioning”
or “drug reprofiling.” All these terminologies are basically used for describing the
process pertaining to discovering new applications of an existing drug. Drug repo-
sitioning helps pharmaceutical companies to harness existing data to ameliorate
the efficiency of the clinical trial process of existing drugs. This helps pharma-
ceutical companies in finding means to explore approved or clinically abandoned
drugs against the new disease. In this regards, it can be ascertained that while only
10% of new drugs make it to the market from Phase II clinical trials and 50% from
TRADITIONAL DRUG DEVELOPEMENT

~ 6.5 years ~ 7 years ~ 1.5 years
Discovery & Preclinical Discovery &

Clinical FDA Review
Development Research Development
Research
M
A
R
K
E
Compound Target ID T
Clinical
identification from validation & Registration
Studies
Drug library Preclinical research
~ 1-2 years ~ 0-2 years ~ 1-6 years ~ 1-2 years

DRUG REPOSITIONING
Fig. 2 Different phases in drug development against drug repositioning
Phase III, the rates for repurposed compounds are high from 25 to 65%. For example,
Fasudil, a Rho-kinase inhibitor with vasodilatory effects was repurposed for use in
Alzheimer’s disease [19]. Furthermore, drug repositioning governs high investment
potential of old drugs, which were initially banned owing to toxicity. For illustra-
tion, the drug Thalidomide given to prevent morning sickness in pregnant women
was banned from 1962 as there were serious reports related to the development of
phocomelia in infants worldwide, where the limbs were severely underdeveloped
or absent. However, with a safer and more careful approach, the company Celgene
with success was able to reposition Thalidomide for multiple myeloma treatment and
garnered a whopping $271 million revenue in 2003 [20]. Besides, drug repositioning
is a great boon for drug development against Orphan diseases (ODs) that affect only
a small population and for which no effective drug treatment options are accessible
as pharmaceutical companies find investing against such drugs non-profitable. For
example, closantel, a veterinary anthelmintic, was repurposed against tropical disease
Onchocerciasis (river blindness) [21]. Besides, drug repositioning has also been
achieved by combining approved drugs to synergistically treat a wide spectrum of
diseases, including HIV infection, cancer, and Mycobacterium tuberculosis infection
[5]. Besides serendipity and careful observations, high-throughput screening using
systematic or computational methods is a very vital approach for finding drugs for
repositioning. Moreover, data mining approaches based in the literature are gaining
significant impetus for finding ideal candidates for drug repositioning.
Presently viruses such as Ebola, MERS-CoV, Nipah, and COVID-19 are rising
as a global menace and thus developing strategies and drugs to encounter them
has become the call of the hour. There is a pressing need to find new antivirals
endowed with not only lower toxicity and greater activity properties but also have the
ability to encounter drug-resistance to counteract these viral infections [2]. Although

momentous efforts have been made and around 30 antivirals are approved mostly
for the treatment of hepatitis C virus or HIV, their number is too low with respect
to the number of viruses actively affecting humankind. These last 10 years, has
witnessed remarkable research and use of repurposed drugs in the field of antiviral
drug discovery. For example, Nitazoxanide, a thiazolidine, accredited for treatment
of parasitic infections was also documented to have anti-influenza properties [22].
Similarly, Favipiravir, a polymerase inhibitor is mostly administered to patients in
which other influenza antiviral drugs are ineffective since 2002 [23]. In the case
of infectious diseases, repositioning involves the amalgamation of bioinformatics
and cheminformatics know-how to discover a drug target. Furthermore, drug reposi-
tioning also renders a secondary source of data for comprehending metabolic repro-
gramming in viral infections that expand our knowledge regarding virus biology [24].
In this regard, antivirals, anti-parasitic drugs, immunosuppressors, immunomodula-
tors, nutritional drugs, in addition to combination therapies are being implemented
as repositioned drugs for COVID-19 treatment. Some of these drugs which are in
clinical trials as well as being researched have been elaborated below.
5 Drugs Repositioning Strategies for COVID-19
During the past few decades, a lot of encouragement was seen in the repositioning
of the older drugs for new applications. A plethora of drugs showed significant
advancements in treating various bacterial and viral diseases lately. This strategy
during any novel disease might show promising effects. Currently, COVID-19 had
become a devastating pandemic and new drug candidates to treat the SARS-CoV-
2 are not yet available. Hence repositioning of the existing antimicrobial candi-
dates might be the best strategy to treat COVID-19. The usage of few successful
existing antiviral/antimicrobial chemotherapeutics is not only mentioned below but
also tabulated (Table 1).
5.1 Chloroquinone
Chloroquinone (CQ) is one of the intensely used malarial drug discovered during
World War-I and gained popularity during World War-II owing to its stability and ease
of transportation even during extreme conditions. The use of CQ gained insights after
several researchers reported its antiviral mechanisms with respect to pH-dependent
inhibition of viral replication in retroviruses, coronaviruses and flaviviruses [56, 57].
Based on several reports about the suppression of key viral-induced inflammatory
markers, the Chinese investigators were the first to use CQ in clinical studies. They
had reported that in more than 100 patients, CQ showed exacerbation of pneumonia,
reducing symptoms, radiological improvement eventually leading to virus-negative
Table 1 Different studies conducted on the repositioning of drugs against COVID-19 and more
strategies to be employed for combating it
Drug used Type of study Probable effects/mechanism References
of action
Azithromycin In vivo Acidification of endosomes. [25]
Interference with virus
trafficking
Baricitinib In vivo Inhibition of JAK-STAT [26]
Pathway and improved
respiration
Camostat mesylate In vitro Blockade of viral entry [27]
Chloroquinone In vitro Increasing of endosomal pH [28]
required for cell-viral fusion
and disrupts the
glycosylation of SARS-CoV
cellular receptors, thus
blocking virus infectivity
Chloroquinone In vivo Affecting of endosomal [29]
fusion
Dexamethasone In vivo Effective in reduce [30]
inflammation and proved an
effective treatment for those
on ventilators
Enalpril In vivo Interaction and interference [31]
with the complexes formed
between viral and ACE-2
Eculizumab In vivo Anti-complement C5 [32]
therapy
Flavipiravir In vivo Inhibition of [33]
RNA-dependent RNA
polymerase (RdRp)
Hydroxychloroquinone In vivo Blockade of viral transport [24, 34]
within cell
Ivermectin In vitro Nuclear transport inhibitory [35]
activity of viral proteins
Remdesivir In vitro Premature termination of [28]
viral replication
Ritonavir/Lopinavir In vivo Inhibition of coronavirus [36]
proteases
Oubain In vivo Inhibition of [37]
clathrin-mediated
endocytosis
Sarilumab Combinatory In vivo IL-6 antagonist. Helps in [38]
reducing the cytokine burst
(continued)
Table 1 (continued)
of action
Teicoplanin In vitro Inhibition of the entry of [39]
viral particles into the cells
Tocilizumab In vivo Decrease of [40]
hyper-inflammatory
reactions associated with
IL-6
Amodiaquine Hypothetical Antiparasitic. Proven to be [41]
effective in SARS-CoV-1
Bafilomycin Hypothetical Interrupts the function of [42]
ACE2 receptors thus
blocking viral entry
Captropil Hypothetical Antiparasitic. Antiviral. [43]
Observed to inhibit ACE2
receptors
Cimetidine Hypothetical Effective against several [44]
viral diseases (herpes,
papilloma, cold, etc.).
Restricts viral propagation in
the cells
Clomipramine Hypothetical An antidepressant which was [41]
known to recover neural
dysfunction associated with
SARS-CoV-1
Cyclosporin A Hypothetical Inhibition of interaction of [45]
viral particles with the
cytoplasmic content of the
host
Dablavancin Hypothetical Regulation of lysosome [46]
mediated apoptosis in
bronchial cells during
pneumonia
Dasatinib Hypothetical An anticancer drug which [41]
can inhibit kinase signaling.
Found effective during
SARS-CoV-1
Disulfiram Hypothetical Competitive inhibitor of [47]
SARS-CoV papain-like
protease
Dypiridamole Hypothetical Anti-inflmmatory and [48]
antioxidant agent which
showed recovery during
SARS-CoV-1
(continued)
Table 1 (continued)
of action
Gemcitabine hydrochloride Hypothetical An anti-cancer agent which [41]
can block DNA metabolism
as observed in SARS-CoV-1
Imatinib mesylate Hypothetical An anticancer drug which [41]
can inhibit kinase signaling.
Found effective during
SARS-CoV-1
Mefloquine Hypothetical Antiparasitic/Antimalarial [41]
drug. Proven to be effective
in SARS-CoV-1
Nitazoxanide Hypothetical Inhibition of viral replication [49]
Oritavancin Hypothetical Proven to be effective in [50]
SARS-CoV1 and other viral
diseases
Oseltamivir Hypothetical Neuraminidase inhibitor [51]
Promethazine hydrochloride Hypothetical Antihistamine. Used for [45]
neurodegeneration during
SARS-CoV-1
Ribavarin Hypothetical Guanine analogue inhibits [52]
viral RNA Dependent RNA
Polymerases
Sildenafil Hypothetical Used in pulmonary [44]
hypertension. Can be a
potent drug as
anti-inflammatory,
antioxidant and vasodilatory
agent
Tamoxifen and Toremifene Hypothetical Used against Breast cancer [41]
for inhibiting Estrogen
receptor actions
Teicoplanin Hypothetical Antiparasitic. Inhibits the [53]
low pH cleavage of viral
spike proteins by cathepsin
1. Proven to be effective in
combinational therapies
Telavancin Hypothetical Antibacterial drug found to [54]
be effective in cystic fibrosis
and
Terconazole Hypothetical Used as an antifungal agent [41]
and during SARS-CoV-1 it
was used to for inhibiting
Sterol actions
(continued)
Table 1 (continued)
of action
Umifenovir Hypothetical Required for inhibiting [55]
ACE2 interaction with viral
particles
conditions. The initial dosage recommended during viral infection was 500 mg of
CQ twice a day for 10 days [2, 58].
5.2 Hydroxychloroquinone
Hydroxychloroquinone (HQ) is one of the active derivatives of the intensely used

malarial drug CQ. HCQ was found to be less toxic than CQ and hence the administra-
tion of higher doses of HQ for a longer period is an added vantage during treatment of
malaria. This property of HCQ with good tolerability led to its applications in arthritis
and several chronic autoimmune diseases. The Chinese were the first to report its
usage (hydroxychloroquine sulphate tablets 400 mg/d) where they had treated 61
subjects and found a faster recovery with increased absorption of pneumonia when
treated during the initial 5 days [59]. However, eventual studies did show allevia-
tion of clinical symptoms but did not show promising results with respect to higher
negative conversion as described earlier by Chen et al. (2020) [60, 61].
5.3 Remdesivir
Remdesivir is a nucleotide analogue that targets viral RNA-dependent RNA poly-

merase (RdRp) proteins and has proven to be effective against several zoonotic
and human coronaviruses including SARS-CoV-2. Many researchers had shown
promising benefits of the drug especially in cases with severe pneumonia. However,
the total mortality rate after drug administration was reported to be 13% [17, 62, 63].
5.4 Ritanovir
Ritanovir, a booster of Lopinavir is combined with Lopavir to treat HIV. This

combination has shown promising results in vitro. However, in vivo studies lacked
effectiveness and exhibited the same morality with respect to controls [64, 65].
5.5 Umifenovir
This antiviral agent used for influenza treatment was effective against SARS-CoV
in vitro. In a cohort study at a dosage of 200 mg every 8 h in combination with
Lopinavir/Ritonavir, the drug exhibited better clinical response [66].
5.6 Ivermectin
Ivermectin a broad range anti-parasitic drug, which demonstrated the antiviral effect
in vitro and in vivo against SARS-CoV-2. Surprisingly, this drug reduced the viral
materials by 99.8% after 48 h of administration. The acceptance of this drug by the
FDA and its safety profile might help it to be an emerging strategy for COVID-19
treatment [35, 67].
5.7 Nitazoxanide
This anti-parasitic drug in earlier studies showed broad activity with respect to
rotavirus and influenza virus. It was demonstrated to show anti-viral effects in vitro
against SARS-CoV-2. The mechanism of action was indicated that viral replication
is affected followed by decreased production of several pro-inflammatory cytokines
[68].
5.8 Dexamethasone
Dexamethasone is a steroid which showed potential therapeutic benefits in several

inflammatory disorders and several types of cancers. According to recent studies
across the globe, administration of this steroid with other antiviral drugs has shown
a significant reduction in mortality in COVID-19 patients who require oxygen or
ventilation.
5.9 Antibodies/Immunomodulators
Many of the antibodies are repurposed in combination with corticosteroids and other
drugs for reducing the effects during late stages of COVID-19, especially ARDS.
Administration of immunoglobulin IVIG with a moderate dose of corticosteroids
showed significant improvements. According to FDA Report 2020, convalescent
plasma containing neutralizing antibody specific to SARS-CoV-2 when adminis-

tered (400 ml) in a clinical trial showed gradual improvement with radiological
improvements within 3 days [69]. Similarly, Tocilizumab along with corticosteroids
was reported to reduce hyperinflammatory reactions which eventually lead to multi-
organ dysfunction. Preliminary data suggest that this combination is efficient in stage
III patients with respect to dysregulated inflammatory responses [70]. The Universal
BCG Vaccine was one of the vaccines employed to see its effects on COVID-19.
Interestingly a study found that morbidity and mortality rates were tenfold lesser in
countries with a BCG program compared to countries without BCG program [71, 72].
5.10 Antioxidants
Tissue damage in several COVID-19 studies have been observed which is attributed
to elevated levels of free radicals in patients [39]. Phototherapy has been found to
be one of the effective ways to enhance the antioxidant capacity and modulate the
cytokines. Additionally, phototherapy was also reported to have a vital impact on
pulmonary tissue repair where its sequential effects included enhanced vasodila-
tion and increased O2 delivery which is crucial for pulmonary proliferation [73].
The presence of the antioxidant enzyme, catalase was observed in different cases
(human alveolar epithelial cells, human leukocytes and rhesus macaques) of SARS-
CoV-2 infection which reduced oxidative injury, regulated cytokine production and
repressed replication of SARS-CoV-2, without noticeable toxicity. Similar treatment
strategies including several antioxidants for oxidative and nitrosative stresses could
be potential for treatment of COVID-19. Melatonin, another neurohormone secreted
from pineal glands has proved to be an efficient antioxidant in several disorders. As
the COVID-19 patients were reported to experience circadian disruption, adminis-
tration of melatonin can be a potential therapeutic strategy in restoring the circadian
rhythms and acting as a potent antioxidant which can lead to decreased tissue damage
and increased repair mechanisms [74].
5.11 Herbal Medications
Much before the discovery of synthetic drugs, herbal formulations have been the
potential source of medicine for treating a wide range of diseases and disorders.
Based on anecdotal evidence of SARS and flu prevention, herbal drugs are consid-
ered as a management strategy for treating and prevention of COVID-19. Consid-
ering the potential effects of herbal formulations with respect to anti-inflammatory,
antioxidant, anti-viral, anti-parasitic, regenerative abilities, the most commonly used
herbal medicines are Allium sp., Anacardium occidentale, Andrographis panic-
ulate, Atractylodis macrocephalae, Astragali radix, Azadirachta indica, Borreria
verticillate, Cannabis sp., Curcuma longa, Echinacea purpurea, Fructus forsythia
Glycyrrhizae radix, Lonicerae japonicae, Ocimum sp. Phyllanthus amarus, Salvia

officinalis, Saposhnikoviae radix, Sida cordifolia, Withania somniferum, Zingiber
officinale, etc. However, rigorous clinical trials on large populations should be
conducted to confirm the potential preventive effect of these herbal medicine [75].
5.12 Nutraceuticals
The therapy with micronutrients and macronutrients management has been

successful in several known and novel disease management. In COVID-19, mito-
chondrial biogenesis is found to be imbalanced which in turn is associated with the
imbalance of cellular pH which facilitates the interaction of the virus with ACE2
receptor. The mitochondrial biogenesis was demonstrated to be improved on supple-
mentation of different nutrients which could restore the mitochondrial abilities.
During the last few months, the recovery rate of infected patients has increased
and nutritional management along with appropriate medications had proven to be
beneficial [75]. Along with adequate amounts of sugars and proteins in the diet, the
inclusion of curcumin, hydroxytyrosol, quercetin, resveratrol, vitamin C, vitamin
D and zinc in the diet plan has boosted recovery rates in the majority of patients.
Additionally, these also were shown to have antioxidant properties and the majority
of them were reported to reduce the free radical activity both in vitro and in vivo.
Vitamins such as Vitamin C and D were shown independently to have antiviral prop-
erties and the mechanism of action was through increased production of interferons
and decreased expression of pro-inflammatory markers [76, 77].
5.13 On-Going Vaccine Trials
Besides establishing a potential management strategy for treating COVID-19, it is

also essential to find a working vaccine which can prevent the occurrences. Many
countries are working hand in hand to invent the most active viral therapeutics. A brief
update of all the vaccine candidates which are in preclinical trials is mentioned here.
Sinovac is a whole virus inactivated with formaldehyde and alum which is a vaccine
candidate in clinical trials. Similarly, deoptimized live attenuated vaccines are being
produced by Codagenix. Majority of the vaccine candidates falls into the category
of non-replicating viral vectors. There are several types such as MVA encoded VLP
(Bravo vax), oral vaccine platform (Vaxart), Adenovirus-based NasoVAX (Altim-
mune), ChAdOx1 (University of Oxford), Ad26 alone or with MVA boost (Japanese
pharmaceutical company), etc. The repositioning of other vaccines is also in progress.
The replicating viral vectors specific for measles and horse-pox have shown signif-
icant improvement and are being manufactured by Zydus Cadila, Institute Pasteur
and Tonix Pharma/Southern Research. Along with this several DNA (DNA alone or
DNA Plasmid vaccine), and RNA (mRNA alone, LNP-encapsulated mRNA, LNP-
encapsulated mRNA cocktail encoding VLP or encoding RBD) based vaccines are
in preclinical trials [78].
6 Artificial Intelligence and Drug Repositioning
The advance of new medications and de novo drug discovery is a very long time
consuming and expensive process. Though speculation in research and development
has continued to increase however, there are not much-approved drugs coming to
market, particularly drugs with novel mechanisms of actions. Therefore, it requires
an imperative innovative approach to progress the development of drug production
to combat COVID-19. Drug repositioning or drug repositioning possibly is a sustain-
able substitute concerning the productivity problem. Maximum of the effective drug
repositioning functional so far have relied on an accidental discovery. Thus, current
research and development should focus on systematic drug repositioning approaches.
Application of Machine Learning (ML) algorithms on the widely available biolog-
ical and therapeutic data contribute anticipation to design the new drug. ML is a
subfield of Artificial intelligence (AI) in computer science. Here, an ML algorithm
designates any computational method where results from past actions or decisions,
or past observations, are used to improve predictions for future decision making. ML
techniques are now extremely popular in drug development and repositioning. In this
regards, many computational methods for drug repositioning have been introduced
like AI, ML [16], network analysis, and analysis of omics data [4]. AI and ML are
the advanced screening methods used to improve the accuracy of prediction for the
screening of drugs with aid to improve the potential for repositioning. The application
of AI towards health care commences with the advent of MYCIN (an AI program) in
1976. It practises 450 rules brought together from medical experts to treat bacterial
infection by suggesting antibiotics to the patients. It is a knowledge-based consul-
tation program for infectious disease diagnosis. Recently, ML and AI technology
support various health care system to combat various non-communicable diseases
and communicable diseases like SARS, EBOLA, HIV including COVID-19. The
gathering of huge data of information’s associated with diseases and therapeutic
drugs has led to the improvement of several AI-based computational approaches
for drug repositioning. Many companies mostly using AI platform for repositioning
existing medications for COVID-19 and most prominent organisations are listed in
Table 2. This chapter mainly highlights all these points comprehensively.
6.1 Prediction of Protein–ligand Interaction
Application of AI to predict protein–ligand interactions has attracted great interest

in recent years. Currently, many kinds of research with an aim to apply AI to predict
Table 2 List of companies applying AI for the repositioning of existing drugs against COVID-19
[16]
Company name Description and status
BenevolentAI • The organization founded in the United Kingdom, is known as a mammoth
in the AI medicate revelation industry
• It is a developer of AI and computational medicine technologies for drug
designing, development, test and marketing
• Using AI platform BenevolentAI has identified baricitinib. The potential
drug, owned by Eli Lilly and currently entered clinical trials
Innoplexus • Indo-German Company announces the potential findings in Combination
Therapies for COVID-19. It successful in proposed three combination
therapies against COVID-19 and right now these combinations are
invalidation process both in-vitro & in-vivo:
(a) Chloroquine and tocilizumab
(b) Chloroquine and Remdesivir
(c) Hydroxychloroquine with clarithromycin or plerixafor
Deargen • A firm based on Korea and in collaboration with Dankook University came
up with an antiviral drug named atazanavir (a drug known for HIV treatment)
with high efficacy. However, its clinical trials are currently going on
• It predicted a drug with high potential for the treatment of a new coronavirus
using the deep-learning technology-based AI model MT-DTI
Gero • AI company Gero leader is a Singaporean company has used its AI platform
to identify the potential anti-COVID-19 agents that have been previously
tested on humans
• Nine drugs have been identified by using its AI platform. Niclosamide and
Nitazoxanide have predicted as most potent molecules against COVID 19
Cyclica • The Canadian organization reported screening of 6700 atoms that are FDA
affirmed or if nothing else in Phase I human preliminaries on their AI-based
medication repurposing stage MatchMaker
• Cyclica has been working frantically with Beijing institution Materia
Medica on finding existing drugs, already approved by the FDA, to be
repurposed as coronavirus treatments
Healx • The UK based organization is utilizing its foundation to reveal bi-and
tri-mixes of affirmed drugs against the infection
• While the organization’s capacities lie in uncommon infections, they are
remarkably situated to use the information on why mortality is higher with
comorbidities of respiratory and heart frameworks
• It uses AI platform to develop drug combinations from approved drugs to
contribute towards the global efforts to find treatments for COVID-19
VantAI • A company based in New York is utilizing a frameworks science way to deal
with comprehend the interchange between collaborations of the viral
proteins with perhaps over 500 human proteins through the span of disease
• It has revealed a few promising objective pathways, for instance obstructing
the infection’s movement in the Golgi contraption (a viral re-bundling
framework in the human cell that helps in additionally spread), and is at
present screening around 300 leads with a CRO to tentatively research sway
on viral contamination further
the strength of binding interaction between approved drugs and target proteins of
SARS-CoV-2 are underway. In a recent study, AI-based binding affinity predic-
tion platform has used to screen about 657 FDA approved drugs in regards to
its possible affinity towards ACE2. Piperacillin (β-lactam antibiotic), two antiviral
agents (Fosamprenavir and Emricasan) and glutathione were predicted to show a
strong affinity for ACE2 receptor of SARS-CoV-2. Further, it is noteworthy that
the drug Hydroxychloroquine predicted to interact more effectively with ACE2
however, many prospective therapeutic drugs for COVID-19 viz. Azithromycin and
various anti-IL-6 agents have shown no affinity [79]. Further, Ke et al. applied
the AI platform proficient on anti-SARS-CoV-2 drugs and 3CLpro like protease
inhibitors to envisage several therapeutic molecules to combat COVID-19. The study
revealed that the drug-like Bedaquiline, Brequinar, Celecoxib, Clofazimine, Coni-
vaptan, Gemcitabine, Tolcapone, and Vismodegib were effective against SARS-CoV-
2. In another study, Molecule Transfer Drug Target Interaction (MT-DTI) model
has successfully employed to screen and repositioning the established anti-viral
drug to target the proteins of SARS-CoV-2 viz. 3 CLpro, RdRp, helicase, endoR-
NAase, 3 -5 exonuclease and 2 -O-ribose-methyltransferase. The result confirmed
that Atazanavir (anti-retroviral drug) found to be more effective to inhibit 3CLpro
compared to Remdesivir, Efavirenz, ritonavir, and Dolutegravir [80].
6.2 Molecular Docking Simulations for Drug Repositioning
Structure-based virtual screening (molecular docking) has been extensively used

nowadays to discover new ligands based on target structures. It is a form of structure-
based drug discovery or drug repositioning that quantifies the binding affinities
between small molecules and macromolecular targets (proteins). The computational
approach by combining ML-based models in conjunction with molecular docking
simulations enable rapid screening of possible therapeutic molecules (or ligands).
This screening is based on the binding affinity which is potentially reduced and/or
disrupted following the host-virus interactions. In a study, Karki et al. researched
on structural interactions between ACE2 and SARS-CoV-2. They demonstrated
three states of the ACE2 receptor, i.e. open, closed, and a closed conformation in
complex with the S protein [81]. The group identified compounds with high-binding
affinities and evaluated the potential efficacy of more than billion compounds from
large compound libraries. Grazoprevir, and Glecaprevir, as well as Velpatasvir (viral
protease inhibitor), which targets the non-structural protein, important for replication
and alteration of the host immune response, demonstrated high affinity via smina.
These findings suggest that in addition to their primary functions, they may modulate
COVID-19 pathology via affecting the ACE2 receptor [81]. ML models screened
FDA approved drugs and confirmed that many therapeutics medications used for
hepatitis C virus namely Paritaprevir, Simeprevir, Grazoprevir, and Velpatasvir and
many drugs meant for cancer and other disease were effective against SARS-CoV-2
[82].
6.3 Study of Gene Expression Signatures for Drug

Repositioning
Gene expression-based methods are recently grabbing the attention owing to is accu-
rate construction of a detailed map of connections between diseases and drug actions.
Gene expression signatures are collected and equated through genome-wide metrics
and are used to discover drug-disease and drug-drug ‘connections’ by matching
corresponding signatures. Zhu et al. established a deep neural network-based model
called Infinity Phenotypehas and used it for the study of gene expression analysis.
The group studied the antiviral efficacy of natural herbal therapeutic molecule or
FDA approved drugs and confirmed that Liquiritin has scored the highest antiviral
activity. To explore the molecular mechanism of inhibition, it was found that Liquir-
itin significantly inhibited replication of SARS-CoV-2 by mimicking type I interferon
[83].
6.4 Biomedical Knowledge Graph for Drug Repositioning
Biomedical knowledge graphs link biomedical things (such as diseases, proteins,

and drugs) through certain defined relationships. These are the ideal tools for drug
repositioning, which relies on identifying novel interactions among biological entities
such as proteins and compounds. Recently, a research group used a data-driven drug
repositioning framework that combines with ML and statistical analysis methods to
study several marketed approved therapeutics. The screening result confirmed that
CVL218 (PARP1 inhibitor) exhibited maximum inhibitory activity against SARS-
CoV-2 replication without any toxicity. This makes the drug CVL218 a deserving
candidate to treat COVID-19 [84].
6.5 Cell Image Analysis for Drug Repositioning
Cell image analysis is the technique used in the pre-clinical study to allow scalable and
systematic phenotypic profiling of small molecules and also acts as a corresponding
method to target based in vitro screening. In a recent study, HRCE monolayer cell
lines were infected with active, inactive, or mock preparations of SARS-CoV-2 and
then cell image analysis was done to study the image of cytological structures. Out
of the several tested compounds, the drug Remdesivir showed a strong ability to
suppress the impacts of the SARS-CoV-2 on phenomic profiles of human cells.
However, Chloroquine and Hydroxychloroquine have not shown any antiviral effi-
cacy as observed in the human cell model. Thus, cell image-based analysis is an
attracting, scalable and versatile tool to select or screen the efficacy of drugs and also
to make a hypothesis for drug synergism and repositioning [85].
6.6 Identification of Progeny Drugs for Repositioning
Progeny drugs are the second-pass drugs that are analogous to the parent drugs which
are already being tested. Like the parental drug, it has the prospective to interact at
a molecular level to show its therapeutic efficacy. Upon failure of the parental drug
in laboratory or clinical trials, the progeny drugs can be used as an alternative or re-
purposed against the COVID-19 on the timescales relevant to the current pandemic.
Many groups have used AI algorithms to find progeny drugs that show the same
antiviral potency as the drugs already being tested for COVID-19 [86]. In another
study, the researchers used AI algorithms to assess the similarity of the therapeutic
molecule against COVID-19 by the 3D distribution of pharmacophores. In this way,
they screened hundreds of progeny compounds that can be repurposed [87].
6.7 Vaccine and Antibody Development
Researchers worldwide are working around the clock to develop an effective vaccine
against COVID-19. A recent report states that presently more than 100 COVID-19
vaccine candidates are under development, with a number of these in the human trial
phase. AI-based approaches are being implemented to develop the various vaccine
and to screen the antibodies to combat COVID-19 pandemic. For example, bioin-
formatics and AI-based approach that is neoantigen prediction platform has been
employed to identify an optimal set of neoantigens as targets for cancer vaccines or
adoptive cell therapies is being used for the development of a SARS-CoV-2 vaccine
[88]. In another study, ML along with other bioinformatics tools was used by the
scientist to predict T-cell epitopes, with strong MHC-I and MHC-II presentation
scores, as well as two potential neutralizing B-Cell epitopes on the S protein. This
prediction certainly will be useful to develop effective vaccines and neutralizing
antibodies in near future [89].
7 Conclusion and Future Perspectives
This book chapter is mostly centred on the most recent developments in drug reposi-
tioning which can be beneficial for COVID-19. Since drug development is an arduous
task and involves a multistage process which is both time and money consuming, this
type of innovative ideas and novel concepts will hasten the drug development process.
Drug repositioning has been one of the promising strategies in treating various novel
and existing diseases and broad chances of affecting different signalling pathways
as observed in major outbreaks during the past two decades. By this process not
only drawbacks associated with conventional new drugs like drug resistance and
drug-drug interaction can be reduced but also simplified pharmacokinetic and phar-
macodynamic profile and synergism elevates the effect of the therapy. Furthermore,
this approach can be optimised using data available in many public platforms, such as
PubChem, CheEMBL, DrugBank, DrugCentral, etc. These further can help in estab-
lishing a correlation between physical and chemical properties of multiple drugs,
which is possible by integrating through in silico prediction and in vitro validation.
Thus AI and ML will help to find suitable repurposed drugs for a particular disease,
and in regards to SARS-CoV2, an appreciable amount of already approved drugs were
investigated for their effectiveness against COVID-19. This book chapter provides an
update of such identified drugs which are either approved or in the late-stage clinical
trial against SARS-CoV2. Baricitinib identified by BenevolentAI, dexamethasone
predicted by CoV-KGE, and melatonin from network medicine-based findings are
some promising example for AI-based drug repurposing. However, it needs advance
in vitro and in vivo models and studies to decrease further failed of drug repur-
posing between preclinical studies and clinical trials for COVID-19. Personalised
drug repurposing that is taking into account the gene expression profile is an effec-
tive approach that might further improve the success rate of the clinical trial. Methods
of AI integrated with big data have progressed the drug repositioning field and may
possibly support the decision making of therapeutic benefits against various deadly
disease including the current COVID-19.
Drug repositioning has its limitations like technical challenges, legal requirements
of IPR, the emergence of drug resistance and selected targeting ability. Similarly,
these field associated with many challenges with the development of AI tools, infe-
rior data collection and receiving of inadequate pharmaceutical data. However, it still
stands to be the best possible solution during this outbreak and can be modulated to
find a definite answer to many issues in near future. The discussed review revealed that
the AI startups could help AI-based drug repositioning pharma companies to digi-
tally bridge the gap between thousands of repurposed drug molecules, clinical
trials and final drug authorisation. Thus, AI-based drug repositioning research holds
significant assistance for biopharmaceutical companies to expedite the drug repur-
posing process. In conclusion, the drug repositioning integrates with AI has shown
great potential for combating COVID-19 outbreak.
References
1. Altay, O., Mohammadi, E., Lam, S., Turkez, H., Boren, J., Nielsen, J., Uhlen, M., Mardinoglu,
A.: Current status of COVID-19 therapies and drug repositioning applications. Iscience 23,
101303 (2020). https://doi.org/10.1016/j.isci.2020.101303
2. Gao, K., Nguyen, D.D., Chen, J., Wang, R., Wei, G.W.: Repositioning of 8565 existing drugs
for COVID-19. J. Phys. Chem. Lett. 11, 5373–5382 (2020)
3. Serafin, M.B., Bottega, A., Foletto, V.S., da Rosa, T.F., Hörner, A., Hörner, R.: Drug reposi-
tioning is an alternative for the treatment of coronavirus COVID-19. Int. J. Antimicrob. Agents
55, 105969 (2020). https://doi.org/10.1016/j.ijantimicag.2020.105969
4. Zhou, Y., Wang, F., Tang, J., Nussinov, R., Cheng, F.: Artificial intelligence in COVID-19 drug
repurposing. Lancet Digit Health 2, e667–e676 (2020)
5. Pizzorno, A., Padey, B., Terrier, O., Rosa-Calatrava, M.: Drug repurposing approaches for the
treatment of influenza viral infection: reviving old drugs to fight against a long-lived enemy.
Front. Immunol. 10, 531 (2019). https://doi.org/10.3389/fimmu.2019.00531
6. Ciliberto, G., Mancini, R., Paggi, M.G.: Drug repurposing against COVID-19: focus on anti-
cancer agents. J. Exp. Clin. Cancer Res. 39, 86 (2020). https://doi.org/10.1186/s13046-020-
01590-2
7. Smalley, E.: AI-powered drug discovery captures pharma interest. Nat. Biotechnol. 35, 604–605
(2017)
8. Ino, H., Nakazawa, E., Akabayashi, A.: Drug repurposing for COVID-19: ethical considerations
and roadmaps. Camb. Q. Healthc. Ethics 1–8 (2020)
9. Wang, L., Wang, Y., Ye, D., Liu, Q.: A review of the 2019 novel Coronavirus (COVID-19)
based on current evidence. Int. J. Antimicrob. Agents 56(3), 106137 (2020). https://doi.org/10.
1016/j.ijantimicag.2020.106137
10. Swayamsiddha, S., Mohanty, C.: Application of cognitive internet of medical things for
COVID-19 pandemic. Diabetes Metab. Syndr. 14, 911–915 (2020)
11. Al-Mandhari, A., Samhouri, D., Abubakar, A., Brennan, R.: Coronavirus disease 2019
outbreak: preparedness and readiness of countries in the Eastern Mediterranean region. East
Mediterr. Health J. 26:911–91136–137 (2020). https://doi.org/10.26719/2020.26.2.136
12. Yue, H., Zhang, M., Xing, L., Wang, K., Rao, X., Liu, H., Tian, J., Zhou, P., Deng, Y., Shang,
J.: The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza
viruses in patients during COVID-19 outbreak. J. Med. Virol. 12 (2020). https://doi.org/10.
1002/jmv.26163
13. Hu, B., Guo, H., Zhou, P., Shi, Z.L.: Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev.
Microbiol. 6, 1–14 (2020)
14. Brendish, N.J., Poole, S., Naidu, V.V., Mansbridge, C.T., Norton, N., Borca, F., Phan, H.T.,
Wheeler, H., Harvey, M., Presland, L., Clark, T.W.: Clinical characteristics, symptoms and
outcomes of 1054 adults presenting to hospital with suspected COVID-19: a comparison of
patients with and without SARS-CoV-2 infection. J. Infect. 28, (2020). S0163-4453(20)30638-1
15. Zhang, W., Govindavari, J.P., Davis, B.D., Chen, S.S., Kim, J.T., Song, J., Lopategui, J.,
Plummer, J.T., Vail, E.: Analysis of genomic characteristics and transmission routes of patients
with confirmed SARS-CoV-2 in Southern California during the early stage of the US COVID-
19 pandemic. JAMA Netw. Open 3(10), e2024191 (2020). https://doi.org/10.1001/jamanetwo
rkopen.2020.24191
16. Mohanty, S., Harun Ai Rashid, M., Mridul, M., Mohanty, C., Swayamsiddha, S.: Application of
artificial intelligence in COVID-19 drug repurposing. Diabetes Metab. Syndr. 14, 1027–1031
(2020).
17. McCreary, E.K., Pogue, J.M.: Coronavirus disease 2019 treatment: a review of early and
emerging options. Open Forum Infect. Dis. 7, (2020). https://doi.org/10.1093/ofid/ofaa105.
18. Low, Z.Y., Farouk, I.A., Lal, S.K.: Drug repositioning: new approaches and future prospects
for life-debilitating diseases and the COVID-19 pandemic outbreak. Viruses 12, 1058 (2020).
https://doi.org/10.3390/v12091058
19. Takata, M., Tanaka, H., Kimura, M., Nagahara, Y., Tanaka, K., Kawasaki, K., Seto, M.,
Tsuruma, K., Shimazawa, M., Hara, H.: Fasudil, a rho kinase inhibitor, limits motor neuron
loss in experimental models of amyotrophic lateral sclerosis. Br. J. Pharmacol. 170, 341–351
(2013)
20. Khalil, A., Kamar, A., Nemer, G.: Thalidomide-revisited: are COVID-19 patients going to
be the latest victims of yet another theoretical drug-repurposing? Front. Immunol. 11, 1248
(2020). https://doi.org/10.3389/fimmu.2020.01248
21. Gloeckner, C., Garner, A.L., Mersha, F., Oksov, Y., Tricoche, N., Eubanks, L.M., Lustigman,
S., Kaufmann, G.F., Janda, K.D.: Repositioning of an existing drug for the neglected tropical
disease Onchocerciasis. Proc. Natl. Acad. Sci. U.S.A. 107, 3424–3429 (2010)
22. Kumar, R., Gupta, N., Kodan, P., Mittal, A., Soneja, M., Wig, N.: Battling COVID-19: using
old weapons for a new enemy. Trop. Dis. Travel Med. Vaccines 6, 6 (2020). https://doi.org/10.
1186/s40794-020-00107-1
23. Shiraki, K., Daikoku, T.: Favipiravir, an anti-influenza drug against life-threatening RNA virus
infections. Pharmacol. Ther. 209, 107512 (2020). https://doi.org/10.1016/j.pharmthera.2020.
107512
24. Liu, T.P., Hsieh, Y.Y., Chou, C.J., Yang, P.M.: Systematic polypharmacology and drug repur-
posing via an integrated L1000-based connectivity map database mining. R. Soc. Open Sci. 5,
181321 (2018). https://doi.org/10.1098/rsos.181321
25. Cavalcanti, A.B., Zampieri, F.G., Rosa, R.G., et al.: Hydroxychloroquine with or without
azithromycin in mild-to-moderate Covid-19. N. Engl. J. Med. 383, 2041–2052 (2020)
26. Rodriguez-Garcia, J.L., Sanchez-Nievas, G., Arevalo-Serrano, J., Garcia-Gomez, C., Jimenez-
Vizuete, J.M., Martinez-Alfaro, E.: Baricitinib improves respiratory function in patients
treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study.
Rheumatology (Oxford) (2020). https://doi.org/10.1093/rheumatology/keaa587
27. Ragia, G., Manolopoulos, V.G.: Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2
pathway: a promising approach for uncovering early COVID-19 drug therapies. Eur. J. Clin.
Pharmacol. 21, 1–8 (2020)
28. Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., Xiao,
G.: Remdesivir and Chloroquine effectively inhibit the recently emerged novel coronavirus
(2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020)
29. Gao, J., Tian, Z., Yang, X.: Breakthrough: Chloroquine phosphate has shown apparent efficacy
in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends 14, 72–73
(2020)
30. Perez-Belmonte, L.M., Lopez-Carmona, M.D., Quevedo-Marin, J.L., et al.: Differences
between clinical protocols for the treatment of coronavirus disease 2019 (COVID-19) in
Andalusia, Spain. Int. J. Environ. Res. Public Health 17, 6845 (2020). https://doi.org/10.3390/
ijerph17186845
31. Wu, C., Ye, D., Mullick, A.E., Li, Z., Danser, A.H.J., Daugherty, A., Lu, H.S.: Effects of
Renin-Angiotensin inhibition on ACE2 (Angiotensin-Converting Enzyme 2) and TMPRSS2
(Transmembrane Protease Serine 2) expression: insights into COVID-19. Hypertension 76,
e29–e30 (2020). https://doi.org/10.1161/HYPERTENSIONAHA.120.15782
32. Laurence, J., Mulvey, J.J., Seshadri, M., et al.: Anti-complement C5 therapy with eculizumab
in three cases of critical COVID-19. Clin. Immunol. 219, 108555 (2020). https://doi.org/10.
1016/j.clim.2020.108555
33. Shrestha, D.B., Budhathoki, P., Khadka, S., Shah, P.B., Pokharel, N., Rashmi, P.: Favipiravir
versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review
and meta-analysis. Virol. J. 17, 141 (2020). https://doi.org/10.1186/s12985-020-01412-z
34. Ayerbe, L., Risco-Risco, C., Ayis, S.: The association of treatment with hydroxychloroquine
and hospital mortality in COVID-19 patients. Intern. Emerg. Med. 15, 1501–1506 (2020)
35. Caly, L., Druce, J.D., Catton, M.G., Jans, D.A., Wagstaff, K.M.: The FDA-approved drug
ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 178, 104787 (2020).
https://doi.org/10.1016/j.antiviral.2020.104787
36. Li, Y., Xie, Z., Lin, W., et al.: Efficacy and safety of Lopinavir/Ritonavir or Arbidol in adult
patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med
(2020). https://doi.org/10.1016/j.medj.2020.04.001
37. Cho, J., Lee, Y.J., Kim, J.H., et al.: Antiviral activity of digoxin and ouabain against SARS-
CoV-2 infection and its implication for COVID-19. Sci. Rep. 10, 16200 (2020). https://doi.org/
10.1038/s41598-020-72879-7
38. Caballero Bermejo, A.F., Ruiz-Antoran, B., Fernandez Cruz, A., et al.: Sarilumab versus stan-
dard of care for the early treatment of COVID-19 pneumonia in hospitalized patients: SARTRE:
a structured summary of a study protocol for a randomised controlled trial. Trials 21, 794 (2020).
https://doi.org/10.1186/s13063-020-04633-3
39. Zhang, J., Ma, X., Yu, F., et al.: Teicoplanin potently blocks the cell entry of 2019-nCoV.
BioRxiv (2020). https://doi.org/10.1101/2020.02.05.935387
40. Galvan-Roman, J.M., Rodriguez-Garcia, S.C., Roy-Vallejo, E., et al.: IL-6 serum levels predict
severity and response to Tocilizumab in COVID-19: an observational study. J. Allergy Clin.
Immunol. S0091–6749(20), 31329–31334 (2020)
41. Dyall, J., Coleman, C.M., Hart, B.J., et al.: Repurposing of clinically developed drugs for
treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob. Agents
Chemother. 58, 4885–4893 (2014)
42. Hu, C.J., Chen, Y.T., Fang, Z.S., Chang, W.S., Chen, H.W.: Antiviral efficacy of nanoparticulate
vacuolar ATPase inhibitors against influenza virus infection. Int. J. Nanomed. 13, 8579–8593
(2018)
43. Serafin, M.B., Bottega, A., Foletto, V.S., da Rosa, T.F., Horner, A., Horner, R.: Drug reposi-
tioning is an alternative for the treatment of coronavirus COVID-19. Int. J. Antimicrob. Agents
55, 105969 (2020)
44. Rogosnitzky, M., Berkowitz, E., Jadad, A.R.: Delivering Benefits at speed through real-world
repurposing of off-patent drugs: the COVID-19 pandemic as a case in point. JMIR Public
Health Surveill. 6, e19199 (2020). https://doi.org/10.2196/19199
45. de Wilde, A.H., Zevenhoven-Dobbe, J.C., van der Meer, Y., et al.: Cyclosporin A inhibits the
replication of diverse coronaviruses. J. Gen. Virol. 92, 2542–2548 (2011)
46. Blaess, M., Kaiser, L., Sauer, M., Csuk, R., Deigner, H.P.: COVID-19/SARS-CoV-2 infection:
lysosomes and lysosomotropism implicate new treatment strategies and personal risks. Int. J.
Mol. Sci. 21, 4953 (2020). https://doi.org/10.3390/ijms21144953
47. Lin, M.H., Moses, D.C., Hsieh, C.H., et al.: Disulfiram can inhibit MERS and SARS coronavirus
papain-like proteases via different modes. Antiviral Res. 150, 155–163 (2018)
48. van der Harst, P., Slart, R.H., Tio, R.A., et al.: Effects of rosuvastatin on coronary flow reserve
and metabolic mismatch in patients with heart failure (from the CORONA Study). Am. J.
Cardiol. 105, 517–521 (2010)
49. Yamamoto, K.A., Blackburn, K., Migowski, E., et al.: Quantitative proteomic analysis of the
tizoxanide effect in vero cells. Sci. Rep. 10, 14733 (2020). https://doi.org/10.1038/s41598-020-
71634-2
50. Ianevski, A., Zusinaite, E., Kuivanen, S., et al.: Novel activities of safe-in-human broad-
spectrum antiviral agents. Antiviral Res. 154, 174–182 (2018)
51. Qi, T., Limin, D.: Is oseltamivir suitable for fighting against COVID-19: in silico assessment,
in vitro and retrospective study. Bioorg. Chem. 104, 120–131 (2020)
52. Guo, Y.R., Cao, Q.D., Hong, Z.S., et al.: The origin, transmission and clinical therapies on
coronavirus disease 2019 (COVID-19) outbreak—an update on the status. Mil. Med. Res. 7,
11 (2020). https://doi.org/10.1186/s40779-020-00240-0
53. Jean, S.S., Lee, P.I., Hsueh, P.R.: Treatment options for COVID-19: the reality and challenges.
J. Microbiol. Immunol. Infect. 53, 436–443 (2020)
54. Kidd, J.M., Sakon, C.M., Oleksiuk, L.M., et al.: Pharmacokinetics of telavancin in adult patients
with cystic fibrosis during acute pulmonary exacerbation. Antimicrob. Agents Chemother. 64,
e1914–e1919 (2019). https://doi.org/10.1128/AAC.01914-19
55. Wang, Y., Chen, L.: Tissue distributions of antiviral drugs affect their capabilities of reducing
viral loads in COVID-19 treatment. Eur. J. Pharmacol. 889, 173634 (2020). https://doi.org/10.
1016/j.ejphar.2020.173634
56. Devaux, C.A., Rolain, J.M., Colson, P., Raoult, D.: New insights on the antiviral effects of
chloroquine against coronavirus: what to expect for COVID-19? Int. J. Antimicrob. Agents 55,
105938 (2020). https://doi.org/10.1016/j.ijantimicag.2020.105938
57. Savarino, A., Boelaert, J.R., Cassone, A., Majori, G., Cauda, R.: Effects of chloroquine on viral
infections: an old drug against today’s diseases? Lancet Infect. Dis. 3, 722–727 (2003)
58. Kearney, J.: Chloroquine as a potential treatment and prevention measure for the 2019 novel
coronavirus: a review. Preprints 2020030275 (2020). https://doi.org/10.20944/preprints202
003.0275.v1
59. Chen, Z., Hu, J., Zhang, Z.J.D.: Efficacy of hydroxychloroquine in patients with COVID-19:
results of a randomized clinical trial. medRxiv 10, 22.20040758 (2020). https://doi.org/10.
1101/2020.03.22.20040758
60. Gautret, P., Lagier, J.C., Parola, P., et al.: Hydroxychloroquine and azithromycin as a treatment
of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents
56, 105949 (2020). https://doi.org/10.1016/j.ijantimicag.2020.105949
61. Tang, W., Cao, Z., Han, M., et al.: Hydroxychloroquine in patients with mainly mild to moderate
coronavirus disease 2019: open label, randomised controlled trial. BMJ 369, m1849 (2020).
https://doi.org/10.1136/bmj.m1849
62. Grein, J., Ohmagari, N., Shin, D., et al.: Compassionate use of Remdesivir for patients with
severe COVID-19. N. Engl. J. Med. 382, 2327–2336 (2020)
63. Holshue, M.L., DeBolt, C., Lindquist, S., et al.: First case of 2019 novel Coronavirus in the
United States. N. Engl. J. Med. 382, 929–936 (2020)
64. Cao, B., Wang, Y., Wen, D., et al.: A trial of Lopinavir-Ritonavir in adults hospitalized with
severe COVID-19. N. Engl. J. Med. 382, 1787–1799 (2020)
65. Sanders, J.M., Monogue, M.L., Jodlowski, T.Z., Cutrell, J.B.: Pharmacologic treatments for
Coronavirus disease 2019 (COVID-19): a review. JAMA 323, 1824–1836 (2020)
66. Deng, L., Li, C., Zeng, Q., Liu, X., Li, X., Zhang, H., Hong, Z., Xia, J.: Arbidol combined with
LPV/r versus LPV/r alone against Corona virus disease 2019: a retrospective cohort study. J.
Infect. 81, e1–e5 (2020). https://doi.org/10.1016/j.jinf.2020.03.002
67. Wagstaff, K.M., Sivakumaran, H., Heaton, S.M., Harrich, D., Jans, D.A.: Ivermectin is a specific
inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and
dengue virus. Biochem. J. 443, 851–856 (2012)
68. Rossignol, J.F.: Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory
syndrome coronavirus. J. Infect. Public Health 9, 227–230 (2016)
69. Ho, J.C., Wu, A.Y., Lam, B., et al.: Pentaglobin in steroid-resistant severe acute respiratory
syndrome. Int. J. Tuberc. Lung Dis. 8, 1173–1179 (2004)
70. Michot, J.M., Albiges, L., Chaput, N., et al.: Tocilizumab, an anti-IL-6 receptor antibody, to
treat COVID-19-related respiratory failure: a case report. Ann. Oncol. 31, 961–964 (2020)
71. Hegarty, P.K., Kamat, A.M., Zafirakis, H., Dinardo, A.J.P.: BCG vaccination may be protective
against COVID-19. Preprint (2020). https://doi.org/10.13140/RG.2.2.35948.10880
72. Miller, A., Reandelar, M.J., Fasciglione, K., Roumenova, V., Li, Y., Otazu, G.H.J.M.: Corre-
lation between universal BCG vaccination policy and reduced morbidity and mortality for
COVID-19: an epidemiological study. MedRxiv (2020). https://doi.org/10.1101/2020.03.24.
20042937
73. Hanna, R., Dalvi, S., Sălăgean, T., Bordea, I.R., Benedicenti, S.J.A.: Phototherapy as a
rational antioxidant treatment modality in COVID-19 management; new concept and strategic
approach: critical review. Antioxidants 9, 875 (2020). https://doi.org/10.3390/antiox9090875
74. Bahrampour Juybari, K., Pourhanifeh, M.H., Hosseinzadeh, A., Hemati, K., Mehrzadi, S.:
Melatonin potentials against viral infections including COVID-19: current evidence and new
findings. Virus Res. 287, 198108 (2020). https://doi.org/10.1016/j.virusres.2020.198108
75. Panyod, S., Ho, C.T., Sheen, L.Y.: Dietary therapy and herbal medicine for COVID-19
prevention: a review and perspective. J. Tradit. Complement. Med. 10, 420–427 (2020)
76. Colunga Biancatelli, R.M.L., Berrill, M., Catravas, J.D., Marik, P.E.: Quercetin and vitamin C:
an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related
disease (COVID-19). Front. Immunol. 11, 1451 (2020). https://doi.org/10.3389/fimmu.2020.
01451
77. Quiles, J.L., Rivas-García, L., Varela-López, A., Llopis, J., Battino, M., Sánchez-González,
C.J.E.R.: Do nutrients and other bioactive molecules from foods have anything to say in the
treatment against COVID-19? Environ. Res. 191, 110053 (2020). https://doi.org/10.1016/j.env
res.2020.110053
78. Oroojalian, F., Haghbin, A., Baradaran, B., Hemmat, N., Shahbazi, M.A., Baghi, H.B.,
Mokhtarzadeh, A., Hamblin, M.R.: Novel insights into the treatment of SARS-CoV-2 infection:
an overview of current clinical trials. Int. J. Biol. Macromol. 165, 18–43 (2020)
79. Kim, J., Zhang, J., Cha, Y., Kolitz, S., Funt, J., Escalante Chong, R., Barrett, S., Kusko, R.,
Zeskind, B., Kaufman, H.: Advanced bioinformatics rapidly identifies existing therapeutics for
patients with coronavirus disease-2019 (COVID-19). J. Transl. Med. 18, 257 (2020). https://
doi.org/10.1186/s12967-020-02430-9
80. Beck, B.R., Shin, B., Choi, Y., Park, S., Kang, K.: Predicting commercially available antiviral
drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction
deep learning model. Comput. Struct. Biotechnol. J. 18, 784–790 (2020)
81. Karki, N.K., Verma, N., Trozzi, F., Tao, P., Kraka, E., Zoltowski, B.: Predicting potential SARS-
COV-2 drugs-in depth drug database screening using deep neural network framework SSnet,
classical virtual screening and docking. Class. Virtual Screen. Docking 18, 18 (2020). https://
doi.org/10.26434/chemrxiv.12362213.v1
82. Kadioglu, O., Saeed, M., Johannes Greten, H., Efferth, T.J.B.: WHO Identification of novel
compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening
and supervised machine learning. Bull. World Health Organ. (2020). https://doi.org/10.2471/
BLT.20.255943
83. Zhu, J., Deng, Y.-Q., Wang, X., et al.: An artificial intelligence system reveals liquiritin inhibits
SARS-CoV-2 by mimicking type I interferon. bioRxiv (2020). 05.02.074021. https://doi.org/
10.1101/2020.05.02.074021
84. Ge, Y., Tian, T., Huang, S., et al.: A data-driven drug repositioning framework discovered a
potential therapeutic agent targeting COVID-19. bioRxiv (2020) 03.11.986836. https://doi.org/
10.1101/2020.03.11.986836
85. Han, L., Shan, G., Wang, H., Gao, S., Zhou, W.: Japa accelerating drug repurposing for COVID-
19 via modeling drug mechanism of action with large scale gene-expression profiles. arXiv
preprint 37 (2020). arXiv:2005.07567v1
86. Olena, A.: Machine learning has pegged existing drugs to repurpose for COVID-19 clinical
trials. The Scientist (2020)
87. Moskal, M., Beker, W., Roszak, R., et al.: Suggestions for second-pass anti-COVID-19 drugs
based on the Artificial Intelligence measures of molecular similarity, shape and pharmacophore
distribution. ChemRxiv Preprint. (2020). https://doi.org/10.26434/chemrxiv.12084690.v2
88. Writers HIs: Artificial intelligence helps identify T-cell targets for development of SARS-CoV-2
vaccine. HospiMedica Int. (2020)
89. Fast, E., Chen, B.J.B.: Potential T-cell and B-cell epitopes of 2019-nCoV. bioRxiv (2020).
https://doi.org/10.1101/2020.02.19.955484
Understanding COVID-19 in Brazil:
Socioeconomic Impacts, Statistical
Analysis and Future Challenges
Yaohao Peng, Alex Rodrigues do Nascimento, Igor Ferreira do Nascimento,

João Gabriel de Moraes Souza, Tatsuya Nagata,
Pedro Henrique Melo Albuquerque, Herbert Kimura,
and Mateus Hiro Nagata
Abstract In this chapter, we analyzed the impacts of the COVID-19 outbreak in

Brazil, one of the most severely affected countries by the pandemic in the world. We
discussed the overall characteristics of the pathogen (SARS-CoV-2) and its diffusion
in Brazil over time and its main differences compared to other common infectious
diseases in Brazil, such as Dengue and Zika. We then performed quantitative exper-
iments to forecast the trend of confirmed cases and deaths from COVID-19 using a
machine learning method for both country and state levels. We also estimated the
instantaneous reproducing number over time for each Brazilian state and grouped
them into clusters, aiming at identifying the heterogeneity between the Brazilian
States. We also analyzed the magnitude of underreporting of COVID-19 cases in
Y. Peng (B)
Brazilian Ministry of Economy, Brasilia, Distrito Federal 70048–900, Brazil
e-mail: peng.yaohao@economia.gov.br
A. R. Nascimento
Brazilian Federal Savings Bank Foundation, SCN Quadra 2 Bloco A Edifício Corporate
Financial Center, Asa Norte, Brasilia, Distrito Federal 70712–900, Brazil
e-mail: alex.rodrigues@lamfo.unb.br
I. F. Nascimento
Federal Institute of Piauí, Avenida Presidente Jânio Quadros, 330,
Teresina, Piauí 64053–120, Brazil
e-mail: igor.ferreira@lamfo.unb.br
J. G. de M. Souza · T. Nagata · P. H. M. Albuquerque · H. Kimura · M. H. Nagata
University of Brasilia, Campus Darcy Ribeiro, Brasilia, Distrito Federal 70910–900, Brazil
e-mail: joaogabrielsouza@lamfo.unb.br
T. Nagata
e-mail: tatsuya@unb.br
P. H. M. Albuquerque
e-mail: pedroa@unb.br
H. Kimura
e-mail: herbertkimura@unb.br
M. H. Nagata
e-mail: mateus.hiro@lamfo.unb.br
674 Y. Peng et al.
Brazil’s most affected states during the early stages of the pandemic. Moreover, we
summarized the impacts of the pandemic on Brazil’s economic activities and social
life, analyzing the dynamics of macroeconomic indicators, the effectiveness of the
emergency financial assistance granted by the Brazilian government, and the relative
level of adherence to social distancing in the Brazilian states since the beginning of
lockdown measures. Finally, we presented the main challenges for Brazil after the
pandemic fades away, focusing on the economic recovery and future public policies.
Keywords Epidemics spreading · Statistical modelling · Public policies ·

Time-series forecasting · Unsupervised learning
1 Introduction
COVID-19 (Coronavirus disease 2019) is an ongoing pandemic that registered, up to

September 27, 2020, more than 33 million confirmed cases globally and almost a
million fatal victims. On the same date, Brazil was the country with the second
most number of deaths (140537) and the third most number of cases (4689613)
[89]. Taking into account global numbers, Brazil encompasses respectively 14.2 and
14.3% of all cases and deaths worldwide. Brazil also recorded the first confirmed
case of COVID-19 in Latin America on February 25, 2020 [46].
Given the severity of the COVID-19 pandemic and its direct impacts on public
health, social life, and economic activities, and bearing in mind the geopolitical
relevance of Brazil, this chapter presents an overview of the COVID-19 pandemic
in Brazil, with emphasis on the socioeconomic implications of the disease and the
heterogeneities of the outbreak in different regions of the country. In light of the
large population and territorial extension of Brazil, it is particularly important to have
an accurate diagnosis at State-level of the virus’ behavior and the levels of social
awareness; in this sense, this chapter provides a portrayal of Brazil’s responses to
COVID-19 and proposes quantitative methods that may contribute to assisting timely
interventions and effective public policy planning.
First, we briefly discuss COVID-19 evolution in Brazil at both country and State
levels, identifying the impacts of lockdown and social distancing measures on the
spreading of this disease in the different States. The results show that there are distinct
States in different phases of the pandemic, emphasizing the potential importance of
synergistic efforts or strict local lockdown measures, such as preventing people from
traveling within the country.
Second, aiming at contributing to the understanding of COVID-19’s spreading in
Brazil, we use machine learning techniques to forecast the number of cases and deaths
from COVID-19. We use predictive models also taking into account both country
and State-level data. We also estimate the instantaneous reproduction number (R0 )
of COVID-19 for each Brazilian State and apply cluster analysis to identify States
with similar patterns. The results may help decision-makers coordinate actions to
better allocate resources and define policies that reduce the pathogen’s contagion.
Understanding COVID-19 in Brazil: Socioeconomic Impacts … 675
Third, we also study the underreporting of COVID-19 cases in Brazilian states,

using the pandemic dynamics observed in Italy and South Korea as benchmarks.
We build a statistical model considering temporal and spatial dimensions to analyze
COVID-19’s dispersion on the three most affected States in the early stages of the
outbreak. We investigate geographical distance and transportation networks and their
relation to the spread of the disease. Since underreporting can be significant, better
estimates of cases may help decision-makers anticipate the need for treatment and
reduce the likelihood of collapse in the healthcare system. It is important to highlight
that Brazil has universal healthcare, and the majority of the population has access to
a public and free health system.
Finally, given the severity of COVID-19 in Brazil and the direct impacts of the
pandemic on the economic activities and social life, we analyze the magnitude of
Brazil’s main macroeconomic indicators, with a focus on income levels and labor
market dynamics, as well as their correlations with the virus’ dispersion and overall
adherence to social distancing. In particular, we also discuss the overall effectiveness
of the emergency financial aid granted by the Brazilian government to mitigate the
aforementioned impacts on the economy and the fiscal burden associated with this
implementation of this program, and its implications on post-pandemic economic
recovery.
This chapter is structured as follows: section 2 discusses the characteristics of the
virus and the evolution of COVID-19 in Brazil; section 3 addresses the quantitative
analysis of country and State-level data concerning the heterogeneous dynamics and
responses to the disease across different States, as well as time-series forecasting,
estimation of the instantaneous basic reproduction number, and the magnitude of
underreporting in the early stages; section 4 discusses the impacts of COVID-19 on
the economy and the social life, as well as public responses to the outbreak; finally,
section 5 summarizes the finding of this chapter and describe some post-pandemic
challenges for the Brazilian economic recovery.
2 Characteristics of the Virus and COVID-19’s Evolution

in Brazil over Time
2.1 Characteristics of the Virus
COVID-19 is caused by the virus SARS-CoV-2 (Severe Acute Respiratory Syndrome

Coronavirus 2), which uses the routes of transmission of (semi)airborne, droplet, and
(in)direct contact [5, 73, 77]. Many respiratory viruses, such as the influenza virus,
use this transmission manner [24]. Influenza virus also caused many pandemics
formally and, in some cases, caused many deaths due to high pathogenicity [16].
Moreover, in human virology, the appearance of deadly influenza viruses is still a
critical matter for discussion; due to this relevance, the scientific community has
worked a lot to fight against this virus. For example, the knowledge and tools for
676 Y. Peng et al.
vaccines and their development are accumulated during a long period [17]. Also,
several antiviral drugs are currently available [27], and many efforts for developing
anti-influenza drugs are still ongoing. Even though the influenza viruses are still
threatening for us, we have experience in choosing the strategies on how to fight
this class of pathogens. However, we have very few experiences and poorly prepared
tools for counter-attack the coronaviruses.
In the long history of the war between humans and viruses, many virologists have
paid more attention to “deadly viruses” such as Ebola, Avian Influenza, hantavirus,
and so on. Since these viruses are considered to be more “dangerous” for human
health, and consequently also for the economy and the society as a whole, only
the minority of virologists are worried about viruses with less mortality than these
“deadly” viruses. Two coronaviruses, SARS-CoV-1, which emerged in 2002 [30],
and MERS, which emerged in 2012 [90], were of significant interest on corona-
virology due to their high pathogenicity and mortality. Still, a human being can
control the dissemination of these viruses, which ended being limited to local occur-
rences. Nonetheless, the SARS-CoV-2 virus possesses milder pathogenicity and mor-
tality, although the impact that it has been causing is more significant than the former
two coronaviruses [83]. This difference was caused due to the fact that SARS-CoV-2
can hide among asymptomatic people or people that appear to have only a flu-like
infection [69]. Interestingly, in all age groups, including the group of older people,
about 4–60% (or even potentially more) were symptomless infections [13, 69]. In
this sense, the big issue for the SARS-CoV-2 virus is that this mild-mortality virus
can cause death to around 3% of the patients in which infection was confirmed [83].
This “bad-luck infection” leading to death is a big issue for this SARS-CoV-2, and
to this date, the specialized scientific community still doesn’t have the means to
determine precisely which patients have “bad luck”.
Brazil has a history of mosquito-transmitted diseases, such as Dengue and Zika;
in special, bursts of the former are occasional in Brazil. However, COVID-19 brings
along additional challenges over Dengue and Zika since there are quite different
biological characteristics among those diseases and SARS-CoV-2. Firstly, we can’t
see viruses in daily life because of the particle size; nevertheless, we can see how
Dengue and Zika try to infect the human body, since these viruses can only infect
through the mosquito’s bite, with a few exceptions [58]. If a patient is free from the
mosquito, he/she normally will not have to worry about the infection by these viruses.
Therefore, these viruses are called as “arthropod-borne viruses” or “arboviruses”
[36]. Conversely, HIV is known as one of the most dangerous and life-threatening
viruses; however, the society as a whole is more aware of which behaviors tend to
raise the contamination risk by HIV [88]. On the other hand, COVID-19 is totally
different: there is no way for a person to feel or visualize oncoming SARS-CoV-2
pathogens to his/her body, and the patient will neither be sure about which behavior
can reduce the risk of the contamination or not. This scenario is one of the main
reasons to adopt general isolation or social distance measures in order to avoid being
infected by the virus.
The virus circulation will decrease and eventually finish when one patient infects
less than one person on average, which is measured by a parameter called “basic
reproduction number”—that is, when R0 < 1; to achieve this, lockdown measures

can be effective, as pointed out by studies like [49]. However, this “less deadly” [83]
and “bad luck” virus [69] tend to make isolation and social distance looser. Economic
pressure to avoid city-level lockdown is another factor that may perpetuate the virus
circulation. This fear is likely to finish when effective vaccines are distributed to
more than half of the population in the world (or achieving 67% of the population
would have gotten infected and recovered, providing herd immunity [60]), since the
development of an affordable antiviral drug is more time-consuming than vaccine
development. However, how the memory of immunity works against SARS-CoV-2
is still under investigation: as reported in some studies like [50], the memory of
immunity by the type G antibody (Immunoglobulin G—IgG) became weak after
three months of recovery from infection. If this result is a general feature for a large
number of “recovered” or “immunized” persons, even the vaccine can only be a
“partial solution” for the COVID-19 pandemics.
2.2 COVID-19’s Evolution in Brazil
In this subsection, we performed a descriptive analysis of the evolution of COVID-19

cases in Brazil. The data were retrieved from [23] and [66], ranging from February
25, 2020, to September 15 2020. Moreover, additional statistics were collected from
the Brazilian National Council of Health Secretaries (CONASS) [54].
Brazil is the largest country in Latin America, with a territorial area of over 8.5
million square kilometers (fifth largest in the world) and a population of over 211
million people (sixth most populous in the world). Brazil has 27 States grouped into
five Regions: North, Northeast, Southeast, South and Central-West, listed as follows:
1. North Region: Acre (AC), Amapá (AP), Amazonas (AM), Pará (PA), Rondônia
(RO), Roraima (RR), and Tocantins (TO);
2. Northeast Region: Alagoas (AL), Bahia (BA), Ceará (CE), Maranhão (MA),
Paraíba (PB), Pernambuco (PE), Piauí (PI), Rio Grande do Norte (RN), and
Sergipe (SE);
3. Southeast Region: Espírito Santo (ES), Minas Gerais (MG), Rio de Janeiro (RJ),
and São Paulo (SP);
4. South Region: Paraná (PR), Rio Grande do Sul (RS), and Santa Catarina (SC);
5. Central-West Region: Distrito Federal (DF), Goiás (GO), Mato Grosso (MT), and
Mato Grosso do Sul (MS)
In terms of COVID-19 incidence, Brazil is the third most affected country by

COVID-19 and was the second most affected until September 7, 2020, when India
took this place, as shown in Fig. 1. The first confirmed COVID-19 case dated back to
February 26, 2020, and in 203 days, it reached the number of 4 million accumulated
infected cases on September 15, 2020. Dividing the analysis of each region’s cases,
we see a geographic heterogeneity, as the incidence was not uniform in the country.
678 Y. Peng et al.
6,000,000
Country
Argentina
Brazil
4,000,000
Colombia
Cases
India
Mexico
Peru
Russia
South Africa
2,000,000 Spain
United States
Jan Feb Mar Apr May Jun Jul Aug Sep

Month
Fig. 1 Total COVID-19 confirmed cases in the most affected countries, as of September 15, 2020
Central−West North Northeast
750,000
State Name
500,000
AC PB
AL PE
250,000 AM PI
AP PR
BA RJ
0
Cases
CE RN
South Southeast Mar Apr May Jun Jul Aug Sep DF RO
ES RR
GO RS
750,000
MA SC
MG SE
500,000 MS SP
MT TO
PA
250,000
0
Mar Apr May Jun Jul Aug Sep Mar Apr May Jun Jul Aug Sep
Month
Fig. 2 COVID-19 confirmed cases in Brazil, by geographic region
The State of São Paulo (SP) has the greatest share of the cases, having reached almost
1 million at the end of our analyzing period, which is one-fourth of Brazil’s total
cases. On the other hand, most of the States showed less than 250 thousands cases,
as displayed in Fig. 2.
However, since SP is the most populated State in Brazil, it is relevant to compare
the States’ per capita case incidence. In this sense, we analyzed the COVID-19
Brazil Central−West North

8.0%
6.0%
State Name
4.0% AC PB
AL PE
AM PI
Cases_Per_Capita
2.0%
AP PR
BA RJ
0.0% CE RN
Northeast South Southeast DF RO
8.0%
ES RR
GO RS
6.0% MA SC
MG SE
4.0% MS SP
MT TO
PA TOTAL
2.0%
0.0%
Mar Apr May Jun Jul Aug Sep Mar Apr May Jun Jul Aug Sep Mar Apr May Jun Jul Aug Sep
Month
Fig. 3 COVID-19 cases per capita in Brazil, by geographic region
60,000
40,000
State Name
AC PB
20,000
AL PE
AM PI
AP PR
New Cases
0 BA RJ
CE RN
ES RR
60,000 GO RS
MA SC
40,000
MG SE
MS SP
MT TO
20,000 PA TOTAL
Month
Fig. 4 Daily variation of COVID-19 cases in Brazil, by geographic region
infection dynamics according to the population size in Fig. 3: notice that even though
São Paulo had the biggest share of total cases in the previous figure, proportionality,
SP’s incidence is not so high (1.9%), and it is close to the Brazilian average of 2.0%.
The North Region showed the highest rate of infected population and a high growth
rate, as seen in Fig. 4. The states of Roraima (RR) (7.7%), Distrito Federal (DF)
(5.9%), and Amapá (AP) (5.4%) had the largest per capita incidences.
680 Y. Peng et al.
The literature points out that meteorological conditions (such as an average humid-
ity close to 80% and temperatures close to 27.5 ◦ C) can influence the spread of the
virus [6]. However, a brief descriptive analysis demonstrates that this feature alone is
not enough to understand the spread in each State. Instead, variables related to cultural
aspects, to the economic incentives to stay in lockdown or resume working activities,
are also crucial for understanding the contagion patterns. Even though there has been
a steady increase in the COVID-19 cases in Brazil in the past months (see Fig. 1),
the latest numbers indicate that the infection rates are likely decreasing or reaching
a “plateau”, as shown in Fig. 4. Whether a significant percentage of the population
has already been infected, or the response policies were able to contain the spread of
the disease with effectiveness, the trend and the most plausible explanations are not
yet clear, and this chapter will not intend to categorically answer those questions.
Table 1 Statistical summary of COVID-19 in the Brazilian states

Region State Pop(106 ) Cases(103 ) Deaths(103 ) Cases/capita Lethality (%)
(%)
– Brazil – 210.15 4382.26 133.12 2.0 3.04
1 Southeast SP 45.92 901.27 32.96 1.9 3.66
2 Northeast BA 14.87 285.45 6.04 1.9 2.12
3 Southeast MG 21.17 255.61 6.33 1.2 2.48
4 Southeast RJ 17.26 244.42 17.18 1.4 7.03
5 Northeast CE 9.13 229.07 8.74 2.5 3.81
6 North PA 8.60 216.32 6.39 2.8 2.95
7 South SC 7.16 200.24 2.57 2.7 1.28
8 Central-West DF 3.02 178.75 2.97 5.9 1.66
9 Central-West GO 7.02 170.06 3.88 2.4 2.28
10 Northeast MA 7.08 163.80 3.60 2.3 2.20
11 South RS 11.38 160.94 4.17 1.4 2.59
12 South PR 11.43 155.82 3.92 1.4 2.51
13 Northeast PE 9.56 137.87 7.91 1.4 5.74
14 North AM 4.14 128.15 3.91 3.0 3.05
15 Southeast ES 4.02 120.92 3.37 3.0 2.79
16 Northeast PB 4.02 113.90 2.65 2.8 2.33
17 Central-West MT 3.48 107.49 3.12 3.0 2.91
18 Northeast PI 3.27 87.21 1.99 2.6 2.28
19 Northeast AL 3.34 82.59 1.99 2.4 2.41
20 Northeast SE 2.30 75.20 1.96 3.2 2.61
21 Northeast RN 3.51 65.65 2.33 1.8 3.54
22 North RO 1.78 61.26 1.27 3.4 2.07
23 North TO 1.57 60.73 0.82 3.8 1.35
24 Central-West MS 2.78 60.30 1.11 2.1 1.83
25 North RR 0.61 46.85 0.61 7.7 1.30
26 North AP 0.85 46.12 0.68 5.4 1.48
27 North AC 0.88 26.29 0.64 2.9 2.44
0.100%
0.075%
State Name
0.050% AC PB
AL PE
AM PI
Deaths Per Capita
0.025%
AP PR
BA RJ
0.000% CE RN
0.100% ES RR
GO RS
0.075% MA SC
MG SE
MS SP
0.050%
MT TO
PA TOTAL
0.025%
0.000%
Month
Fig. 5 COVID-19 deaths per capita in Brazil, by geographic region
Table 1 is a summary of Brazil and its States’ overall situation. Note that the
situation of each State is different; the most affected in absolute terms (SP) is not the
same as the most affected proportional to the population (RO), which is also not the
same as the one with the biggest lethality (RJ).
Analogously, deaths per capita may not be a consistent source to define the
expected chance of surviving the disease, neither since the temporal aspect is an
important concern related to this variable, and notification of the death is lagged to
the infection of the disease. Thus, deaths per capita, as displayed in Fig. 5, is an
important measure to analyze the healthcare system’s readiness, but it should not be
considered alone, because States that have more incidence of the disease naturally
tend to have greater deaths per capita. Another concern is underreporting (further
discussed in Sect. 3.3). Finally, treating only the COVID-19 infected could increase
indirect deaths incurred by the healthcare system overload or concern of people with
other illnesses other than COVID-19 but needed hospitalization or intensive care.
Those aspects will be discussed later in this subsection (5).
The temporal distribution of lethality (case-fatality rate) is displayed in Fig. 6. This
variable is calculated by the ratio between the number of deceased due to COVID-19
and the number of infected. The graph shows a spike at the beginning of the outbreak,
especially in the Northeast region. Since it is a temporal variable, the lethality cannot
precisely indicate the survival rate of people to COVID-19 because the death may
officially registered much later.
After analyzing the direct deaths caused by COVID-19, a cardinal discussion
is whether or not there was an increase in the pandemic’s indirect deaths. These
could be due to the overload of healthcare services, and therefore some treatments
of patients with other diseases would be postponed or receive a smaller priority.
682 Y. Peng et al.
20.0%
15.0% State Name

AC PB
10.0%
AL PE
AM PI
5.0%
AP PR
BA RJ
Lethality
0.0% CE RN
ES RR
20.0% GO RS
MA SC
15.0% MG SE
MS SP
10.0% MT TO
PA TOTAL
5.0%
0.0%
Months
Fig. 6 Lethality (case-fatality rate) of COVID-19 in Brazil, by geographic region
Resistance to going to hospitals is also a potential factor for the increase in indirect
deaths. As indicated by the data provided by CONASS [54], which investigated
the excess of deaths in 2020 by estimating the expected fatality rate of this year
using forecasts over historical data, the expected mortality for the year 2020 until
September 15 is 529659 people; however, the actual death toll already exceeds this
number by 132668 people, implying in a proportion of excess mortality of 25%—
this result is illustrated by Fig. 7. This number is an estimator for the deaths that
could be avoided if the healthcare system were fully capable of dealing with all
COVID-19 cases without overload or resource scarcity. The most affected regions
by these indirect deaths were the Southwest, Northeast, and North Regions, as shown
in Fig. 8. Similarly, excess deaths were not uniformly distributed over the country,
in both geographical and demographical terms. In general, men were more affected
than women; the population with less than 60 years had a proportionally larger excess
mortality, although elders represent larger deaths in absolute terms.
30000
Deaths
25000
20000
5 10 15 20 25 30 35 40 45 50
Epidemiological Week
Fatalities Expected Observed
Fig. 7 Estimated and observed death toll in Brazil (as of September 14, 2020). The ribbon in gray
indicate the maximum and minimum values for death tolls observed between 2015 and 2019
0
125000
6.7%
25000
12.8%
Region
36.3%
Central_West
North
100000
x
Northeast
South
Southeast
40.1% 4.1%
50000
75000
Excess_Proportion
Fig. 8 Distribution of excess fatalities in 2020 in Brazil, by geographic region

684 Y. Peng et al.
3 Understanding the Data with Quantitative Analysis:

Heterogeneous Dynamics and Responses Across the
Brazilian States
3.1 Number of Confirmed Cases and Deaths: Time-Series

Forecasting Using Machine Learning
In this subsection, we performed an empirical experiment regarding the prediction

of the number of COVID-19 confirmed cases and deaths in Brazil. As of September
20, 2020, Brazil is the country with the third most confirmed cases and second most
deaths, thus being one of the most heavily affected countries by the pandemic in
the world. Particularly for Brazil, many studies analyzed the spreading patterns of
COVID-19 over time and tested the effectiveness of forecasting models, as well as
the potential impacts on the country’s healthcare system capability, as seen in the
papers of [8, 14] and [75].
As discussed in [74], the severity of the ongoing pandemics emphasizes the impor-
tance of information dissemination, not only in terms of reliability but also in terms
of the speed in which the information is generated and notified to the people. In
special, as pointed out by [59], machine learning methods may be sensible to the
complexity level of the decision functions and to small variations in user-specified
hyperparameters, which may, in turn, lead to significant impacts in the context of
real-world decision making regarding COVID-19, such as public policies and social
awareness. Researches that applied machine learning methods in time-series predic-
tion for COVID-19 in Brazil include [62, 76].
In this sense, we used daily data of COVID-19 collected from the Brazilian Min-
istry of Health and state-level Health Secretariats, since the first confirmed case, reg-
istered in February 25, 2020, and used the data up to May 31, 2020 as the first training
set. Starting from June 1, 2020, we recursively computed the one-step ahead predic-
tion for the number of confirmed cases (ct ) and deaths (dt ) for country-level and state-
level data. For each time period t, we used the seven last observations of confirmed
cases and deaths at each location as predictors—i.e.: we fitted decision functions
fc (.) and fd (.) such that ĉt = fc (ct−7 , ct−6 , ..., ct−1 ) and d̂t = fd (dt−7 , dt−6 , ..., dt−1 ).
After predicting the values for t, the observed values at this period were included in
the training dataset, and then the process was repeated to generate the predictions
ĉt+1 = fc (ct−6 , ct−5 , ..., ct ) and d̂t+1 = fd (dt−6 , dt−5 , ..., dt ), and so on. The last pre-
dicted period was August 31, 2020.
For the decision functions fc (.) and fd (.), in this chapter, we applied gradient
boosting machines, using decision trees as base-learners. Introduced by [32], the
basic idea of gradient boosting machines (henceforth GBM) is to combine a set
of weak models, using the residuals of previous training rounds to calibrate the
model’s subsequent rounds and updating the previously trained model in an amount
that minimizes the loss function for the updated model—as pointed out by [55],
this mechanism is analogous to a functional gradient descent applied recursively,
such that a differentiable loss function is updated towards the direction with higher
decrease, hence the name of the algorithm. Recent examples of gradient boosting
machine applications for time-series prediction include [43] and [52]; specifically
for COVID-19 data, this method was applied in [38] and [53].
In operational terms, GBM starts with a constant value, and in each training epoch
the in-sample residuals are included as features to be fitted into the base-learner,
and summed to the previous model weighted by the gradient and a regularization
parameter ν that works as a learning rate to prevent overfitting, as discussed in [12].
Therefore, the steps of the GBM training can be summarized in algorithm 1:
Algorithm 1 Gradient boosting

1: procedure GBM(In-sample dataset {xtrain i , yitrain }, i = 1, 2, ..., n, number of training epochs E ,
loss function L(y, f (x)) = 21 (y − f (x))2 , regularization parameter ν, 0 < ν ≤ 1)

n
2: Initialize f (0) (x) = arg min L(y, γ )
γ i=1
3: for e ∈ {1, ..., E } do
(e) (e−1)
4: Compute residuals ri = − ∂ L∂f(y,f(e−1) (x(x) i )) = y − f (e−1) (xi )
i
5: Fit base learner h(e) (x) using {xtrain

i , ri(e) }, i = 1, 2, ..., n as training set
n
6: Compute update weight γm = arg min L yi , f (e−1) (xi ) + γ · h(e) (xi )
γ i=1
7: Update f (e) (x) = f (e−1) (x) + ν · γm · h(e) (x)
Return final model f (E ) (x) Calculate prediction f (E ) (xtest ) for out-of-sample data
In this chapter, we used regression decision trees as the base-learners h(.) (x),
training with E = 800 epochs and using a fixed value of ν = 0.3, although these
hyperparameter could be tuned using techniques such as k-fold cross-validation. As
a benchmark, we used the 7-day moving average, which is simply the mean value
between the last seven observations. Although this is a very simple model, it gives a
fairly good indication of the pandemic figures’ trend, being widely applied in updates
and information reports, as seen in datahubs like [35, 57]. We opted to use a 7-day
rolling window because it gives away a short-run information, and also because it
corrects for potential underreporting in weekend days, as empirically occurs for the
Brazilian data—the data for Saturdays and Sundays have been consistently lower
than weekdays, compensated by frequent “spikes” in the data during working days
that match the overall dispersion pattern when “distributed” to weekend days.
At the end of the training, we obtained the prediction errors between the forecasts
(ĉ and d̂ ) and the actual values (c and d ) for each day between June 1, 2020 and
August 31, 2020. Finally, for each location (country and States), we calculated the
Mean Absolute Error (MAE) of the forecasts, given by:
|ŷi − yi |
MAE = (1)
N
686 Y. Peng et al.
Table 2 Average in-sample MAEs for gradient boosting machine and 7-day moving average daily
forecasts of COVID-19 confirmed cases and deaths in the Brazilian states (ordered by the number
of confirmed cases at August 31, 2020)
State Confirmed cases Deaths
GBM MA7 GBM MA7
Brazil 0.66 55349.94 0.00 2494.72
(country-level)
SP 0.06 11251.07 0.00 618.35
BA 0.00 3410.40 0.00 95.27
RJ 0.00 4101.87 0.00 393.19
MG 0.00 2556.68 0.00 69.72
CE 0.00 4535.79 0.00 248.90
PA 0.00 4215.28 0.00 210.92
SC 0.00 1721.09 0.00 26.74
DF 0.00 2223.62 0.00 36.74
MA 0.00 3373.71 0.00 90.93
GO 0.00 1436.48 0.01 37.79
PR 0.00 1529.33 0.00 45.17
RS 0.00 1482.04 0.00 44.05
PE 0.00 2448.46 0.00 203.88
AM 0.00 2761.34 0.00 113.20
ES 0.10 1858.47 0.00 76.72
PB 0.00 2016.23 0.00 50.16
MT 0.00 1111.01 0.00 43.29
AL 0.05 1393.21 0.00 47.96
PI 0.00 1175.13 0.01 34.21
SE 0.00 1236.27 0.01 36.69
RN 0.04 1173.72 0.00 49.15
RO 0.00 946.39 0.01 24.13
TO 0.00 630.63 0.01 13.06
MS 0.00 540.50 0.00 9.10
RR 0.00 758.63 0.01 15.17
AP 0.00 1028.71 0.00 19.27
AC 0.00 538.25 0.00 17.17
where yi is the observed value at day i, ŷi is the predicted value at day i, and N is the
number of predicted days. We repeated the process for both GBM and 7-day moving
average models: the in-sample results are displayed in Table 2 and the out-of-sample
results are displayed in Table 3.
The results showed that the GBM model exhibited lower MAEs for both vari-
ables (confirmed cases and deaths) and all locations (Brazil and its 27 States). As
Table 3 Average out-of-sample MAEs for gradient boosting machine and 7-day moving average
daily forecasts of COVID-19 confirmed cases and deaths in the Brazilian states (ordered by the
number of confirmed cases at August 31, 2020)
GBM MA7 GBM MA7
Brazil 36942.78 146517.67 1002.73 4023.19
(country-level)
SP 7550.48 30260.83 243.47 981.39
BA 2590.60 10270.77 51.41 203.82
RJ 1850.47 7527.43 116.53 475.37
MG 2240.14 8803.47 55.04 215.86
CE 1809.39 7426.53 58.68 240.75
PA 1772.00 7089.78 38.48 144.14
SC 1834.13 6243.05 23.01 90.47
DF 1655.02 6548.85 25.55 100.35
MA 1264.33 5141.65 26.85 108.41
GO 1414.25 5531.75 32.99 128.18
PR 1382.11 5398.93 34.58 132.31
RS 1266.10 4958.22 34.90 136.72
PE 990.10 3990.00 52.02 212.98
AM 857.80 3534.03 17.63 71.40
ES 1060.58 4226.19 27.76 111.70
PB 1006.70 4055.64 22.72 90.82
MT 975.87 3829.98 29.87 117.43
AL 744.74 3023.51 15.70 63.65
PI 790.65 3144.58 18.21 72.23
SE 712.27 2854.83 18.47 73.89
RN 625.12 2379.42 21.20 85.40
RO 545.77 2172.67 10.78 42.57
TO 515.79 2020.95 6.67 25.93
MS 524.48 2044.59 9.45 36.22
RR 434.95 1742.15 5.18 20.78
AP 365.12 1482.93 4.77 19.67
AC 200.30 814.91 5.04 20.74
688 Y. Peng et al.
4000000
3500000
Number of confirmed cases
3000000
2500000
Model
Observed
2000000 GBM
7−day Moving Average
1500000
1000000
500000
20 /28
20 /04
20 /11
20 /18
20 /25
20 /02
20 /09
20 /16
20 /23
20 /30
20 /06
20 /13
20 /20
20 /27
03
9/
20 /05
20 /06
20 /06
20 /06
20 /06
20 /07
20 /07
20 /07
20 /07
20 /07
20 /08
20 /08
20 /08
20 /08
/0
20
20
Date
Fig. 9 Prediction for the number of COVID-19 confirmed cases in Brazil
expected, the overall error levels were lower for the predictions of deaths since the
number of persons infected with COVID-19 is naturally much larger than the num-
ber of deceased due to this disease. To provide a visual summary of the results, the
predictions and observed values for COVID-19 confirmed cases in Brazil and in the
three most affected States as of August 31, 2020 (namely São Paulo, Rio de Janeiro,
and Bahia) are displayed in Figs. 9, 10, 11 and 12; similarly, the predictions and
observed values for COVID-19 deaths at the same locations are displayed in Figs.
13, 14, 15 and 16.
It is interesting to note that, while the GBM model had, on average, an empir-
ical out-of-sample MAE 4 times smaller than the 7-day Moving Average for both
variables, this discrepancy would not be noted by evaluating the Coefficient of deter-
mination (R2 ) of a linear regression of the models’ predictions on the observed values:
for all locations and variables, the R-squared values were very similar and almost
equal to 1. These results are displayed in Table 4 and indicate that, despite its popu-
larity as a measure of overall fitness of a model, R2 may not always be informative
as a measure of predictive accuracy.
Comparatively, the proportion in which the moving average model underestimated
the real observed data is similar between the forecasts of the number of cases and
deaths, and the GBM model managed to follow the actual trend of the data with much
more accuracy over time. This can be attributed to the fact that, by construction, the
800000
700000
600000
500000 Model
GBM
400000 Observed
300000
200000
100000
20 /28
20 /04
20 /11
20 /18
20 /25
20 /02
20 /09
20 /16
20 /23
20 /30
20 /06
20 /13
20 /20
20 /27
03
9/
20 /05
20 /06
20 /06
20 /06
20 /06
20 /07
20 /07
20 /07
20 /07
20 /07
20 /08
20 /08
20 /08
20 /08
/0
20
20
Date
Fig. 10 Prediction for the number of COVID-19 confirmed cases in the state of São Paulo
260000
240000
220000
200000
180000
160000
Model
140000 Observed
GBM
120000 7−day Moving Average
100000
80000
60000
40000
20000
20 /28
20 /04
20 /11
20 /18
20 /25
20 /02
20 /09
20 /16
20 /23
20 /30
20 /06
20 /13
20 /20
20 /27
03
9/
20 /05
20 /06
20 /06
20 /06
20 /06
20 /07
20 /07
20 /07
20 /07
20 /07
20 /08
20 /08
20 /08
20 /08
/0
20
20
Date
Fig. 11 Prediction for the number of COVID-19 confirmed cases in the state of Rio de Janeiro
Number of deaths Number of confirmed cases
690
20 20
20 20
30000
40000
50000
60000
70000
80000
90000
100000
110000
120000
40000
60000
80000
100000
120000
140000
160000
180000
200000
220000
20 /05 20 /05
20 /28 20 /28
20 /06 20 /06
20 /04 20 /04
20 /06 20 /06
20 /11 20 /11
20 /06 20 /06
20 /18 20 /18
20 /06 20 /06
20 /25 20 /25
20 /07 20 /07
20 /02 20 /02
20 /07 20 /07
20 /09 20 /09
20 /07 20 /07
20 /16 20 /16
Date
Date
20 /07 20 /07
20 /23 20 /23
20 /07 20 /07
20 /30 20 /30
20 /08 20 /08
20 /06 20 /06
20 /08 20 /08
20 /13 20 /13
20 /08 20 /08
20 /20 20 /20
Fig. 13 Prediction for the number of COVID-19 deaths in Brazil

20 /08 20 /08
20 /27 20 /27
/0 /0
9/ 9/
03 03
Model
Model
GBM
GBM
Observed
Observed
Fig. 12 Prediction for the number of COVID-19 confirmed cases in the state of Bahia

Y. Peng et al.
30000
28000
26000
24000
Number of deaths
22000
20000 Model
Observed
18000 GBM
16000
14000
12000
10000
8000
6000
20 /28
20 /04
20 /11
20 /18
20 /25
20 /02
20 /09
20 /16
20 /23
20 /30
20 /06
20 /13
20 /20
20 /27
03
9/
20 /05
20 /06
20 /06
20 /06
20 /06
20 /07
20 /07
20 /07
20 /07
20 /07
20 /08
20 /08
20 /08
20 /08
/0
20
20
Date
Fig. 14 Prediction for the number of COVID-19 deaths in the state of São Paulo
moving average gives the same weight for all the 7 last days; in this sense, this model is
implicitly underestimating the growth rate of the series by including smaller values
into the calculation since most States in Brazil have not yet reached the “peak”
(i.e.: the point when the first-order derivative reaches zero) for the daily number
of infected/dead, which implies that the overall growth rate for both variables was
mostly accelerating (i.e.: with a second-order derivative larger than zero) during the
whole period of the respective time-series.
Moreover, it is noteworthy the fact that the error margins of the models were vari-
able across the States, which indicates the heterogeneous patterns of COVID-19’s
evolution in each different location in Brazil, potentially influenced by factors such as
lockdown/reopening measures, climate, and demographic characteristics. Nonethe-
less, the experiment described in this subsection still showed evident superiority
of GBM over the commonly used 7-day moving average forecasting. Therefore,
policy-makers can make use of more sophisticated quantitative methods to inform
the population about the figures of the pandemic’s evolution, consequently provid-
ing more accurate information about the severity in specific regions and the optimal
timing of social distancing and reopening measures in different States.
692 Y. Peng et al.
5500
5000
4500
4000
Number of deaths
3500
Model
3000 Observed
GBM
2500
2000
1500
1000
500
20 28
20 04
20 11
20 18
20 25
20 02
20 09
20 16
20 23
20 30
20 06
20 13
20 20
20 27
03
20 /05/
20 /06/
20 /06/
20 /06/
20 /06/
20 /07/
20 /07/
20 /07/
20 /07/
20 /07/
20 /08/
20 /08/
20 /08/
20 /08/
9/
/0
20
20
Date
Fig. 15 Prediction for the number of COVID-19 deaths in the state of Rio de Janeiro
3.2 State-Level Instantaneous Reproduction Number

Estimation and Clustering Analysis
This subsection aims to compare the strategies used to restrain the dissemination
of COVID-19 based on the number of infected cases in the Brazilian States and
the respective trajectories of the basic reproduction number. We propose a model to
estimate the Basic Reproduction Number (R0 ) and the instantaneous reproduction
number (Rt ). Afterward, a clustering method was applied to cluster the States sets of
the current period, as well as to provide the scenarios of contagious in Brazil.
3.2.1 Motivation
To evaluate the effectiveness of any containment strategy, it is essential to quantify

the transmissibility of the emerging virus [28]. This quantification, in its turn, is
achieved through the basic reproduction number R0 , defined as the average num-
ber of secondary cases generated by a typical primary case in an entirely suscepti-
ble population—if R0 > 1, there will be a continuous transmission from human to
human. The public control policies aim to reduce R0 to a value lesser than 1, which
16000
15000
14000
13000
Number of deaths
12000
11000 Model
Observed
10000 GBM
9000
8000
7000
6000
5000
20 /28
20 /04
20 /11
20 /18
20 /25
20 /02
20 /09
20 /16
20 /23
20 /30
20 /06
20 /13
20 /20
20 /27
03
9/
20 /05
20 /06
20 /06
20 /06
20 /06
20 /07
20 /07
20 /07
20 /07
20 /07
20 /08
20 /08
20 /08
20 /08
/0
20
20
Date
Fig. 16 Prediction for the number of COVID-19 deaths in the state of Bahia
means the transmission would gradually start to diminish, eventually reaching the
minimum necessary to mitigate damage to the health system.
[64] used a computationally intensive approach to estimate the epidemic param-
eter. The method consists of running stochastic simulations of the initial outbreak
trajectories and verifying which are consistent with the epidemiological findings
up to that point. For each primary case, the author generates secondary cases accord-
ing to a negative binomial distribution with average value R0 and dispersion k. The k
parameter quantifies the variability in the number of secondary cases considering a
gamma distribution to generate the time intervals. With a grid search and more than
3 million simulations, the authors estimated R0 as being close to 2.2. A similar result
was found in [48].
Considering the estimate of [29, 48, 64] verified the impact of non-pharmaceutical
interventions on reducing COVID-19 mortality. The author sets the values of R0 and
analyzes the virus mortality rate for each possible intervention policy to be taken by
governments. A relevant point in this context is the fact that starting from the intro-
duction of interventions, changes in the virus reproduction rate, and consequently in
the basic reproduction number, are expected.
For control intervention to be optimized, the values of the parameters governing
the pathogen spread must be estimated from surveillance data, and temporal changes
in these values must be tracked [79]. Thereby, to evaluate the current control policy,
694 Y. Peng et al.
Table 4 Coefficient of determination (R2 , rounded to 4 significant figures) from the regressions of
the predicted values of COVID-19 confirmed cases and deaths in the Brazilian States (ordered by
the number of confirmed cases at August 31, 2020) on their respective observed values
GBM MA7 GBM MA7
Brazil 0.9999 0.9996 0.9999 0.9998
(country-level)
SP 0.9996 0.9989 0.9997 0.9995
BA 0.9996 0.9987 1.0000 0.9998
RJ 0.9994 0.9982 0.9995 0.9990
MG 0.9997 0.9990 0.9996 0.9988
CE 0.9996 0.9992 0.9992 0.9989
PA 0.9997 0.9994 0.9986 0.9973
SC 0.9957 0.9942 0.9995 0.9968
DF 0.9999 0.9993 0.9997 0.9990
MA 0.9997 0.9994 0.9999 0.9990
GO 0.9994 0.9978 0.9996 0.9988
PR 0.9998 0.9987 0.9996 0.9984
RS 0.9992 0.9989 0.9997 0.9984
PE 0.9998 0.9993 0.9998 0.9995
AM 0.9997 0.9995 0.9997 0.9988
ES 0.9998 0.9990 0.9999 0.9995
PB 0.9997 0.9993 0.9999 0.9993
MT 0.9997 0.9985 0.9998 0.9984
AL 0.9999 0.9993 1.0000 0.9998
PI 0.9997 0.9988 0.9999 0.9991
SE 0.9996 0.9968 0.9997 0.9981
RN 0.9982 0.9951 0.9993 0.9970
RO 0.9996 0.9985 0.9996 0.9985
TO 0.9998 0.9995 0.9997 0.9992
MS 0.9998 0.9992 0.9997 0.9987
RR 0.9991 0.9963 0.9983 0.9946
AP 0.9986 0.9924 0.9995 0.9981
AC 0.9997 0.9993 0.9996 0.9987
the Rt value, which is the expected number of secondary cases resulting from a
primary infected case at the moment t, also must be considered.
[51] proposed, apart from the estimation of R0 , the estimation of Rt : by using
the Poisson Regression Method with a Gamma as a prior distribution and a Rolling-
Window of ten days, they estimated Rt to all of China and to the city of Wuhan, which
was the starting location of the virus. The authors identified a decrease in the basic
reproduction number that varies in time (Rt ) in the country, as well as in the city, after
January 16, 2020, which suggests that the intervention was successful, according to
the official numbers. In this sense, in this subsection, we followed a similar approach
and estimated Rt using the method described in [21].
3.2.2 Methods
The parameter R0 reflects the future transmissibility of the virus, but it is not the
most suitable parameter to assess the outbreak’s evolution in real-time, as discussed
in [21]. For this purpose, Rt is used instead. There are two concepts linked to Rt , as
presented by [31]: the first represents the number of reproduction of secondary cases
resulting from an infected primary case up to time t, which we will denote here as
R0 because we understand that this is the average number with an available sample.
In contrast, the instantaneous reproduction number, which we will denote here as Rt ,
considers a rolling window to estimate the basic reproduction number and provides
a real-time image of the outbreak [21].
A Bayesian approach was used to estimate the instantaneous reproduction num-
t Rt . Considering It as the number of new infections generated at time step t and
ber
s=1 It−s ps as the total infectiousness of infected individuals at time t, we can esti-
mate Rt as the ratio of this two quantities. The ps term showed in the expression above
represents the infectivity function and can be approximated by the distribution of the
generation time. We assumed a gamma prior distribution for Rt because it leads to a
simple analytical expression of the posterior distribution, as seen in [21].
More specifically, the transmission is modeled with a Poisson process and Rt ps is
the rate that someone infected in time step t − s generates new infection in time step
t. Using Gamma distributed prior with parameters (α, β),
the posterior distribution

of Rt is also a Gamma distribution with parameters α + ts−w+1 Is , 1 +t 1 I p .
β s=1 t−s s
The w in the aforementioned expression is the length of time window the resulting Rt
estimates, and can be highly variable and hence difficult to interpret when the time
step of data is small [21]. We opted to use a generation time with mean value of 4.7
days and standard deviation of 2.9 days, following [56].
Considering xi as the number of infected in time i, n the total number of days with
the available sample, and w the length of the window, the sample Xiw is defined as
the rolling window of the number of infected:
Xiw = {xi , xi+1 , ..., xi+w }, i + w ≤ n.

696 Y. Peng et al.
The suppression intervention policies policy is expected to interfere with this

parameter, as discussed in [47] and [3]. Note that we will not only have Rt , but
values for n − w, thus being possible to evaluate in real-time the trend and evolution
of the reproduction number. There are cases registered in all States, and each State
has adopted different interventions at different stages of the epidemic. Since the
instantaneous reproduction number is considered to be a good measure of real-time
outbreak assessment, we will do a comparative study between the Brazilian States
taking this into account.
The State-level patterns of Rt over time were used to identify groups using the
clustering method. There are some methods for clustering time series: the subse-
quence clustering approach considers only a time series and divides it into more
similar segments to form the clusters. We use in this application the whole time
series, treating each time-series as one observation and the variable of the problem
as the specific time point, as reported in [1]. Similarity measures are important in
any cluster analysis and can also be used in a time-series context. In general, we can
divide them into shape-based, feature-based, and model-based. The Dynamic Time
Warping algorithm [68] was used in this subsection—it is a shape-based method that
calculates the smallest distance between all points, with the benefit of not requiring
an equal length of time series and not considering pairs of data points. For more
details see [85].
The instantaneous reproduction number was calculated for all 27 States of Brazil
and the aggregated country-level data, considering a rolling window of 10 days. The
objective of including the estimated parameter for the whole country is to identify
the most similar states to the Brazil country-level pattern. After calculating Rt in
various periods of time for all States, we used the cluster approach to identify the
groups of most similar States. We used data from the start of the pandemics in Brazil
until August 31, 2020.
3.2.3 Results
Each State Governor adopted restrictive measures with different intensities, and at
different times, so it is expected that the Rt would capture this variability and identify
groups of states that the control policy has caused the same pattern of contagion. The
choice of the number of clusters was preceded by an analysis of gap statistics [80];
the result of the clustering analysis is presented in Fig. 17 and the map of the States
that compose them are displayed in Fig. 18.
The States grouped in cluster 1, namely São Paulo (SP), Espírito Santo (ES),
and Sergipe (SE), showed a drop in the estimated parameter at the beginning of the
series, with a stabilization of the level after the 30-day rolling window and a new
downward trend after the 60th-day rolling window. The initial drop can be attributed
to the implementation of isolation measures and, from the moment that the measures
were relaxed, an increase in the instantaneous reproduction number can be observed.
The States of São Paulo and Espírito Santo are neighboring states in the Southeast
Region, while Sergipe is located in the country’s Northeast Region.
Cluster 1: ES,SE,SP Cluster 2: AP,GO,MG,RR,RS,SC
1
Rt
Cluster 3: DF,MS,MT,PR,RN Cluster 4: AC,AL,AM,BA,BR,CE,MA,PA,PB,PE,PI,RJ,RO,TO
0 30 60 90 120 0 30 60 90 120
Days
Fig. 17 Cluster for Brazilian states considering the parameters of a 10-days rolling window
The States that compose cluster 2, namely Amapá (AP), Goiás (GO), Minas Gerais
(MG), Roraima (RR), Rio Grande do Sul (RS), and Santa Catarina (SC), were the
ones that showed the greatest variability in the estimated parameter, with no apparent
downward trend and some isolated peaks.
The pattern of parameter estimates for the States of cluster 3, namely Distrito
Federal (DF), Mato Grosso do Sul (MS), Mato Grosso (MT), Paraná (PR), and Rio
Grande do Norte (RN), is similar to the pattern observed in cluster 1, with an earlier
increase in Rt and a new downward trend just after the 90th-day rolling window.
The States that form cluster 4, which comprises the remaining States not assigned
to the first three clusters (namely Acre (AC), Alagoas (AL), Amazonas (AM), Bahia
(BA), Brazil (BR, country-level), Ceará (CE), Maranhão (MA), Pará (PA), Paraíba
(PB), Pernambuco (PE), Piauí (PI), Rio de Janeiro (RJ), Rondônia (RO) and Tocantins
(TO)), showed a drop in the instantaneous reproduction number in the initial period,
with a stabilization after the 20th-day rolling window but with a downward trend.
This cluster is the one that grouped the largest number of UFs and also included the
aggregated number of Brazil, which suggests that the pattern of Rt observed in this
grouping reflects a general Brazilian pattern.
The downward pattern observed in the first 30 rolling windows of 3 clusters sug-
gests the effectiveness of the restriction measures at the beginning of the pandemic
on reducing the instantaneous reproducing number at their respective States. Never-
theless, an increase was also observed in these 3 clusters, at different time periods,
698 Y. Peng et al.
0°
10°S
Cluster
1
2
3
4
20°S
30°S
1000 km
70°W 60°W 50°W 40°W
Fig. 18 Map of the Brazilian states based on the respective clusters of their instantaneous repro-
duction number evolution
which are in turn aligned to gradual reopening measures, which will be better dis-
cussed in Sect. 4.3. While it is not possible to guarantee that States in the same
group have adopted the same suppression strategy, it is possible to see that the set
of interventions adopted individually resulted in a pattern of dealing with the virus.
The presence of neighboring States in the same cluster and their implications in
their overall contagion patterns can also be better investigated using spatial statistics
techniques in future researches.
3.3 Evaluating the Underreporting of COVID-19 in Brazil at

the Early Stages of the Pandemics
This subsection investigates the underreporting of COVID-19 in Brazilian states,

based on South Korea and Italy’s data as testing benchmarks; moreover, we estimated
the relative magnitude of underreporting based on the case-fatality rates of these

two countries. We also developed a statistical model that incorporates temporal and
spatial aspects, which analyzed the dispersion of COVID-19 from an epicenter for 3
Brazilian States. Finally, we also verified the relative influence of the road network
for the dispersal of COVID-19 in these states.
The results indicated that 16 of the 27 Brazilian States presented higher notification
levels than the ones observed in Italy, but all States showed evidence of underreporting
when compared with the levels observed in South Korea. We also discussed the
evidences of underreporting from the interior in relation to the State capital. The
findings can contribute to a better understanding of the underreporting heterogeneities
for different regions of Brazil.
3.3.1 Motivation
In order to understand the disease caused by SARS-CoV-2 and to plan effective

methods of controlling its spread, a fundamental aspect of gathering information is the
performance of tests. However, the limited testing capacity of several countries leads
to underreporting in the numbers of infected and deaths, which makes it challenging
to identify the real evolution of the epidemic [61]. On the other hand, the exponential
growth characteristic of an epidemiological outbreak can cause a collapse in health
systems, such that the knowledge of the true number of infected is essential to guide
public policies to combat the pandemic, as discussed in the works of [82] and [4].
Based on this scenario, this subsection is motivated to propose an approach based
on statistical techniques, combined with temporal and spatial analysis, to assess the
underreporting of cases of COVID-19 infection for the municipalities of the State
of São Paulo, Rio de Janeiro, and Ceará, three of the Brazilian most affected States
by the pandemic in its early stages. The developed model investigated the spatio-
temporal pattern of the number of notifications, as well as the number of deaths
from the interior to the respective State capitals. As enunciated by the First Law of
Geography [81], it is expected that municipalities geographically closer to the capital
will present a more similar contagion pattern in comparison to distant municipalities.
Similarly, road networks can increase similarity even over longer spatial distances,
as discussed in [65]. Thus, it is expected that municipalities that share a road network
have greater similarity than those that do not, especially because the road system is
the primary means of transport in Brazil. In addition, we also compared the testing
standard presented by all Brazilian States, based on the relationship between deaths
and confirmed cases in countries that have proven to have a good testing capacity.
Several related works have evaluated the effect of underreporting using the rela-
tionship between deaths and confirmed cases from countries with adequate testing
capacity, such as the study by [42], in which the authors applied a temporal and risk
factor correction to the lethality rate of cases in one country, taking into account its
age pyramid, to estimate the real value of the number of infected people in another
country that is suspected of underreporting.
700 Y. Peng et al.
Other techniques involve the use of behavioral models to estimate the number
of infected people over time, as discussed in the work of [45], in which the differ-
ence between the number estimated by the proposed model and the one observed is
interpreted as the reflection of underreporting—basically, these authors used a model
composed of a system of differential equations, whose parameters were calibrated
according to the data observed in the countries analyzed, and based on the theoret-
ical estimate of this model, obtain an estimate of underreporting in these locations.
Another approach, adopted in studies like [61], used not the estimated number of
infected people but the difference between the epidemiological parameters observed
in different countries.
In our approach, we integrated a temporal-spatial approach with a discussion on
underreporting, incorporating Brazil’s specificities, both regarding its geographical
extension and population abundance compared to the fact that Brazil is one of the
most affected countries by the pandemic. This approach is in line with that addressed
by the study by [42], in which the case-fatality rate observed in South Korea was
used to estimate the actual number of infected people, considering that this country
was one of the first ones to adopt the mass testing strategy, adopting it at the initial
stage of the dissemination of COVID-19.
In this sense, information from South Korea was adopted as an ideal standard
for the purposes of full notification and information from Italy as an intermediate
standard. Finally, in order to apply the findings of the work to the Brazilian context,
this work introduced changes to the study of [42] through the temporal-spatial sta-
tistical models that allowed to provide a comparative analysis of the testing pattern
of infected for the five Brazilian regions.
3.3.2 Methods
We begin by presenting the temporal-spatial statistical model to estimate underre-

porting from the epicenter (capital) to the interior. Consider YijC as the number of
confirmed cases and YijD as the number of deaths from COVID-19 for the municipal-
ity i of a State on the date j. Also, consider the following regression model with a
Negative Binomial response, that is, YijC ∼ BN (μC , φ)Z with systematic part given
by:

log μCij = ηijC
ηijC = β0jC + β1jC X1 + β2jC X2 (2)
where X1 represents the distance in latitude-longitude (lat-long) units to the State

capital and X2 identifies municipalities that are crossed by highways that also pass
through the capital. For the number of cases of death, also consider YijD ∼ BN (μD , φ)
with a systematic part given by:

ij = ηij
log μD D
ηD
ij = β0j + β1j X1 + β2j X2
D D D
(3)
The coefficient exp(βkj ) indicates the percentage change in incidence related to

the variable k, either as an indicator of a dichotomous class or as a measurement on
the scale of real numbers.
Being a cross-section analysis in several periods, the explanatory variables capture
the temporal differences between the municipalities’ contamination patterns. That
is, it is expected that as the epidemic evolves over time, the difference between
municipalities will be reduced, considering that the size of the local population
was regarded as a known part of the linear predictor (offset). That is, the exp β1C
coefficient, related to the incidence of confirmed cases based on distance in lat-
long units to capital, is expected to be at least greater than exp β1D —related to the
incidence of confirmed death records based on the distance variable in lat-long units
to the capital—for the same period of analysis.
A similar relationship is expected for exp β2c , a term related to the incidence
of confirmed
cases based on the road network variable, so that it is at least greater
than exp β2d —related to the incidence of death records based on the road network
variable
- in the same
period of analysis. Thus, this work uses the difference between
exp βid and exp βic to evaluate evidence of underreporting in the analyzed states.
The models 2 and 3 were adjusted for municipalities in the states of São Paulo,
Rio de Janeiro, Ceará—3 of the Brazilian states most affected by the pandemic.
Accumulated daily data were used for the number of confirmed cases, and deaths
per municipality between April 01, 2020, and June 01, 2020, collected from [23]. In
this sense, we adjusted 62 models for all States, considering their municipalities as
observations. An analysis of model selection preceded the choice of regression with
a Binomial Negative response: in order to compare the analyzed states, the same
model, Binomial Negative, was used, which presented, in general, the lowest Akaike
information criterion [2].
Below, we present the method of estimating the cumulative number of cases
exclusively based on the cumulative number of deaths, using as reference a country
that has proven to have a good testing capacity. The case fatality rate in period t is
defined as:
number of deaths
CFR = . (4)
number of confirmed cases
The use of gross rates can significantly influence the analysis of results in studies
with a low frequency of observations, as the index deals in general with two numbers;
when the value in the denominator is low, the rate tends to be inflated, and some
corrections can be used, as discussed in [15]. Here, as we use an aggregation by
State, we understand that the impact of few occurrences would be given only at the
very start of the pandemic, and an analysis was made with a broader time horizon.
702 Y. Peng et al.
0.15
0.10
CFR
0.05
0.00
01/02 01/03 01/04 01/05 01/06 01/07 01/08 01/09

Date
Brazil Italy United Kingdom

Germany South Korea United States
Fig. 19 Case-fatality rates for selected countries, as of 31 August, 2020
The age of the infected individual is a risk factor for the severity of the disease;
that is, the older, the greater the chances of the person needing critical care and
dying due to COVID-19, given the high incidence of comorbidities in more aged
people [63]. Thus, countries with an older population tend to have a higher value
for lethality than countries with a younger population. Although age is a significant
factor in the relationship between deaths and cases, as well as the quality of the health
system, heterogeneity is identified in this reason for several countries [25] not only
for these factors but also due to underreporting. With the number of confirmed cases
underreported, the denominator in expression 4 has a lower value, thus inflating its
value.
Figure 19 shows the case-fatality rate of six countries over time, and it is possible
to notice that Germany and South Korea had a case-fatality rate lower than Brazil’s,
even with a proportionately older population. In addition, there is a heterogeneity of
the measure between countries.
Considering that underreporting is a cause for the difference between countries’
CFRs, the proposed underreporting correction allows for the comparison of two
countries with different demographic characteristics of the population. This compar-
ison is made using a vulnerability factor VFAB which reflects the number of cases in
country A, corrected in relation to another reference country B, defined as [42]:
N
fA r i
VFAB = Ni=0 , (5)
i=0 fB ri
Table 5 Case-fatality rate by age for South Korea and Italy [41]
Age South Korea Italy
Deaths CFR (%) Deaths CFR (%)
0–9 0 0 3 0.20
10–19 0 0 0 0
20–29 0 0 12 0.10
30–39 1 0.001 60 0.40
40–49 1 0.001 259 0.90
50–59 8 0.006 1069 2.70
60–69 20 0.,017 3135 10.40
70–79 38 0.064 8258 25.50
80+ 52 0.136 7087 29.70
where fA is the fraction of the population with age i in the country A, fB is the fraction
of the population with age i in the country B and ri is country B’s fatality rate at the
age i. The reference countries adopted were Italy and South Korea, whose values of
ri are shown in Table 5:
Values of VFAB above 1 show that the population of the country with suspected
underreporting has a higher risk of death, while a VFAB below 1 indicates a lower
relative risk of death. Hence, if VFAB < 1 then the population of the country under
study is younger than the population of the reference country and, consequently, has
a lower risk of death; on the other hand, if VFAB > 1 then the population of country
A has a higher risk of death because its population is older.
When considering CFRB as the case fatality rate of the country B, the estimate of
the number of cases accumulated in time t for the country under study is given by:
M(t + d)
NC(t) = ,
VFAB × CFRB
with M representing the number of deaths in the country A and d representing the
number of days between infection and death, assumed in this study to be 12 days, in
view of the variability presented by the works of [67, 70, 84].
3.3.3 Results
The influence of the geographical distance and the presence of a road network in the
spread of the disease was assessed using the Euclidean distance from each municipal-
ity to the epicenter of the disease, São Paulo, Rio de Janeiro, and Fortaleza—capital
cities for the States of São Paulo, Rio de Janeiro, and Ceará, respectively. Figures
20, 21 and 22 presents the estimated coefficients of the equations 2 and 3 for each
State over time.
704 Y. Peng et al.
São Paulo
1.00
0.75
Distance
0.50
0.25
Estimate
0.00
5
4
Road
3
2
1
01/04 01/05 01/06 01/07 01/08 01/09

Date
Confirmed Death Significant at 5% Not significant
Fig. 20 Estimates of the parameters of the negative binomial model for the state of São Paulo. The
markers indicate the results of the significance test against H0 : beta = 0 at each timestamp, and the
bands indicate the confidence interval with α = 95%
In most of the sample for all the states analyzed, the significance (at the 95% con-
fidence level) presented by the coefficient linked to the variable distance between the
municipalities and the capital, the results suggest that the distance from the munici-
pality to the State’s epicenter is relevant to understand the dissemination disease in
the municipalities. Moreover, we identified that, for the municipalities of the states
of São Paulo and Rio de Janeiro, the estimated coefficients linked to the distance
variable of the death model present higher values than the coefficients of the case
model before May, a pattern that showed changes after May, so that there was no
intersection between the limits of the respective confidence intervals for the State of
Rio de Janeiro. For the State of Ceará, the pattern is similar to the other Brazilian
states before May and, after, they present similar values.
When considering the capital as an epicenter, it is expected that case records
for people infected by COVID-19 happen earlier than the death record, so if the
coefficient linked to the number of cases model is less than the coefficient related to
the number of cases deaths is indicative of underreporting.
In view of the results found for the models 2 and 3, a similar behavior was found
for São Paulo (SP) and Rio de Janeiro (RJ), and a quite different one for Ceará. For
SP and RJ, the assumption that the parameter βC would be greater or equal than βD is
only verified after April 28. Before that, we have βD > βC , that is, the dissemination
Rio de Janeiro
Distance
1
Estimate
7.5
Road
5.0
2.5
0.0
01/04 01/05 01/06 01/07 01/08 01/09
Date
Fig. 21 Estimates of the parameters of the negative binomial model for the state of Rio de Janeiro.
The markers indicate the results of the significance test against H0 : β = 0 at each timestamp, and
the bands indicate the confidence interval with α = 95%
of death cases, centralized in the capitals, is greater than that of registered cases. The
results for the State of Ceará suggest that there is still underreporting in the interior,
in relation to the capital Fortaleza. Thus, we have an indication of underreporting in
the interior of this State, in contrast to what was observed in the states of São Paulo
and Rio de Janeiro.
Considering the states’ heterogeneity, Fig. 23 shows the comparison of the state-
level estimates of the number of infected people based on the number of deaths and
the CFR, taking South Korea as reference. Figure 24 performs the same comparison
using Italy as reference. The results are presented in relative terms—that is, the
number of cases observed is compared to the number of cases estimated using the
CFR of South Korea and Italy assumed as proxies for testing capacity.
The proposed CFR methodology indicated the presence of heterogeneity between
the testing capacity of the regions and states: all states presented, except for the
States of Mato Grosso, Rio de Janeiro, and Pernambuco, a testing standard superior
or equivalent to that of Italy after June 1. This indicates that these states were able
to carry out the confirmation tests in proportion to the number of registered deaths,
equivalent to the Italian standard. However, considering that the relative spread of
the disease was greater in Italy than in these states, future studies may use this finding
706 Y. Peng et al.
Ceará
Distance
2
1
Estimate
10.0
7.5
Road
5.0
2.5
0.0
01/04 01/05 01/06 01/07 01/08 01/09
Date
Fig. 22 Estimates of the parameters of the negative binomial model for the State of Ceará. The
markers indicate the results of the significance test against H0 : β = 0 at each timestamp, and the
bands indicate the confidence interval with α = 95%
North Northeast Southeast South Central−West
0%
SC
−25%
MS
South Korea
DF
Relative
PB
BA
TO MG RS
−50% PI
RR
AP SE ES
MA
ALRN PR GO
ROAC SP
CE MT
−75%
PA
AM PE RJ
−100%
01/06 01/09 01/06 01/09 01/06 01/09 01/06 01/09 01/06 01/09
Date
Fig. 23 Comparison of the testing standard in the Brazilian states based on the CFR for South
Korea
North Northeast Southeast South Central−West
400%
300%
SC
MS
DF
Relative
200%
Italy
TO PB
BA
RR MG RS
AP PI
SE ES
100%
AL
MARN PR GO
RO
AC SP MT
PA CE
0% AM PE RJ
−100%
01/06 01/09 01/06 01/09 01/06 01/09 01/06 01/09 01/06 01/09
Date
Fig. 24 Comparison of the testing standard in the Brazilian states based on the CFR for Italy
to assess the relative effectiveness of social isolation measures in order to achieve

success in containing the advance of the pandemic compared to other locations.
On the other hand, the North, Northeast, and Southeast regions showed less testing
capacity before June 1. Thus, there is evidence that, until May, all states in these
regions have a ratio proposed by the CFR below Italy’s. When compared to the
South Korea standard, there are indications, according to the CFR methodology, that
some degree of underreporting was observed in all Brazilian states in the early stages.
Figure 25 shows the correlation between various socioeconomic indexes and the
underreporting parameter. Apart from indicators of employment, income, mortality,
and educations, we also analyzed the Social Vulnerability Index (IVS), which is
built based on indicators of urban infrastructure, human capital, income, and labor
statistics; IVS with values closer to one indicate higher social vulnerability [22].
We used only the South Korea testing rates as reference because, under a linear
transformation of one of the variables, the correlation with the Italian levels would
remain unchanged. A positive correlation was observed between underreporting and
indexes in which larger values indicate better social welfare and a negative corre-
lation between underreporting and indexes in which smaller values indicate better
social welfare. For both categories, the correlations were, in absolute value, close
to 30% in the early stages of the pandemic, and gradually approximating towards
smaller degrees of association over time, evidencing a relative improvement of the
notifications of COVID-19 figures as the virus reached the vast majority of cities in
Brazil.
This subsection’s contribution from the theoretical point of view is through the
indirect comparison of the number of confirmed deaths and cases using the estimated
coefficients for a generalized linear model that considers spatial aspects. From the
708 Y. Peng et al.
Pearson correlation coefficient
0.3
% employed adults
% self−employed
0.0 education level of employed adults

IVS
1−year mortality
Per capita income
−0.3
01/04 01/05 01/06 01/07 01/08 01/09

Date
Fig. 25 Correlation between socioeconomic indexes and underreporting during the COVID-19
pandemic
empirical point of view, on the other hand, the contributions of this article lie in the
estimates obtained from underreporting from COVID-19 comparing mortality rates
from other countries, which showed the heterogeneity of testing conditions between
the Brazilian States, which in turn can be relevant for policy-makers to better adapt
to the specificities of each region.
The methodology for determining the existence of the road network used in the
model can be improved in future researches, allowing the expansion of comparative
capacity between states or countries. In addition, the assumption of a single epicenter
of the spread of the disease may be insufficient to represent the reality of the spread
of the disease. In this sense, a dynamic study to characterize a disease disseminating
center may reveal additional patterns that are potentially valuable to assist in decision-
making and formulation of public policies. Finally, we emphasize that, in order to
obtain a more accurate estimate of the real dimension of non-notified cases, sampling
surveys are encouraged in order to incorporate data with greater granularity, which
can allow to more accurately measure the impacts of COVID-19 in the public health,
but also in economic implications and social awareness, which are discussed in the
following section of this chapter.
20% COVID−19
Variation (%)
Self−employed
10% Unemployed
Income
0%
17Q1 17Q2 17Q3 17Q4 18Q1 18Q2 18Q3 18Q4 19Q1 19Q2 19Q3 19Q4 20Q1 20Q2
Quarter
Fig. 26 Socioeconomic indicators in Brazil, quarterly data from Q1 2017 to Q2 2020
4 COVID-19’s Impacts on the Economy and Social

Awareness
4.1 Impacts of COVID-19 on Brazil’s Macroeconomic

Indicators
Brazil is the fifth largest country in terms of geographic area, seventh in population,
and eighth in GDP [19]; on the other hand, its Gini Index in the eighth worse in the
world [78]. Therefore, the country’s extension and income distribution inequality
among the population represents additional challenges for the Brazilian administra-
tion to manage the COVID-19 outbreak. Apart from the severe impacts on public
health, COVID-19 has also impacted the Brazilian economy in many ways, as we
shall discuss in this subsection.
In a more macroscopic view, we developed three aggregate indexes that represent
the Labor market and income: in Fig. 26 the blue line represents the growth income in
percent variation—the series shows that, before the lockdown (first quarter of 2020),
the income levels were in a recovery trend after the 2014 domestic recession and the
political instability scenario; after the lockdown, which occurred in March of 2020,
the income had a negative impact arising from COVID-19 pandemic. In the green
line at Fig. 26, we can see the unemployment increasing after the COVID-19 impacts;
the lockdown and the several aspects in health at the COVID-19 Brazil’s induced a
negative balance in the formal employment starting in March when the COVID-19
imposed the closure of a series of economic activities. Simultaneously, the red line
(Self-employed workers) didn’t suffer a significant impact, which indicates that the
labor market did not have a strong transition from formal jobs for self-employed
workers.
710 Y. Peng et al.
215000
Income (Millions R$)
210000
205000
200000
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
15
15
16
16
17
17
18
18
19
19
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Date
Fig. 27 Total Income levels (Millions of BRL), monthly data from March 2015 to June 2020
Figure 27 represents the Total Income in Millions of Brazilian Reais, measuring

the total Brazilian income for formal workers; the dashed red line represents the
median of this income. As we can see, the Brazilian Total Income was in a recovery
trend after the 2014 political crisis that culminated in the Impeachment of then
Brazilian president Rousseff. Due to poor allocations in fiscal policies and massive
spending in inefficient initiatives, the Brazilian economy suffered from severe fiscal
distresses, which in turn contributed to the advent of one of the worst economic
recessions in Brazil’s history. In this context, the approval of the public expenditure
upper bound helped Brazil in terms of recovering the confidence of the market and
foreign investors, thus made possible the growth of the total income. However, the
COVID-19 pandemic crisis represented a setback in this trend and induced a negative
impact on the overall income levels, as unemployment increased from the pandemic
due to the drop in consumption and investment levels.
Observing the Fig. 28, which illustrates the exchange rate between the Brazilian
Real and the US$, we can see the Brazilian currency is depreciated in compari-
son to the US$, oscillating between 5 reais per dollar, which favored the Brazilian
agriculture exports, which had a record volume of crop production and implicitly
benefited from the food supply decrease in leading importers, notably China. As
for the monthly Inflation rate, which shows the price level increases for a basket of
main products consumed in the Brazilian economy, Figs. 28 and 29 show that this
inflation index increased in the last two years, as a consequence of the impact of
the relative depreciation of Brazilian Real and the high levels of public deficit. As
economic activities began to resume, these indices responded by slightly increasing;
in particular, the food prices had more substantial increases due to the high demand
Exchange Rate = USD/BRL
5.7
5.4
5.1
0
0
02
02
02
02
02
02
−2
−2
−2
−2
−2
−2
04
05
06
07
08
09
Date
Fig. 28 USD/BRL exchange rate, daily data from March 23, 2020 to September 11, 2020
2
Inflation (% p.m.)
−1
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
15
15
16
16
17
17
18
18
19
19
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Date
Fig. 29 Inflation Index (% per Month), monthly data from March 2015 to June 2020
712 Y. Peng et al.
0
GDP (% per Year)
−4
−8
−12
−1
−4
−7
−1
−4
−7
−1
−4
−7
−1
−4
−7
−1
−4
−7
−1
−4
15
15
15
16
16
16
17
17
17
18
18
18
19
19
19
20
20
Date
Fig. 30 GDP Growth (% per Year)), quarterly data from Q1 2015 to Q2 2020
for food delivery services and the exchange rate levels, which encouraged the export
of Brazilian rice, which is the main item in the country’s food diet.
Figure 30 displays the economic impacts of COVID-19 in Brazil’s GDP growth:
in a very short period, the pandemic dramatically affected the Brazilian economy,
causing it to shrink 12% per year between the first and second quarters of 2020.
Notably, in early 2020, the market had strong expectations of a structural recovery
movement that would lead to a more stable and sustainable growing trend for the
next years [7]. Naturally, COVID-19 represented a structural break that altered this
pattern and brought along severe restrictions on both supply and demand sides. The
measures of social lockdown to contain the spread of the virus in Brazil and the rest
of the world, coupled with the sharp worsening of consumer and business confidence,
is likely to provoke the most significant drop in Brazilian GDP since the beginning
of the historical series in 1901 [40]. Indeed, as of September 21, 2020, the Focus
Market Report from the Central Bank of Brazil [18] estimates a 5.05% fall for the
Brazilian GDP in 2020 and a growth of 3.5% in 2021. As for the interest rates, which
reached a historical low of 2% per year in 2020, they are estimated to maintain at
a low value of 2.5% per year in 2021. In Fig. 30, we can see that after the sanitary
crises for COVID-19, the GDP growth rate fell sharply.
According to [40], the magnitude of the shock caused by the new coronavirus
required the adoption of a wide range of emergency measures support for health and
preservation of employment and income. On the side of public revenue, it is worth
highlighting the reductions and temporary exemptions from taxes and contributions
on goods needed to combat the pandemic; suspension payments of social security
debts; and deferral, for some months, of several taxes and tributes. Regarding the
Admission to the labor market
1250000
1000000
750000
−1
−2
−3
−4
−5
−6
−7
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Date
Fig. 31 Total admissions in the Brazilian labor market, monthly data from January 2020 to July
2020
expenditure of public institutions, federal-level actions include the maintenance of

the “Bolsa Família” program, one of the main social assistance programs in Brazil;
the creation of the COVID-19 Emergency Aid Program, a financial assistance to
the needy population and informal workers; and resource transfers to states and
municipalities for health actions.
These government efforts to maintain the employment and income levels showed
their first results in early June/2020, when admissions (formal hirings in the labor
market) started to show a more sustainable upward trend structure. However, these
efforts need more precise calibrations to resolve the trade-off between maintaining
fiscal efforts and policies to support income and employment maintenance.
Figure 31 displays the job admissions in the labor market in 2020: at the end of
February and the beginning of March, the admissions in the labor market fell severely,
resuming its growth from mid-April to early June. The red dashed line represents the
median of admissions to the labor market in this period. On the other hand, in terms
of layoffs in the market, we can see an increase during the period of social isolation,
but after the relaxation of restrictive measures, layoffs fell sharply, indicating the
quick reaction of the market to the gradual reopening policies. The Fig. 32, on the
other hand, has the red dashed line that represents the median of layoffs in this
period. These figures indicate that the Brazilian economy is slowly recovering from
the severe impact of restrictive mobility measures in response to COVID-19, while
restrictive social distance measures are gradually being relaxed.
It is noted that the aid policies that guaranteed or minimally insured the jobs and the
income level of vulnerable Brazilian populations must be precise, both regarding the
714 Y. Peng et al.
Layoff in the labor market
1400000
1200000
1000000
−1
−2
−3
−4
−5
−6
−7
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Date
Fig. 32 Total layoffs in the Brazilian labor market, monthly data January 2020 to July 2020
magnitude of resources transferred to the most needy and the time of application of
these policies. This argument is supported by the implications of the history of fiscal
unbalance in the Brazilian economy over the past recent years: the Brazilian public
budget is quite rigid and has been growing over the years, as we can see in Fig. 33,
which displays the debt-to-GDP ratio of the Brazilian States and Municipalities.
As we can see, the proportion of public debt in relation to GDP has been growing
dramatically, especially after the COVID-19 pandemic, due to the additional fiscal
burden of intervention policies.
Finally, we analyzed in Tables 6, 7 and 8 the dynamics of employment and income
using State-level data. In general, there has been a slight drop in the average income
comparing the periods before and after the severe restrictive lockdown measures of
the COVID-19 crisis, an unvarying trend of the numbers of self-employed persons
in the economy and an increase in the number of unemployed, which is aligned to
the results shown in Fig. 26.
In terms of social assistance and income preservation, the COVID-19 Emergency
Aid program was the main Federal-level policy created in response to the pandemic.
In the next subsection, we will analyze this program separately, addressing its eligi-
bility criteria and overall effectiveness regarding social focusing and resource transfer
to the most vulnerable population.
13
Debt/GDP
12
11
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
−3
−6
15
15
16
16
17
17
18
18
19
19
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Date
Fig. 33 Brazilian debt-to-GDP ratio, monthly data from March 2015 to June 2020
4.2 COVID-19 Emergency Aid Program
The COVID-19 Emergency Aid Program is a social assistance program created by the
Brazilian Government with the aim to mitigate the impacts of COVID-19 on social
vulnerability. Regulated by law number 13982/2020, the emergency aid determined
a monthly transfer of 600 BRL per month (initially for three months) to informal and
low-income workers, individual micro-entrepreneurs, and individual contributors
to the National Social Security Institute in Brazil. Benefit recipients registered at
the Unified Registry for Social Programs (“CadÚnico”) had a “fast-track” for the
payments—since this platform is the mandatory registry for recipients of the “Bolsa
Família” program (the main social assistance program in Brazil), this action was
taken to allow the benefit to be transferred to the most vulnerable individuals as fast
as possible; furthermore, single mothers and women who are heads of a household
had the right to receive twice the amount for the program.
The eligibility criteria to receive the emergency aid are listed below:
1. Be over 18 years old;
2. Not be formally employed;
3. Not be receiving other benefits (like unemployment insurance);
4. Having a monthly per capita family income up to 522.50 BRL or a total family
income up to 3135.00 BRL;
5. Not having received taxable income, in 2018, above 28559.50 BRL;
6. Be unemployed or perform activities under one of the following conditions:
716 Y. Peng et al.
Table 6 Quarterly average income in Brazilian states, aggregated by regions

Region State Q3 2019 Q4 2019 Q1 2020 Q2 2020
North RO 2049.1 2060.5 2167.4 2025.8
AC 1832.6 1885.7 1951.2 1866.8
AM 1739.1 1742.7 1861.8 1884.6
RR 2404.9 2234.5 2485.6 2406.4
PA 1549.5 1658.6 1797.1 1702.1
AP 1920 1951.4 2106.6 1938.1
TO 1858.7 1894.7 2038.2 1941.3
Northeast MA 1323.1 1362.3 1443.9 1315.1
PI 1390.4 1351.5 1524.3 1354.1
CE 1640.6 1676 1815 1691.6
RN 1799.4 1975.8 2134.7 1924.8
PB 1666.3 1692.9 1806.8 1605.4
PE 1714.7 1750.2 1909.9 1612.6
AL 1529.9 1508 1759.2 1454.8
SE 1588.3 1595.3 1807 1661.9
BA 1524.8 1634.2 1793.4 1610
Southeast MG 1962.2 2112.5 2261.4 1962.9
ES 2176.4 2245.5 2358.9 2063.3
RJ 2795.9 2907.9 3209.9 2938.1
SP 2940.1 3104.2 3371.3 2891.4
South PR 2529.2 2640.9 2858.2 2420.8
SC 2549.4 2653.9 2835.8 2581.8
RS 2573.9 2639 2898.7 2503.3
Central-West MS 2281.5 2367.9 2541.4 2329.1
MT 2263.8 2354.2 2507 2343.9
GO 2087.2 2187.6 2378.3 2118.6
DF 3957 4152.5 4320.6 3803.2
a. Individual micro-entrepreneur;
b. Individual or optional contributor to the General Social Security System;
c. Informal worker.
7. Not be a worker for the public administration, including temporary contracts, or
be in exercise on an elective mandate.
In terms of economic theory, according to the Neoclassical tradition, the con-

cession of private charity is usually insufficient due to the fact that the benefits can
be indirectly obtained by “neighborhoods”: in small communities, social pressure
can provide a sufficient amount of private charity, and government interventions on
welfare would be unnecessary; in contrast, a large community is more impersonal,
Table 7 Quarterly proportion of self-employed labor in Brazilian states, aggregated by regions

Region State Q3 2019 (%) Q4 2019 (%) Q1 2020 (%) Q2 2020 (%)
North RO 30.3 29.74 30.17 31.77
AC 32.42 32.09 32.74 30.19
AM 33.33 32.62 34.29 31.67
RR 26.83 27.51 27.92 28.01
PA 35.75 35.86 35.17 32.95
AP 36.66 37.27 39.49 36.69
TO 24.87 25.68 27.09 24.86
Northeast MA 33.21 32.68 32.76 32.12
PI 31.45 32.05 32.53 29.62
CE 29.15 29.08 29.15 30.08
RN 27.96 28.39 28.51 25.03
PB 30.82 31.47 30.38 34.22
PE 27.82 29.08 29.04 28.41
AL 28.29 26.97 27.33 26.61
SE 30.2 27.91 27.85 28.69
BA 29.35 30.03 29.71 29.62
Southeast MG 24.17 24.91 24.89 23.72
ES 25.87 25.28 25.61 25.68
RJ 28.03 28.28 28.62 26.91
SP 22.36 21.44 21.92 22.29
South PR 24.93 24.6 24.43 25.35
SC 21.73 22.26 22.85 23.64
RS 25.41 25.22 25.86 26.67
Central-West MS 21.17 22.54 24.73 24.58
MT 25.74 26.12 26.08 27.34
GO 25.63 25.59 25.39 25.91
DF 20.69 19.38 19.25 19.13
making the building of an aggregated social pressure for private charity much harder,
a scenario in which a governmental action to mitigate poverty would be a better solu-
tion. As pointed out by [33], there are two key premises when fighting poverty: 1)
the program should be designed to help people as people, and not as members of a
specific label (such as occupational groups, age groups, ethnic groups, etc.); and 2)
this type of program should not affect the market as little as possible—i.e., it should
not distort the market or stagnate its operation.
The COVID-19 Emergency Aid, according to [9], meets its overall goals by focus-
ing more on the informal and unemployed, especially in the lower deciles of the
distribution. In this sense, the program had a more noticeable impact among house-
holds with low per capita income, where the effects of the COVID-19 pandemic
718 Y. Peng et al.
Table 8 Quarterly proportion of unemployment in Brazilian states, aggregated by regions

Region State Q3 2019 (%) Q4 2019 (%) Q1 2020 (%) Q2 2020 (%)
North RO 8.23 8.03 8.38 10.65
AC 12.83 13.62 13.51 14.19
AM 13.28 12.91 14.47 16.46
RR 14.95 14.75 16.48 16.34
PA 11.18 9.17 10.63 9.07
AP 16.74 15.57 17.24 11.42
TO 10.5 9.09 11.23 12.55
Northeast MA 14.14 12.15 16.1 16.04
PI 12.75 13.04 13.68 12.68
CE 11.28 10.1 12.09 12.09
RN 13.4 12.63 15.38 15.03
PB 11.23 12.07 13.75 12.83
PE 15.85 14 14.53 15.02
AL 15.36 13.6 16.52 17.85
SE 14.68 14.79 15.49 19.77
BA 16.78 16.42 18.7 19.86
Southeast MG 9.9 9.47 11.51 12.94
ES 10.56 10.3 11.14 12.32
RJ 14.52 13.72 14.51 16.42
SP 11.99 11.48 12.21 13.59
South PR 8.94 7.29 7.94 9.57
SC 5.78 5.35 5.65 6.93
RS 8.83 7.14 8.28 9.43
Central-West MS 7.54 6.52 7.64 11.38
MT 8 6.39 8.5 10.21
GO 10.83 10.42 11.34 12.81
DF 13.18 12.52 13.65 15.55
were more severe. In fact, for the poorer families, more than 93% of their household
income during the pandemic period came from this aid. It is noteworthy that these
households are characterized by people who do not have a source of income from
the formal job market, as well as people without any income; therefore, in general,
these people basically had the emergency aid as their only income source [9].
According to [9], in the first decile of the per capita income for Brazil’s work-
ing force, approximately 76% of the people outside the formal working force was
benefited by the COVID-19 Emergency Aid. The initial results indicated that the
emergency aid impacted low-income households per person, where the effects of the
COVID-19 pandemic were more severe. Additionally, the COVID-19 Emergency
Aid is strongly concentrated in the poorest 30% of the Brazilian population, a focus-
100%
Accumulated specific income
90%
80%
70% Covid−19 Emergency Aid

Continuous Benefit Aid (BPC)
60%
Bolsa Família Program
50% Social Security
40% Retirement Benefit

Other Programs
30%
Pension
20%
10%
0%
10º 20º 30º 40º 50º 60º 70º 80º 90º 100º
Total of other income by deciles
Fig. 34 Social focusing of the COVID-19 emergency aid in comparison to other Brazilian social
assistance programs
ing efficiency only inferior to that of the “Bolsa Família” program; as shown in
Fig. 34, other programs in Brazil distribute most of their resources to individuals
with income levels above the median value of the distribution [9].
This conclusion can be further evidenced by the Income Concentration Index
(CI) that we propose, which is calculated using the accumulated percentage of the
population (Xi ) and the accumulated percentage of income (Yi ), expressed as:

i=k−1
CI = 1 − (Xi+1 − Xi ) (Yi+1 + Yi ) (6)
i=1
The concentration index gives an idea of the concentration of the income for
specific aid per person. As shown in the Table 9, only the “Bolsa Família” program and
the COVID-19 Emergency Aid were strongly concentrated in the most impoverished
individuals, as their impacts are more concentrated in the lowest deciles of income
level in Brazil.
Finally, in accordance with the transition matrix provided in [9], the COVID-19
Emergency Aid managed to directly improve the living standard of more than 23
million Brazilian households, which is the number of families that went out from
their original income level decile to end a higher income decile after the introduction
of the emergency aid.
In summary, the numbers and analysis presented in these two subsections illustrate
that, while the assurance of the safety and health of the population is a duty for any
government, especially to the most vulnerable ones, resources are scarce, and it is
vital to be balance the social assistance and the maintenance of an equally healthy
fiscal balance, as inefficient resource allocations represent a direct diminishment of
the conditions to intervene and invest on critical spots of the economy, notably to
720 Y. Peng et al.
Table 9 Focusing analysis for Brazilian social assistance programs

Brazilian social assistance program Concentration index
COVID-19 emergency aid 0.0020
Continuous benefit aid (BPC) 0.3602
“Bolsa Família” program −0.0220
Retirement benefit 0.6433
Pension 0.4785
Other programs 0.5271
Social security 0.3631
allow a swift and stable road for economic recovery after the pandemic ends. In the
next subsection, we will discuss the magnitude of social isolation in the Brazilian
States over time, which also showed direct correlation not only with the number of
COVID-19’s cases and fatal victims in the country but also with the evolution of the
aforementioned macroeconomic indicators and the events that conditioned them.
4.3 Social Awareness in the Brazilian States During the

Pandemic
In order to counter the spread of SARS-CoV-2, generally, an analytical model con-

centrates on specific mechanisms of the big picture of the spread of Coronavirus,
consequently proposing solutions to contain the virus. Therefore, the reliability of
the underlying assumptions of the models plays an important role in their practical
usefulness [72]. One result that is shown both theoretically [26, 37, 71, 86], and
empirically [72] is that social distancing is an important metric for the pandemic’s
evolution. One concern found in infectious diseases is the fact that the spread’s behav-
ior cannot be observed ex-ante. In this sense, [86] incorporates that uncertainty and
simulates the effects of different structures and compositions that affect the overall
infection rate. Another uncertainty is the infectability of each individual, some of
them showing the behavior of super-spreaders [44].
Although predictions are indeed important, there is a limitation on what models
can tell us. Specifically, [71] argue that it is not advisable to suppose mild assumptions
simply, and much of the errors of policy-making were based on people not under-
standing the underlying assumptions in which academic models were made, also on
the reliability of the assumption in reality. [20] emphasizes that much of the model-
ing have given optimistic results because of the assumption of normality. Whereas
studying the distribution of pandemics, the author claims that pandemics like that
display extraordinarily heavy-tailed distributions. In this way, the overall behavior of
wars and epidemic deaths is different from conventional flu, car accidents, or heart
attacks, which exhibit thin tails and less extreme events.
State Name
AC PB
0.6 AL PE
AM PI
Social Distancing
AP PR
BA RJ
CE RN
DF RO
ES RR
0.4 GO RS
MA SC
MG SE
MS SP
MT TO
PA
0.2
Feb Mar Apr May Jun

Month
Fig. 35 Daily social distancing index by States, February 2020 to June 2020
Policy-wise, what has been emphasized are strict lockdowns, travel restrictions,
mass testing, and mask usage [87]. As a general rule, these actions aim to decrease
social distancing and therefore decrease the risk of spreading the disease. Hence,
in this section, we will examine the dynamics of the Social Distance Index (SDI),
elaborated by the company InLoco [39]. We found out that the behavior towards
isolation is relatively uniform among different States and regions and that it had
decayed rapidly. Moreover, we found that local variables such as incidences per
million and GDP per capita may be critical variables to understand people’s behavior.
Next, we present the Social Distancing Index (SDI) for all the Brazilian states
in Fig. 35. Not surprisingly, Social Distancing has risen highly due to the restricted
circulation and school closing rules after March 16, 2020—this phenomenon was
evident in all Brazilian states. Therefore, the SDI index had a recurrent movement of
ups and downs within a fixed range; spikes prevailed cyclically, which is probably
due to the fact that people tend to stay home much more during the weekdays than
during weekends.
Conversely, analyzing the region-wise average of Brazilian states in Fig. 36, we
can see some interesting patterns: The southern region, which is the richest in Brazil,
showed higher SDI, alongside other wealthier regions performed better than the
others. About the dynamics that happened after implementing the restrictions, one
possible interpretation could be the prevalence of informal workers, thus forcing
them to go to work in poorer regions. The labor composition could also differ in
regions that are more intensive in occupations that are more prone to automation or
home-office.
722 Y. Peng et al.
0.7
0.6
Average Social Distancing
Region
0.5
Central−West
North
Northeast
South
0.4
Southeast
0.3
0.2
Feb Mar Apr May Jun
Month
Fig. 36 Daily social distancing index by regions, February 2020 to June 2020
Another trend that could be inferred is that the perception of fear could influ-
ence Social Distancing. Regions that were more affected by COVID-19, shown by
the incidence per 100 thousand inhabitants, are the ones that showed higher Social
Distancing in the latter period, while these regions had smaller distancing in earlier
stages. This points to an interpretation: the small amount of Social Distancing made
the incidence significantly high in these regions; after that, people started to isolate
themselves more than in other regions. However, the general trend in all regions is
that the Social Distancing is decreasing, following gradual reopening measures and
consequent economic reactivation.
Another approach taken to analyze the social distancing was to assess the index’s
weekly average, which is found in Fig. 37. We find that, despite the efforts, the
weekly average is not dramatically different from pre-intervention levels. SDI levels
increased, but as time passes, they decreased.
Analyzing the SDI index’s volatility levels, we can see in Fig. 38 a shift in the
trend of the social distancing index before the onset of lockdown. As a result, we
see between weeks 4 and 5 a much higher standard deviation for all the states. It
means that the behavior for the weekend and the weekdays differ very much from
that point. This could indicate that from that point, people were much less inclined
to go out on weekends to the detriment of weekdays. Hence, people were less prone
to have leisure time out of home and were methodically only going out to work.
Near the tenth and eleventh week, though, the standard deviation passed through
a structural change again. This coincides with the period in which the local gov-
ernments relaxed the restriction rules and permitted some shops and commercial
services to reopen. This is to say that from that point on, many people started to have
a much more uniform trend of Social Distancing on weekdays and weekends.
0.55
State Name
AC PB
AL PE
0.50 AM PI
Social Distancing
AP PR
BA RJ
CE RN
DF RO
ES RR
0.45
GO RS
MA SC
MG SE
MS SP
MT TO
0.40 PA
5 10 15
Week
Fig. 37 Social distancing index by states and epidemiological weeks, February 2020 to June 2020
State Name
0.06 AC PB
AL PE
Standard Deviation
AM PI
AP PR
0.05 BA RJ
CE RN
DF RO
ES RR
0.04
GO RS
MA SC
MG SE
0.03 MS SP
MT TO
PA
5 10 15
Week
Fig. 38 Standard deviation of the social distancing index by states and epidemiological weeks,
February 2020 to June 2020
In summary, Social Distancing has varied during the period of strict rules, showing
behaviors influenced by both individual wealth and incidence of the disease per
millions. Also, regions and states with less Social Distancing showed an increased
incidence of the disease later, leading them to re-adopt more strict social distancing.
In this sense, this parameter has a very dynamic nature but quickly responds to the
incentives to resume regular daily routine and to avoid a potentially deadly disease.
724 Y. Peng et al.
5 Conclusions and Post-pandemics Challenges for Brazil
In this chapter, we presented a case study of the ongoing COVID-19 pandemic in

Brazil, one of the world’s most affected countries. We firstly analyzed the evolution
of the disease in Brazil, describing the overall characteristics of the virus (SARS-
CoV-2), its main differences to other typical virus-caused diseases—such as Dengue
and Zika—that Brazil deals with on an occasional basis; besides, we briefly presented
Brazil’s geography and demography, as well as the overall statistics concerning the
number of infected people and deaths due to COVID-19 and the virus’ spread over
time.
Motivated by Brazil’s continental territorial and populational size, and the het-
erogeneous geographical conditions and administrative strategies when considering
State-level data, we performed quantitative experiments concerning the prediction
of the trends of infected and dead for each Brazilian State, using a machine learning-
based model and comparing it to a commonly used benchmark model. Moreover,
we estimated the instantaneous reproducing number—which is a summary statistic
that reflects the “strength” of the virus in contaminating more people, serving as a
measure of whether the contagion is decelerating as well; these estimates were used
to group the Brazilian States into clusters, which can help policy-makers to identify
further the specificities of the pandemic in each location, which can, in turn, lead to
better priority assignment of counter-measures, from both the government and the
civil society. Finally, we proposed a statistical model to estimate the relative mag-
nitude of underreporting of COVID-19 in key States that suffered the most in the
early stages of the pandemic, using data from South Korea and Italy as references;
this approach allowed to identify the differences of the testing rates of each State,
which can also be of potential interest for policy-makers and the public healthcare
administration.
We also analyzed the economic impacts of COVID-19 in Brazil, which is a his-
torical event that will most likely to hold back the world’s economy in a coordinated
way in the short-run: as shown by [10], 80% of the countries in the world are esti-
mated to suffer from a retraction of the Gross Domestic Product by the end of 2020,
a larger percentage than the observed on the aftermath of the 2007/2008 financial
crisis. In terms of GDP retraction at the global level, the impacts of COVID-19 and
comparable to events like World War I and the Great Depression [10]. Specifically
regarding the Brazilian economy, while the exchange rate and a record grain pro-
duction have been favoring Brazil’s agriculture exports, industry and services have
suffered from the worldwide impacts due to the pandemic. Brazil’s labor market
was heavily affected by lockdown measures, which can be seen from the statistics
of admissions and layoffs, as well as from the time-series of social isolation at both
the Country and State-level. After the months of June and July, as commerce started
to reopen gradually alongside other economic production sectors, the labor market
figures also started to react, jointly with a decrease in the overall social isolation.
The Brazilian Federal government has responded to the pandemic by a series of
economic policies, notably the emergency financial aid, which aimed to mitigate
the impacts of COVID-19 on the economy’s income level. The official data showed
that, due to the impacts of COVID-19 on the labor market and to the existence of
numerous households that work in informal occupations, the sums distributed through
the emergency aid corresponded to a considerable percentage of the total income
for a great number of households; in addition, since this program was launched to
prioritize the quick payment to the population with higher vulnerability, its overall
social focusing was shown to be better than other social assistance programs, such
as the social security.
During the period the COVID-19 pandemic persists, a major challenge—both in
public policies and in social awareness—is to provide agile and accurate information
to allow good decision-making. As highlighted from the analysis presented in this
chapter, policy-makers are encouraged to make use of more sophisticated quantitative
methods to inform the population about the figures of the pandemic’s evolution and
its subsequent implications in the economy, in the healthcare system, and in the
social reactions to the pandemic. From a data analysis point of view, the methods
and models proposed in this chapter have the potential to provide more accurate
information about the severity in specific regions and the optimal timing of social
distancing and reopening measures in different States.
As for the main challenges of Brazil’s economic recovery after the COVID-19
crisis, the issue of fiscal responsibility remains one of the most critical cornerstones.
As shown in the forecasts of [34], the global levels of government debt are likely to
rise 18.7% of the GDP, a much larger value than the 10.5% observed in response to
the 2007/2008 financial crisis; similarly, the overall fiscal balance burden due to the
COVID-19 pandemic is estimated to be almost twice in comparison to that global
financial crisis. Specifically, Brazil has long been struggling with severe fiscal deficits
and misallocations in public investment, which culminated in a deteriorated fiscal
framework. The fiscal effort to counter the pandemic’s impacts on public welfare was
necessary, but also very costly at the same time: since the beginning of the pandemics
up to July 2020, the Brazilian government has spent 505.4 billion BRL in responsive
measures against COVID-19 programs, with the Emergency Aid being responsi-
ble for 254.2 billion BRL of this sum [11]. In relative terms, Brazil’s expenditure
on COVID-19 counter-actions represents 7.3% of the country’s estimated GDP for
2020, which is larger than the average value of both developing countries (4.1%)
and developed countries (6.3%). In this sense, while the assistance programs are
being important to avoid further life losses and heavier damages to the economy, the
maintenance of the fiscal discipline after the pandemic’s fading away will be just as
important for the economic recovery, in both short-term and long-term.
Disclaimer: The views expressed in this work are of entire responsibility of the
authors and do not necessarily reflect those of their respective affiliated institutions
nor those of its members.
726 Y. Peng et al.
References
1. Aghabozorgi, S., Shirkhorshidi, A.S., Wah, T.Y.: Time-series clustering—a decade review. Inf.
Syst. 53, 16–38 (2015)
2. Akaike, H.: A new look at the statistical model identification. IEEE Trans. Autom. Control
19(6), 716–723 (1974)
3. Althaus, C.L.: Estimating the reproduction number of ebola virus (ebov) during the 2014
outbreak in west Africa. PLoS Curr.6 (2014)
4. Arabi, Y.M., Murthy, S., Webb, S.: Covid-19: a novel coronavirus and a novel challenge for
critical care. Intensive Care Med. 1–4 (2020)
5. Asadi, S., Bouvier, N., Wexler, A.S., Ristenpart, W.D.: The coronavirus pandemic and aerosols:
does covid-19 transmit via expiratory particles? (2020)
6. Auler, A., Cássaro, F., da Silva, V., Pires, L.: Evidence that high temperatures and intermediate
relative humidity might favor the spread of covid-19 in tropical climate: a case study for the
most affected Brazilian cities. Sci. Total Environ. 139090 (2020)
7. Bastos, E.K.X.: Letter of Situation—N◦ 46 (2020). https://www.ipea.gov.br/cartadeconjuntura/
wp-content/uploads/2020/02/Boletim-expectativas-Fevereiro-IV.pdf
8. Bastos, S.B., Cajueiro, D.O.: Modeling and forecasting the covid-19 pandemic in brazil. arXiv
preprint arXiv:2003.14288 (2020)
9. Brazilian Ministry of Economy: Analysis of the scope, focus and distributive effect of emer-
gency aid based on the covid-19 national household sample survey (2020)
10. Brazilian Ministry of Economy: Macrofiscal Report (September 2020). https://www.gov.
br/economia/pt-br/centrais-de-conteudo/publicacoes/boletins/boletim-macrofiscal/2020/
boletim-macrofiscal-setembro-2020.pdf/view (2020)
11. Brazilian Ministry of Economy: Summary of Fiscal Impacts of Measures in Response to
the Pandemic and Projections of the SPE Fiscal Prism in July 2020. https://www.gov.br/
economia/pt-br/centrais-de-conteudo/publicacoes/notas-informativas/2020/ni-impactos-
fiscais-prisma.pdf/view (2020)
12. Bühlmann, P., Hothorn, T., et al.: Boosting algorithms: regularization, prediction and model
fitting. Stat. Sci. 22(4), 477–505 (2007)
13. Byambasuren, O., Cardona, M., Bell, K., Clark, J., McLaws, M.L., Glasziou, P.: Estimating the
extent of true asymptomatic covid-19 and its potential for community transmission: systematic
review and meta-analysis. MedRxiv preprint (2020)
14. Canabarro, A., Tenorio, E., Martins, R., Martins, L., Brito, S., Chaves, R.: Data-driven study
of the covid-19 pandemic via age-structured modelling and prediction of the health system
failure in brazil amid diverse intervention strategies. medRxiv (2020)
15. Carvalho, A., Silva, G., Almeida, G.J., Albuquerque, P.: Bayesian rates for homicide mapping
in Brazilian municipalities. Cadernos de saude publica 28(7), 1249–1262 (2012)
16. Centers for Disease Control and Preventions: Influenza Type A Viruses. https://www.cdc.gov/
flu/avianflu/influenza-a-virus-subtypes.htm (2020)
17. Centers for Disease Control and Preventions: Influenza Vaccination: A Summary for Clinicians.
https://www.cdc.gov/flu/professionals/vaccination/vax-summary.htm (2020)
18. Central Bank of Brazil: Focus Market Report, September 21, 2020. https://www.bcb.gov.br/
content/focus/focus/R20200918.pdf (2020)
19. Central Intelligence Agency: The World Factbook. https://www.cia.gov/library/publications/
the-world-factbook/fields/208rank.html#BR/ (2020)
20. Cirillo, P., Taleb, N.N.: Tail risk of contagious diseases. Nature Physics 16(June), 606–613
(2020). https://doi.org/10.1038/s41567-020-0921-x. http://dx.doi.org/10.1038/s41567-020-
0921-x
21. Cori, A., Ferguson, N.M., Fraser, C., Cauchemez, S.: A new framework and software to estimate
time-varying reproduction numbers during epidemics. Am. J. Epidemiology 178(9), 1505–
1512 (2013)
22. Costa, M.A., dos Santos, M.P.G., Marguti, B., Pirani, N., Pinto, C.V.d.S., Curi, R.L.C., Ribeiro,
C.C., de Albuquerque, C.G.: Vulnerabilidade social no brasil: conceitos, métodos e primeiros
resultados para municípios e regiões metropolitanas brasileiras. Tech. rep., Texto para Dis-
cussão (2018)
23. Cota, W.: Number of confirmed cases of covid-19 in Brazil. https://covid19br.wcota.me/en
(2020)
24. Cowling, B.J., Ip, D.K., Fang, V.J., Suntarattiwong, P., Olsen, S.J., Levy, J., Uyeki, T.M., Leung,
G.M., Peiris, J.M., Chotpitayasunondh, T., et al.: Aerosol transmission is an important mode
of influenza a virus spread. Nature Commun. 4(1), 1–6 (2013)
25. Dudel, C., Riffe, T., Acosta, E., van Raalte, A.A., Myrskyla, M.: Monitoring trends and dif-
ferences in covid-19 case fatality rates using decomposition methods: contributions of age
structure and age-specific fatality. medRxiv (2020)
26. Farboodi, M., Jarosch, G., Shimer, R.: Internal and External Effects of Social Distancing in a
Pandemic. Tech. Rep, National Bureau of Economic Research (2020)
27. Farrukee, R., Hurt, A.C.: Antiviral drugs for the treatment and prevention of influenza. Curr.
Treat. Options Infect. Dis. 9(3), 318–332 (2017)
28. Ferguson, N.M., Cummings, D.A., Cauchemez, S., Fraser, C., Riley, S., Meeyai, A., Iamsiritha-
worn, S., Burke, D.S.: Strategies for containing an emerging influenza pandemic in southeast
Asia. Nature 437(7056), 209–214 (2005)
29. Ferguson, N.M., Laydon, D., Nedjati-Gilani, G., Imai, N., Ainslie, K., Baguelin, M., Bhatia, S.,
Boonyasiri, A., Cucunubá, Z., Cuomo-Dannenburg, G., et al.: Impact of non-pharmaceutical
interventions (npis) to reduce covid-19 mortality and healthcare demand. Tech. rep., Imperial
College COVID-19 Response Team (2020)
30. Fouchier, R.A., Kuiken, T., Schutten, M., Van Amerongen, G., Van Doornum, G.J., Van Den
Hoogen, B.G., Peiris, M., Lim, W., Stöhr, K., Osterhaus, A.D.: Koch’s postulates fulfilled for
SARS virus. Nature 423(6937), 240 (2003)
31. Fraser, C.: Estimating individual and household reproduction numbers in an emerging epidemic.
PloS One 2(8), (2007)
32. Friedman, J.H.: Greedy function approximation: a gradient boosting machine. Ann. Stat. 1189–
1232 (2001)
33. Friedman, M.: Capitalism and Freedom. University of Chicago Press (2002). https://doi.
org/10.7208/chicago/9780226264189.001.0001. http://www.bibliovault.org/BV.landing.epl?
ISBN=9780226264219
34. Fund, I.M.: A crisis like no other, an uncertain recovery. World Economic Outlook Update
(June 2020) (2020)
35. Gazeta do Povo: Moving average of cases and deaths by covid-19 in Brazil. https://infograficos.
gazetadopovo.com.br/saude/media-movel-covid-19-no-brasil (2020)
36. Go, Y.Y., Balasuriya, U.B., Lee, C.k.: Zoonotic encephalitides caused by arboviruses: transmis-
sion and epidemiology of alphaviruses and flaviviruses. Clin. Exp. Vaccine Res. 3(1), 58–77
(2014)
37. Greenstone, M., Nigam, V.: Does Social Distancing Matter? University of Chicago, Becker
Friedman Institute for Economics Working Paper 26 (2020)
38. Haimovich, A., Ravindra, N.G., Stoytchev, S., Young, H.P., PerryWilson, F., van Dijk, D.,
Schulz, W.L., Taylor, R.A.: Development and validation of the quick covid-19 severity index
(qcsi): a prognostic tool for early clinical decompensation. Ann. Emerg. Med. (2020)
39. InLoco: Map of COVID-19 in Brazil: Social Distancing Index. https://mapabrasileirodacovid.
inloco.com.br/pt (2020)
40. Institute for Applied Economic Research: Brazil Post-Covid-19: Contributions from the Insti-
tute for Applied Economic Research (2020)
41. Istituto Superiore di Sanití: Integrated surveillance of covid-19 in Italy. https://www.epicentro.
iss.it/en/coronavirus/bollettino/Infografica_15maggio%20ENG.pdf (2020)
42. Jagodnik, K., Ray, F., Giorgi, F.M., Lachmann, A.: Correcting under-reported covid-19 case
numbers: estimating the true scale of the pandemic. Preprint medRvix 14 (2020)
728 Y. Peng et al.
43. Johnson, N.E., Ianiuk, O., Cazap, D., Liu, L., Starobin, D., Dobler, G., Ghandehari, M.: Patterns
of waste generation: a gradient boosting model for short-term waste prediction in New York
City. Waste Manag. 62, 3–11 (2017)
44. Kim, Y., Ryu, H., Lee, S.: Agent-based modeling for super-spreading events: a case study of
MERS-CoV transmission dynamics in the republic of korea. Int. J. Environ. Res. Pub.Health
15(11), 2369 (2018)
45. Krantz, S.G., Rao, A.S.S.: Level of under-reporting including under-diagnosis before the first
peak of covid-19 in various countries: Preliminary retrospective results based on wavelets and
deterministic modeling. Infect. Control Hosp. Epidemiol. 1–8 (2020)
46. Lancet, T.: COVID-19 in brazil: “so what?”. The Lancet 395(10235), 1461 (2020). https://doi.
org/10.1016/s0140-6736(20)31095-3
47. Lekone, P.E., Finkenstädt, B.F.: Statistical inference in a stochastic epidemic SEIRmodel with
control intervention: ebola as a case study. Biometrics 62(4), 1170–1177 (2006)
48. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K.S., Lau, E.H.,
Wong, J.Y., et al.: Early transmission dynamics in Wuhan, China, of novel coronavirus infected
pneumonia. N. Engl. J. Med. 382(13), 1199–1207(2020)
49. Li, Y., Wang, L.W., Peng, Z.H., Shen, H.B.: Basic reproduction number and predicted trends
of coronavirus disease 2019 epidemic in the mainland of china. Infect. Dis. Poverty 9(1), 1–13
(2020)
50. Liu, A., Wang, W., Zhao, X., Zhou, X., Yang, D., Lu, M., Lv, Y.: Disappearance of antibodies to
SARS-CoV-2 in a COVID-19 patient after recovery. Clin. Microbiol. Infect. 26(12), 1703–1705
(2020)
51. Liu, T., Hu, J., Xiao, J., He, G., Kang, M., Rong, Z., Lin, L., Zhong, H., Huang, Q., Deng, A.,
et al.: Time-varying transmission dynamics of novel coronavirus pneumonia in China. bioRxiv
(2020)
52. Lopez-Martin, M., Carro, B., Sanchez-Esguevillas, A.: Neural network architecture based on
gradient boosting for IoT traffic prediction. Future Gener. Comput. Syst. 100, 656–673 (2019)
53. Malki, Z., Atlam, E.S., Hassanien, A.E., Dagnew, G., Elhosseini, M.A., Gad, I.: Associa-
tion between weather data and covid-19 pandemic predicting mortality rate: machine learning
approaches. Chaos, Solitons Fractals 110137 (2020)
54. Marinho, F., Torrens, A., Teixeira, R., Franía, E., Nogales, A.M., Xavier, D., Fujiwara, T.:
Increase in deaths in brazil, regions, states and capitals in time of covid-19: excess of deaths
due to natural causes that shouldn’t have happened. Tech. rep, Brazilian National Council of
Health Secretaries (2020)
55. Mason, L., Baxter, J., Bartlett, P.L., Frean, M.R.: Boosting algorithms as gradient descent. In:
Advances in neural information processing systems, pp. 512–518 (2000)
56. Nishiura, H., Linton, N.M., Akhmetzhanov, A.R.: Serial interval of novel coronavirus (covid-
19) infections. Int. J. Infectious diseases (2020)
57. Oswaldo Cruz Foundation: MonitoraCovid-19 – COVID-19 data in Brazil visualizer. https://
bigdata-covid19.icict.fiocruz.br (2020)
58. Paixão, E.S., Teixeira, M.G., Rodrigues, L.C.: Zika, chikungunya and dengue: the causes and
threats of new and re-emerging arboviral diseases. BMJ Glob. Health 3(Suppl 1) (2018)
59. Peng, Y., Nagata, M.H.: An empirical overview of nonlinearity and overfitting in machine
learning using covid-19 data. Chaos, Solitons Fractals 110055 (2020)
60. Randolph, H.E., Barreiro, L.B.: Herd immunity: understanding covid-19. Immunity 52(5),
737–741 (2020)
61. Reis, R.F., de Melo Quintela, B., de Oliveira Campos, J., Gomes, J.M., Rocha, B.M., Lobosco,
M., dos Santos, R.W.: Characterization of the covid-19 pandemic and the impact of uncertain-
ties, mitigation strategies, and underreporting of cases in South Korea, Italy, and Brazil. Chaos,
Solitons Fractals 109888 (2020)
62. Ribeiro, M.H.D.M., da Silva, R.G., Mariani, V.C., dos Santos Coelho, L.: Short-term forecasting
covid-19 cumulative confirmed cases: Perspectives for brazil. Chaos, Solitons Fractals 109853
(2020)
63. Richardson, S., Hirsch, J.S., Narasimhan, M., Crawford, J.M., McGinn, T., Davidson, K.W.,
Barnaby, D.P., Becker, L.B., Chelico, J.D., Cohen, S.L., et al.: Presenting characteristics, comor-
bidities, and outcomes among 5700 patients hospitalized with covid-19 in the New York City
area. Jama 323(20), 2052–2059(2020)
64. Riou, J., Althaus, C.L.: Pattern of early human-to-human transmission of Wuhan 2019 novel
coronavirus (2019-ncov), December 2019 to January 2020. Eurosurveillance 25(4) (2020)
65. Rivas, A.L., Chowell, G., Schwager, S., Fasina, F.O., Hoogesteijn, A.L., Smith, S.D., Bisschop,
S., Anderson, K., Hyman, J.M.: Lessons from nigeria: the role of roads in the geo-temporal
progression of avian influenza (h5n1) virus. Epidemiol. Infect. 138(2), 192–198 (2010)
66. Roser, M., Ritchie, H., Ortiz-Ospina, E., Hasell, J.: Our world in data—coronavirus pandemic
(covid-19). https://ourworldindata.org/coronavirus (2020)
67. Russell, T.W., Hellewell, J., Jarvis, C.I., Van Zandvoort, K., Abbott, S., Ratnayake, R., Flasche,
S., Eggo, R.M., Edmunds, W.J., Kucharski, A.J., et al.: Estimating the infection and case
fatality ratio for coronavirus disease (covid-19) using age-adjusted data from the outbreak on
the diamond princess cruise ship, February 2020. Eurosurveillance 25(12), 2000256 (2020)
68. Sakoe, H., Chiba, S.: Dynamic programming algorithm optimization for spoken word recog-
nition. IEEE Trans. Acoust. Speech Signal Process. 26(1), 43–49 (1978)
69. Sakurai, A., Sasaki, T., Kato, S., Hayashi, M., Tsuzuki, S.i., Ishihara, T., Iwata, M., Morise, Z.,
Doi, Y.: Natural history of asymptomatic SARS-CoV-2 infection. New Engl. J. Med. (2020)
70. Salje, H., Kiem, C.T., Lefrancq, N., Courtejoie, N., Bosetti, P., Paireau, J., Andronico, A., Hozé,
N., Richet, J., Dubost, C.L., et al.: Estimating the burden of SARS-CoV-2 in France. Science
(2020)
71. Siegenfeld, A., Bar-Yam, Y.: What models can and cannot tell us about covid-19 pp. 1–3. New
England Complex Systems Institute (2020)
72. Siegenfeld, A.F., Bar-Yam, Y.: Eliminating covid-19: the impact of travel and timing. arXiv
preprint arXiv:2003.10086 (2020)
73. Somsen, G.A., van Rijn, C., Kooij, S., Bem, R.A., Bonn, D.: Small droplet aerosols in poorly
ventilated spaces and SARS-CoV-2 transmission. The Lancet. Respir. Med. (2020)
74. Song, P., Karako, T.: Covid-19: Real-time dissemination of scientific information to fight a
public health emergency of international concern. Biosci. Trends (2020)
75. Sousa, G.J.B., Garces, T.S., Cestari, V.R.F., Moreira, T.M.M., Florêncio, R.S., Pereira,
M.L.D.: Estimation and prediction of covid-19 cases in brazilian metropolises. Revista Latino-
Americana de Enfermagem 28 (2020)
76. Souza, F.S.H., Hojo-Souza, N.S., Santos, E.B., Silva, C.M., Guidoni, D.L.: Predicting the
disease outcome in covid-19 positive patients through machine learning: a retrospective cohort
study with Brazilian data. medRxiv (2020)
77. Stadnytskyi, V., Bax, C.E., Bax, A., Anfinrud, P.: The airborne lifetime of small speech droplets
and their potential importance in SARS-CoV-2 transmission. Proc. Natl. Acad. Sci. 117(22),
11875–11877 (2020)
78. The World Bank: The world bank data—gini index (world bank estimate)—Brazil. https://
data.worldbank.org/indicator/SI.POV.GINI?locations=BR (2020)
79. Thompson, R., Stockwin, J., van Gaalen, R., Polonsky, J., Kamvar, Z., Demarsh, P., Dahlqwist,
E., Li, S., Miguel, E., Jombart, T., et al.: Improved inference of time-varying reproduction
numbers during infectious disease outbreaks. Epidemics 29 (2019)
80. Tibshirani, R., Walther, G., Hastie, T.: Estimating the number of clusters in a data set via the
gap statistic. J. R. Stat. Soc. Ser. B (Stat. Methodol.) 63(2), 411–423 (2001)
81. Tobler, W.R.: A computer movie simulating urban growth in the Detroit region. Econ. Geogr.
46(sup1), 234–240 (1970)
82. Verelst, F., Kuylen, E., Beutels, P.: Indications for healthcare surge capacity in European coun-
tries facing an exponential increase in coronavirus disease (covid-19) cases, March 2020.
Eurosurveillance 25(13), 2000323 (2020)
83. Wang, C., Horby, P.W., Hayden, F.G., Gao, G.F.: A novel coronavirus outbreak of global health
concern. The Lancet 395(10223), 470–473 (2020)
730 Y. Peng et al.
84. Wang, W., Tang, J., Wei, F.: Updated understanding of the outbreak of 2019 novel coronavirus
(2019-ncov) in wuhan, china. J. Med. Virol. 92(4), 441–447 (2020)
85. Wang, X., Mueen, A., Ding, H., Trajcevski, G., Scheuermann, P., Keogh, E.: Experimental
comparison of representation methods and distance measures for time series data. Data Min.
Knowl. Discov. 26(2), 275–309 (2013)
86. Wolfram, C.: An agent-based model of covid-19. Complex Syst. 29, 87–105 (2020)
87. World Health Organization: Coronavirus disease (COVID-19) advice for the public. https://
www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public (2020)
88. World Health Organization: HIV/AIDS fact sheet. https://www.who.int/news-room/fact-
sheets/detail/hiv-aids (2020)
89. World Health Organization: WHO Coronavirus Disease (COVID-19) Dashboard. https://
ourworldindata.org/coronavirus (2020)
90. Zaki, A.M., Van Boheemen, S., Bestebroer, T.M., Osterhaus, A.D., Fouchier, R.A.: Isolation of
a novel coronavirus from a man with pneumonia in Saudi Arabia. New Engl. J. Med. 367(19),
1814–1820 (2012)
COVID-19: Automated Detection
and Monitoring of Patients Worldwide
Using Machine Learning
Gaurav Gupta, Ahmad Waleed Salehi, Brijbhushan Sharma,

Nagesh Kumar, Sonia, and Pankaj Vaidya
Abstract Novel COVID-19 or commonly known as Corona-Virus epidemic which

was identified in Nov–Dec 2019, needs special consideration due to its future
outbreaks and a possible threat to the world. Ever since, apart from clinical prog-
nosis and diagnosis, AI (Artificial Intelligence) provides a novel paradigm for health-
care, ML (Machine Learning) algorithms are employed in evaluating data and deci-
sion making processes. This means that AI–ML driven models help in identifying
COVID-19 epidemic as well as predict their nature of spread across the world.
Unlikely other health-care issues, for Corona-virus or COVID-19, for its detection,
AI/ML-driven prediction models are anticipated to work as cross-population train
and test models are the main perseverance of this chapter. The objective of this
chapter is to know the novel COVID-19 epidemiology, its major prevention from
spreading, and to assess the machine/deep learning-based architecture performance
that is proposed in the present year for classification of COVID-19 images such as,
X-Ray and CT. Especially, deep-learning centered algorithms known as the Convo-
lutional Neural Network, which plays an excessive effect on mining highly essential
features, mostly in terms of medical images. The performance of the technique is
shown to be impressive with X-Ray and CT image scans, has been adopted in most of
the recently published articles on the COVID-19/Coronavirus with notable results.
Also, according to this chapter, that machine learning, as well as deep learning
technology, has prospective clinical solicitations.
Keywords Corona-Virus · COVID-19 · Artificial intelligence · Machine learning ·

Support vector machine · Linear regression · Bayesian ridge · Cross-population
G. Gupta (B) · A. W. Salehi · B. Sharma · N. Kumar · Sonia · P. Vaidya

Yogananda School of AI Computers and Data Science, Shoolini University, Solan, Himachal
Pradesh 173229, India
A. W. Salehi
Faculty of Computer Science, Rana University, Kabul, Afghanistan
732 G. Gupta et al.
1 Introduction
The novel corona-virus is termed as a pandemic in March 2020 by World Health

Organization (WHO) since it was identified in December 2019 [1]. It started from
Wuhan city of China and spread thereafter across the world at a rapid speed. Today
almost every country is struggling from corona-virus. Till date, no cure for this deadly
virus is in existence. The Ministry of Health & Family Welfare (MHFW) as well as
National Center Disease Control (NCDC) report [2] has mentioned the following
(India, Feb 2020): Spread of corona-virus which is commonly known as COVID-
19 seems to happen mostly by respiratory-transmission. It is not clear yet how this
virus is transmitted among persons. Signs and symptoms of corona-virus include
running nose, cough, fever as well as dumpiness of breath [3]. The incubation period
of Epidemics of coronavirus-related diseases such as SARS-CoV [4] (Severe Acute
Respiratory Syndrome) and MERS-CoV [5] (Middle East Respiratory Syndrome)
coronaviruses, as well as observational travel-related data from reports of Corona-
Virus/COVID-19, MHFW and NCDC, evaluate that indications of coronavirus occur
within two-to-fourteen days after contact.
WHO report on coronavirus [6], October 29, 2020, confirmed cases in China are
91,821 and 4746 people died due to this virus. In Rest of the world, Italy is the most
affected country followed by USA, India, Brazil, Russia, France and no country in
the world remains unaffected from this virus, about 44,351,506 are confirmed cases
and about 11,71,255 died from this till date (29-10-2020), stats for the same is shown
in Fig. 1. Based on confirmed cases, mortality rate, till-date, is still less than other
respiratory diseases: the study of plus 24,00,000 COVID-19 patients finds 3.4% death
rate [7]. Seeing its global coverage, the WHO has declared COVID-19 as pandemic
Coronavirus Stats Worldwide

3,00,00,000
2,50,00,000
Cases in Lacs
2,00,00,000
1,50,00,000
1,00,00,000
50,00,000
0
USA India Brazil Russia France Spain Argen na Colombia Rest of
-50,00,000 the World
Countries
Confirmed Cases Confirmed Deaths Confirmed Recovered
Fig. 1 COVID-19 confirmed/death cases Country wise

COVID-19: Automated Detection and Monitoring of Patients … 733
[8]. The worrying case in Wuhan China and upcoming epidemics require special
consideration [3, 8, 9].
1.1 Artificial Intelligence/Machine Learning for Coronavirus
Machine Learning (ML) provides methods, techniques, and tools that can help in
solving diagnostic and prognostic problems in a variety of medical domains. ML
is being used for the analysis of the importance of clinical parameters and their
combinations for prognosis, e.g. prediction of disease progression, extraction of
medical knowledge for outcome research, therapy planning and support, and for the
overall patient management. ML is also being used for data analysis, such as detection
of regularities in the data by appropriately dealing with imperfect data, interpretation
of continuous data used in the Intensive Care Unit, and intelligent alarming resulting
in effective and efficient monitoring. It is argued that the successful implementation
of ML methods can help the integration of computer-based systems in the healthcare
environment providing opportunities to facilitate and enhance the work of medical
experts and ultimately to improve the efficiency and quality of medical care (Table
1).
As of today, it is very vital to footnote that COVID-19 [10] was not a surprise
to us, same type corona-virus was identified in patients with SARS-CoV [4], it
is also caused by a contagious agent which is still not known to the world. Ever
since, apart from clinical prognosis and diagnosis, machine learning provides a novel
archetype for health-care. Machine Learning algorithms are employed in evaluating
data and also in decision making methods more reliable [11]. Machine Learning
(ML) provides methods, techniques, and tools that can help in solving diagnostic
and prognostic problems in a variety of medical domains. ML is being used for
the analysis of the importance of clinical parameters and their combinations for
prognosis, e.g. prediction of disease progression, extraction of medical knowledge for
outcome research, therapy planning and support, and the overall patient management
[12, 13]. ML is also being used for data analysis, such as detection of regularities in
the data by appropriately dealing with imperfect data, interpretation of continuous
data used in the Intensive Care Unit, and intelligent alarming resulting in effective
and efficient monitoring [14]. It is argued that the successful implementation of ML
methods can help the integration of computer-based systems [15] in the healthcare
environment providing opportunities to facilitate and enhance the work of medical
experts and ultimately to improve the efficiency and quality of medical care.
Coronaviruses are a large group of viruses that are common among animals. In
rare cases, they can be transmitted from animals to humans. The spikes protruding
from the virus’s membrane look like the sun’s corona. It is from this that the virus
gets the name ‘coronavirus’. It causes illnesses of the respiratory tract, ranging from
the common cold to severe conditions like SARS. According to the World Health
Organization (WHO), a novel coronavirus (nCoV) is a new strain that has not been
previously identified in humans (Fig. 2).
734 G. Gupta et al.
Table 1 Comparative chart of different machine learning techniques

Techniques Advantages Disadvantages Specific problem
K-Means Clustering If variables are few, It does not work well K-Means used to
Algorithm then K-Means faster with clusters of segment the abnormal
than hierarchical different size and portion on the datasets
clustering, if we keep different density classified by its type,
k smalls size, and the number
of clusters
Random Forest (RF) It’s used to estimate It has a noisy It’s based on majority
the missing data and classification with voting and produces
maintains good some datasets good results
accuracy when a large
proportion of the data
are missing
Support Vector SVM is a powerful It gives poor SVM for pattern
Machine (SVM) classification performances and it recognition,
algorithm does not directly classification and
provide probability accuracy was good
estimates
K-Nearest Neighbour It’s the simplest It has a slow running Classification is
(KNN) technique that time satisfactory in terms of
provides good accuracy
classification accuracy
Artificial Neural It can handle a large The images go ANN is the
Networks (ANN) number of data sets through many stages biologically inspired
Programming is by connections inside
difficult. Again to run the brain used to carry
the program, experts information
are not needed. ANNs
are black-box
modelling
Magnetic Resonance MRI is used for MRI scanners are MRI used to find
Imaging (MRI) detecting and very expensive changes in tissue
scanning of atrophy. It is more
abnormalities in soft specific in grey matter
tissue like the
cartilage tissues and
soft organs like the
brain or the heart
Positron Emission Can help diagnose, Radioactive material It’s used to find
Tomography (PET) treat, or predict the may cause allergic or changes in cerebral
outcome for a wide injection-site perfusion
range of conditions? reactions in some
people
(continued)
Table 1 (continued)
Techniques Advantages Disadvantages Specific problem
Single Photon Tracing the blood Radioactive It’s used to find
Emission Computed flow and the compounds are quite changes in glucose
Tomography (SPECT) metabolic activities expensive metabolism
are occurring and
enabling of brain
functions
Non-Negative Matrix Reduce the large No negativity NMF is used to find
Factorization (NMF) dimensionality of the constraints can restrict the reduced linear
input data correct clustering to representations of
only non-negative non-negative data,
data being a useful
decomposition tool for
multivariate data
Partial Least Squares Feature extraction is Measuring process PLS yields a
(PLS) more effective for more complex significant
extracting the exactly improvement in the
correct information out-of-bag error rate
from the data
Gaussian Mixture GMM requires fewer GMM take GMM mainly for
Model (GMM) feature vectors and time-consuming and classical clustering
produce a good result more samples and also used
intensively for density
estimation
Neuropsychological NM was performed Different assessment NM achieved better
And Functional using a filter method procedures for nearly prediction
Measures (NM) NMs are very every patient. performance and good
separable between NC Different assessment accuracy
and AD groups procedures across
different examiners
Principal Component Reduce the redundant PCA only takes into PCA used to extract
Analysis (PCA) features and large account pair-wise the most significant
dimensionality of the relationships between features from a dataset
data voxels of the brain
images
Independent The ICA Don’t exist a criterion The basic concept is
Component Analysis transformation is used for determining how motivated by the
(ICA) for capturing group many components theory of redundancy
differences from high represent the dynamic reduction
order voxel relations, of the data
generating from the
original average
images sources
736 G. Gupta et al.
100
80 Corona Virus (COVID-19) Symptoms Percentage
Percentage 60
40
20
0
-20
Coughi
ng up
Bone Nause
sputu Shortn Coughi
Dry Fa gu or Sore Heada a or Stuﬀy Diarrh Swolle
Fever m, or ess of Chills ng up
cough e joint throat che vomi nose ea n eyes
thick breath blood
pain ng
phleg
m,…
Percentage 88 68 38 33 19 15 14 14 11 5 5 4 1 1
Symptoms
Percentage Linear (Percentage)
Fig. 2 Coronavirus symptoms percentage
1.2 Epidemics of Coronavirus-Related Diseases
We have carefully chosen publications for review of literature that have evaluated
machine/deep learning algorithms applied in medical images as well as pandemic
diseases to solve a clinical problem and related each algorithm concerning their
output and performance (Table 2).
• SARS-CoV—Severe Acute Respiratory Syndrome Outbreak, SARS-COV [4]
outbreaks in 2003 in Foshan city of China and about 774 persons died due to this
virus (Fig. 3).
• MERS-CoV—Middle East Respiratory Syndrome Coronavirus Outbreak,
MERS-COV [5] outbreaks in 2012 in Saudi Arabia and about 400+ persons died
due to this virus (Fig. 4).
• MERS-CoV—Middle East Respiratory Syndrome Coronavirus Outbreak in
South Korea, MERS-COV outbreaks in 2012 in South Korea and about 36 persons
died due to this virus (Fig. 5).
Table 2 Epidemics of corona-virus types of relatively-high death are as follows

Year Virus epidemics Virus type Starting country Total deaths
2003 Severe acute respiratory syndrome SARS-CoV Foshan, China 774
outbreak
2012 Middle East respiratory syndrome MERS-CoV Saudi Arabia 400+
coronavirus outbreak
2015 Middle East respiratory syndrome MERS-CoV South Korea 36
outbreak in South Korea
2018 Middle East respiratory syndrome MERS-CoV Saudi Arabia 41
outbreak
2019–2020 Coronavirus pandemic SARS-CoV-2 Wuhan, China 1,154,312+
Fig. 3 SARS-CoV—Severe acute respiratory syndrome outbreak in 2002 [16]
Fig. 4 MERS-CoV—Middle East respiratory syndrome outbreak in 2012 [17]

738 G. Gupta et al.
Fig. 5 MERS-CoV—Middle East respiratory syndrome outbreak in 2015 [18]
• COVID-19—Coronavirus Pandemic, COVID-19 outbreaks in 2019–2020 in

Wuhan city of China and about 10,000+ persons died due to this virus till March
2020 (Fig. 6).
Fig. 6 COVID-19 Coronavirus pandemic outbreaks in 2019–2020 [19]

2 Covid-19: Corona Virus Outbreaks Analysis Using

Machine Learning
Coronavirus epidemic [10, 20] and the disease has become a full-carried pandemic.
According to WHO statistics, more than 15,000 people have died from the secretive
virus. The ongoing coronavirus epidemic is a major public health worry, with the
number of cases confirmed in mainland China having recently gone through rapid
growth. In this chapter, we are using different algorithms such as Support Vector
Machine (SVM), Linear Regression (LR), Bayesian Ridge (BR) for future prediction
of corona-virus across the world which includes the future prediction of corona-virus
confirmed cases, death cases as well as recoveries from this deadly virus (Table 3).
Table 3 Comparison of various techniques used for COVID-19 detection

Ref Technique Data type Data source Accuracy
[21] Transfer deep learning X-Ray Kaggle and GitHub 98%
for automatically
predicting COVID-19
[22] Automated technique CT and X-Ray X-Ray, CT Dataset 96%
for detecting and publicly available on
classifying the internet
pneumonia-based
using deep learning
[23] Deep learning for CT Hospital of Zhejiang, 86.7%
screening COVID-19 China
pneumonia
[24] Deep CNN X-Ray X-ray images of a VGG19, DenseNet
public dataset models:
f-scores = 0.89
normal &
Coronavirus-19 = 0.91
[25] Automated deep X-Ray 50 Coronavirus 98%
convolutional neural patients (GitHub)
network 50 normal X-ray
(Kaggle)
[26] Support vector CT Total = 150 CT Classification accuracy
machine images result obtained from
Coronavirus = 53 GLSZM = 99.68%
[27] Support vector X-Ray Coronavirus cases = Accuracy: SVM +
machine based on 25 ResNet50
deep learning Normal cases = 25 (FPR = 95.52%, F1
approach (Deep (GitHub, Kaggle) score = 95.52%, MCC
Features) = 91.41% and Kappa
= 90.76%)
[14] Support vector Apps Review Review
machine
740 G. Gupta et al.
Table 4 SVR Parameters

c [0.01, 0.1, 1] cross-validation [3]
gamma [0.01, 0.1, 1] iteration [30]
epsilon [0.01, 0.1, 1] verbose [1]
shrinking [True/False] kernel ‘Poly’
degree [3–5] scoring neg_mean_squared_error
2.1 Material and Methods
All the data used in this paper is taken from COVID-19 real-time dataset available
online on at https://covid19.who.int/. Dataset consists of cases starting from 1st
March 2020 stats.
2.2 Results
We are using support vector machine, linear regression, and bayesian ridge for model
prediction of confirmed cases.
• Support Vector Machine: The SML (Supervised Machine Learning) method, the
SVM (Support Vector Machine) algorithm [28] has validated high-performance
in explaining prediction complications in many biomedical fields, particularly in
bio-informatics. The SVM-classifier has set good performance inappropriately
classifying many datasets in various biomedical/bioinformatics fields [15]. Here
we are using SVR means support vector for regression [29], parameters used for
SVR are as follows (Table 4).
The optimization function for SVM for regression is given by

N
1
C (ξn + ξ n ) + w2
n=1
2
Data is divided into testing and training i.e., 15% of total data is used for testing
and the remaining 85% is used for training purpose. SVM check against testing data
comes out to be (Fig. 7; Table 5).
Where, MAE stands for Mean Absolute Error and MSE stands for Mean Squared
Error.
• Linear Regression: Linear Regression [30] is a machine learning algorithm based
on supervised learning. It performs a regression task. Regression models a target
prediction value based on independent variables [31]. It is mostly used for finding
out the relationship between variables and forecasting. Here we have to first change
our data into polynomial regression (normalize = True, fit_intercept = False).
Fig. 7 Orange is for SVM Test Predict and Blue is for Test Confirmed
Table 5 SVM check against

MAE 3,881,782.676934942
testing data
MSE 15,094,953,607,795.5
Polynomial/Linear Regression check against testing data comes out to be (Fig. 8;

Table 6)
• Bayesian Ridge Polynomial Regression: Bayesian regression techniques [32]
can be used to include regularization parameters in the estimation procedure: the
regularization parameter is not set in a hard sense but tuned to the data at hand.
The parameter used for Bayesian ridge are as follows (Table 7).
Here we are using Fitting 3 folds for each of 40 candidates, totalling 120 fits.
Fig. 8 Orange is for polynomial regression test predict and Blue for test confirmed
742 G. Gupta et al.
Table 6 Polynomial/linear regression check against testing data

MAE 1,107,548.92420577
MSE 1,463,375,869,959.0403
Linear model coefficient −1.21501603e+07
4.37001469e+05
−5.67229893e+03
3.71881318e+01
−9.75068480e−02
9.29543166e−05
Table 7 Bayesian ridge parameters

tol [1e-6, 1e-5, 1e-4, 1e-3, 1e-2, cross-validation [3]
0.01]
alpha_1 [1e-7, 1e-6, 1e-5, 1e-4, 1e-3] iteration [40]
alpha_2 [1e-7, 1e-6, 1e-5, 1e-4, 1e-3, verbose [1]
0.0001]
lambda_1 [1e-7, 1e-6, 1e-5, 1e-4, 1e-3, scoring neg_mean_squared_error
0.001]
lambda_2 [1e-7, 1e-6, 1e-5, 1e-4, 1e-3] normalize True/False
Bayesian Ridge Polynomial Regression randomized search for cv is given by

(Figs. 9 and 10; Table 8)
• Corona-Virus cases over time (since 1st March 2020): Since the inception of
corona-virus its toll rises on a day-to-day basis. Same can be depicted in the
Fig. 9 Randomized search for CV in BRPR

Fig. 10 Orange is for Bayesian ridge test predict and Blue for test confirmed
Table 8 Bayesian ridge

MAE 944,684.9527801722
regression check against
testing data MSE 1,112,079,070,243.3467
form of graphical representation after we conducted the simulation of the data

available and also the future prediction for the same is also conduction with the
help of machine learning algorithm discussed previously in this paper (Fig. 11).
• Increase in Coronavirus Cases worldwide: here we are calculating and repre-
senting graphically the increase in coronavirus cases worldwide taking moving
average of 7 days (Figs. 12 and 13).
• Coronavirus (Graphical Representation of India Status): Here we are repre-
senting the status of coronavirus in India subcontinent (Fig. 14).
• Comparison of Coronavirus among top affected countries: Here we are
comparing countries which are affected by a coronavirus (top 4 countries)
(Fig. 15).
• Future prediction of Corona-Virus using Machine Learning Algorithm: We
can predict the future increase in corona-virus cases over time with the help of ML
algorithms such as SVM, Linear Regression and Bayesian Ridge. We conducted
several simulations with the help of these algorithms and deduce the following
result as follows (Figs. 16, 17, 18; Table 9)
• Mortality Rate Susceptible to change (Worldwide): Mortality rate/death rate,
is a measure of the number of deaths (due to a specific cause) in a particular region
population, scaled to the size of that population, per unit of time (Fig. 19).
• Recovery Rate Susceptible to change (Worldwide): World recovery rate is about
45% whereas India recovery rate is 80% (Fig. 20).
• Countries with the most confirmed cases: Here we are representing after
machine learning simulation, the countries which are affected the most due to
744 G. Gupta et al.
Fig. 11 a Corona-Virus prediction of cases since 01-03-2020, b Corona-Virus prediction of cases

since 01-03-2020 using SVM, c Corona-Virus prediction of cases since 01-03-2020 using LR,
d Corona-Virus prediction of cases since 01-03-2020 using BRPR
Fig. 11 (continued)
746 G. Gupta et al.
Fig. 12 Increase in Coronavirus cases worldwide, a Confirmed cases, b Confirmed deaths,

c Confirmed recoveries
Fig. 12 (continued)
corona-virus. In this simulation, we are only taking the top 10 countries which
are affected the most and rest are grouped as other countries (Fig. 21).
3 Discussion and Conclusion
Aimed at the cure of COVID-19 patients, there is no drug present till now and due to
the fast increase in the numeral of cases of COVID-19 patient’s effective medicinal
tactic is urgently needed to treat the patients across the world [33]. Diagnosis and
prognosis of COVID-19 cases can decrease the spread of diseases [34]. The COVID-
19 patient’s data will be useful for the researchers working on Artificial Intelligence,
Deep Learning and Machine Learning to develop an automatic indicative tool, salu-
tary strategy against COVID-19 patients, and for the similar type of pandemics for
the coming future [33, 35].
In this chapter, we stated the importance of the Machine Learning is driven predic-
tion models for such type of virus outbreaks and their suitable train and test models
have been introduced and discussed. The main purpose of our research here, scientists
working on data analysis do not always wait for the complete datasets to train/test and
validate the predicted models. On the contrary, AI/ML-driven prediction models are
essential to be executed from the very beginning of data collection, in corresponding
with the experts available in the field, where vigorous learning needs to be engaged.
To attain higher-assurance during the decision-making process, several data types
are expected to be engaged rather than trusting on one data type. As in future, more
748 G. Gupta et al.
Fig. 13 Logarithmic View of Coronavirus cases worldwide. a Coronavirus cases over time,
b Coronavirus deaths over the time, c Coronavirus recoveries over the time
Fig. 13 (continued)
data will be available we can work on building a deep learning-based model for the
prediction of corona-virus another disease which is dangerous to mankind.
Due to the early stage of COVID-19, there are still some precincts of the related
studies that can be subjugated or astounded in the future researches. Specifically, an
in-depth analysis requires a lot more patient data, particularly those patients suffering
from the novel Coronavirus. So, the main point of focus for research work in the
future could be differentiating the patients indicating mild symptoms, instead of
pneumonia symptoms, however, these symptoms might not be visualized on X-Rays
more precisely, or even not at all to be envisioned. As more authentic dataset will be
available shortly, a more precise ML-based prediction model can be formed.
ML-based approaches are very useful for the automatic detection of COVID-
19/Coronavirus patients using X-ray and CT images. The imperative point is to
increase the number of datasets for COVID-19/Coronavirus patients and using
advance machine/deep learning algorithms to achieve better performance for the
diagnosis and prognosis of Coronavirus. Also, even though proper treatment or cure
cannot be determined only from an X-Ray or CT images, these techniques would be
valuable as a preliminary screening of the patients.
750 G. Gupta et al.
Fig. 14 Status of Coronavirus in India. a India confirmed cases, b India daily increase in confirmed
cases, c India daily increase in deaths, d India daily increase in recoveries
Fig. 14 (continued)
752 G. Gupta et al.
Fig. 15 Comparison of Coronavirus among top affected countries (US, Brazil, India, Russia).
a Coronavirus confirmed cases across (US, Brazil, India, Russia), b Coronavirus confirmed deaths
across (US, Brazil, India, Russia), c Coronavirus confirmed recoveries across (US, Brazil, India,
Russia)
Fig. 15 (continued)
Fig. 16 Predictions for confirmed coronavirus cases worldwide using Support vector machine
754 G. Gupta et al.
Fig. 17 Predictions for confirmed coronavirus cases worldwide using Polynomial regression
predictions
Fig. 18 Predictions for confirmed coronavirus cases worldwide using Bayesian ridge regression
predictions
Table 9 Future prediction of COVID-19 confirmed cases

Sr. No. Date SVM LR BR
1 7-12-2020 49,043,188.00 42,804,124.00 42,994,803.00
2 8-12-2020 49,553,584.00 43,106,470.00 43,299,031.00
3 9-12-2020 50,067,612.00 43,409,035.00 43,602,817.00
4 10-12-2020 50,585,286.00 43,711,827.00 43,906,123.00
5 11-12-2020 51,106,618.00 44,014,854.00 44,208,915.00
6 12-12-2020 51,631,622.00 44,318,125.00 44,511,155.00
7 13-12-2020 52,160,310.00 44,621,648.00 44,812,805.00
8 14-12-2020 52,692,695.00 44,925,435.00 45,113,830.00
9 15-12-2020 53,228,789.00 45,229,497.00 45,414,190.00
10 16-12-2020 53,768,607.00 45,533,846.00 45,713,847.00
Fig. 19 Mortality rate worldwide

756 G. Gupta et al.
Fig. 20 Recovery rate worldwide

Fig. 21 a Total deaths due to corona-virus country wise. b Mortality rate by country. c Corona-
virus confirmed cases in different countries. d The logarithmic scale of corona-virus confirmed
cases country wise. e Corona-virus confirmed cases in different states of different countries. f The
logarithmic scale of corona-virus confirmed cases in different states of different countries
758 G. Gupta et al.
Fig. 21 (continued)
Fig. 21 (continued)
760 G. Gupta et al.
References
1. Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., et al.: A new coronavirus
associated with human respiratory disease in China. Nature 579(7798), 265–269 (2020)
2. National Center Disease Control N. COVID-19 (Corona Virus). 21 Mar 2020. Available from:
https://ncdc.gov.in/index4.php?lang=1&level=0&linkid=127&lid=432
3. Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al.: Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive
study. Lancet 395(10223), 507–513 (2020)
4. Xiao, X., Chakraborti, S., Dimitrov, A.S., Gramatikoff, K., Dimitrov, D.S.: The SARS-CoV S
glycoprotein: expression and functional characterization. Biochem. Biophys. Res. Commun.
312(4), 1159–1164 (2003)
5. de Groot, R.J., Baker, S.C., Baric, R.S., Brown, C.S., Drosten, C., Enjuanes, L., et al.: Commen-
tary: Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the
Coronavirus study group. J. Virol. 87(14), 7790–7792 (2013)
6. WHO Report Cd. Situation Report—49 (2020). Accessed 18 Mar 2020
7. Fang, Z., Yi, F., Wu, K., Lai, K., Sun, X., Zhong, N., et al.: Clinical characteristics of 2019
coronavirus pneumonia (COVID-19): an updated systematic review. medRxiv (2020)
8. Santosh, K.: AI-driven tools for coronavirus outbreak: need of active learning and cross-
population train/test models on multitudinal/multimodal data. J. Med. Syst. 44(5), 1–5
(2020)
9. Long, J.B., Ehrenfeld, J.M.: The role of Augmented Intelligence (AI) in Detecting and
Preventing the Spread of Novel Coronavirus. Springer (2020).
10. Bai, Y., Yao, L., Wei, T., Tian, F., Jin, D.-Y., Chen, L., et al.: Presumed asymptomatic carrier
transmission of COVID-19. JAMA (2020)
11. Martinez-Carrasco, A.L., Juarez, J.M., Campos, M., Morales, A., Palacios, F., Lopez-
Rodriguez, L., (eds.): Interpretable patient subgrouping using trace-based clustering. In:
Conference on Artificial Intelligence in Medicine in Europe. Springer (2019)
12. Gupta, G., Gupta, A., Barura, P., Jaiswal, V., (eds.): Mobile health applications and android
toolkit for Alzheimer patients, caregivers and doctors. Biol. Forum–An Int. J. (2019)
13. Magoulas, G.D., Prentza, A., (eds.): Machine learning in medical applications. In: Advanced
Course on Artificial Intelligence. Springer (1999)
14. Gupta, G., Gupta, A., Jaiswal, V., Ansari, M.D., (eds.): A review and analysis of mobile health
applications for Alzheimer patients and caregivers. In: 2018 Fifth International Conference on
Parallel, Distributed and Grid Computing (PDGC). IEEE (2018)
15. Sharma, L., Gupta, G., Jaiswal, V., (eds.): Classification and development of tool for heart
diseases (MRI images) using machine learning. In: 2016 Fourth International Conference on
Parallel, Distributed and Grid Computing (PDGC). IEEE (2016)
16. Outbreak, S.: Severe Acute Respiratory Syndrome Outbreak (November 2002)
17. Coronavirus MErs: 2012 Middle East respiratory syndrome coronavirus outbreak. (April 2012)
18. Syndrome MER: 2015 Middle East respiratory syndrome outbreak in South Korea (May 2015)
19. World Health Organization: 2019–20 coronavirus pandemic (March 2020)
20. Salehi, A.W., Baglat, P., Gupta, G.: Review on machine and deep learning models for the
detection and prediction of coronavirus. Mater. Today: Proc. (2020)
21. Apostolopoulos, I.D., Mpesiana, T.A.: COVID-19: automatic detection from x-ray images
utilizing transfer learning with convolutional neural networks. Phys. Eng. Sci. Med. 1 (2020)
22. Asnaoui, K.E., Chawki, Y., Idri, A.: Automated methods for detection and classification
pneumonia based on x-ray images using deep learning. arXiv preprint arXiv:200314363 (2020)
23. Xu, X., Jiang, X., Ma, C., Du, P., Li, X., Lv, S., et al.: Deep learning system to screen coronavirus
disease 2019 pneumonia. arXiv https://arxiv.org/abs/200209334 (2020). Accessed 23 June 2020
24. El-Din Hemdan, E., Shouman, M.A., Karar, M.E.: COVIDX-Net: a framework of deep learning
classifiers to diagnose COVID-19 in X-ray images. arXiv arXiv:2003.11055 (2020)
25. Narin, A., Kaya, C., Pamuk, Z.: Automatic detection of coronavirus disease (COVID-19) using
x-ray images and deep convolutional neural networks. arXiv preprint arXiv:200310849 (2020)
26. Barstugan, M., Ozkaya, U., Ozturk, S.: Coronavirus (covid-19) classification using CT images
by machine learning methods. arXiv preprint arXiv:200309424 (2020)
27. Sethy, P.K., Behera, S.K., Ratha, P.K., Biswas, P.: Detection of Coronavirus Disease (COVID-
19) based on Deep Features and Support Vector Machine
28. Noble, W.S.: What is a support vector machine? Nat. Biotechnol. 24(12), 1565–1567 (2006)
29. Balabin, R.M., Lomakina, E.I.: Support vector machine regression (SVR/LS-SVM)—an alter-
native to neural networks (ANN) for analytical chemistry? Comparison of nonlinear methods
on near infrared (NIR) spectroscopy data. Analyst. 136(8), 1703–1712 (2011)
30. Saunders, C., Gammerman, A., Vovk, V.: Ridge Regression Learning Algorithm in Dual
Variables (1998)
31. Salehi, A.W., Baglat, P., Sharma, B.B., Gupta, G., Upadhya, A., (eds.): A CNN model: earlier
diagnosis and classification of Alzheimer disease using MRI. In: 2020 International Conference
on Smart Electronics and Communication (ICOSEC). IEEE (2020)
32. van der Walt, C.M., Botha, N., (eds.): A comparison of regression algorithms for wind speed
forecasting at Alexander Bay. In: 2016 Pattern Recognition Association of South Africa and
Robotics and Mechatronics International Conference (PRASA-RobMech). IEEE (2016)
33. Alimadadi, A., Aryal, S., Manandhar, I., Munroe, P.B., Joe, B., Cheng, X.: Artificial Intelligence
and Machine Learning to Fight COVID-19. American Physiological Society, Bethesda, MD
(2020)
34. Narin, A., Kaya, C., Pamuk, Z.: Department of Biomedical Engineering, Zonguldak Bulent
Ecevit University, 67100, Zonguldak, Turkey. ArXiv Prepr. ArXiv2003.10849 (2020). 2003.
35. Salehi, A.W., Baglat, P., Gupta, G.: Review on machine and deep learning models for the
detection and prediction of Coronavirus. Mater. Today: Proc. 33, 3896–3901 (2020)
36. Salehi, A.W., Baglat, P., Gupta, G.: Alzheimer’s disease diagnosis using deep learning
techniques. Int. J. Eng. Adv. Technol. 9(3), 874–880 (2020)
37. Yousef, R., Gupta, G., Vanipriya, C.H., Yousef, N.: A comparative study of different machine
learning techniques for brain tumor analysis. Mater. Today: Proc. (2021)
38. Baglat, P., Salehi, A.W., Gupta, A., Gupta, G.: Multiple machine learning models for detection
of alzheimer’s disease using OASIS dataset. In: International Working Conference on Transfer
and Diffusion of IT, pp. 614–622. Springer, Cham (2020)
39. Upadhyay, V., Upadhya, A., Salehi, W., Gupta, G.: The medical aspects of EMI effect on
patients implanted with pacemakers. Mater. Today: Proc. 45, 5243–5248 (2021)
A Mathematical Model and Strategy
to Guide the Reopening of BRICS
Economies During the COVID-19
Pandemic
Habib Noorbhai and Ridhwaan Suliman
Abstract There is limited attention directed towards strategies and guidance for
reopening BRICS (Brazil, Russia, India, China and South Africa) economies during
the COVID-19 pandemic. A simpler model has recently been demonstrated to guide
various countries on the possible reopening of the economy (in stages/phases) along-
side risk categories and ratios. In this chapter, a more comprehensive model has been
applied among the BRICS nations, as these countries are currently among the top 10
countries (except for China) infected with the virus and have similar socio-economic
circumstances. The chapter also provides a possible strategy in counteracting the
spread of the virus and reopening of the economy. Factors that need to be considered
when applying the model include the healthcare capacity in terms of the number of
hospitals, beds and healthcare workers that are available to capacitate this virus. In
addition, population size, population density, physical distancing measures, infec-
tion rates, test positivity rates, socio-economic disparities, lockdown regulations in
each country, and more importantly—the amount, quality and accuracy of testing
conducted, is also imperative to consider (especially among BRICS nations where
both common and varied threads are identified). This chapter demonstrates the overall
risk model of each of the BRICS nations as at 1st October 2020. Following this model
and strategy would allow countries to reduce the complacency towards the virus and
assist in the reopening of their economy/country. Leaders around the world have the
most difficult decision to make, and have to weigh up on what really matters; health
or wealth, or lives versus livelihoods. It is suggested that the discussed strategies
and model demonstrated in this chapter be applied in a number of states/counties
and countries (and not just BRICS nations) in order to gauge the overall risk of their
economy being reopened.
H. Noorbhai (B)
Biomedical Engineering and Healthcare Technology Research Centre, Faculty of Health Sciences,
University of Johannesburg, Johannesburg, South Africa
e-mail: habibn@uj.ac.za
R. Suliman
Advanced Mathematical Modelling, CSIR Next Generation Enterprises and Institutions, Council
for Scientific and Industrial Research, Pretoria, South Africa
e-mail: rsuliman@csir.co.za
764 H. Noorbhai and R. Suliman
Keywords Mathematical model · Strategy · Economy · BRICS · COVID-19
1 Introduction
Although there have been rigorous global containment and quarantine efforts, the
incidence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
also known as COVID-19, continues to surge, with more than 37 million laboratory-
confirmed cases and over 1,000,000 deaths worldwide (as of 1st October 2020) [31].
Aside from the continued surge in cases, the imperatives of public health concern
over a number of diseases, and saving lives, economic devastation is also mounting
with a global depression now seeming inevitable.
1.1 Economic Stagnation
The COVID-19 pandemic has disrupted the lives of many people as well as the global
economy. Major countries, aside from China where the virus originated, have shown
a negative adaptation of growth [25]. As a result of this significant hemorrhage to
economic growth, the United Nations predicts that foreign direct investments could
have a reduction somewhere between 5 and 15%, resulting in the lowest levels since
the 2008 financial recession. It is estimated that the gross domestic product (GDP)
growth would be massively affected, ranging from 3 to 6% (depending on the country)
[8]. As a consequence, in approximately 30 countries, a median decline in GDP in
2020 of −2.8% would be observed. In other scenarios, the GDP can fall more than
10%, and in some countries, more than 15% [8]. It is further estimated that on average,
each additional month of lockdown or restrictions will cost 2.5–3% of global GDP.
It is projected that if the ongoing crisis lasts beyond 2020, the global economy faces
the gravest threat seen in the last two centuries [8, 21].
1.2 BRICS Nations
Despite these economic concerns and the various warnings issued by the World
Health Organization (WHO) about the severity of the disease and the most commonly
used forms to combat COVID-19 in an environment where there are no confirmed
treatments [17], responses differed among countries, both at the level of public poli-
cies and at the individual level [24, 37]. It has been suggested that even the health
promotion community must ensure that considerations of health equity and social
justice principles remain at the forefront of the pandemic responses [16]. It is evident
that each country around the globe will tackle the COVID-19 pandemic in their own
way. While there are contextual similarities and differences between countries, there
A Mathematical Model and Strategy to Guide the Reopening of BRICS … 765
also seems to be interesting perspectives among developing and developed countries.

So far, the most vulnerable nations are those that arise from developing countries
[30]. For example, the BRICS population and member countries (Brazil, Russia,
India, China and South Africa) corresponds to almost 45% of the world’s popula-
tion, which is equivalent to almost 3.3 billion people. The total number of confirmed
COVID-19 cases on the 1st October 2020 in these countries is almost 13.2 million,
which is equivalent to a third (approximately 36%) of all cases identified in the world.
Of these, 286,000 people have died, equating to 27% of all deaths recorded due to
COVID-19 [7].
The situation experienced by the BRICS nations is concerning. Brazil, Russia,
India, and South Africa are among the ten countries with the highest number of
confirmed cases, except China [11]. Special attention should be given to Brazil due
to the lack of support from the federal government in combating the disease [6]. The
COVID-19 pandemic outbreak in India is also a concern, whereby projections by
the Massachusetts Institute of Technology (MIT) placed the country at having the
highest number of infections in March 2021 [20]. On the contrary, China, despite
being the most populous country in the world, has very low indicators, and these
factors seem to have been controlled as a result of more effective actions from social
isolation to the sanitary cords implemented by the government [22]. This chapter
will, therefore, document findings and provide a delineated focus on testing, hospital
capacity, incidence rate, recovery rate and population density amongst the BRICS
nations.
1.3 Mathematical Modelling
In order to provide a robust focus alongside a strategy, efficient methods are required.
One form of these methods in the context of epidemics and pandemics in the global
health literature is mathematical modelling. It has been suggested that mathematical
modelling can be used as a powerful tool for understanding transmission of COVID-
19 and exploring different scenarios [23]. One model looked at different policies that
yield the same transmission rate and have the same health outcomes, but can have
very different economic costs [33]. It has also been highlighted that understanding
the dynamics of case-fatality and recovery rates of COVID-19 would enhance the
knowledge base on the current trends of the severity of the epidemic [5]. Based
on pattern recognition, the Auto-Regressive Integrated Moving Average (ARIMA)
model, Autoregressive Distributed Lag Model (ADLM) and Double Exponential
Smoothing (DES) techniques were tested and was deemed sufficient to forecast the
pandemic of USA, UK, and Russia [13]. A similar model is yet to be determined for
developing nations.
1.3.1 Rationale
In the literature, there has only been one study that sought to compare the number of
confirmed cases and deaths caused by COVID-19 among the BRICS nations, and to
ascertain the number of cases in each country to the total number of cases isolated
worldwide [6]. In addition, there is limited attention directed towards people who
have recovered from the virus and whether this metric can be useful in guiding when
the global economy can be reopened. A simpler model has recently been published
[21] to guide various countries on the possible reopening of the economy or reopening
in phases, alongside risk categories and ratios.
As such, in this chapter, a similar model has been applied among the BRICS
nations (Brazil, Russia, India, China and South Africa), as these countries are
currently among the top 10 countries infected with the virus. The chapter also
provides a possible strategy in counteracting the spread of the virus and reopening of
the economy. Factors that need to be considered when applying the model include the
healthcare capacity in terms of the number of hospitals, beds and healthcare workers
that are available to capacitate this virus [21]. In addition, population size, population
density, physical and social distancing measures, socio-economic disparities, lock-
down regulations in each country, and more importantly—the amount and accuracy
of testing conducted, is also imperative to consider (especially among BRICS nations
where both common and varied threads are identified) [27].
Other important proponents such as climate and environmental factors as well as
socio-economic disparities also needs to be understood, with an integration of such
considerations alongside proposed models and strategies. Providing and dissecting
a holistic picture through an integrated model and strategy will significantly assist
countries to apply it in their unique contexts and circumstances as a guide to reopening
of BRICS economies during the COVID-19 pandemic.
1.3.2 Structure
This chapter is organised in six major sections. Section 1 is an introductory section

which discusses the problem statement, motivations, objectives, rationale and contri-
butions. This is followed by the methods in Sect. 2. The subsequent Sects. 3 and 4
present the results and discussion, which constitutes important data of the various
proponents and factors that contribute to the development of the model and strategy.
This is followed by Sects. 5 (Conclusion) and 6 (References) with a way forward
and recommendations.
2 Methods
The methodology used in this commentary chapter involves the collation of data and
evidence from primary and secondary resources, with an integration of statistical data
for the five BRICS countries. Most of the literature was published in 2020 as this
was the period of the greatest infection. The data presented reflects all information
from the start of the pandemic in that specific country up to and including the 1st
October 2020. Any subsequent data or events after this date are not included in the
analysis or discussion, prior to the submission of this manuscript.
2.1 Study Design
In analytical research studies, one has to use the facts and information that are
already available, and analyse these to make a critical evaluation of the material at
hand [14]. Furthermore, cross-sectional studies are used to determine epidemiology
(mainly) and are relatively quick, but do not permit conclusions based on causality of
relationships between variables [18]. As a result, a descriptive study design involving
an analytical approach was implemented for this chapter.
2.2 Data Sources and Searches
This chapter did not use a formal systematic review format, and a search strategy was
used to identify the relevant literature for each of the BRICS countries. Scientific liter-
ature was identified by searching electronic databases (PubMed, Scopus, and Google
Scholar). Keywords searched for were: healthcare capacity, hospital capacity, testing,
population size, population density, incidence rate, physical distancing, and socio-
economic disparities/challenges. In addition, the reference lists of all the identified
articles were used to search for other relevant articles.
2.3 Inclusion and Exclusion Criteria of Studies
Original articles, commentaries (due to the absence of evidence or pending data) and
systematic reviews were prioritised as these synthesise the information and represent
the highest level of evidence-based literature. Studies that were not related to the
chapter or did not contribute to the model presented in this chapter, were excluded.
Titles and abstracts were screened for eligibility. The full texts of the remaining
studies were then retrieved and read in full, independently by the authors, to determine
whether the studies met the inclusion criteria.
2.4 Data Analysis
The statistical data for the five BRICS nations were all sourced from publicly acces-
sible databases. These include: Our World in Data, European Centre for Disease
Control and Prevention, John Hopkins University, Worldometers, National Institute
for Communicable Diseases (SA), and the South African Ministry of Health. Data
specific to the BRICS countries was collated and checked for accuracy and complete-
ness by cross-checking between the databases. The figures were all generated using
open-source plotting software packages, GNU Octave 3.8.1 and Python 2.7.6.
2.5 Ethical Considerations
Due to the literature and statistical data available in the public domain, on credible
sites, no ethical approval from an institution was deemed necessary. This is consistent
with ethical guidelines published in the literature regarding online research [12, 34].
3 Results
3.1 Demographics
Firstly, we look at the overall picture of COVID-19 within the countries in this study.
Table 1 lists the cumulative total confirmed cases of COVID-19 and reported deaths
due to COVID-19 as at 1st October 2020.
While Table 1 above provides a current snapshot of the overall COVID-19 cases
and deaths statistics, it does not inform us of how these numbers have changed
Table 1 Statistical COVID-19 metrics and population measures in BRICS countries

Country Total cases Total Population Population Median age Global
as on 1 Oct deaths size density (No. of (years) rank of
2020 as on 1 people/m2 ) COVID-19
Oct cases
2020
Brazil 4,849,229 144,767 212,559,409 25.04 33.5 3
Russia 1,185,231 20,891 145,934,460 8.82 39.6 4
India 6,391,960 99,804 1,380,004,385 450.42 28.2 2
China 85,414 4634 1,439,323,774 147.67 38.7 50
South 676,084 16,866 59,308,690 46.75 27.3 11
Africa
Total 13,187,918 286,962 3,237,130,718 Mean = 135.74 Mean = 33.46 /
over time. Figures 1 and 2 therefore track the COVID-19 trajectories of these coun-
tries. Figure 1 shows the cumulative confirmed COVID-19 cases for each country,
while Fig. 2 shows the cumulative confirmed COVID-19 deaths. The graph for
total COVID-19 cases for each country begins on the day when the total number
of confirmed cases in that country first passed 100, while the graph for COVID-19
deaths starts on the day when the country first reported five total deaths. This is done
because the speed at which the outbreak spreads varies from country to country, but
showing the trajectories from the same starting point allows for better comparison.
The logarithmic scale allows us to quantify the rate of growth of cases and deaths
by considering the slope or gradient of each curve. Whilst China showed the highest
rate of increase in the early stages and a sudden drop off, the other nations followed
similar, yet, more prolonged increases over a much longer period of time. It should
be noted, however, that the number of confirmed COVID-19 cases is lower than the
actual number of infections. The reason for this is that confirmed cases are limited by
laboratory testing. Similarly, the number of reported COVID-19 deaths may not be
a true count of the actual number of deaths from COVID-19 due to the challenges in
the attribution of the cause of death, as well as limited testing to confirm a COVID-19
case.
Fig. 1 Cumulative confirmed COVID-19 cases

Fig. 2 Cumulative confirmed COVID-19 deaths
3.2 Population Density
The population sizes of each country are also shown in Table 1 above, as well as the
population density and median age of the population of that country. The population
density is defined as the number of inhabitants per square kilometer. It is well-known
that COVID-19 is spread through close contact and within close distances. Densely
populated and crowded areas, therefore, present a higher risk to the transmission of
the virus. The following risk categories in Table 2 have been defined based on the
population density.
Table 2 Population density risk criteria and risk values

Population density (No. of people per square kilometer) Risk category Risk value
0–50.00 Low risk 0.04
50.01–100.00 Mild risk 0.08
100.01–150.00 Moderate risk 0.12
150.01–200.00 Moderate-to-high risk 0.16
>200 High risk 0.20
3.3 Incidence Rate
The number of COVID-19 cases as confirmed by laboratory testing is the most

widely used measure to determine the scale of the outbreak in a country. It allows
for determining the rate of transmission, as well as the spread of the infection across
regions. However, decision makers need to consider recoveries and the number of
active cases instead of just cumulative cases as a useful measure in decision-making.
Although we do not yet know how reinfections occur, many cases that were confirmed
months ago are no longer important as a risk factor as they are considered closed and
have either recovered and are no longer infectious or have succumbed to death. It is
therefore more prudent to consider open or active cases. A high-risk area or hotspot
should take into account two factors: the number of current active cases in the region
and the attack rate or incidence rate. The incidence rate is defined as the number of
confirmed cases, as a seven-day rolling average, per million people.
The previous graphs looked at the total number of cases over time. Figure 3 shows
the number of daily new confirmed cases in each of the BRICS nations. The graph for
daily COVID-19 cases for each country begins when the number of confirmed cases
in that country first reached 30 per day, such that the curves begin at the same starting
point. Due to fluctuations in daily reported numbers, as well as generally reduced
testing across all countries over weekends, the number of cases is smoothed and
shown as a seven-day rolling average as this eliminates the daily spikes in reporting
Fig. 3 Daily new confirmed COVID-19 cases

and the weekend effects. The reported number of cases may not reflect the actual
number of cases on that day due to delays in data processing and reporting. The actual
number of cases may also be higher than that confirmed due to limited testing. From
Figs. 2 and 3, we can already see the concerning trajectory of the virus for Brazil and
India. The curves for Brazil, India and South Africa increased exponentially over a
prolonged period and, while South Africa has passed a peak, the rate of infection in
Brazil and India still remains high. The curve for Russia had initially passed a peak
but is showing signs of a resurgence in infection rates once again.
The difference in the population sizes between the BRICS countries is large. In
order to make relevant comparisons it may be useful to compare the number of
confirmed cases per million people in that country. Figure 4, therefore, shows the
same daily count of confirmed cases per country, as in Fig. 3, but scaled by the size
of the population of that country, with the total population sizes as listed in Table
1. The figure shows the daily new confirmed cases, as a seven-day rolling average,
per million people or incidence rate per capita and begins when the number of daily
confirmed cases per million people first reached one. Brazil and South Africa had the
highest incidence rates, well above levels of concern, when compared to the size of
the population of the countries. While the incidence rate for South Africa reduced to
manageable levels, the incidence rate for Brazil is still high and remains a concern.
Fig. 4 Daily new confirmed COVID-19 cases per million people

Table 3 Incidence rates risk

New confirmed cases per Risk category Risk value
criteria and risk values
million people
<25.0 Low risk 0.04
25.1–50.0 Mild risk 0.08
50.1–75.0 Moderate risk 0.12
>100 High risk 0.20
The incidence rate is defined as the number of new cases as a seven-day rolling
average per million people in that country. An incidence rate of greater than 100 is
considered to be very high-risk, while incidence rates below 25 are desired. In Table
3, we define risk criteria and corresponding risk values based on the incidence rates.
These risk criteria are also shown plotted by the dashed lines in Fig. 4.
3.4 Recovery Rate
As mentioned earlier, decision makers need to consider recoveries and the number
of active cases instead of just cumulative cases as a useful measure in decision-
making. Although we do not yet know how reinfections occur, many cases that were
confirmed months ago are no longer important as a risk factor as they have either
recovered and are no longer infectious or have succumbed to death.
Recoveries and deaths are considered closed cases, and the active or open cases,
are therefore, the total cases minus the closed cases. Table 4 lists the total cumulative
confirmed COVID-19 cases, reported deaths, and known recoveries in the BRICS
countries as at 1st October 2020. Current active cases are also shown in Table 4.
As an example, the total cases, recoveries and deaths for South Africa are shown
tracked over time in Fig. 5. These are indicated by the solid lines, while the vertical
dashed lines in the figure indicate the different lockdown restriction levels in the
country. The number of active or open cases in South Africa, which is the total
confirmed cases less recoveries and deaths, is shown by the solid blue line. A region
Table 4 Total COVID-19 cases, recoveries, deaths and active cases in BRICS countries as at 1st
October 2020
Country Total cases Total recoveries Total deaths Active cases
Brazil 4,849,229 4,212,772 144,767 491,690
Russia 1,185,231 964,242 20,891 200,098
India 6,391,960 5,348,653 99,804 943,503
China 85,414 80,594 4634 186
South Africa 676,084 609,584 16,866 49,634
Fig. 5 Cumulative confirmed COVID-19 cases, recoveries, deaths and active cases in South Africa
is considered a high-risk when the number of active cases is high or recovery rate
is low, which will be examined further below. As seen in Fig. 5, while the number
of active cases in South Africa increased exponentially until about Day 140, the
numbers began to decrease thereafter and have stabilised to around 50,000 at the
time of writing, representing approximately 7.5% of total confirmed cases.
In another paper, a simple risk model that takes into account the total recoveries
was presented in order to guide various countries on the (possible) reopening of the
economy (or in stages/phases) alongside risk categories and ratios.
The calculation was as follows:
Total Recoveries = RT|Total Cases = CT|Ratio = r
Mathematical Model : RT/CT = r
A high recovery rate implies fewer active cases and, with less infectious people,
a lower risk to the spread of the virus. In Table 6 we define risk criteria and
corresponding risk values based on the risk ratio as shown in Table 5.
Table 5 Risk/ratio guide for

Ratio Risk Level/phase of lockdown
reopening of the economies
out of lockdown 0.0–0.40 High 5
0.41–0.66 Moderate 4
0.67–0.85 Mild 3
0.86–0.99 Low 2
Adapted from Noorbhai [21]
Table 6 Recovery rates risk

Ratio, r Risk category Risk value
criteria and risk values
0.0–0.40 High 0.20
0.41–0.66 Moderate 0.15
0.67–0.85 Mild 0.10
0.86–0.99 Low 0.05
3.5 Test Positivity Rate
Testing is a critically important tool in combating the virus and understanding how
the infection is spreading. Sufficient testing, with quick test turnaround times, and
together with efficient contact tracking and tracing allows a country to get ahead of
the epidemic curve and understand the rate of transmission and spread of the virus.
Table 7 lists the total number of coronavirus tests conducted by each of the BRICS
countries up to 1st October 2020, as well as the percentage of the population in that
country that has been tested. The testing numbers vary significantly between the
countries. This is due to the different testing resources, capacity constraints and
varying test strategies.
As per Table 7, Russia has conducted the most tests in proportion to their popula-
tion size. With India and Brazil being the most concerning countries for the virus, this
concern is further emphasised by these countries conducting lower tests in proportion
to their population size. The testing rate for South Africa also remains a concern.
China’s testing rate in proportion to their population size is not large. However,
China was able to quickly change the trajectory of the virus due to early responses
and control measures adopted.
Table 7 Total COVID-19

Country Total tests Percentage of population (%)
tests conducted in BRICS
countries as at 1st October Brazil 17,900,000 8.4
2020 Russia 48,042,343 32.9
India 79,982,394 5.8
China 160,000,000 11.1
South Africa 4,280,340 7.2
Fig. 6 Cumulative coronavirus tests
The cumulative number of tests conducted for each country is shown plotted over
time in Fig. 6. It is noted that Brazil and China do not report the daily number of
coronavirus tests conducted on a regular basis. It is, therefore, not possible to track
the testing numbers for Brazil and China, and these two countries are not analysed
in this section. The curves for total coronavirus tests for each country begins on the
day when the total number of confirmed cases in that country first passed 10.
The number of daily new coronavirus tests per country is shown plotted in Fig. 7,
beginning when the number of new confirmed cases in that country first reached 10
per day. In Fig. 8, the daily testing numbers are scaled by the size of the population
and shown as the number of new daily tests per one thousand people. As can be
seen in Fig. 7, the number of daily tests in India and South Africa has ramped up
over time but it may still not be sufficient based on the size of the population, as
shown in Fig. 8, and the rate of transmission of the virus. Further, the number of
tests conducted in South Africa has been steadily decreasing after reaching a peak.
This is due to a reduced demand for tests and strict testing criteria employed across
the country. The testing capacity in Russia is much more favourable in proportion to
their population size, as seen in Fig. 8.
It may not always be useful to look at the COVID-19 case counts in isolation nor
is it useful to look at the absolute number of tests conducted in isolation. It is more
helpful to look at whether the timing and extent of testing has kept up in relation to
the scale of the outbreak [28]. This can be done by plotting the daily tests versus the
Fig. 7 Daily new coronavirus tests
daily new confirmed cases. The testing numbers and case counts for South Africa
are used here as an example. Figure 9 shows the daily number of tests conducted
in South Africa, as a seven-day rolling average, on the vertical axis and the daily
number of confirmed cases in South Africa, also as a seven-day rolling average, on the
horizontal axis. A curve that bends towards the vertical means that cases are steady,
while testing is ramping up. A curve that bends towards the horizontal indicates that
testing has plateaued and cases are rising. The ideal scenario would be for this curve
to move towards the top left of the graph, indicating that testing is increasing and
new confirmed cases are decreasing.
It can be seen that the testing decreased significantly soon after the introduc-
tion of lockdown restrictions in South Africa, which had a notable effect on the
number of confirmed cases. The curve has generally moved towards the top right,
indicating that the rate of transmission of COVID-19 has increased even as testing
has increased, but the rate of testing has not kept up with the rate of spread of the
infection through lockdown levels five, four and the beginning of level three. Since
the latter part of lockdown level three, the curve for South Africa is moving towards
the bottom left, indicating a decline in the number of confirmed cases, but also a
decrease in the number of tests being conducted. The primary reason for this is a
reduction in demand for tests due to fewer people presenting for testing. Prior to the
implementation of lockdown level 1 restrictions, South Africa had very strict testing
criteria with only healthcare workers, those at high risk and those being admitted
Fig. 8 Daily new coronavirus tests per 1000 people
Fig. 9 Daily tests versus daily new confirmed cases in South Africa
for hospital procedures allowed to be tested for COVID-19. With the rate of trans-
mission decreasing the number of people meeting the above criteria also decreased
with a resulting reduction in overall tests conducted. It is suggested that testing be
increased even as confirmed cases are decreasing, in order to fully understand the
rate of transmission and spread of the infection. Also shown in Fig. 9 are diagonal
dashed lines each of which indicate the number of tests conducted per confirmed
case. This metric will be discussed more below.
Confirmed COVID-19 cases are limited by confirmation through laboratory
testing. In addition, testing capacities, strategies and priorities vary across countries.
A measure used to indicate whether a country has got the epidemic under control is
the test positivity rate. It is a crucial measure in also understanding the spread of the
virus. The test positivity rate is defined as the number of confirmed cases divided
by the number of tests conducted, reported as a percentage. This metric is useful in
understanding whether a country is doing adequate testing, in relation to the scale
of the outbreak it is experiencing, as well as an indication of how widespread the
infection is in that country.
The daily positivity rate (new cases as a percentage of new tests) is shown in
Fig. 10, for Russia, India, and South Africa. Of concern is the rise in the test positivity
rate well above 5% for South Africa and India. This is a threshold that the World
Health Organisation (WHO) on 12th May 2020 [38] advised should raise concern and
Fig. 10 The share of daily coronavirus tests that are positive

Table 8 Test positivity rates

Test positivity rate (%) Risk category Risk value
risk criteria and risk values
<2 Low risk 0.04
2.1–5.0 Mild risk 0.08
>20 High risk 0.20
indicate the need for imposing restrictions on the movement of people and activities
allowed.
Table 8 defines the risk criteria and values based on the test positivity rate. A
test positivity rate below 5% should be maintained before easing of restrictions,
and a positivity rate below 2% indicates an adequate amount of testing and that the
epidemic is under control [38]. A test positivity rate above 10% should raise concern
and indicate the necessity for further interventions, while a value above 20% indicates
a high-risk with the epidemic not under control.
Test positivity rates can also be expressed as the number of tests conducted for
every positive COVID-19 case identified and is another way of looking at whether
a country is doing adequate testing. It is calculated by dividing the number of tests
by the number of confirmed cases, and is shown in Fig. 11. It is simply the inverse
of the test positivity rate as shown in Fig. 10. A 10% test positivity rate means a
positive case is found for every 10 tests conducted, while the positivity rate between
20 and 25% indicates that a new case is confirmed for every 4–5 tests conducted.
A country is not testing adequately when the number of tests per confirmed case is
low. This also implies many undetected cases and that the actual number of cases is
higher than reported.
Countries want to be doing many tests per confirmed case in order to be confident
that they are testing widely enough and detecting all the infections. The WHO has
suggested that 10–40 tests per confirmed case is a general benchmark that adequate
testing is being done [38, 39]. Table 9 shows the risk criteria and values based on the
number of tests per confirmed COVID-19 case.
3.6 Hospital Capacity
Ultimately, lockdown and restrictions should be used to build up hospital capacity

and we should only be closing the economy so as to prevent hospitals from being
overwhelmed, and to allow people the best access to healthcare facilities to minimise
deaths. Healthcare capacities should be a crucial factor to the reopening of economies.
Figure 12 shows the number of current COVID-19 hospital admissions across
South African hospitals, based on data from hospitals that are part of the NICD
sentinel hospital surveillance network. The number of admissions rose rapidly
Fig. 11 Tests conducted per confirmed COVID-19 case
Table 9 Tests per confirmed

Number of tests per Risk category Risk value
case risk criteria and risk
confirmed cases
values
>50 Low risk 0.04
20.1–50.0 Mild risk 0.08
<5 High risk 0.20
from May 2020 and reached a peak during the months of July and August 2020,
corresponding with trend seen in the number confirmed infections across the country.
In Table 10 we list the hospital capacity in each of the BRICS countries, defined as
the number of hospital beds per thousand people [28]. Also shown is the population
size and population density for each of the countries.
Countries with low hospital capacities have the greatest risk of their healthcare
facilities being overwhelmed by a surge in hospital admissions due to COVID-19,
while countries with many hospital beds per thousand people are able to re-purpose
excess bed capacity to handle COVID-19 risk. In Table 11, we define the risk criteria
and risk values based on the number of hospital beds per thousand people.
Fig. 12 Current COVID-19 hospital admissions in NICD surveillance network in South Africa
Table 10 Population size and hospital capacity in BRICS countries

Country Population size Population density (No. of Hospital capacity (beds per
people per m2 ) thousand people)
Brazil 212,559,409 25.04 2.20
Russia 145,934,460 8.82 8.05
India 1,380,004,385 450.42 0.53
China 1,439,323,774 147.67 4.34
South Africa 59,308,690 46.75 2.32
Table 11 Hospital capacity

Hospital capacity Risk category Risk value
risk criteria and risk values
>10.01 Low risk 0.04
6.01–10.00 Mild risk 0.08
<1.00 High risk 0.20
3.7 Climatic Effect
The daily confirmed COVID-19 cases since the first reported case, as well as a seven-
day rolling average of cases, is shown for each of the BRICS countries in Figs. 13,
14, 15, 16 and 17.
The peak of the virus for Brazil, Russia, and South Africa (Figs. 13, 14 and 17) all
occurred during the winter months. In the case of Russia, their second wave started
during their colder months. The only exception is with India (Fig. 15), where their
pandemic started exactly the same time as their summer. This indirectly suggests
that their population density and hospital capacity were the main contributors to
their surge in cases. China’s situation is unique. Although their surge in cases (start
of the COVID-19 pandemic) started during their summer months (December 2019),
China (Fig. 16) was able to contain the virus within a few months due to their strict
and early adoption of control measures. Based on the BRICS nations, we observe
that colder months are a contributing factor to a resurgence in COVID-19 cases, but
is not a key determinant, due to the other risk factors taking precedence.
Fig. 13 Daily confirmed COVID-19 cases in Brazil

Fig. 14 Daily confirmed COVID-19 cases in Russia
3.8 Mathematical Model
The overall risk formula is applied for each of the BRICS nations in the Discussion.
The overall risk for each country is obtained by summing the risk values for each of
the previously defined risk categories: Population density (Table 2), Incidence rate
(Table 3), Recovery rate (Table 6), Test positivity (Table 8), and Hospital capacity
(Table 11).
Overall Risk = Risk(Population density)

+ Risk(Incidence rate) + Risk(Recovery rate)
+ Risk(Test positivity) + Risk(Hospital capacity)
Table 13 shows the overall risk categories (safe, moderate, substantial, severe and
critical) based on the calculated overall risk, R, ranges. Also shown are the suggested
lockdown levels/phases for reopening of the economies.
Fig. 15 Daily confirmed COVID-19 cases in India
4 Discussion
The main aim of this chapter is to demonstrate the similarities and differences of a
number of parameters (testing, hospital capacity, incidence rate, recovery rate and
population density) between the BRICS nations. A common thread among Brazil,
India and South Africa are the socio-economic disparities, paucity of testing and
low hospital capacity (this is also true, to an extent, with Russia). A common thread
among Brazil, India and China is the high population density which makes physical
distancing and human mobility a challenge. However, China had been able to mitigate
the spread of the virus earlier on due to strict control measures. Below, a closer look is
cast on a number of factors contributing to the COVID-19 pandemic among BRICS
nations and how the countries are tackling the pandemic.
Fig. 16 Daily confirmed COVID-19 cases in China
Fig. 17 Daily confirmed COVID-19 cases in South Africa

4.1 How Are the BRICS Nations Tackling the COVID-19

Pandemic?
To control COVID-19, it is said that effective prevention and control measurements

should include early detection, diagnosis, treatment, and quarantine to block human-
to-human transmission and reduce secondary infections among close contacts and
health care workers [39, 40]. Although this is ideal, in reality, especially among devel-
oping countries such as the BRICS nations, this is not the case, and such countries
have adopted unique ways of tackling the COVID-19 pandemic.
India’s unprecedented measures to contain further transmission was the cancel-
lation of all visas to the country. States were also asked to invoke the Epidemics
Diseases Act, a legislation that allows officials to quarantine suspected cases or
close down public places. Some states, such as Karnataka, have also taken the liberty
to announce a weeklong shutdown of malls, movie theatres, and schools [35].
While other BRICS nations are still in the midst of the pandemic, the Chinese
authorities have embraced their success of strict and thorough measures, including
a complete lockdown of the epidemic centre of Wuhan and surrounding Hubei
province, as well as major cities such as Beijing and Shanghai. Worldwide cases
have surpassed total cases in China, and China has indicated that their actions helped
see the country through the peak of infections and has bought time for other countries
to prepare for their peak or subsequent wave(s) [35]. Another reason why China was
relatively quicker in tackling the virus was due to the drastic control measures imple-
mented for human mobility and counteracting travel restrictions, which substantially
mitigated the spread of COVID-19 [15]. Travel restrictions are useful in the early
stages of an outbreak (similar adoption by New Zealand) when it is confined to a
certain area that acts as a major source, but can be less effective once the outbreak
has already spread far and wide.
In South Africa, the government responded early, but not as early and rapidly
compared to China. The country had confirmed a State of Disaster on 15 March
2020 [32]. Initial restrictions were mild (restaurants, tourism, travel restrictions,
etc.) but from 27th March 2020, a full lockdown was implemented which prohibited
individuals leaving the home for any non-essential purposes and included a list of
restrictive movements and essential activities [4]. There were five levels of lockdown.
The most severe lockdown level was level 5, where most of the economic activity
was shut down. Subsequently, in order to gradually open up the economy, there was a
gradual shift to levels 4, 3, 2, and 1 between May and September 2020 (approximately
a month apart between each level).
4.2 Climate and Environmental Factors
One of the main predictors of the COVID-19 pandemic in Russia is climatic patterns
[26]. The survival and rate of infections is mostly higher in the regions with low
Table 12 Seasonal months (summer and winter) and temperature (°C) according to country
Country Summer months Winter months Average temperature (°C)
Brazil October–March April–September 25
India April–September October–March 30
Russia June–August September–May 19
China April–September October–March 16
South Africa October–March April–September 23
Note The weather in each region or state/county/province of a country can vary. This is an estimate
Table 13 Overall Risk and

Overall risk, R Overall risk category Level/phase of
guide for reopening of the
lockdown
economies out of lockdown
0.0–0.29 Safe 1
0.30–0.44 Moderate 2
0.45–0.59 Substantial 3
0.60–0.74 Severe 4
0.75–1.0 Critical 5
humidity and cold temperature [9]. As such, the higher the relative humidity and
temperature, the lower the number of coronaviruses cases. Unlike India and Brazil
with a relatively higher temperature and humidity, a lower temperature has been
a key determinant for increased cases in Russia. In comparison to South Africa,
the peak of COVID-19 occurred during its winter season. A similar trajectory was
found with China, when their peak occurred during the winter months between
December 2019 and February 2020. More recently, we currently witness a second
wave of infections among Russia, which is at the start of their colder/winter months
approaching (October–March) (Table 12).
Furthermore, it has been stated that most cases of COVID-19 have been identified
in countries that are located in the northern hemisphere, also known as the winter
“influenza/flu” season. Similarly, the SARS-CoV global outbreak in 2003 did not
affect Africa or South America on a larger scale [10]. This confirms that respiratory
conditions spread more rapidly in the winter. This also poses a risk on the southern
hemisphere to be more affected in the latter parts of the year. There are also a number
of factors that contribute to the survival of the virus based on the climate location:
living more outdoors than indoors, the effect of ultraviolet light on the survival of
COVID-19, immunological differences of the population and higher temperatures
and humidity levels. To date, most identified cases of COVID-19 in Africa originated
from Europe and not from China [10]. It is, therefore, suggested that the government
should implement stricter measures for winter months in each country to prevent the
subsequent waves of the COVID-19 outbreak [26].
4.3 Healthcare and Capacity (South Africa Only)
A major challenge from a South African healthcare perspective is the amount of

hospital beds and personnel trained in critical care which are limited to (mainly)
tertiary hospitals. In addition to the South African response to the pandemic, there is
no data available on the response of the healthcare system. The Minister of Health
made a statement on the intention to add beds during the peak phase of the pandemic
[29] but this data seems inaccessible. Therefore, mortality associated with COVID-
19 is likely to exceed the reported case fatality rates. Furthermore, it is plausible
if low-and middle-income countries (LMICs), alongside their weakened infection
prevention and control (IPC) programmes, with their limited health budgets, can fill
the financial void of the additional costs associated with critical care units [10].
4.4 Challenges Among BRICS Nations
There are a number of challenges that Russia has faced in the context of the pandemic.
Russia is largely under-financed and under-equipped, with seldom personal protec-
tive equipment (PPE), masks, ventilators, and testing (a similar challenge to the other
BRICS nations) [2]. As a result, Russia was quite vulnerable and likely to under-
state the number of infected and dead people. Despite these challenges, Russia has a
number of advantages, namely: a large number of small hospitals, hospital beds, and
medical doctors in relation to the population [2]. This allows Russia to run less risk of
running out of hospital capacity than many Western countries that have rationalised
their medical care [36].
4.5 Socio-Economic Disparities
Another major challenge in South Africa (and in other BRICS nations) is the socio-
economic disparity. The COVID-19 pandemic has really cast an eye into how unequal
society is, not just in South Africa, but in other BRICS nations as well. For example,
the lockdown measures that South Africa has put into place to contain COVID-19 had
(and still has) negative implications for the distribution of income [1]. Labour with
low education levels are much more strongly affected than labour with secondary
or tertiary education. Furthermore, the impact on the economy is also very large.
Specifically, a reduction in hours for workers who have (at most) a primary school
education exceeded 40%, while tertiary educated workers suffered a much smaller
but very large reduction of approximately 26% [1].
Focusing broadly at developing countries with strong lockdown measures to
counter the spread of COVID-19 but weak social protection networks, food security
also becomes questioned for low income households and appears to be dismal. Even
with the socio-economic protection measures (social grants) present in some BRICS
nations, the sustainability of the lockdown beyond a few weeks is open to question as
it counter-affects the sustainability of people’s livelihoods [1]. In developing coun-
tries where food insecure households receive no or very limited support, low income
households will soon, at a rapid rate, confront a choice between seeking to generate
income to prevent starvation and accept the risk of becoming infected, or prevent
becoming infected and accept the risk of starvation. For many, preventing starvation
has been far more imperative than contracting the virus, despite any official lockdown
measures imposed by the BRICS nations [1].
4.5.1 The Mathematical Model
There are limited papers documenting models in conjunction with risk categories
and correlating these to specific ratio values. The calculation and risk model was
shown in the Results section and Table 5.
As an application of this model globally, as of 1st October 2020, there are
approximately 26,000,000 recoveries and 37,000,000 cases. This would work out
as: 26,000,000/37,000,000 = a ratio of 0.70. Table 5 guides the risk-to-ratio guide
for reopening of the economies out of lockdown. Where r is 0.0–0.40, it is a high
risk; 0.41–0.66 is a moderate risk; 0.67–0.85 is a mild risk; and 0.85–0.99 is a low
risk. The risk category classifications (high, moderate, mild and low) are based on
the number of countries who have opened their economy after observing a decline
in the amount of COVID-19 cases. The risk category classifications are, however,
generic as each state/county/province and country would need to use it as a guide in
order to apply the ratio to their unique circumstances as well as the level/phase of
lockdown/restrictions. The United States of America have a high risk ratio of 0.30,
whereas Russia and India (with an imminent resurgence) have a mild risk ratio of
0.81 and 0.84, respectively. Despite the above model and normative guide, caution
must be exercised when applying it in each country. One theory that comes to mind is
the social determinants of health inequalities. “These determinants are important to
consider and include: income and social status, social support networks, employment
and working conditions, physical environments, education, healthy child develop-
ment, biology and genetic endowment, health services, personal health practices
(including hygiene) and coping skills, and transport” [19]. Table 14 applies this
simpler model among the BRICS nations with suggested lockdown levels for data at
1st October 2020.
This chapter further builds on the simple model above by incorporating and inte-
grating other key parameters to inform the overall risk of the pandemic. The overall
risk, R, for each of the countries is then calculated by summing the risk values of
each of the individual risk categories as shown by the formula below:
Overall Risk, R = Risk(Population density) + Risk(Incidence rate)

+ Risk(Recovery rate) + Risk(Test positivity) + Risk(Hospital capacity)
Table 14 Total cases, recoveries, ratios and suggested lockdown levels among BRICS countries
(1st October 2020)
Country Total cases Total recoveries Ratio Suggested lockdown level for reopening the
economy
Brazil 4,849,229 4,212,772 0.87 2
Russia 1,185,231 964,242 0.81 3
India 6,391,960 5,348,653 0.84 3
China 85,414 80,594 0.94 2
South Africa 676,084 609,584 0.90 2
The risk values and overall risk, R, for data as at 1st October 2020 are shown in
Table 15:
Table 16 demonstrates the overall risk of each of the BRICS nations as at 1st
October. In proportion to their global rank of the number of COVID-19 cases, the
overall risk of Brazil, Russia and India is directly proportional to their global rank.
However, with South Africa and China, this is not the case. This indicates that
the overall risk can provide an indication of how the country is coping during the
pandemic but does not provide an absolute risk value due to the unique determi-
nants and complexities involved in each country. The suggested lockdown levels for
reopening the economy as at 1st October 2020 are also shown in Table 16.
Table 15 Risk values and overall risk, R, of BRICS countries as at 1st October 2020
Country Population Incidence Recovery Test Hospital Overall
density rate rate positivity capacity Risk, R
Brazil 0.04 0.20 0.05 0.20 0.16 0.65
Russia 0.04 0.08 0.10 0.04 0.08 0.34
India 0.20 0.12 0.10 0.12 0.20 0.74
China 0.12 0.04 0.05 0.04 0.12 0.37
South 0.04 0.08 0.05 0.12 0.16 0.45
Africa
Table 16 Overall risk of BRICS countries as at 1st October 2020

Country Overall risk, R Overall risk category Suggested lockdown level for reopening
the economy
Brazil 0.65 Severe 4
Russia 0.34 Mild 2
India 0.74 Severe 4
China 0.37 Mild 2
South Africa 0.45 Substantial 3
4.5.2 Strengths and Limitations
It should be noted that all statistical data has its limitations. In particular, all of
the COVID-19 data and metrics have their own limitations and nuances. Confirmed
cases are limited by testing, and the actual number of cases in any region may
be higher than that confirmed by laboratory testing. Testing is subject to varying
testing criteria, priorities, and differing strategies between countries in combating
the virus. Test results are also subject to delays in reporting and hence hinder the
accuracy of the daily data and trends. Hospital admission data may not be complete
due to insufficient reporting processes or simply because healthcare facilities that do
not report their daily numbers to national reporting databases. Reported COVID-19
deaths are subject to undercounting and challenges or delays in the attribution and
reporting of the cause of death. Some countries make use of excess death tracking by
comparing total deaths with expected deaths based on historical trends over previous
years. However, this metric also has its limitations as it cannot quantify the exact
burden of COVID-19 alone. For the limitations outlined above, it becomes even
more important to track all metrics and note the trends in the various measures.
The limitations for each country exist for all metrics, and therefore, tracking and
comparing the trends allows researchers and scientists to pick up any anomalies in
the measures. By also not focusing on any single metric in isolation, but instead
many different metrics, a more complete and holistic understanding of the situation
and risk is determined. There was also a paucity of data in some instances when
representing the BRICS nations, in the case for China and Brazil, specifically. An
additional limitation is that the data and figures presented in this chapter do not reflect
the reality experienced by these countries, due to underreporting, and it is expected
that there are differences in underreporting between countries [3].
A strength of this chapter is the mathematical model described in the previous
section which takes into account a number of different measures and allows for a
complete understanding of the risk involved and strategy to guide for the reopening
of economies during the COVID-19 pandemic. Another strength of this chapter was
the collation of relevant data, metrics, comparisons and parameters across all the
BRICS nations. Currently, there is no literature that documents the consensus of the
COVID-19 pandemic in alignment with a strategy and model for BRICS nations. An
additional strength of this chapter is that a vast majority of the literature sourced and
identified were published/available in 2020.
5 Conclusion
All BRICS nations discussed in this chapter have both similarities and differences
between each other. The distinctions between these nations are helpful as countries
and states can use this information to either strengthen or improve parameters where
there are noticeable gaps. The most common thread among the BRICS nations is the
socio-economic disparity and the relatively large population density (especially with
India and China).
Leaders around the world have the most difficult decision to make (yet), and
have to weigh up on what really matters; health or wealth. The critical question that
most countries have been faced with to date is: do we protect lives or livelihoods?
Without livelihoods, it would be difficult to live. Following this model and strategy
would allow countries to reduce the complacency towards the virus and assist in the
reopening of their economy/country. It is suggested that the discussed strategies and
model demonstrated in this chapter be applied in a number of states/counties and
countries (and not just BRICS nations) in order to gauge the overall risk of their
economy being reopened.
6 Way Forward for Future Research
China has demonstrated that the COVID-19 pandemic can be limited when public
health outbreak response strategies and tactics are implemented early and effec-
tively. In LMICs, IPCs have their limitations and challenges. Based on the literature,
it is encouraged that IPCs are strengthened by ensuring that at least the minimum
requirements for IPCs are in place as soon as possible [10]. However, in order to
disseminate such IPCs among BRICS nations, there is also a need for more robust
metrics and measures. In this chapter, an absence of some parameters was outlined.
Physical distancing measures have been an important factor contributing to the trajec-
tory of the virus. As a result of human mobility, it is suggested that further work is
also required to determine how to optimally balance the expected positive effect on
public health with the negative impact on freedom of movement, the economy, and
society at large [15]. Although COVID-19 research is at its infancy, further research
is encouraged to conduct objective studies in order to obtain data and metrics that
will allow countries and states/counties/provinces to understand the trajectory of the
virus, social and human behaviour [37] as well as form an ecological understanding
of the factors contributing to combating the virus and reopening the economies.
References
1. Arndt, C., Davies, R., Gabriel, S., Harris, L., Makrelov, K., Robinson, S., Anderson, L.: Covid-
19 lockdowns, income distribution, and food security: an analysis for South Africa. Glob. Food
Secur. 26, 100410 (2020)
2. Åslund, A.: Responses to the COVID-19 crisis in Russia, Ukraine, and Belarus. Eurasian Geogr.
Econ. 1–14 (2020)
3. Baud, D., Qi, X., Nielsen-Saines, K., Musso, D., Pomar, L., Favre, G.: Real estimates of
mortality following COVID-19 infection. Lancet Infect. Dis. (2020). https://doi.org/10.1016/
S1473-3099(20)30195-X
4. Broadbent, A., Combrink, H., Smart, B.: COVID-19 in South Africa. Glob. Epidemiol. 100034
(2020). https://doi.org/10.1016/j.gloepi.2020.100034
5. Dhillon, P., Sampurna Kundu, C.S., Ram, U., Dwivedi, L.K., Yadav, S., Unisa, S.: Case-fatality
ratio and recovery rate of COVID-19: scenario of most affected countries and Indian States.
International Institute for Population Sciences, Mumbai (2020). Accessed 15 Sept 2020
6. Dias Jr, C.S., Verona, A.P.: Confirmed cases and deaths by COVID-19: a comparison among
the BRICS countries. Unpublished (2020)
7. Dong, E., Du, H., Gardner, L.: An interactive web-based dashboard to track COVID-19 in real
time. Lancet Infect. Dis 20(5), 533–534 (2020)
8. Fernandes, N.: Economic effects of coronavirus outbreak (COVID-19) on the world economy.
Available at: https://ssrn.com/abstract=3557504.SSRN (2020). Accessed 9 Oct 2020
9. Ficetola, G.F., Rubolini, D.: Climate affects global patterns of COVID-19 early outbreak
dynamics. medRxiv (2020). https://doi.org/10.1101/2020.03.23.20040501v3
10. Hopman, J., Allegranzi, B., Mehtar, S.: Managing COVID-19 in low-and middle-income
countries. JAMA 323(16), 1549–1550 (2020)
11. Johns Hopkins University: COVID-19 Dashboard by the Center for Systems Science and
Engineering (CEES). Available at: https://coronavirus.jhu.edu/map.html (2020). Accessed 8
Oct 2020
12. Kitchin, H.A.: The tri-council policy statement and research in cyberspace: Research ethics,
the Internet, and revising a ‘living document.’ J. Acad. Ethics 1(4), 397–418 (2003). https://
doi.org/10.1023/B:JAET.0000025671.83557.fa
13. Konarasinghe, K.M.U.B.: Modeling COVID-19 epidemic of USA, UK and Russia. J. New
Front. Healthc. Biol. Sci. 1(1), 1–14 (2020)
14. Kothari, C.R.: Research Methodology: Methods and Techniques. New Age International, India
(2004)
15. Kraemer, M.U., Yang, C.H., Gutierrez, B., Wu, C.H., Klein, B., Pigott, D.M., Brownstein,
J.S.: The effect of human mobility and control measures on the COVID-19 epidemic in China.
Science 368(6490), 493–497 (2020)
16. Lagarde, M., Palmer, N.: The impact of user fees on access to health services in low- and
middle-income countries. Cochrane Database Syst. Rev. (4), CD009094 (2011)
17. Lewnard, J.A., Lo, N.C.: Scientific and ethical basis for social-distancing interventions against
COVID-19. Lancet Infect. Dis 20(6), 631 (2020)
18. Mann, C.J.: Observational research methods. Research design II: cohort, cross sectional, and
case-control studies. Emerg. Med. J. 20(1), 54–60 (2003). https://doi.org/10.1136/emj.20.1.54
19. Marmot, M.: Social determinants of health inequalities. Lancet 365(9464), 1099–1104 (2005)
20. Massachusetts Institute of Technology: Corona analytics. Available at: https://www.covidanal
ytics.io/projections (2020). Accessed 9 Oct 2020
21. Noorbhai, H.: A mathematical model to guide the re-opening of economies during the COVID-
19 pandemic. Ann. Med. Surg. 57, 5–6 (2020)
22. Pan, A., Liu, L., Wang, C., Guo, H., Hao, X., Wang, Q., Wei, S.: Association of public health
interventions with the epidemiology of the COVID-19 outbreak in Wuhan, China. JAMA
323(19), 1915–1923 (2020)
23. Panovska-Griffiths, J.: Can mathematical modelling solve the current Covid-19 crisis? BMC
Public Health 20, 551 (2020)
24. Paules, C.I., Marston, H.D., Fauci, A.S.: Coronavirus infections—more than just the common
cold. JAMA 323(8), 707–708 (2020)
25. Popkova, E., DeLo, P., Sergi, B.S.: Corporate social responsibility amid social distancing during
the COVID-19 Crisis: BRICS versus OECD Countries. Res. Int. Bus. Finan. 55, 101315 (2020)
26. Pramanik, M., Udmale, P., Bisht, P., Chowdhury, K., Szabo, S., Pal, I.: Climatic factors influence
the spread of COVID-19 in Russia. Int. J. Environ. Health Res. 1–15 (2020)
27. Qiu, H., Tong, Z., Ma, P., Hu, M., Peng, Z., Wu, W., Du, B.: Intensive care during the coronavirus
epidemic. Intensive Care Med. 46, 576–578 (2020)
28. Roser, M., Ritchie, H., Ortiz-Ospina, E., Hasell, J.: Coronavirus pandemic (COVID-19). Our
World in Data.org. Available at: https://ourworldindata.org/coronavirus (2020). Accessed 9
Oct 2020
29. SA Coronavirus Online Portal: Increasing bed capacity in the midst of the COVID-19 peak.
Available at: https://sacoronavirus.co.za/2020/07/10/increasing-bedcapacity-in-the-midst-of-
the-covid-19-peak/; 10-Jul-2020. Accessed 8 Oct 2020
30. Smith, J.A., Judd, J.: COVID-19: Vulnerability and the power of privilege in a pandemic. Health
Promot. J. Austr. 31(2), 158 (2020)
31. Sohrabi, C., Alsafi, Z., O’Neill, N., Khan, M., Kerwan, A., Al-Jabir, A., Agha, R.: World Health
Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19).
Int. J. Surg. 76, 71–76 (2020)
32. South African Government: Regulations issued in terms of Section 27(2) of the Disaster
Management Act 2002. Government Gazette South Africa; 18-Mar-2020.
33. Stock, J.H.: Data gaps and the policy response to the novel coronavirus (No. w26902). National
Bureau of Economic Research (2020). https://doi.org/10.3386/w26902
34. Sugiura, L., Wiles, R., Pope, C.: Ethical challenges in online research: public/private
perceptions. Res. Ethics 13(3–4), 184–199 (2017). https://doi.org/10.1177/1747016116650720
35. Tanne, J.H., Hayasaki, E., Zastrow, M., Pulla, P., Smith, P., Rada, A.G.: Covid-19: how doctors
and healthcare systems are tackling coronavirus worldwide. BMJ 368 (2020)
36. Twigg, J.: What lies behind Russia’s Coronavirus containment effort. Kennan Institute. Avail-
able at: https://www.wilsoncenter.org/blog-post/what-lies-behind-russias-coronavirus-contai
nment-effort (2020). Accessed 8 Oct 2020
37. Van Bavel, J.J., Baicker, K., Boggio, P.S., Capraro, V., Cichocka, A., Cikara, M., Drury, J.:
Using social and behavioural science to support COVID-19 pandemic response. Nat. Human
Behav. 1–12 (2020)
38. World Health Organization: Coronavirus disease (COVID-19) situation report—113. May 12,
2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/
20200512-sitrep-113.pdf?sfvrsn=feac3b6d_2 (2020). Accessed 18 Oct 2020
39. World Health Organization: Coronavirus Disease 2019 (COVID-19): situation report—30.
February 20, 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situat
ion-reports/20200219-sitrep-30-covid-19.pdf?sfvrsn=6e50645_2 (2020). Accessed 8 Oct 2020
40. Zu, Z.Y., Jiang, M.D., Xu, P.P., Chen, W., Ni, Q.Q., Lu, G.M., Zhang, L.J.: Coronavirus disease
2019 (COVID-19): a perspective from China. Radiology 200490 (2020)
Epidemic Prediction and Analysis
of COVID-19: A Mathematical
Modelling Study
Khondoker Nazmoon Nabi
Abstract When several scientific expeditions are happening towards a safe and
effective COVID-19 vaccine development, fresh COVID-19 infections in numer-
ous countries are reaching unprecedented levels at breakneck speed. According to
the prudent experts, future waves of COVID-19 are going to be apparently more
dreadful than the initial ones as severity of infections are much higher than before.
After tedious and stringent confinement measures, public apathy and restrictions
fatigue have prompted people to act impetuously in the face of second wave of
infection. The main objective of this study is to quantify the impact of various non-
pharmaceutical interventions in order to battle against the pandemic more strategi-
cally. In this chapter, future projections of daily COVID-19 cases have been discussed
for Argentina, Bangladesh, Brazil and Colombia with the help of a compartmental
mathematical model of COVID-19 pandemic incorporating all possible real life inter-
actions and effective non-pharmaceutical interventions. Model calibration has been
performed exploiting an advanced optimisation algorithm based on well-known trust-
region-reflective algorithm. To quantify the transmissibility of COVID-19 infection,
respective control reproduction numbers (Rc ) for the above-mentioned countries are
also calculated. It has been found in our global sensitivity analysis that efficacious
face coverings with high coverage level could significantly reduce the spread of
coronavirus in the absence of a safe and effective vaccine. Timely implementation
of social-distancing measures and comprehensive use of efficacious face coverings
could significantly lessen the burden of the pandemic.
Keywords COVID-19 · Mathematical model · Forecasting · Non-pharmaceutical

intevention strategies · Sensitivity analysis
K. N. Nabi (B)
Department of Mathematics, Bangladesh University of Engineering and Technology (BUET),
Dhaka 1000, Bangladesh
e-mail: khnabi@math.buet.ac.bd
798 K. N. Nabi
1 Introduction
To date, as there is no world-wide accepted vaccine that can provide full immunity
to the human body against COVID-19, non-pharmaceutical intervention strategies
are the realistic and effective solutions to control second wave of the pandemic.
However, around 65 different coronavirus vaccines are experiencing critical clini-
cal trials on humans and twenty of those have already reached the final stages of
testing. Importantly, two leading vaccine candidates Pfizer-BioNTech and Oxford-
AstraZeneca have already been approved for full use and it is found in clinical trials
that they can trigger an immune response [5]. Generally, an effective vaccine would
take years, if not decades, to develop. As research in this field is happening at a break-
neck speed, scientists believe that an effective vaccine is likely to become widely
available by mid-2021. A false sense of security could evolve among general people
unless approved vaccines work effectively. Lack of transparency could be a vital
issue in future days regarding vaccine production and distribution.
Mathematical models can always provide considerable insights to the transmission
dynamics and complexities of any infectious diseases, which eventually help govern-
ment officials design overall epidemic planning. Importantly, mathematical analysis
always plays a notable role in making vital public health decisions, resource alloca-
tion and implementation of social distancing measures and other non-pharmaceutical
interventions. From the beginning of the COVID-19 outbreak, mathematicians and
researchers have been working relentlessly and have already done tremendous con-
tributions in limiting the spread of the coronavirus in different parts of the world
[4, 7, 10, 11, 15]. In an early contribution, Ferguson et al. [4] showed the impact
of different non-pharmaceutical intervention strategies on COVID-19 mortality by
developing an agent-based model. In another study, Ngonghala et al. [15] showed
that effective and comprehensive usage of face coverings can significantly limit the
spread of the virus and reduce the COVID-induced mortality in different states of the
US in general in the absence of community lockdown measures and stringent social
distancing practice. On the other hand, Nabi [10] projected the future dynamics of
COVID-19 for various COVID-19 hotspots by proposing a compartmental mathe-
matical model and concluded that early relaxation of lockdown measures and social
distancing could bring a second wave in no time. As a matter of reality, inhabitants
in several countries compelled to violate containment measures due to prolonged
lockdown measures and severe economic recession [11]. For instance, Netherlands,
having one of the best health care systems in the world, is grappling with continuous
spikes in daily cases due to aversion to masks.
Epidemic Prediction and Analysis of COVID-19 … 799
In this study, in the absence of a safe, effective and widely available COVID-19
vaccine, a compartmental mathematical model has been discussed incorporating all
possible non-pharmaceutical intervention strategies such as wearing face coverings,
social distancing, home or self-quarantine and self or institutional isolation. In addi-
tion, the impacts of different interventions have been analysed rigorously. The aim of
this work is to project the future dynamics of COVID-19 outbreak in four countries
namely Argentina, Bangladesh, Brazil and Colombia which are one of the worst-hit
countries in the world. Estimation of parameters has been performed by using real-
time data, followed by a projection of the evolution of the disease. Global sensitivity
analysis is applied to determine the influential mechanisms in the model that drive
the transmission dynamics of the disease.
The entire chapter is organized as follows. Materials and methods are presented
in Sect. 2. In Sect. 3, model calibration and forecasting results have been discussed
using daily confirmed COVID-19 cases data of Argentina, Bangladesh, Brazil and
Colombia. In addition, to quantify the impact of different non-pharmaceutical inter-
ventions, global sensitivity analysis of the proposed model has been performed. The
chapter ends with some insightful findings and strategies, which could control the
second wave of the pandemic successfully.
2.1 Mathematical Model Formulation
A compartmental mathematical has been discussed to describe the transmission

dynamics of the COVID-19 incorporating all possible real-life interactions [14].
The entire human population (denoted by N (t) at time t) has been categorized
into nine mutually-exclusive compartments considering different infection status.
The compartments are susceptible individuals (S(t)), early-exposed individuals
(E 1 (t)), pre-symptomatic individuals (E 2 (t)), symptomatically-infectious (I (t)),
asymptomatically-infectious or infectious individuals with mild-symptoms (A(t)),
quarantined infectious (Q(t)), hospitalised or isolated individuals (L(t)), recovered
individuals (R(t)), disease-induced death cases (D(t)). Hence,
N (t) = S(t) + E 1 (t) + E 2 (t) + I (t) + A(t) + Q(t) + L(t) + R(t) + D(t)
The flow diagram of the proposed model is illustrated in Fig. 1, where suscep-
tible individuals can become infected by an effective contact with individuals in
the pre-symptomatic (E 2 (t)), symptomatically-infectious (I (t)), asymptomatically-
infectious (A(t)), quarantined-infectious (Q(t)) and isolated-infectious (L(t)). Effec-
tive contact rates are λ E2 , λ I , λ A , λ Q , and λ L respectively and the expressions are
defined in (2). Importantly, the compartment E 1 (t) consists of early-infected individ-
uals who are still not infectious, whereas the individuals in pre-symptomatic cohort
E 2 (t) have the capability of transmitting coronavirus before the end of the dis-
800 K. N. Nabi
ease incubation period. A proportion of individuals in newly-exposed compartment

(E 1 (t)) progress to pre-symptomatic class (E 2 (t)) at a rate κ1 . After the completion
of disease mean incubation period, at a rate ρκ2 , a fraction of individuals who have
clear clinical symptoms of COVID-19 progress to I (t) compartment. Individuals in
E 2 (t) class who do not have any clear symptoms progress to A(t) class at a rate
(1 − ρ)κ2 . Pre-symptomatic individuals are assumed to be self-quarantined at a rate
q. With the help of diagnostic or surveillance testing approaches, symptomatically-
infectious individuals and asymptomatically-infectious individuals are brought under
institutional or home isolation at rates τ I and τ A respectively. Moreover, the parameter
γ I (γ A )(γ Q )(γ L ) represents the recovery rate for individuals in the I (A)(Q)(L) class.
Finally, the disease-induced mortality rate for individuals in the I (Q)(L) compart-
ment is defined by the parameter δ I (δ Q )(δ L ). Considering all the above-mentioned
interactions, the transmission dynamics of COVID-19 can be described by the fol-
lowing system of nonlinear ordinary differential equations.
Fig. 1 Flow diagram of the COVID-19 transmission dynamics

⎧
⎪ dS
⎪
⎪ = − λ I + λ A + λ Q + λ L + λ E2 S,
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪ d E1
⎪
⎪ = λ I + λ A + λ Q + λ L + λ E 2 S − κ1 E 1 ,
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪
⎪
⎪ d E2
⎪
⎪ = κ1 E 1 − (κ2 + q) E 2 ,
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪ dI
⎪
⎪ = ρκ2 E 2 − (τ I + γ I + δ I ) I,
⎪
⎪
⎪
⎪ dt
⎪
⎪
⎨
dA
= (1 − ρ)κ2 E 2 − (τ A + γ A ) A, (1)
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪ dQ
⎪
⎪ = q E 2 − γ Q + δ Q Q,
⎪
⎪
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪ dL
⎪
⎪ = τ I I + τ A A − (δ L + γ L ) L ,
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎪ dR
⎪
⎪ = γI I + γ A A + γQ Q + γL L ,
⎪
⎪
⎪
⎪ dt
⎪
⎪
⎪
⎪
⎪
⎩ dD = δ I I + δ L L + δ Q Q.
dt
where the forces of infection are defined below
⎧
⎪ E2
⎪
⎪ λ E2 = β E2 (1 − mζ ) ,
⎪
⎪ N
⎪
⎪
⎪
⎪
⎪
⎪ I
⎪
⎪ λ I = β I (1 − mζ ) ,
⎪
⎪
⎪
⎪ N
⎪
⎪
⎨
A
λ A = β A (1 − mζ ) , (2)
⎪
⎪ N
⎪
⎪
⎪
⎪
⎪
⎪ Q
⎪
⎪ λ Q = β Q (1 − mζ ) ,
⎪
⎪
⎪
⎪ N
⎪
⎪
⎪
⎪
⎪
⎩ λ L = β L (1 − mζ ) L ,
N
The parameters are described in Table 1.
We set x = (S, E 1 , E 2 , I, A, Q, L , R, D) the vector of state variable, Let f :
R → R9 the the right hand side of system (1), which is a continuously differentiable
9
function on R9 . According to [20, Theorem III.10.VI], for any initial condition in
, a unique solution of (1) exists, at least locally, and remains in

for its maximal
802 K. N. Nabi

Parameter Description
β I (β A ) (β Q ) (β L ) (β E 2 ) Effective contact rate
m Proportion of individuals who use face
coverings or surgical masks
ζ Efficacy of face coverings at reducing outward
transmission by infected individuals as well as
preventing acquisition
κ1 Rate of progression from early-exposed class
(E 1 (t)) to pre-symptomatic class (E 2 (t))
ρκ2 Rate of progression from pre-symptomatic
class (E 2 (t)) to symptomatically-infectious
class (I (t))
(1 − ρ)κ2 Rate of progression from pre-symptomatic
class (E 2 (t)) to asymptomatically-infectious
class (A(t))
q Confinement efficacy
τI Rate of self or institutional isolation for
symptomatically-infectious patients
τA Rate of isolation for
asymptomatically-infectious patients
γI Recovery rate for symptomatically-infectious
patients
γA Recovery rate for asymptomatically-infectious
individuals
γQ Recovery rate for quarantined-infectious
individuals
γL Recovery rate for isolated or hospitalised
individuals
δI Disease-induced death rate for
symptomatically-infectious individuals
δL Disease-induced death rate for isolated
individuals
δQ Disease-induced death rate for
quarantined-infectious individuals
interval of existence [20, Theorem III.10.XVI]. Hence, model (1) is biologically

well-defined. The positivity, boundedness of model solutions and global dynamics
of disease free equilibrium can be found in [14].
2.2 Data Sources
Center of Disease Control and Prevention (CDC) and the COVID Tracking Project
(testing and hospitalizations) are providing authoritative and genuine data for the
daily confirmed COVID-19 cases from the beginning of the outbreak. We have
collected daily confirmed data of four different countries named Argentina, Bangladesh,
Brazil and Colombia using that data repository. Johns Hopkins University Center for
Systems Science and Engineering (JHU CSSE) is maintaining the data repository
which is supported by ESRI Living Atlas Team and the Johns Hopkins University
Applied Physics Lab (JHU APL). The repository is really convenient to compile and
has been made publicly available [2].
In the next section, calibration of model parameters using observed historical
data has been discussed. Based on these estimated parameters, robust forecasting
technique is exploited to project the future dynamics of COVID-19 in Argentina,
Bangladesh, Brazil and Colombia.
3 Model Calibration and Forecasting
The model (1) calibration has been performed using a newly developed optimization
algorithm based on trust-region-reflective (TRR) algorithm, which can be regarded
as an evolution of Levenberg-Marquardt algorithm [10]. This robust optimization
procedure can be used effectively for solving nonlinear least-squares problems. This
algorithm has been implemented using the lsqcurvefit function, which is available
in the Optimization Toolbox in MATLAB. Necessary model parameters have been
estimated using this optimization technique. Daily infected cases data have been
collected from a trusted data repository, which is available online. A 7-day moving
average of the daily reported cases has been used for our model calibration due to
moderate volatile nature of real data. It has been observed that the numbers of daily
testing in Argentina, Bangladesh, Brazil and Colombia have been really inconsistent.
With an aim to capture the real outbreak scenario, the 7-day moving average has been
used in this regard.
3.1 Argentina
Argentina, a country of South America, is one of the worst-hit countries in the

world having the 12th highest tally of confirmed coronavirus cases (1,730,921 cases)
worldwide as of January 12, 2021. When the pandemic first emerged, Argentina
was one of the first countries to deploy strict lockdown, quarantine and isolation
measures to curb the spread of the novel coronavirus in the community. After seven
months of lockdown inhabitants started violating staying at home and quarantine
804 K. N. Nabi
orders due to devastating economic crisis. The model fitting performance for daily
confirmed COVID-19 cases and cumulative cases have been depicted in Figs. 2 and
3. In addition, projection results for daily and cumulative cases in Argentina from
mid January 2021 to late March 2021 have been presented in Figs. 4 and 5. Daily
observed data from March 4, 2020 to January 12, 2021 have been used to calibrate
the model parameters illustrated in Table 2.
Projection results from the proposed model illustrate the fact that model results
really complement the real-time data. Projection results from Fig. 4 illustrate that the
number of confirmed symptomatically-infectious cases in Argentina could decline
in near future, as a strong downward trend is projected in our analysis. The control
reproduction number (Rc ) is estimated to be ∼1.2 (95% C I : 1.07–1.4) as of January
12, 2021 and prior established findings really complement this estimation [9, 10].
The tally of cumulative infected cases is projected to reach 2130K by the end of
March 2021 and the estimated total death cases could reach to 52.6K in the same
period. Table 2 illustrates model calibration results and baseline parameter values.
3.2 Bangladesh
With an aim to quell the spread of the novel coronavirus, a nationwide lockdown
effective from March 26, 2020 was deployed by the government officials. The model
fitting results from early March 2020 to mid January 2021 for Bangladesh, have been
shown in Figs. 6 and 7. As time progresses, the estimated error declines and is hover-
ing around 10% for the cumulative cases and daily new cases according to our calcu-
lated daily projected mean error. The estimated case-fatality rate in Bangladesh is at
Fig. 2 Fitting performance of the model for daily infected cases in Argentina from March 04, 2020
to January 12, 2021
Table 2 Calibrated parameters of the proposed model (1) using trust-region-reflective algorithm and daily COVID-19 cases data of Argentina
Parameter Range (Unit) Baseline value TRR output References
βI 0.1–1.5 day−1 0.55 0.3 [8, 10]
βA 0.1–0.9 day−1 0.3 0.15 [8, 10]
βQ 0.1–0.9 day−1 0.5 0.3 [8, 10]
βL 0.1–0.9 day−1 0.3 0.35 [10, 15]
β E2 0.05–0.3 day−1 0.3 0.1 [15]
m 0.01–0.3 (dimensionless) 0.1 0.15 [15]
ζ 0.5 (dimensionless) 0.5 0.5 [15]
1 1 1
κ1 day−1 [7, 15]
4 4 4
κ2 1 day−1 1 1 [7]
q 0.1–0.6 day−1 0.3 0.25 Estimated
ρ 0.6–0.7 (dimensionless) 0.65 0.65 [15]
Epidemic Prediction and Analysis of COVID-19 …
1 1
τI − day−1 1/10 1/10 [10, 15]
14 5
1 1
τA − day−1 1/10 1/10 [10, 15]
14 5
1 1
γI − day−1 1/7 0.143 [17, 22]
14 7
1 1
γA − day−1 1/7 0.143 [17, 22]
10 7
1 1
γQ − day−1 1/14 0.071 [17, 22]
21 10
1 1
γL − day−1 1/14 0.071 [17, 22]
21 10
δI 0.0001–0.01 day−1 0.001 0.00033 [4, 10]
δL 0.0001–0.01 day−1 0.001 0.001 [4, 10]
δQ 0.0001–0.01 day−1 0.001 0.00033 [4, 10]
805
806 K. N. Nabi
Fig. 3 Fitting performance of the model for cumulative infected cases in Argentina from March
04, 2020 to January 12, 2021
Fig. 4 Daily new reported cases calibrated and projected for Argentina from early March to late
March 2021
1.49% which is kind of satisfactory. Importantly, without an aggressive level mass-

testing program, it is impossible to portray the real outbreak scenario in Bangladesh.
It is clearly visible from Figs. 6 and 7 that the model fitting performance is really
well. Projection results from Figs. 8 and and 9 illustrate that the number of confirmed
symptomatically-infectious cases in Bangladesh could maintain a strong downward
trend in near future. The control reproduction number (Rc ) is estimated to be ∼0.85
(95% C I : 0.67–1.1) as of January 12, 2021. The tally of cumulative infected cases
is projected to reach 582.8K by the end of March 2021 and the estimated total death
cases could reach 9100 in the same period. However, in the absence of strict non-
Fig. 5 Cumulative infected cases fitted and projected for Argentina early March to late March 2021
Fig. 6 Fitting performance of the model for daily infected cases in Bangladesh from March 08,
2020 to January 12, 2021
pharmaceutical intervention strategies, this numbers could blow up in near future.

Table 3 illustrates model calibration results and baseline parameter values.
3.3 Brazil
The coronavirus disease 2019 (COVID-19) pandemic headed toward Latin America
later than other continents. On Feb 25, 2020, the first infected case was documented.
But now, Brazil has surpassed the records in Latin America in terms of deaths and
808 K. N. Nabi
Fig. 7 Fitting performance of the model for cumulative infected cases in Bangladesh from March
08, 2020 to January 12, 2021
Fig. 8 Daily new reported cases calibrated and projected for Bangladesh from early March 2020
to late March 2021
new infected cases (8,146,823 cases and 203,735 deaths as of January 12, 2021).
The model fitting and projection results for Brazil from late February 2020 to mid
January are shown in Figs. 10, 11, 12 and 13. We took daily observed data from
February 25 to January 12, 2020 to calibrate the model parameters. As we can see,
the results from the proposed model fit the historical data very well. The control
reproduction number is estimated about ∼1.4 (95% C I : 1.3–1.63) as of January 12,
2021 which matches well with prior estimations [9, 10]. According to the projection
results from Fig. 13, the number of cumulative infected cases is projected to reach
11538.6K by the end of March 2021 if current trend is held, and the estimated total
Fig. 9 Cumulative infected cases fitted and projected for Bangladesh early March 2020 to late
March 2021
Fig. 10 Fitting performance of the model for daily infected cases in Brazil from February 25, 2020
to January 12, 2021
death cases could mount upto 273.8K in this time period. Table 4 illustrates the key
features used to calibrate this scenario following prior clinical studies and relevant
literature.
810 K. N. Nabi
Table 3 Calibrated parameters of the proposed model (1) using trust-region-reflective algorithm
and daily COVID-19 cases data of Bangladesh
βI 0.1–1.5 day−1 0.55 0.15 [8, 10]
βA 0.1–0.9 day−1 0.3 0.1 [8, 10]
βQ 0.1–0.9 day−1 0.5 0.1 [8, 10]
βL 0.1–0.9 day−1 0.3 0.12 [10, 15]
β E2 0.05–0.3 day−1 0.3 0.11 [15]
m 0.01–0.3 0.1 0.3 [15]
(dimensionless)
ζ 0.5 (dimensionless) 0.5 0.5 [15]
1 1 1
κ1 day−1 [7, 15]
4 4 4
κ2 1 day−1 1 1 [7]
q 0.1–0.6 day−1 0.3 0.47 Estimated
ρ 0.6–0.7 (dimensionless) 0.65 0.65 [15]
1 1
τI − day−1 1/10 1/8 [10, 15]
14 5
1 1
τA − day−1 1/10 1/8 [10, 15]
14 5
1 1
γI − day−1 1/7 1/12 [17, 22]
14 7
1 1
γA − day−1 1/7 1/10 [17, 22]
10 7
1 1
γQ − day−1 1/21 0.071 [17, 22]
21 10
1 1
γL − day−1 1/21 0.071 [17, 22]
21 10
δI 0.0001–0.01 day−1 0.001 0.0004 [4, 10]
δL 0.0001–0.01 day−1 0.001 0.0009 [4, 10]
δQ 0.0001–0.01 day−1 0.001 0.0007 [4, 10]
3.4 Colombia
With an aim to quell the spread of COVID-19, the Colombian government has
extended the selective quarantine phase until the end of October. As of January
12, the number of COVID-19 infections mounted to 1,801,903 cases and the coun-
try’s death toll climbed to 46,451. Our model fitting performance is quite outstanding
depicted in Figs. 14 and 15. According to our projection results illustrated in Figs. 16
and 17, the tally of cumulative cases could reach approximately 2927.8K cases by
the end of March 2021. The control reproduction number (Rc ) is estimated to be
∼1.69 (95% C I : 1.45–1.85) as of January 12, 2021. According to our analysis, the
spread of COVID-19 could be worsened by in coming days. The situation could be
Fig. 11 Fitting performance of the model for cumulative infected cases in Brazil from February
25, 2020 to January 12, 2021
Fig. 12 Daily new reported cases calibrated and projected for Brazil from early March 2020 to late
March 2021
brought under control by following strict distance maintaining protocol and mass-
level usage of efficacious face coverings on a daily basis. Table 5 illustrates the key
features used for the model calibration and projection following established clinical
findings.
812 K. N. Nabi
Fig. 13 Cumulative infected cases fitted and projected for Brazil early March 2020 to late March
2021
Fig. 14 Fitting performance of the model for daily infected cases in Colombia from March 06,
2020 to January 12, 2021
4 Global Sensitivity Analysis
With an aim to quantify the most dominant mechanisms in the proposed model, a
renowned global sensitivity analysis approach Partial Rank Correlation Coefficient
(PRCC) method has been carried out. This method can provide considerable insights
about the relationship between model responses (state variables) and model param-
eters (sampled by Latin Hypercube Sampling method) in an outbreak setting [12].
PRCC values are generally bounded between −1 and 1. The PRCC method assumes
a monotonic relationship between the model input parameters and the model out-
and daily COVID-19 cases data of Brazil
βI 0.1–1.5 day−1 0.55 0.15 [8, 10]
βA 0.1–0.9 day−1 0.3 0.1 [8, 10]
βQ 0.1–0.9 day−1 0.5 0.21 [8, 10]
βL 0.1–0.9 day−1 0.3 0.23 [10, 15]
β E2 0.05–0.3 day−1 0.3 0.1 [15]
m 0.01–0.3 0.1 0.1 [15]
(dimensionless)
ζ 0.5 0.5 0.5 [15]
(dimensionless)
1 1 1
κ1 day−1 [7, 15]
4 4 4
κ2 1 day −1 1 1 [7]
q 0.1–0.6 day −1 0.3 0.2 Estimated
ρ 0.6–0.7 0.65 0.65 [15]
(dimensionless)
1 1
τI − day−1 1/10 1/12 [10, 15]
14 5
1 1
τA − day−1 1/10 1/12 [10, 15]
14 5
1 1
γI − day−1 1/10 0.143 [17, 22]
14 7
1 1
γA − day−1 1/10 0.143 [17, 22]
10 7
1 1
γQ − day−1 1/17 0.071 [17, 22]
21 10
1 1
γL − day−1 1/18 0.071 [17, 22]
21 10
δI 0.0001–0.01 0.001 0.004 [4, 10]
day−1
δL 0.0001–0.01 0.001 0.0099 [4, 10]
day−1
δQ 0.0001–0.01 0.001 0.007 [4, 10]
day−1
puts. Quantitative relationship between model inputs and model responses can be
determined by calculating the PRCC values. Intuitively, a positive PRCC value can
be described as a positive correlation between model input parameters and model
outputs, whereas a negative PRCC value indicates a negative correlation between the
model input and model response.
When it comes to analyse a complex model, it often get really challenging to
control the parameters. In this context, sensitivity analysis can give considerable
814 K. N. Nabi
Fig. 15 Fitting performance of the model for cumulative infected cases in Colombia from March
06, 2020 to January 12, 2021
Fig. 16 Daily new reported cases calibrated and projected for Colombia from early March 2020
to late March 2021
insights regarding the quantitative relationship between model responses and model
input parameters. However, it is really challenging for complex models to determine
the relationship with sufficient accuracy. As we can see from Fig. 18, nearly the
same qualitative relationship has been found between the number of symptomatic
infectious individuals (one of the crucial model responses) and three parameters
which are effective contact rate with isolated infected individuals (β L ), efficacy of
face coverings (ζ ) and face coverings compliance for our studied four countries.
The public health implications of these findings are the dynamics of COVID-19
could be controlled by encouraging mass-level usage of efficacious face coverings.
Fig. 17 Cumulative infected cases fitted and projected for Colombia early March 2020 to late
March 2021
In addition, the high significance of β L indicates that immediate isolation of detected

patients is highly required.
In the next section, based on the forecasting and sensitivity results, some consid-
erable insights have been reported which would help policy makers develop strategic
planning to battle against COVID-19 in near future.
5 Conclusions
Different mathematical modeling paradigms always play significant role in provid-

ing considerable insights and scientific evidences on future dynamics of an ongoing
epidemic and designing potential control strategies. Since the outbreak of COVID-19
in China, researchers are relentlessly working on developing several mathematical
modeling approaches to understand the progression dynamics of COVID-19 in the
world. Various effective public health interventions can be deployed on the basis
of forecasting results of reliable epidemiological models. In this chapter, a com-
partmental mathematical has been designed to describe the transmission dynamics
of the COVID-19 incorporating all possible real-life interactions and effective non-
pharmaceutical interventions. In addition, advanced forecasting techniques have also
been applied for Argentina, Bangladesh, Brazil and Colombia to portray the future
dynamics of the pandemic. It has been enlightened in our study that mass-level using
of highly effective face coverings could be a crucial factor in controlling imminent
future waves of COVID-19. Moreover, strict social-distancing measures and compre-
hensive contact-tracing are also effective strategies in battling against this pandemic.
The public health implication of these insightful findings is government officials can
816 K. N. Nabi
and daily COVID-19 cases data of Colombia
βI 0.1–1.5 day−1 0.55 0.11 [8, 10]
βA 0.1–0.9 day−1 0.3 0.1 [8, 10]
βQ 0.1–0.9 day−1 0.5 0.1 [8, 10]
βL 0.1–0.9 day−1 0.3 0.12 [10, 15]
β E2 0.05–0.3 day−1 0.3 0.11 [15]
m 0.01–0.3 0.1 0.3 [15]
(dimensionless)
ζ 0.5 0.5 0.5 [15]
(dimensionless)
1 1 1
κ1 day−1 [7, 15]
4 4 4
κ2 1 day−1 1 1 [7]
q 0.1–0.6 day−1 0.3 0.1 Estimated
ρ 0.6–0.7 0.65 0.65 [15]
(dimensionless)
1 1
τI − day−1 1/10 1/9 [10, 15]
14 5
1 1
τA − day−1 1/10 1/11 [10, 15]
14 5
1 1
γI − day−1 1/7 1/12 [17, 22]
14 7
1 1
γA − day−1 1/7 1/10 [17, 22]
10 7
1 1
γQ − day−1 1/14 1/20 [17, 22]
21 10
1 1
γL − day−1 1/14 1/21 [17, 22]
21 10
δI 0.0001–0.01 0.001 0.0002 [4, 10]
day−1
δL 0.0001–0.01 0.001 0.00058 [4, 10]
day−1
δQ 0.0001–0.01 0.001 0.0005 [4, 10]
day−1
undertake crucial clinical and public health decisions by analyzing all mathematical
results and scientific evidences.
Fig. 18 Sensitivity of the symptomatically-infectious cases while changing parameters in the pro-
posed model as indicated by the PRCC index for four different countries
818 K. N. Nabi
Fig. 18 (continued)
References
1. Asadi, S., Cappa, C.D., Barreda, S. et al. Efficacy of masks and face coverings in controlling
outward aerosol particle emission from expiratory activities. Sci Rep, 10, 15665 (2020)
2. Center for Systems Science and Engineering at Johns Hopkins University. COVID-19 Github
Repository. https://github.com/CSSEGISandData/COVID-19. Last accessed 19 Oct. 2020
3. Diekmann, O., Heesterbeek, J.A.P., Metz, J.A.J.: On the definition and the computation of the
basic reproduction ratio R0 in models for infectious diseases in heterogeneous populations. J.
Math. Biol. 28(4), 365–382 (1990)
4. Ferguson, N., Laydon, D., Nedjati Gilani, G., Imai, N., Ainslie, K., Baguelin, M., Dighe, A.:
Report 9: impact of non-pharmaceutical interventions (NPIs) to reduce COVID19 mortality
and healthcare demand (2020)
5. Folegatti, P.M., Ewer, K.J., Aley, P.K., Angus, B., Becker, S., et al.: Safety and immunogenicity
of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2,
single-blind, randomised controlled trial. The Lancet 396(10249), 447–512 (2020)
6. Kirkilionis, M., Walcher S.: On comparison systems for ordinary differential equations. J.
Math. Anal. Appl, 299 (1), 157–173 (2004)
7. Kucharski et. al.: Effectiveness of isolation, testing, contact tracing, and physical distancing on
reducing transmission of SARS-CoV-2 in different settings: a mathematical modelling study.
Lancet Infect. Dis. 20(10), 1151–1160 (2020)
8. Li, R., Pei, S., Chen, B., Song, Y., Zhang, T., Yang, W., & Shaman, J.: Substantial undocumented
infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science, 368
(6490), 489–493 (2020)
9. Liu, Y., Gayle, A.A., Smith, A.W., Rocklöv, J.: The reproductive number of COVID-19 is
higher compared to SARS coronavirus. J. Travel Med. 27 (2), taaa021 (2020)
10. Nabi, K.N.: Forecasting COVID-19 pandemic: a data-driven analysis. Chaos, Soliton Fractals
139 (2020)
11. Nabi, K.N., Abboubakar, H., Kumar, P.: Forecasting of COVID-19 pandemic: from integer
derivatives to fractional derivatives. Chaos Solitons Fractals 141 (2020)
12. Nabi, K.N. & Podder, C.N.: Sensitivity analysis of chronic hepatitis C virus infection with
immune response and cell proliferation. Int. J. Biomath., 13, 2050017 (2020)
13. Nabi, K.N., Tahmid, M.T., Rafi, A., Kader, M.E., Haider, M.A.: Forecasting COVID-19 cases:
a comparative analysis between recurrent and convolutional neural networks. Results Phys.
24, 104137 (2021)
14. Nabi, K.N., Kumar, P., Erturk, V.S.: Projections and fractional dynamics of COVID-19 with
optimal control strategies, Chaos, Solitons Fractals 145 (2021)
A.B.: Mathematical assessment of the impact of non-pharmaceutical interventions on curtail-
ing the 2019 novel Coronavirus. Math. Biosci. 325 (2020)
16. Rothe, C., Schunk, M., Sothmann, P., et al.: Transmission of 2019-nCoV infection from an
asymptomatic contact in Germany. N. Engl. J. Med. 382 (2020)
17. Tang, B., Bragazzi, N.L., Li, Q., Tang, S., Xiao, Y., Wu, J.: An updated estimation of the risk of
transmission of the novel coronavirus (2019-nCoV). Infectious Disease Modelling 5, 248–255
(2020)
18. Tillett, R.L., et al.: Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet
Infect. Dis. (2020)
19. Van Den Driessche, P., Watmough, J.: Reproduction numbers and sub-threshold endemic
equilibria for compartmental models of disease transmission. Math. Biosci. 180(1–2), 29–48
(2002)
20. Walter, W.: Ordinary Differential Equations. Springer (1998)
21. Wölfel, R., Corman, V.M., Guggemos, W., et al.: Virological assessment of hospitalized
patients with COVID-2019. Nature 581, 465–469 (2020)
22. Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Guan, L.: Clinical course and risk factors for
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
The Lancet 395(10229), 1054–1062 (2020)
Ensemble Learning Models Coupled
with Urban Mobility Information
Applied to Predict COVID-19 Incidence
Cases
Matheus Henrique Dal Molin Ribeiro, Ramon Gomes da Silva,

José Henrique Kleinübing Larcher, Viviana Cocco Mariani,
and Leandro dos Santos Coelho
Abstract The coronavirus disease (COVID-19), according to the World Health
Organization, by July 15th, 2021, has infected more than 188 million people, and
more than 4 millions have died from it in the worldwide. It is important to forecast the
incidence of cases in a short-term horizon to help the public health system develop
strategic planning to deal with the COVID-19. In this chapter, several artificial intelli-
gence (AI) models including extreme gradient boosting, extreme learning machine,
long short-term memory, and support vector regression are used stand-alone, and
coupled with the ensemble empirical mode decomposition (EEMD) employed to
decompose the time-series into intrinsic mode functions and residual signals. All AI
techniques are evaluated in the task of forecasting daily incidence COVID-19 cases in
ten Brazilian states, with a high number of cases by September 4th, 2020, with seven
and fourteen-days-ahead. Previous COVID-19 incidence cases and urban mobility
M. H. D. M. Ribeiro · R. G. da Silva (B) · L. S. Coelho

Industrial and Systems Engineering Graduate Program (PPGEPS), Pontifical Catholic University
of Parana (PUCPR), 1155 Rua Imaculada Conceicao, Curitiba, Brazil
e-mail: gomes.ramon@pucpr.edu.br
M. H. D. M. Ribeiro
e-mail: mribeiro@utfpr.edu.br
L. S. Coelho
e-mail: leandro.coelho@pucpr.br
M. H. D. M. Ribeiro
Department of Mathematics, Federal Technological University of Parana (UTFPR), Via do
Conhecimento, KM 01 - Fraron, Pato Branco, Brazil
J. H. K. Larcher · V. C. Mariani
Mechanical Engineering Graduate Program (PPGEM), Pontifical Catholic University of Parana
(PUCPR), 1155 Rua Imaculada Conceicao, Curitiba, Brazil
e-mail: jose.kleinubing@pucpr.edu.br
V. C. Mariani
e-mail: viviana.mariani@pucpr.br
V. C. Mariani · L. S. Coelho
Department of Electrical Engineering, Federal University of Parana (UFPR), 100 Avenida
Coronel Francisco Heraclito dos Santos, Curitiba, Brazil
822 M. H. D. M. Ribeiro et al.
information were employed as systems input for all forecasting models. The models’
effectiveness are evaluated based on the performance criteria. In general, the EEMD
approach outperformed the compared models regarding the accuracy in 65% of the
cases. Regarding the exogenous variables, urban mobility information indeed plays a
key role in the forecasting task. Therefore, due to the efficiency of evaluated models
to forecasting cumulative COVID-19 cases up to fourteen-days-ahead, the adopted
models can be recommended as promising for forecasting and can be used to assist
in development of public policies to mitigate the effects of COVID-19 outbreak.
1 Introduction
By the end of 2019 a new coronavirus was identified in Wuhan, the capital of Hubei
located in Central China, currently named SARS-CoV-2 (Severe Acute Respira-
tory Syndrome CoronaVirus 2), causing the coronavirus disease 2019, as known as
COVID-19, a respiratory syndrome that has the potential to be deadly. According
to [1], up to July 15th, 2021, more than 188 millions of people have been infected
worldwide, and more than 4 millions have died. In Brazil, the first case of COVID-19
was registered on February 26th, 2020, and as of September 4th, 2020, more than
4 million cases have been confirmed, with more than 125 thousand deaths. Since
the first cases of the outbreak, COVID-19 has caused a public health crisis in many
countries [1]. The rapid spread of the virus became a problem to Brazil’s public
health system, causing overcrowding of beds and a lack of medical supplies to treat
patients more severely affected by the disease [2].
Global measures have been taken by governments to delay the spread and mitigate
the public health problems of this pandemic. Lifestyle changes have been adopted by
many people in attempt to prevent further spread of the virus. Likewise, the scientific
community has been contributing in many fields, from Biology and Health Sciences
[3–8] to Mathematical Modeling and Computer Science, as shown further in this
work.
Furthermore, epidemiological time series forecasting plays an important role in
the health public system, once it allows the managers to develop strategic planning to
avoid possible epidemics. Forecasting diseases as accurate as possible is important
due to their impact on the public health system [9]. Considering the importance
of knowing the difficult epidemiological scenario for COVID-19 on a short-term
horizon, to mitigate the effects of this pandemic, the development of efficient and
effective forecasting models also has a positive impact on product reasonably accurate
success rates forecasts the immediate future [10].
Regarding this context, the objective of this chapter is to explore and compare
the predictive capacity of extreme learning machine (ELM), long short-term memory
(LSTM), support vector regression (SVR), and extreme gradient boosting (XGBoost)
models when are used stand-alone, and an ensemble learning framework composed
by ensemble empirical mode decomposition (EEMD) coupled with previously men-
tioned models to forecast the daily incidence of COVID-19 cases for seven and four-
Ensemble Learning Models Coupled with Urban Mobility … 823
teen days ahead. Also, the Autoregressive Integrated Moving Average (ARIMA)
model is used to the comparison. In proposed framework, the EEMD decomposes
the time series in basis functions, also called intrinsic mode functions (IMF). Each
IMF is trained by models and integrated to forecast COVID-19 incidence cases. The
forecasting structure and models used in this chapter are chosen because ensem-
ble learning methods play a key role in the time series forecasting as observed in
several areas such as price forecasting [11–13], electrical power systems [14], and
wind power forecasting [15, 16]. Data for ten most affected states in Brazil, from
the first officially recorded case until September 4th is collected, in conjunction with
Google Mobility Reports [17] for these states, to form the dataset. Data were divided
and used to train and test the models. The out-of-sample error metrics are computed
using mean absolute error (MAE), and root mean square error (RMSE) to evaluate
the forecasting models’ performance and compare them.
The main contributions of this chapter can be summarized as follows:
• The first contribution is related to the proposal of two frameworks, non-decomposed
and decomposed models, applied in the task of forecasting the daily incidence
cases of COVID-19 in ten most affected Brazilian states. It is expected that these
evaluated models can be used as the most accurate approaches to perform decision-
making by the health system to avoid overcrowding in hospitals, and preventing
new deaths.
• As the second contribution, we can highlight the use of diverse AI approaches
regarding their learning structure, as well as the use of EEMD pre-processing to
forecasting new cases of COVID-19 from Brazil.
• Last, this study evaluates the AI models in a multi-day-ahead forecasting strategy,
seven and fourteen days ahead. Further, urban mobility information is employed
as inputs of the system. These inputs, plus the previous COVID-19 daily cases,
coupled with the multi-day-ahead strategy, allow us to verify the effectiveness of
the predicting models in different scenarios.
The remainder of this chapter is structured as follows: Sect. 2 presents other works
that have contributed to research employing AI and forecasting models applied to
COVID-19 related data. Section 3.1 describes the dataset used in details. Section 3.2
reports the AI models applied in the forecasting procedure. Section 4 presents the
proposed framework. The results and findings of this study are depicted in Sect. 5.
Finally, Sect. 6 concludes the paper and presents future research directions.
2 Related Works
Several studies have contributed to research related to COVID-19 forecasting and

other applications. This section highlights some of these related works, their approach
and their main results.
Some efforts have been made using chest radiograph images to detect COVID-19
presence. Brunese et al. [18], which employed transfer learning of deep convolu-
tional neural networks, achieved an accuracy of 0.97 with a detection time of 2.5 s.
Hassantabar et al. [19] used three different deep learning architectures. The best
approach in that study was a deep convolutional neural network, that achieved 93.2%
accuracy and 96.1% sensitivity. In [20] a deep convolutional neural network model
was utilized as a deep feature extractor, feeding k-nearest neighbor (KNN), support
vector machine, and decision tree classifiers, with hyper-parameters of the machine
learning models optimized via Bayesian optimization. Toraman et al. [21] utilized
a convolutional capsule network which achieved an accuracy of 97.24% for binary
classification and 84.22% accuracy for multi-class classification. Ucar and Kork-
maz [22] presented a 98.3% overall accuracy, and 100% accuracy for COVID-19
class, using a Deep Bayes-SqueezeNet with offline data augmentation. Minaee et al.
[23] utilizes a dataset of around 5000 chest radiograph images to train four state-of-
the-art convolutional networks for COVID-19 detection, ache to achieve sensitivity
and specificity rates higher than 90% with higher confidence interval. Abraham and
Nair [24] uses multi-CNN for feature selection and Bayesnet classifier to detect
COVID-19 presence, achieving 97.44% accuracy on unseen data. Most efforts made
in this domain concern the use of AI to classify radiograph images, leaving a not
so explored area of data segmentation to find features in images that indicate the
presence of COVID-19 (as in [19]), this way the results could be used to help the
initial diagnosis by physicians, not only classification via computer vision.
Other works use models to estimate epidemiological parameters and, in some
cases, subsequently, forecast COVID-19 cases. Anastassopoulou et al. [25] used
early data of the outbreak in Hubei (China) to estimate epidemiological parameters
of a Susceptible-Infected-Recovered-Dead (SIRD) model and forecast incidence, for
this model the number of confirmed cases, deaths and recovered in Hubei were within
the lower bounds of the model for the next 19 days of out-of-sample data. Cooper et
al. [26] applied a modified community-based Susceptible-Infected-Recovered (SIR)
model, estimating its parameters, showing that the use of proper policies can control
the infection rates. Lalwani et al. [27] utilizes a three-phase SIRD model and predicts
the optimal lockdown period, for example, 73 days for China, 69 days for India and
88 days for Italy. In [28] a SIR model were estimated and used to forecast future cases
for the United States of America, Canada, Italy, France, Germany, Sweden, Russia,
Brazil, Bulgaria, Japan, South Korea and New Zealand, with variable results for
each country. de Oliveira et al. [29] used a Bayesian estimation with beta regression
model to estimate incidence rate/100,000, mortality rate by cause/100,000 and case-
fatality rate/100 for different regions (Asia, Middle East, Central America, Central
Asia, Caribbean, East Asia, Europe, North Africa, North America, Oceania, South
America, and Sub Saharan Africa). Postnikov [30] showed that the simplest SIR
model can adequately reproduce the dynamics of COVID-19 pandemic and be used
to evaluate measures applied to reduce the virus spread, using data for Italy, Spain,
Germany, France, Russia, USA (United States of America), and South Korea. Neves
and Guerrero [31] proposed fitting a SIR model to Lombardy region (Italy) and Sao
Paulo state (Brazil) using only the number of deaths, to overcome the problem of not
knowing the number of individuals with no symptoms, showing good fits, but big
differences in unseen data, probably due to social distance measures and the uncer-
tainty of the probability of an individual being symptomatic. A common difficulty in

fitting compartment models to real-world data is the number of asymptomatic cases.
As pointed out by Neves and Guerrero [31], there is some confidence in the number
of deceased, but the number of cases confirmed tends to be a lot less than the total
cases, as well as a significant part can be asymptomatic, with publications indicating
from 30.8% [32] to 56.1% [33], which can sometimes lead to misleading parameters
on fitting those models.
The last group of contributions reviewed here is related to the use of AI and
statistical methods to forecast COVID-19 cases. Chimmula and Zhang [34] used a
LSTM network to forecast future COVID-19 cases with an out-of-sample RMSE
of 45.70 for Canada. Machine learning models (Bayesian Regularization of Neu-
ral Networks, Cubist Regression, KNN, quantile random forests, and SVR) were
utilized in [10] with climatic exogenous data and decomposition pre-processing to
forecast Brazilian and USA states incidence, concluding that Cubist regression model
coupled with the variational mode decomposition is suitable to forecast COVID-19
for most of the adopted states and that climatic variables have a great influence
on the forecasting accuracy. Decock et al. [35] employed a diffusion model for
different scenarios to predict presenting pathways with the more likely scenarios
towards maximum intensive care unit capacity needed in Belgium all with R 2 > .99
on fitted data and showing good accuracy in new data. Hazarika and Gupta [36]
applied a wavelet-coupled random vector functional link network comparing with
Random Vector Functional Link (RVFL) with 1-D discrete wavelet transform and
SVR, showing that wavelet-coupled RVFL performed better than an SVR in every
cases. Ribeiro et al. [9] employed ARIMA, Cubist regression, Random Forest (RF),
RIDGE regression, SVR, and stacking-ensemble learning to predict cases in Brazil-
ian states, with the ranking of models from the best to the worst in all scenarios being:
SVR, stacking-ensemble learning, ARIMA, Cubist regression, RIDGE regression,
and RF. In [37] vector autoregressive time series models were used to forecast new
daily confirmed cases, deaths and recoveries for Pakistan. The results showed a max-
imum of 5363 new cases by day with 95% confidence interval from 3013 to 8385,
maximum of 167 deaths/day with 95% confidence interval from 112 to 233 and max-
imum of 4016 recoveries/day with 95% confidence interval of 2182–6405 for the
next 10 days of forecast. Salgotra et al. [38] applied gene expression programming
symbolic regression to generate a mathematical model that predicts future cases
for the 15 most-affected countries, showing different trends for different countries
with highly reliable results. Shastri et al. [39] applied Stacked LSTM, Bidirectional
LSTM and Convolutional LSTM to forecast COVID-19 cases one month ahead for
India. Most works are based solely in the use of COVID-19 series, without trying to
identify possible exogenous data, which could enhance prediction accuracy, or even
help determine factors that contribute to the spread of the virus.
This section presents a description of the dataset used and the models applied to
forecast COVID-19 cases.
3.1 Dataset Description
The dataset used in this work is composed mainly of two parts. The first refers
to data collected from the Brazilian State Health Offices and made available by a
collaborative project with various contributors [40]. This dataset was preferred over
the Brazilian Ministry of Health data considering the delay in data recorded officially
by the ministry. That dataset contain information about the number of cumulative and
daily deaths and incidence. The main indicators for COVID-19 data are presented in
Table 1. For each state, data goes from the first official record of cases by the state’s
Health Office and goes until September 4th, the last day of collected data for this
chapter. The ten states with the most accumulated cases were selected for predictions
and are presented in Fig. 1.
The second part of the dataset is composed of COVID-19 Community Mobility
Reports provided by Google [17]. These reports show trends in activities over time
in different categories of locations and areas. The categories are listed below, with
some of the locations that are part of them.
PA MA CE
Cumulative
confirmed cases
800,000
BA
600,000
DF
GO 400,000
MG
200,000
SP RJ
SC
Fig. 1 Heatmap of COVID-19 total cases from the first reported case up to September 4th, 2020
Table 1 Statistical indicator for the COVID-19 cumulative confirmed cases and daily incidence from first reported case up to September 4th 2020
State Variable No. of days Maximum Mean Median Standard Skewness Kurtosis
deviation (Std.)
BA Total confirmed 183 268,137.00 70,537.73 26,419.00 85,411.52 0.96 −0.53
Daily incidence 183 8822.00 1465.23 899.00 1610.86 1.17 1.30
CE Total confirmed 173 221,828.00 85,379.80 71,947.00 77,104.59 0.35 −1.42
Daily incidence 173 9427.00 1282.24 813.00 1264.07 1.92 8.21
DF Total confirmed 182 167,200.00 45,469.50 15,029.00 54,609.82 0.90 −0.68
Daily incidence 182 3171.00 918.68 768.50 855.75 0.37 −1.25
GO Total confirmed 177 146,441.00 31,167.97 6302.00 42,340.05 1.27 0.30
Daily incidence 177 4758.00 827.35 191.00 1139.11 1.37 0.63
MA Total confirmed 169 157,052.00 61,525.12 57,605.00 54,616.13 0.25 −1.48
Daily incidence 169 2805.00 929.30 854.00 739.47 0.53 −0.62
MG Total confirmed 181 228,013.00 54,293.86 14,939.00 70,028.79 1.10 −0.20
Daily incidence 181 6122.00 1259.74 554.00 1398.41 0.88 −0.37
Ensemble Learning Models Coupled with Urban Mobility …
PA Total confirmed 171 206,864.00 77,709.06 65,151.00 72,254.89 0.33 −1.45

Daily incidence 171 4387.00 1209.73 1177.00 1016.57 0.45 −0.71
RJ Total confirmed 184 232,489.00 80,080.07 61,999.00 76,538.35 0.47 −1.22
Daily incidence 184 6061.00 1263.53 836.00 1243.40 1.00 0.45
SC Total confirmed 177 186,596.00 37,856.21 11,742.00 49,937.80 1.33 0.59
Daily incidence 177 30,913.00 1054.21 442.00 2487.11 9.83 114.46
SP Total confirmed 193 845,016.00 234,394.04 109,698.00 266,033.51 0.91 −0.58
Daily incidence 193 19,274.00 4378.32 2610.00 4596.55 1.07 0.30
827
• Retail and recreation (X 1 ): amusement parks, cafes, libraries, movie theaters,

museums, restaurants, shopping malls.
• Grocery and pharmacies (X 2 ): drugstores and pharmacies, farmer’s markets,
food stores, grocery stores, specialty food stores.
• Parks (X 3 ): public gardens, national forest, camping, observatory, squares, beaches.
• Public transit stations (X 4 ): subway station, bus station. harbor, taxi rank, road-
side stop, car rental agency.
• Workplaces (X 5 ): workplace mobility information.
• Residential (X 6 ): residential areas.
All categories are presented as percent change from values on a pre-established

baseline date. Statistical indicators for Google Mobility data are shown in Table 2.
The correlation matrix for the mobility features compared to the target variable
is shown in Fig. 2 and can be inferred that the mobility has a positive correlation
with COVID-19 cases, except for residential areas, with a small negative correlation.
The biggest direct positive correlation with target variables comes from Grocery
and Pharmacy variation in mobility, suggesting a possible causal relationship. Most
mobility variables have a high to moderate positive correlation between themselves,
except for residential areas mobility, which is to be expected in such cases.
Y
0.8
0.6
0.17 X1
0.4
0.26 0.83 X2
0.2
0.14 0.74 0.74 X3 0
−0.2
0.12 0.85 0.82 0.77 X4
−0.4
0.12 0.73 0.63 0.52 0.71 X5

−0.6
−0.8
−0.07 −0.78 −0.59 −0.53 −0.72 −0.92 X6
−1
Fig. 2 Correlation matrix for the COVID-19 incidence and urban mobility variables
Table 2 Statistical indicators for the urban mobility variables
Variable State Minimum Maximum Mean Std Skewness Kurtosis State Minimum Maximum Mean Std Skewness Kurtosis
Retail and recreation (X1 ) BA −79 −4 −46.93 16.99 0.77 0.03 DF −75 18 −41.16 18.25 0.60 0.21
Grocery and pharmacy (X2 ) −56 31 −9.34 15.58 −0.24 −0.13 −37 35 4.30 13.76 −0.75 0.29
Parks (X3 ) −72 −12 −48.03 12.34 0.58 −0.06 −77 20 −36.76 21.90 0.43 −0.67
Public transit stations (X4 ) −76 4 −49.84 15.93 1.46 2.55 −64 17 −32.76 14.19 0.53 1.80
Workplaces (X5 ) −69 18 −22.22 14.46 0.16 1.31 −76 24 −26.32 18.23 0.36 0.21
Residential areas (X6 ) 0 23 14.08 4.05 −1.49 3.21 −4 28 16.21 5.56 −1.02 2.52
Retail and recreation (X1 ) CE −81 5 −49.46 21.90 0.45 −0.98 GO −73 1 −37.37 16.04 0.11 −0.22
Grocery and pharmacy (X2 ) −44 41 −5.22 18.49 0.12 −0.86 −35 38 3.42 13.63 −0.57 0.04
Parks (X3 ) −84 −32 −62.30 11.57 0.18 −0.61 −56 22 −16.20 14.38 0.00 0.21
Public transit stations (X4 ) −76 −6 −46.60 17.81 0.28 −1.32 −58 5 −27.28 11.02 −0.57 0.84
Workplaces (X5 ) −72 11 −29.32 17.26 −0.04 −0.68 −70 17 −16.21 14.40 −0.94 1.55
Residential areas (X6 ) 1 24 14.51 4.52 −0.24 −0.55 −1 26 12.88 4.24 0.04 2.12
Retail and recreation (X1 ) MA −76 32 −33.30 25.05 0.43 −0.93 PA −72 32 −30.85 24.36 0.37 −0.87
Grocery and pharmacy (X2 ) −70 56 6.26 21.47 −0.21 −0.06 −50 52 6.19 20.21 −0.07 −0.80
Parks (X3 ) −56 31 −19.86 23.19 0.20 −1.23 −64 43 −16.61 29.61 0.33 −1.25
Public transit stations (X4 ) −80 10 −42.73 20.54 0.30 −1.19 −80 22 −33.66 22.84 0.23 −1.12
Workplaces (X5 ) −67 16 −18.73 15.57 −0.31 −0.45 −67 17 −17.19 14.67 −0.43 0.15
Residential areas (X6 ) 4 23 12.18 3.61 0.23 −0.38 2 26 11.99 4.30 0.28 −0.15
Retail and recreation (X1 ) MG −75 11 −37.37 16.97 0.55 0.36 RJ −74 14 −43.53 20.23 0.62 −0.24
Grocery and pharmacy (X2 ) −46 38 2.66 13.88 −0.71 0.69 −41 27 −4.01 13.50 −0.30 −0.57
Parks (X3 ) −59 20 −21.83 13.74 0.49 0.72 −84 −4 −52.10 18.79 0.83 −0.02
Workplaces (X5 ) −73 22 −15.43 14.68 −0.65 2.03 −69 22 −26.13 17.46 0.35 0.25
Residential areas (X6 ) −2 27 11.76 4.28 −0.51 2.63 −2 28 14.14 5.87 −0.59 0.44
Retail and recreation (X1 ) SC −87 −2 −40.85 16.66 −0.72 0.51 SP −76 11 −42.62 19.51 0.80 0.05
Grocery and pharmacy (X2 ) −58 12 −16.45 12.61 −0.77 0.92 −36 25 −2.10 12.00 −0.39 −0.36
Parks (X3 ) −91 −20 −65.18 10.51 0.98 2.69 −71 22 −34.18 17.98 0.66 0.30
Workplaces (X5 ) −76 20 −18.02 15.74 −1.40 2.34 −74 20 −21.73 18.18 0.16 0.14
Residential areas (X6 ) −2 28 12.25 5.04 0.76 2.26 −4 30 13.62 6.30 −0.71 0.67
829
3.2 Methods
3.2.1 Autoregressive Integrated Moving Average
ARIMA is a Box & Jenkins modelling usually employed to deal with non-stationary
time series, it is an autoregressive model based on the idea that current values of a
time-series are a function of past p values of the series [41]. Suppose a time series
in the form of {x1 , x2 , . . . , xt }, an ARIMA model can be written as [42]:
xtd = c + φ1 xt−1
d
+ ... + φ p xt−
d
p + θ1 t−1 + ... + θq t− p + t (1)
With φi representing the autoregressive parameters, θi the moving average param-

eters, the error terms and xid the original time series differentiated d times. The
ARIMA model is fully specified by autoregressive ( p), differentiation degree (d), and
moving average operators (q), usually written as ARIMA( p, d, q). These parame-
ters are usually defined by grid-search, as well as by autocorrelation and partial
autocorrelation function [43].
3.2.2 Ensemble Empirical Mode Decomposition
EEMD [44] is a pre-processing technique based on the empirical mode decompo-

sition (EMD) method. In EEMD white noise is added to prevent mode mixing and
presence of oscillations of very uneven amplitude in a mode [45]. The added noise
appears in the form of artificial observations. With a random value wi coming from
a Gaussian distribution and x(t) a real observation, the artificial observations have
the form of:
xi (t) = x(t) + wi (t) (2)
With added noise to the observations, EEMD consists of applying EMD to this
new series to decompose in IMFs. This procedure is repeated N times, with different
white noise and the IMFs will take the value of the mean of N decomposed values,
forming an ensemble. In EMD decomposition a x(t) series can be described in IMFs
c j in a additive manner [46, 47]:
⎛ ⎞
n
x(t) = ⎝ c j ⎠ + rn (3)
j=1
where rn is the residue of x(t) with IMFs removed. The mode is finded by interpo-
lating between minimum, getting emin , and between maximum, with corresponding
emax , computing the average M(t) = (emin + emax )/2 and than extracting a IMF
with:
c j = x(t) − M(t) (4)
This process is subsequently repeated n − 1 times over M(t). The remainder from
the process will be rn , and the extracted c j are the IMFs.
3.2.3 Extreme Gradient Boosting
XGBoost is a multiplatform library that offers supervised learning machine learning

models based on Gradient Boosted Trees and is designed to be “efficient, flexible and
portable” [48]. Gradient Boosting uses several weak decision trees to form a stronger
ensemble predictor. Give K regression tree predictor functions of the form f (k) (x)
and a dataset with n samples and m features, the pair (x i , yi ) is the i-th sample. A
tree ensemble model prediction can be described as [48–50]:

K
F(x i ) = ŷi = f (k) (x i ). (5)
k=1
Using an objective function to minimize a loss function denoted by l, w the

regression tree weight, eta the learning rate, λ a regularization coefficient, and a
penalization for higher complexity:
1
L( f ) = L( f ) + ( f ) = l( ŷi , yi ) + ηK + λ||w||2 (6)
i k
2
Minimizing L gives the set of functions for F(x i ). Using a second order Taylor
expansion for the objective function, with gi and h i as the first and second order
derivatives of l loss function, the optimal weight w∗ for the j-th leaf will be:

∗ gi
wj = − (7)
hi + λ
and the optimal value of the leaf node:

1 ( gi )2
K
L̃(q) = − + ηK (8)
2 j=1 hi + λ
3.2.4 Extreme Learning Machine
Proposed by Huang et al. [51], Extreme learning machines are multilayer perceptron
(MLP) networks with only a single hidden layer and usually trained via linear regres-
sion. In ELMs the internal weights of the network are assigned randomly, and only
Fig. 3 ELM schematic
the output weights are trained, making a simpler problem than regular feed-forward
neural networks trained by gradient descent. Figure 3 shows a schematic of an ELM.
Given a training set of pairs (x i , yi ), with N as the number of samples, a single
hidden layer neural network output can be expressed as:

K
K
oj = βi gi (x j ) = βi gi (wi · x j + b j ) (9)
i=1 i=1
where g is the activation function, x j is the j-th observation vector, K is the number
of hidden nodes in the single hidden layer, wi is the weights vector for the i-th node
of the layer, b j is the bias for the hidden layer and βi the weight connecting the i-th
node to the output layer. Using a matrix notation:
O = Hβ (10)
where O are the outputs, H the hidden layer information, and β the weights con-
necting the hidden layer to the output layer. As the weights and biases are randomly
assigned, H is completely determined for an ELM, so it remains to solve for β,
which can be done by various methods, such as Ridge Regression or Moore–Penrose
pseudoinverse.
Fig. 4 LSTM unity. Circles indicate point wise operations and squares indicate layers
3.2.5 Long Short-Term Memory
LSTM networks, first described by Hochreiter and Schmidhuber [52], are a kind of
recurrent neural network (RNN) with a “memory” property. A recurring problem in
RNN trained with back-propagation based on gradient descent is called the vanishing
gradient, whereas the weights of the network are iteratively updated in consideration
to the derivative in respect to the last step weight. The gradient can get consistently
small, causing the weights do not have any difference in each update. LSTM networks
can overcome this problem by storing information from the last steps in a vector,
acting as a memory slot [53]. Figure 4 shows a basic LSTM unity in detail.
With xt as the update vector, h t as the hidden state vector and ct the cell state, the
updates for this unity are as follows [52–54]:
• Input gate:
i t = σsigm (Wi xt + Ri h t−1 + bi ) (11)
• Forget gate:
f t = σsigm (W f xt + R f h t−1 + b f ) (12)
• Output gate:
ot = σsigm (Wo xt + Ro h t−1 + bo ) (13)
• New cell state:

c̃t = σtanh (Wc xt + Rc h t−1 + bc ) (14)
• Cell state selectively forgetting and adding to long-term memory:
ct = f t ct−1 + i t c̃t (15)
• Selectively leaking long-term memory to hidden state:
h t = ot σtanh (ct ) (16)

Where σsigm is a sigmoid activation function, σtanh is a hyperbolic tangent activation

function, W is the matrix of weights of the input vector and R is the matrix of weights
of recurrent connections. Subscripts i, o and c indicate weights for the input, output
and cell variables respectively.
3.2.6 Support Vector Regression
SVR is a generalization for regression of a supervised learning group called Support

Vector Machines [55]. As described by Drucker [56], given a “truth” function g(x)
which is unknown in d-dimensional space and f (x, w) a family of functions defined
by parameters w, ŵ is the vector that minimizes the error between g(x) and f (x, w).
If f 1 (x, ŵ) is a SVR representation such as described by Cortes and Vapnik [57]:

n
f 1 (x, ŵ) = (α i∗ − α i )(ν it x + 1) p + b (17)
i=1
where α i∗ and α i and b are constants of the model, ν j ( j = 1, 2, ..., n) is the j-th
training instance, x is the input space ([x1 , x2 , ..., xd ]) . The optimal values for ŵ, αi
and αi∗ can be found by minimizing:

n
U L{y j − F(ν j , ŵ)} + ||ŵ||2 (18)
i= j
where L is a loss function and U a regularization constant. Using this formulation

with L being the -insensitive loss function [57] is possible to solve for the unknowns.
This way, predictions y( p) will take the form of [56]:

n
y( p) = (α i∗ − α i )(ν it x ( p) + 1) p + b (19)
i=1
One of the main advantages of SVR lies in its capacity to capture the predictor
non-linearity and then use it to improve the forecasting cases. It is also advantageous
to employ SVR in COVID-19 forecasting since the samples are small [56].
4 Proposed Forecasting Framework
This section describes the main steps in the data analysis adopted by ELM, SVR,
XGBoost, EEMD based models, and benchmarks approaches.
Step 1: The raw data in the context of the output variable (COVID-19 daily
incident) is decomposed into five IMFs and one residual component by performing
EEMD. The parameters adopted in the EEMD decomposition are 100 ensemble
learning models, 6 components and noise standard deviation equals 0.25. Figures 7,
8, 9, 10, 11, 12, 13, 14, 15 and 16 present the original and decomposed series for
each adopted state.
To define the inputs of the forecasting system, the lag equals to 7 was chosen by
grid-search, applied on the IMFs creating four inputs from the lags. Moreover, for the
exogenous inputs (urban mobility variables) the lags equal to 7 or 14 are adopted,
in the forecasting horizon 7 and 14 days-ahead, respectively. Since the virus has
the capacity to remain incubated between 7 and 14 days [58], this information was
considered to determine the delays adopted for the input variables of the forecasting
system. Further, the new data is split into training and test sets. The test set consists of
the last fourteen observations and the training set defined by the remaining samples.
In the training state, leave one-out-cross-validation with time slice was adopted, such
as developed by Ribeiro et al. [59].
Step 2: Each IMF is trained with each model described in Sect. 3.2 using time-
slice validation approach. Next, the IMF predictions were reconstructed by a simple
summation-grouping model. In other words, the IMF is trained by the same model
and is summed. Then, three prediction outputs were generated named EEMD–ELM,
EEMD–SVR, EEMD–XGBoost. Moreover, heterogeneous ensemble learning mod-
els (EEMD–HEM) are defined by choosing by grid-search the most suitable model
to handle each EEMD based component (i.e., to choose the order of models for each
IMF and residue). The EEMD–HEM models structure is illustrated in Table 3.
Finally, for comparison purposes, the benchmarks ARIMA, LSTM, and EEMD–
LSTM models are considered.
Step 3: For each forecasting horizon, different models are trained due to the use
of exogenous inputs. Also, to reach the forecasting horizon desired, an interactive
approach is employed to develop multi-days-ahead COVID-19 daily incidence fore-
casting 7 or 14-days-ahead. Regarding this, one model is fitted for one-day-ahead
forecasting, then the fitted model uses this forecasting result as an input for the
same model to forecast the next step. In this paper, the aim is to obtain the cases
up to H next days, especially up to 7-days-ahead, and 14-days-ahead. The following
structures are considered,

fˆ ŷ(t + h − 1), . . . , y(t + h − 7), X(t + h − 7) if h = 7,

ŷ(t+h) =
(20)
ˆ
f ŷ(t + h − 1), . . . , ŷ( t + h − 7), X( t + h − 14) if h = 14,
where fˆ is a function that maps the COVID-19 daily incidence, ŷ(t + h) is the
forecast of cumulative cases in horizon h =7 and 14, y(t + h − 1) to y(t + h − 7)
are the previous observed, ŷ(t + h − 1) to ŷ(t + h − 7) are the COVID-19 incidence
in the 7 previous days, X(t + h − n x ) is the exogenous inputs vector at the maximum
lag of inputs (n x = 7 if h = 7 and n x = 14 if h = 14). The analyses which considers
the ELM, SVR, and XGBoost models are developed using R software [60] through of
the {caret} package using the train function. In this respect the hyperparameters
for each model are defined automatically by using the tunelength argument
equals to 5.
836
Table 3 Order of models adopted in the EEMD–HEM structure

State Forecasting Horizon
7 days-ahead 14 days-ahead
IMF1 IMF2 IMF3 IMF4 IMF5 Residual IMF1 IMF2 IMF3 IMF4 IMF5 Residual
BA SVR XGBoost ELM XGBoost SVR SVR XGBoost ELM XGBoost XGBoost SVR ELM
CE XGBoost SVR SVR SVR ELM ELM SVR ELM XGBoost SVR SVR XGBoost
DF ELM XGBoost ELM XGBoost SVR SVR SVR SVR SVR SVR SVR SVR
GO XGBoost ELM ELM ELM ELM ELM ELM SVR XGBoost SVR SVR ELM
MA SVR SVR ELM SVR ELM ELM SVR XGBoost XGBoost XGBoost ELM XGBoost
MG ELM SVR ELM XGBoost SVR ELM SVR XGBoost XGBoost SVR SVR XGBoost
PA SVR ELM SVR XGBoost XGBoost ELM SVR XGBoost SVR SVR ELM SVR
RJ XGBoost SVR ELM SVR ELM SVR XGBoost SVR ELM SVR SVR SVR
SC SVR XGBoost SVR ELM XGBoost ELM ELM XGBoost ELM XGBoost XGBoost ELM
SP XGBoost SVR SVR SVR XGBoost SVR SVR SVR ELM XGBoost XGBoost ELM
M. H. D. M. Ribeiro et al.
Step 4: To evaluate the effectiveness of adopted models, from obtained forecasts

out-of-sample (test set), MAE (21), RMSE (22), and ordered weighted averaging
(OWA) (23) criteria are computed as
n
yi − ŷi
MAE =
n , (21)
i=1

n
1 2
RMSE = yi − ŷi , (22)
n i=1

1 MAEp RMSEp
OWA = + . (23)
2 MAEc RMSEc
RMSEc − RMSEb
IPRMSE = 100 × , (24)
RMSEc
MAEc − MAEb
IPMAE = 100 × , (25)
MAEc
where n is the number of observations, yi and ŷi are the i-th observed and predicted
values, respectively. The Criteriac and Criteriap represent the performance measure
of compared and proposed model, respectively. In the OWA criterion, by computing
1 − OWA value, it is possible to find the percentage of improvement of best and
compared models for each scenario considering two performance criteria MAE and
RMSE simultaneously. Looking for the improvement percentage (IP) (24) and (25),
the IP regarding the best (b) and compared (c) model is computed.
Moreover, the average importance, for all systems input is computed, over all
datasets and forecasting horizons. When a tree-based model is adopted, such as
XGBoost, the feature importance is calculated as reducing the node impurity in a
single decision tree, weighted by the probability of reaching that node. So, in this
approach, the sums the importance over each boosting iteration is computed. For the
remaining models, the importance for each input variable is obtained through the
absolute value of the t-statistic for each model [61].
Finally, Fig. 5 illustrates the methodology employed to forecast COVID-19 daily
incidence.
5 Results and Discussions
This section describes the results of the developed experiments in forecasting out-
of-sample (test set). Section 5.1 compares the results of evaluated models over ten
datasets in the task of forecasting COVID-19 daily incidence 7 days-ahead. Moreover,
Fig. 5 Proposed forecasting framework for COVID-19 daily incidence
in Sect. 5.2 the results for the forecasting horizon of 14 days-ahead are compared
and discussed. In Tables 4 and 5 , the best results regarding accuracy are presented
in bold. Additionally, Figs. 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26 illustrate the
relation between observed and predicted values achieved by models with the best
set of performance measures depicted in Tables 4 and 5. Also, Fig. 6 illustrates the
variable importance of each input (both lags and exogenous inputs) used in the
models’ predictions.
5.1 Comparisons for the Forecasting Horizon

of 7 days-Ahead
In concerning the information presented in Table 4, the main results to forecasting

COVID-19 daily incidence 7 days-ahead are highlighted as follows:
• BA and MA: For these states, the SVR approach can be considered to forecast
COVID-19 daily incidence in the time window of 7 days ahead. In most of the
cases, these support vector-based approaches outperformed the compared models.
The OWA of SVR regarding remaining models ranged between 8.71 and 52.22%.
For BA, the improvement on RMSE and MAE ranges between 7.11 and 50.57%
and 10.32 and 53.87%, respectively.
• MG, PA, and RJ: In the context of these states, the EEMD–HEM approach achieves
better accuracy than compared models. Considering the combination of RMSE and
MAE criteria, the improvement of decomposed heterogeneous ensemble learning
over the compared approaches ranges between 13.22 and 71.42% for MG, 31.94
and 87.50% for PA, as well as 11.96 and 57.51% for RJ. Considering the improve-
ment on RMSE and MAE for MG and PA, SVR achieved similar performance
regarding EEMD–HEM. Moreover, in the context of RJ, the XGBoost has close
performance for RMSE and MAE concerning EEMD–HEM.
Table 4 Performance measures for the evaluated models on the task of forecasting COVID-19 incidence 7-days-ahead
State Criteria ARIMA ELM LSTM SVR XGBoost EEMD– EEMD– EEMD- EEMD– EEMD–
ELM LSTM HEM SVR XGBoost
BA RMSE 1284.66 922.24 967.15 856.69 1111.14 1369.29 1733.12 949.90 1100.60 1088.95
MAE 1041.43 768.75 890.15 689.43 906.56 1071.68 1494.58 693.51 903.05 885.25
CE RMSE 1964.80 934.33 841.77 664.13 721.72 694.61 342.42 372.39 433.74 658.69
MAE 1862.36 794.91 691.51 547.35 587.62 630.12 302.33 296.48 363.71 566.73
DF RMSE 1759.21 502.72 409.85 565.47 514.49 1191.55 518.99 424.96 487.31 525.59
MAE 1653.86 433.77 390.23 467.47 416.67 910.91 516.00 333.21 403.21 381.75
GO RMSE 1263.00 1137.33 1301.93 861.22 878.46 788.21 1668.31 734.44 898.62 908.80
MAE 983.29 1041.91 911.02 748.85 711.64 623.49 1336.05 624.21 712.29 758.88
MA RMSE 2242.83 367.79 241.93 171.40 252.84 380.15 272.66 255.19 331.52 355.84
MAE 2210.93 295.29 229.65 140.48 194.10 297.76 256.46 208.43 273.72 300.30
MG RMSE 886.73 436.17 602.39 414.67 581.61 491.06 1226.82 350.31 528.48 616.08
MAE 659.14 330.87 470.89 353.87 429.65 431.34 1101.84 315.26 446.41 511.30
PA RMSE 1927.01 548.90 572.05 368.37 435.90 457.41 773.20 272.94 486.52 395.24
MAE 1905.86 459.06 561.49 332.75 337.09 394.62 694.64 206.38 374.49 334.38
RJ RMSE 1930.47 1281.02 1465.82 1208.45 1489.92 1402.01 1484.20 855.86 1370.76 968.48
MAE 1682.50 1025.77 1087.29 1011.36 1180.96 1284.69 1348.16 683.97 1092.30 779.81
SC RMSE 7531.31 7929.29 11,424.46 7982.82 7940.51 7761.91 10329.47 6208.60 8783.49 7546.93
MAE 3429.93 2590.59 5158.95 2568.62 2965.32 3754.01 5423.50 4069.38 7011.02 3855.45
SP RMSE 6003.95 2943.62 1483.88 3479.55 4105.92 5214.55 6285.88 3108 3199.32 4227.31
MAE 5182.43 2423.63 1197.83 3114.30 3313.49 4904.55 4325.75 2486.18 2873.69 3939.93
839
• SP: In this state, the deep learning-based approach LSTM presents better per-
formance to forecasting COVID-19 regarding the remaining approaches. In con-
sideration of the RMSE criterion, the improvement ranges between 49.59 and
76.39% in comparison of remaining approaches. For MAE criterion, the improve-
ment over the other approaches ranges between 50.58 and 76.89%. The ELM and
EEMD–LSTM models are the models that have the closest and worst performances
regarding LSTM, respectively.
• Remaining states: For the states of CE, DF, GO, and SC two models between the
adopted presented competitive results.
– First, for CE, the EEMD–HEM and EEMD–LSTM models presented similar
forecasting performance, where the first achieved lower MAE and the second
lower RMSE. By considering the OWA measure, the EEMD–LSTM presented
a better overall improvement regarding remaining approaches, which ranges
between 3.04 and 83.17%.
– For DF state, the EEMD–HEM and LSTM models achieved similar forecasting
errors, where the first approach had lower MAE and the second lower RMSE.
Considering the OWA criterion, which considers a combination of RMSE and
MAE, the EEMD–HEM is more accurate than the remaining approaches. In
the context of EEMD–HEM and LSTM, the EEMD–SVR and ARIMA models
are that have the close and worst performances regarding these approaches,
respectively.
– When the forecasting results are evaluated for the SC state, the SVR and EEMD–
HEM models achieved better performance to forecast COVID-19 daily inci-
dence 7 days-ahead regarding MAE and RMSE, respectively. For SVR, the
improvement in MAE ranges between 0.85 and 63.36% when the results for
ELM and EEMD–SVR models are evaluated. In its turn, for the EEMD–HEM
approach, the improvement on RMSE over the compared approaches ranges
between 17.56 and 45.66% regarding ARIMA and LSTM models.
– Finally, for the GO state, the two decomposed models EEMD–HEM and
EEMD–ELM achieved competitive results considering the RMSE and MAE
criteria. However, looking for OWA the decomposed heterogeneous ensem-
ble learning has better forecasting accuracy. The improvement of EEMD–HEM
regarding the OWA measure ranges between 3.35 and 54.63%, being the EEMD–
ELM and EEMD-LSTM that have the closest and worst performances regarding
this approach, respectively.
5.2 Comparisons for the Forecasting Horizon

of 14 days-Ahead
In respect to the information shown in Table 5, the main results to forecasting COVID-
19 daily incidence of 14 days-ahead are highlighted as follows:
Table 5 Performance measures for the evaluated models on the task of forecasting COVID-19 incidence 14-days-ahead
State Criteria ARIMA ELM LSTM SVR XGBoost EEMD– EEMD– EEMD– EEMD– EEMD–
ELM LSTM HEM SVR XGBoost
BA RMSE 1309.15 2684.74 775.66 883.64 1098.00 3203.92 2030.68 1269.96 1323.38 1664.16
MAE 1022.71 2372.41 633.69 731.29 875.83 2488.05 1811.70 1039.29 1029.41 1337.14
CE RMSE 2079.75 1096.43 662.06 592.87 645.98 1463.07 917.35 436.72 640.28 760.82
MAE 1959.36 953.79 571.97 478.51 429.63 1236.54 822.53 364.29 532.15 582.46
DF RMSE 1848.01 656.22 627.60 585.77 602.50 4527.40 913.79 465.62 477.82 606.43
MAE 1750.86 554.44 581.45 490.28 493.71 3249.71 868.93 370.72 385.62 534.11
GO RMSE 1466.42 2159.04 772.82 904.62 1048.45 853.15 1488.80 699.01 856.38 1378.04
MAE 1093.86 1791.38 617.69 804.42 756.79 680.83 1291.43 613.92 689.17 1091.77
MA RMSE 2347.82 348.33 281.00 210.02 240.88 388.64 696.34 273,51 400.28 400.25
MAE 2307.93 283.42 245.56 153.86 198.90 348.38 596.50 235,88 329.95 332.30
MG RMSE 902.18 479.02 757.03 405.80 573.34 997.87 1201.25 296.22 451.91 631.06
MAE 680.00 402.89 638.36 327.95 445.58 799.04 1096.78 231.51 399.01 570.04
PA RMSE 2041.33 419.89 710.68 380.42 472.80 4277.96 922.13 339.56 360.14 534.14
MAE 2002.86 382.52 491.57 347.44 399.28 2975.66 868.44 274.18 318.34 433.14
RJ RMSE 1964.93 1390.37 1500.39 1194.81 1216.09 1685.67 1341.90 1224.28 1479.99 1311.38
MAE 1662.36 1107.78 1237.04 1043.06 996.39 1548.44 1135.77 1049.43 1231.56 1120.41
SC RMSE 7532.35 8369.15 7896.53 7987.10 8104.49 13913.56 7547.76 6817.78 7385.31 7861.65
MAE 3409.93 3424.16 2971.81 2599.69 2804.91 8613.48 3613.37 4019.08 4374.14 3979.15
SP RMSE 6003.34 3124.92 3494.73 3444.34 3668.40 8606.60 7654.55 3159.22 3931.28 5675.61
MAE 5177.71 2623.79 2817.32 3066.74 3113.39 6264.98 6172.98 2643.47 3129.54 4692.40
841
• BA: In this state, the LSTM model achieved good accuracy in respect of RMSE
and MAE criteria, when the forecasting errors are compared with other models.
In fact, the improvement on RMSE and MAE ranges between 12.22 and 75.79%
and 13.35 and 74.53%, respectively. The SVR model achieved close performance
in respect of LSTM, and EEMD–ELM achieved the worst performance compared
with LSTM. Considering the combination of RMSE and MAE, i.e., OWA mea-
sure, the improvement on the LSTM accuracy regarding compared models ranges
between 12.78 and 75.16%.
• CE, DF, GO, MG, and PA: In the next, for these states, the EEMD–HEM model
outperforms the compared models for both RMSE and MAE criteria. Looking for
the OWA criterion, this approach improves the accuracy of the forecasting sys-
tems, which ranges between 23.80 and 80.20% for CE, 3.21 and 89.15% for DF,
5.08 and 66.68% for GO, 28.20 and 77.12% for MG, and 9.79 and 91.42% for PA.
In most of the cases the SVR or EEMD–SVR models have close forecasting accu-
racy concerning EEMD–HEM, and ELM or EEMD–ELM models have the worst
performance to the decomposed and heterogeneous ensemble learning model.
• MA: For this state, the SVR approach can be considered to forecast COVID-19
daily incidence in the forecasting window of 14 days-ahead. In most of the cases,
these support vector-based approaches outperformed the compared models. The
OWA of SVR regarding remaining models ranged between 17.7 and 92.20%. For
the MA state, the improvement on RMSE and MAE ranges between 12.80 and
91.10% and 22.6 and 93.3%, respectively.
• SP: For this state, the feedforward neural network ELM outperforms the compared
models. In consideration of the RMSE criterion, the improvement ranges between
1.09 and 63.69% in comparison to remaining approaches. For MAE criterion, the
improvement over the other approaches ranges between 0.74 and 58.14%.
• Remaining states: For the states of SC and RJ two models between the adopted
presented competitive results.
– SC: For this southern state of Brazil, the EEMD–HEM and SVR approaches
achieved good and competitive results. The first reached better RMSE, while
the second better MAE. Considering the results of the EEMD–HEM model, the
improvement on RMSE over the compared models ranges between 7.68 and
51%. Moreover, for the SVR model, the improvement on MAE with respect to
the remaining models ranges between 7.32 and 69.82%.
– RJ: Finally, considering this state, the SVR and XGBoost approach achieved
better results than compared models. The first reached better RMSE, while the
second better MAE. Considering the results of the SVR model, the improve-
ment in RMSE over the compared models ranges between 1.75 and 39.19%.
Moreover, for the XGBoost model, the improvement on MAE with respect to
the remaining models ranges between 4.47 and 40.06%.
Remark: In an overview by considering the frequency of models with better
forecasting accuracy in the context of 7 or 14 days-ahead than compared models,
the ranking of models from the most adequate to the less is EEMD–HEM, SVR,
EEMD-LSTM/LSTM/ELM for 7 days-ahead, and remaining approaches. Similar
considerations can be made for the forecasting horizon of 14 days-ahead. From a

broader perspective, the efficiency of the EEMD–HEM models is due to the capa-
bility of this model to deal with data features by using different models to handle
components extracted by EEMD pre-processing. On the other hand, the ARIMA
model had difficulty to forecast the COVID-19 daily incidence due to the absence of
a clear pattern in the data.
In Figs. 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26 the predicted values achieved
by the models with best performance presented in Tables 4 and 5 are presented.
According to the information depicted in Figs. 16 and 17 it is possible to identify
that the behavior of the data is learned by the evaluated models, which can forecast
compatible cases with the observed values. In most states, the obtained forecasting
values have a similar pattern concerning observed values. In Figs. 23, 24, 25 and 26
the models presented some difficulties to capture the behavior of the data.
The variable average importance is an overall quantification of the relationship
between the predictor variables (inputs) and the predicted value. In this study, exoge-
nous variables related to urban mobility are used by the forecasting system. These
variables showed the trend of mobility in some categories.
Finally, Fig. 6 presents the variable importance of each input used to fit and train
the models. As expected, the lag inputs present high importance due to their high
correlation to the output. However, it is important to notice that urban mobility
related to retail and recreation, as well as public transit stations, play a key role in
Fig. 6 Average feature importance of the inputs employed in the forecasting system
the forecasting system. In the next, the trends in the parks, grocery and pharmacies,
and workplaces also have a high influence on the spread of COVID-19. Usually, the
urban mobility inputs are at some level relevant to the prediction of COVID-19 daily
incidence for Brazilian states, for both 7 and 14 days-ahead forecastings.
6 Conclusion and Future Research Directions
In this chapter, four machine learning approaches called ELM, LSTM, SVR, and
XGBoost, as well as ARIMA statistical model and EEMD signal decomposition,
were employed in the task of forecasting seven and fourteen-days-ahead the daily
incidence COVID-19 cases in ten most affected Brazilian states. The daily incidence
of COVID-19 cases for BA, CE, DF, GO, MA, MG, PA, RJ, SC, and SP states were
used. Also, urban mobility information was used as an input system as well. The
MAE and RMSE criteria were adopted to evaluate the performance of the compared
approaches.
In respect of the obtained results, it is possible to infer that the heterogeneous
ensemble learning model (EEMD–HEM) is a suitable tool to forecast COVID-19
cases for most of the adopted states. This approach was able to learn the nonlinearities
inherent to the evaluated epidemiological time series. The efficiency of the EEMD–
HEM models is due to the capability of this model to deal with data features by
using different models to handle components extracted by EEMD pre-processing.
However, even though the models discussed in this paper presented forecasting cases
similar to those observed, they should be used cautiously. This fact is attributed to the
chaotic dynamics of the analyzed data, as well as the diversity of exogenous factors
that can affect the daily notifications of COVID-19.
Further, it is noticed that urban mobility indeed play a key role in the task of
forecasting daily incidence of COVID-19 cases, especially information related to
retail and recreation, public transit stations, parks, grocery and pharmacies, and
workplaces, which have a high influence on the spread of COVID-19.
For future works, it is intended to adopt (i) the signal decomposition approach
combined to stacking-ensemble learning, (ii) other signal decomposition approach
to decompose the IMFs with high-frequency, and (iii) multi-objective optimization
to tune hyperparameters of adopted forecasting models.
Acknowledgements The authors would like to thank the National Council of Scientific and
Technologic Development of Brazil—CNPq (Grants number: 307958/2019-1-PQ, 307966/2019-4-
PQ, 404659/2016-0-Univ, 405101/2016-3-Univ), PRONEX ‘Fundação Araucária’ 042/2018, and
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES)—Finance Code
001 for financial support of this work.
Appendix 1
In Appendix 1, Fig. 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 present the decomposed
time series for each Brazilian state analyzed in this chapter.
7500
Data
5000
2500
0
2000
1000
IMF1
0
-1000
-2000
2000
1000
IMF2
0
-1000
-2000
500
IMF3
0
-500
-1000
400
IMF4
0
-400
-800
600
300
IMF5
0
-300
3000
Residual
2000
1000
0
0 50 100 150
Samples
Fig. 7 Decomposed series of COVID-19 daily incidence for BA state
7500
Data
5000
2500
0
4000
2000
IMF1
0
-2000
-4000
2000
1000
IMF2
0
-1000
-2000
1000
IMF3
0
-1000
500
IMF4
0
-500
300
200
IMF5
100
0
-100
-200
2000
Residual
1500
1000
500
0
0 50 100 150
Samples
Fig. 8 Decomposed series of COVID-19 daily incidence for CE state

3000
Data
2000
1000
0
400
IMF1 0
-400
-800
400
IMF2
0
-400
300
200
100
IMF3
0
-100
-200
-300
200
100
IMF4
0
-100
-200
200
100
IMF5
0
-100
-200
2000
Residual
1500
1000
500
0
0 50 100 150
Samples
Fig. 9 Decomposed series of COVID-19 daily incidence for DF state
4000
Data
3000
2000
1000
0
1500
1000
IMF1
500
0
-500
-1000
-1500
2000
1000
IMF2
0
-1000
-2000
250
IMF3
0
-250
-500
200
100
IMF4
0
-100
-200
200
IMF5
0
-200
2500
Residual
2000
1500
1000
500
0
0 50 100 150
Samples
Fig. 10 Decomposed series of COVID-19 daily incidence for GO state

2000
Data
1000
0
1000
500
IMF1 0
-500
-1000
400
IMF2
0
-400
500
250
IMF3
0
-250
500
250
IMF4
0
-250
5.0
2.5
IMF5
0.0
-2.5
-5.0
Residual
1000
0 50 100 150
Samples
Fig. 11 Decomposed series of COVID-19 daily incidence for MA state
6000
4000
Data
2000
0
1000
IMF1
0
-1000
-2000
1000
500
IMF2
0
-500
-1000
500
IMF3
0
-500
300
IMF4
0
-300
250
IMF5
0
-250
3000
Residual
2000
1000
0
0 50 100 150
Samples
Fig. 12 Decomposed series of COVID-19 daily incidence for MG state

4000
3000
Data
2000
1000
0
1000
IMF1 0
-1000
1000
500
IMF2
0
-500
-1000
300
IMF3
0
-300
250
IMF4
0
-250
100
IMF5
0
-100
2000
Residual
1500
1000
500
0
0 50 100 150
Samples
Fig. 13 Decomposed series of COVID-19 daily incidence for PA state
6000
4000
Data
2000
0
2000
1000
IMF1
0
-1000
-2000
1000
500
IMF2
0
-500
-1000
1000
500
IMF3
0
-500
-1000
500
IMF4
0
-500
200
IMF5
0
-200
-400
2000
Residual
1500
1000
500
0
0 50 100 150
Samples
Fig. 14 Decomposed series of COVID-19 daily incidence for RJ state

30000
20000
Data
10000
0
10000
5000
IMF1 0
-5000
-10000
-15000
10000
5000
IMF2
0
-5000
-10000
2000
IMF3
1000
0
-1000
-2000
2000
1000
IMF4
0
-1000
-2000
1000
IMF5
500
0
-500
-1000
4000
Residual
3000
2000
1000
0
0 50 100 150
Samples
Fig. 15 Decomposed series of COVID-19 daily incidence for SC state
20000
15000
Data
10000
5000
0
5000
IMF1
0
-5000
-10000
6000
3000
IMF2
0
-3000
-6000
4000
2000
IMF3
0
-2000
-4000
1000
IMF4
0
-1000
-2000
500
IMF5
0
-500
7500
Residual
5000
2500
0
0 50 100 150 200
Samples
Fig. 16 Decomposed series of COVID-19 daily incidence for SP state

Appendix 2
In Appendix 2, the Figs. 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26 present the
predicted versus observed COVID-19 incidence in the test set for ten Brazilian states
analyzed.
4000
COVID-19 Incidence
3000
2000
1000
Aug 22 Aug 24 Aug 26 Aug 28 Aug 30 Sep 01 Sep 03

Date
14-Days-ahead 7-Days-ahead Observed
Fig. 17 Predicted versus observed COVID-19 incidence in the test set for BA state
2000
COVID-19 Incidence
1500
1000
500

Date
Fig. 18 Predicted versus observed COVID-19 incidence in the test set for CE state
3000
2500
COVID-19 Incidence
2000
1500
1000

Date
Fig. 19 Predicted versus observed COVID-19 incidence in the test set for DF state
3000
COVID-19 Incidence
2000
1000

Date
Fig. 20 Predicted versus observed COVID-19 incidence in the test set for GO state
1500
COVID-19 Incidence
1000
500

Date
Fig. 21 Predicted versus observed COVID-19 incidence in the test set for MA state
4000
COVID-19 Incidence
3000
2000

Date
Fig. 22 Predicted versus observed COVID-19 incidence in the test set for MG state
2000
1500
COVID-19 Incidence
1000
500

Date
Fig. 23 Predicted versus observed COVID-19 incidence in the test set for PA state
3000
COVID-19 Incidence
2000
1000

Date
Fig. 24 Predicted versus observed COVID-19 incidence in the test set for RJ state
30000
COVID-19 Incidence
20000
10000
0
Date
Fig. 25 Predicted versus observed COVID-19 incidence in the test set for SC state
10000
COVID-19 Incidence
5000

Date
Fig. 26 Predicted versus observed COVID-19 incidence in the test set for SP state
References
1. World Health Organization (WHO).: Coronavirus (COVID-19) (2020). https://www.who.int/

westernpacific/health-topics/coronavirus
2. Requia, W.J., Kondo, E.K., Adams, M.D., Gold, D.R., Struchiner, C.J.: Risk of the Brazilian
health care system over 5572 municipalities to exceed health care capacity due to the 2019 novel
coronavirus (COVID-19). Sci. Total Environ. 730 (2020). https://doi.org/10.1016/j.scitotenv.
2020.139144
3. Guan, W.j., Zy, N.I., Hu, Y., Liang, W.h., Ou, C.q., He, J.X., Liu, L., Shan, H., Lei, C.l., Hui,
D.S.C., Du, B., Li, L.j., Zeng, G., Yuen, K.Y., Chen, R.C., Tang, C.l., Wang, T., Chen, P.Y.,
Xiang, J., Li, S.Y., Wang, J.I., Liang, Z.J., Peng, Y.X., Wei, L., Liu, Y., Hu, Y.h., Peng, P., Wang,
J.M., Liu, J.Y., Chen, Z., Li, G., Zheng, Z.J., Qiu, S.Q., Luo, J., Ye, C.J., Zhu, S.Y., Zhong,
N.S.: Clinical characteristics of coronavirus disease 2019 in China. New Engl. J. Med. (2020).
https://doi.org/10.1056/NEJMoa2002032
4. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schier-
gens, T.S., Herrler, G., Wu, N.H., Nitsche, A., Müller, M.A., Drosten, C., Pöhlmann, S.: SARS-
CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease
inhibitor. Cell 181(2), 271–280.e8 (2020). https://doi.org/10.1016/j.cell.2020.02.052
5. Hollstein, T., Schulte, D.M., Schulz, J., Glück, A., Ziegler, A.G., Bonifacio, E., Wendorff,
M., Franke, A., Schreiber, S., Bornstein, S.R., Laudes, M.: Autoantibody-negative insulin-
dependent diabetes mellitus after SARS-CoV-2 infection: a case report. Nature Metabolism,
pp. 1–4 (2020). https://doi.org/10.1038/s42255-020-00281-8
6. Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi,
Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., Chen, J., Meng,
Y., Wang, J., Lin, Y., Yuan, J., Xie, Z., Ma, J., Liu, W.J., Wang, D., Xu, W., Holmes, E.C., Gao,
G.F., Wu, G., Chen, W., Shi, W., Tan, W.: Genomic characterisation and epidemiology of 2019
novel coronavirus: implications for virus origins and receptor binding. Lancet 395(10224),
565–574 (2020). https://doi.org/10.1016/S0140-6736(20)30251-8
7. Mehta, P., McAuley, D.F., Brown, M., Sanchez, E., Tattersall, R.S., Manson, J.J.: COVID-19:
Consider cytokine storm syndromes and immunosuppression. Lancet 395(10229), 1033–1034
(2020). https://doi.org/10.1016/S0140-6736(20)30628-0
8. Zheng, Y.Y., Ma, Y.T., Zhang, J.Y., Xie, X.: COVID-19 and the cardiovascular system. Nat.
Rev. Cardiol. 17(5), 259–260 (2020). https://doi.org/10.1038/s41569-020-0360-5
9. Ribeiro, M.H.D.M., da Silva, R.G., Mariani, V.C., Coelho, L.S.: Short-term forecasting
COVID-19 cumulative confirmed cases: perspectives for Brazil. Chaos, Solitons Fractals 135
(2020a). https://doi.org/10.1016/j.chaos.2020.109853
10. da Silva, R.G., Ribeiro, M.H.D.M., Mariani, V.C., Coelho, L.S.: Forecasting Brazilian and
American COVID-19 cases based on artificial intelligence coupled with climatic exogenous
variables. Chaos, Solitons Fractals 139 (2020). https://doi.org/10.1016/j.chaos.2020.110027
11. Ribeiro M.H.D.M.„ Ribeiro, V.H.A., Reynoso-Meza, G., Coelho, L.S.: Multi-objective ensem-
ble model for short-term price forecasting in corn price time series. In: International Joint
Conference on Neural Networks (IJCNN), Budapest, Hungary, pp. 1–8 (2019). https://doi.org/
10.1109/IJCNN.2019.8851880
12. Ribeiro, M.H.D.M., Stefenon, S.F., de Lima, J.D., Nied, A., Mariani, V.C., Coelho, L.S.:
Electricity price forecasting based on self-adaptive decomposition and heterogeneous ensemble
learning. Energies 13(19) (2020c). https://www.mdpi.com/1996-1073/13/19/5190
13. da Silva, R.G., Ribeiro, M.H.D.M., Fraccanabbia, N., Mariani, V.C., Coelho, L.S.: Multi-step
ahead Bitcoin price forecasting based on VMD and ensemble learning methods. In: Interna-
tional Joint Conference on Neural Networks (IJCNN) (pp. 1–8), Glasgow, United Kingdom
(2020a). https://doi.org/10.1109/IJCNN48605.2020.9207152
14. Stefenon, S.F., Ribeiro, M.H.D.M., Nied, A., Mariani, V.C., Coelho, L.S., da Rocha, D.F.M.,
Grebogi, R.B., Ruano, A.E.B.: Wavelet group method of data handling for fault prediction in
electrical power insulators. Int. J. Electr. Power Energy Syst. 123 (2020). https://doi.org/10.
1016/j.ijepes.2020.106269
15. Moreno, S.R., da Silva, R.G., Mariani, V.C., Coelho, L.S.: Multi-step wind speed forecasting
based on hybrid multi-stage decomposition model and long short-term memory neural network.
Energy Convers. Manag. 213 (2020). https://doi.org/10.1016/j.enconman.2020.112869
16. da Silva, R.G., Ribeiro, M.H.D.M., Moreno, S.R., Mariani, V.C., Coelho, L.S.: A novel
decomposition-ensemble learning framework for multi-step ahead wind energy forecasting.
Energy 119174 (2020b). https://doi.org/10.1016/j.energy.2020.119174
17. Google.: COVID-19 Community Mobility Report (2020). https://www.google.com/covid19/
mobility?hl=pt-BR
18. Brunese, L., Mercaldo, F., Reginelli, A., Santone, A.: Explainable deep learning for pulmonary
disease and coronavirus COVID-19 detection from X-rays. Comput. Methods Progr. Biomed.
196 (2020). https://doi.org/10.1016/j.cmpb.2020.105608
19. Hassantabar, S., Ahmadi, M., Sharifi, A.: Diagnosis and detection of infected tissue of COVID-
19 patients based on lung x-ray image using convolutional neural network approaches. Chaos
Solitons Fractals 140 (2020). https://doi.org/10.1016/j.chaos.2020.110170
20. Nour, M., Cömert, Z., Polat, K.: A novel medical diagnosis model for COVID-19 infection
detection based on deep features and bayesian optimization. Appl. Soft Comput. 106580 (2020).
https://doi.org/10.1016/j.asoc.2020.106580
21. Toraman, S., Alakus, T.B., Turkoglu, I.: Convolutional capsnet: A novel artificial neural network
approach to detect COVID-19 disease from X-ray images using capsule networks. Chaos,
22. Ucar, F., Korkmaz, D.: COVIDiagnosis-Net: deep Bayes-SqueezeNet based diagnosis of the
coronavirus disease 2019 (COVID-19) from X-ray images. Med. Hypotheses 140 (2020).
https://doi.org/10.1016/j.mehy.2020.109761
23. Minaee, S., Kafieh, R., Sonka, M., Yazdani, S., Jamalipour Soufi, G.: Deep-COVID: predicting
COVID-19 from chest X-ray images using deep transfer learning. Med. Image Anal. 65 (2020).
https://doi.org/10.1016/j.media.2020.101794
24. Abraham, B., Nair, M.S.: Computer-aided detection of COVID-19 from X-ray images using
multi-CNN and Bayesnet classifier. Biocybern. Biomed. Eng. (2020). https://doi.org/10.1016/
j.bbe.2020.08.005
25. Anastassopoulou, C., Russo, L., Tsakris, A., Siettos, C.: Data-based analysis, modelling and
forecasting of the COVID-19 outbreak. PLOS ONE 15(3) (2020). https://doi.org/10.1371/
journal.pone.0230405
26. Cooper, I., Mondal, A., Antonopoulos, C.G.: A SIR model assumption for the spread of COVID-
19 in different communities. Chaos Solitons Fractals 139 (2020). https://doi.org/10.1016/j.
chaos.2020.110057
27. Lalwani, S., Sahni, G., Mewara, B., Kumar, R.: Predicting optimal lockdown period with para-
metric approach using three-phase maturation SIRD model for COVID-19 pandemic. Chaos
28. Marinov, T.T., Marinova, R.S.: Dynamics of COVID-19 using inverse problem for coefficient
identification in SIR epidemic models. Chaos Solitons Fractals: X 5 (2020). https://doi.org/10.
1016/j.csfx.2020.100041
29. de Oliveira, R.P., Achcar, J.A., Nunes, A.A.: Modeling the incidence and death rates of COVID-
19 pandemic in different regions of the world. Epidemiologic Methods -1(ahead-of-print)
(2020). https://doi.org/10.1515/em-2020-0017
30. Postnikov, E.B.: Estimation of COVID-19 dynamics "on a back-of-envelope": does the sim-
plest SIR model provide quantitative parameters and predictions? Chaos. Solitons Fractals 135
31. Neves, A.G.M., Guerrero, G.: Predicting the evolution of the COVID-19 epidemic with the
A-SIR model: Lombardy, Italy and São Paulo state. Brazil. Phys. D: Nonlinear Phenomena
413 (2020). https://doi.org/10.1016/j.physd.2020.132693
32. Nishiura, H., Kobayashi, T., Miyama, T., Suzuki, A., Sm, Jung., Hayashi, K., Kinoshita, R.,
Yang, Y., Yuan, B., Akhmetzhanov, A.R., Linton, N.M.: Estimation of the asymptomatic ratio
of novel coronavirus infections (COVID-19). Int. J. Infect. Dis. 94, 154–155 (2020). https://
doi.org/10.1016/j.ijid.2020.03.020
33. Workman, J.: The proportion of COVID-19 cases that are asymptomatic in South Korea: Com-
ment on Nishiura et al.: Int. J. Infect. Dis. 96, 398 (2020). https://doi.org/10.1016/j.ijid.2020.
05.037
34. Chimmula, V.K.R., Zhang, L.: Time series forecasting of COVID-19 transmission in Canada
using LSTM networks. Chaos Solitons Fractals 135 (2020). https://doi.org/10.1016/j.chaos.
2020.109864
35. Decock, K., Debackere, K., Vandamme, A.M., Van Looy, B.: Scenario-driven forecasting:
Modeling peaks and paths. Insights from the COVID-19 pandemic in Belgium. Scientometrics
124(3), 2703–2715 (2020). https://doi.org/10.1007/s11192-020-03591-6
36. Hazarika, B.B., Gupta, D.: Modelling and forecasting of COVID-19 spread using wavelet-
coupled random vector functional link networks. Appl. Soft Comput. 96 (2020). https://doi.
org/10.1016/j.asoc.2020.106626
37. Khan, F., Saeed, A., Ali, S.: Modelling and forecasting of new cases, deaths and recover cases
of COVID-19 by using Vector Autoregressive model in Pakistan. Chaos Solitons Fractals 140
38. Salgotra, R., Gandomi, M., Gandomi, A.H.: Evolutionary modelling of the COVID-19 pan-
demic in fifteen most affected countries. Chaos, Solitons Fractals 140 (2020). https://doi.org/
10.1016/j.chaos.2020.110118
39. Shastri, S., Singh, K., Kumar, S., Kour, P., Mansotra, V.: Time series forecasting of Covid-
19 using deep learning models: India-USA comparative case study. Chaos, Solitons Fractals
110227 (2020). https://doi.org/10.1016/j.chaos.2020.110227
40. Justen, A.: COVID-19: coronavirus newsletters and cases by municipality per day (2020).
Accessed in 14 Aug. 2020.https://brasil.io/api/dataset/covid19/caso/data/?place_type=state
41. Shumway, R.H., Stoffer, D.S.: Time Series Analysis and Its Applications: With R Examples,
4th edn. Springer Texts in Statistics, Springer International Publishing (2017). https://doi.org/
10.1007/978-3-319-52452-8
42. Hyndman, R.J., Athanasopoulos, G.: Forecasting: Principles and Practice. OTexts (2018)
43. Box, G.E., Jenkins, G.M., Reinsel, G.C., Ljung, G.M.: Time Series Analysis: Forecasting and
Control, 5th edn. Wiley, New York (2015)
44. Wu, Z., Huang, N.E.: Ensemble empirical mode decomposition: a noise-assisted data
analysis method. Adv. Adapt. Data Anal. 01(01), 1–41 (2009). https://doi.org/10.1142/
S1793536909000047
45. Torres, M.E., Colominas, M.A., Schlotthauer, G., Flandrin, P.: A complete ensemble empirical
mode decomposition with adaptive noise. In: 2011 IEEE International Conference on Acous-
tics, Speech and Signal Processing (ICASSP), pp. 4144–4147 (2011). https://doi.org/10.1109/
ICASSP.2011.5947265
46. Flandrin, P., Rilling, G., Goncalves, P.: Empirical mode decomposition as a filter bank. IEEE
Signal Process. Lett. 11(2), 112–114 (2004). https://doi.org/10.1109/LSP.2003.821662
47. Huang, N.E., Shen, Z., Long, S.R., Wu, M.C., Shih, H.H., Zheng, Q., Yen, N.C., Tung, C.C.,
Liu, H.H.: The empirical mode decomposition and the Hilbert spectrum for nonlinear and non-
stationary time series analysis. Proc. R. Soc. Lond. Ser. A: Math. Phys. Eng. Sci. 454(1971),
903–995 (1998). https://doi.org/10.1098/rspa.1998.0193
48. Chen, T., Guestrin, C.: XGBoost: a scalable tree boosting system. In: Proceedings of the
22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining,
Association for Computing Machinery (pp. 785–794). New York, KDD ’16 (2016). https://
doi.org/10.1145/2939672.2939785
49. Hastie, T., Tibshirani, R., Friedman, J.: The Elements of Statistical Learning: Data Mining,
Inference, and Prediction. Springer Science and Business Media (2013)
50. Huang, L., Li, Y., Chen, S., Zhang, Q., Song, Y., Zhang, J., Wang, M.: Building safety monitor-
ing based on extreme gradient boosting in distributed optical fiber sensing. Opt. Fiber Technol.
55 (2020). https://doi.org/10.1016/j.yofte.2020.102149
51. Huang, G.-B., Zhu, Q.-Y., Siew, C.-K.: Extreme learning machine: a new learning scheme of
feedforward neural networks. In: 2004 IEEE International Joint Conference on Neural Net-
works (IEEE Cat. No.04CH37541), vol. 2, pp. 985–990 vol.2 (2004). https://doi.org/10.1109/
IJCNN.2004.1380068
52. Hochreiter, S., Schmidhuber, J.: Long short-term memory. Neural Comput. 9(8), 1735–1780
(1997). https://doi.org/10.1162/neco.1997.9.8.1735
53. Aggarwal, C.C.: Neural Networks and Deep Learning: A Textbook. Springer, Berlin (2018)
54. Gers, F.A., Schmidhuber, J., Cummins, F.: Learning to forget: continual prediction with LSTM.
Neural Comput. 12(10), 2451–2471 (2000). https://doi.org/10.1162/089976600300015015
55. Awad, M., Khanna, R.: Support vector regression. In: Awad, M., Khanna, R. (eds) Efficient
Learning Machines: Theories, Concepts, and Applications for Engineers and System Designers
(pp. 67–80), Apress, Berkeley (2015). https://doi.org/10.1007/978-1-4302-5990-9_4
56. Drucker, H., Burges, C.J.C., Kaufman, L., Smola, A.J., Vapnik, V.: Support vector regression
machines. In: Mozer, M.C., Jordan, M.I., Petsche, T. (eds) Advances in Neural Information
Processing Systems 9 (pp. 155–161). MIT Press (1997)
57. Cortes, C., Vapnik, V.: Support-vector networks. Mach. Learn. 20(3), 273–297 (1995). https://
doi.org/10.1007/BF00994018
58. Wen, X., Li, Y.: Anesthesia procedure of emergency operation for patients with suspected or
confirmed covid-19. Surg. Infect. 21(3), 299 (2020)
59. Ribeiro, M.H.D.M., Mariani, V.C., Coelho, L.S.: Multi-step ahead meningitis case fore-
casting based on decomposition and multi-objective optimization methods. J. Biomed. Inf.
111(103575) (2020b). https://doi.org/10.1016/j.jbi.2020.103575
60. R Core Team.: R: A Language and Environment for Statistical Computing. R Foundation for
Statistical Computing, Vienna, Austria (2020). URL https://www.R-project.org/
61. Kuhn, M., Johnson, K.: Applied Predictive Modeling, 1st edn. Springer, New York (2013).
https://doi.org/10.1007/978-1-4614-6849-3
The Multi-group Susceptible Infected
Recovered Model with Stage Progression:
A Epidemiological Modelling
of Forecasting COVID Cases
in the Philippines
Ricardo L. Dizon
Abstract The chapter discusses the anti-contagion policies of the Philippine govern-
ment through the implementation of different community quarantine in order to
prevent the further exponential spread of Corona Virus (COVID-19) in the Philip-
pines. The study had used the Multi-group Susceptible Recovered model with stage
progression or otherwise known as heterogeneous mixing model in order to forecast
and assess the impact of the anti-contagion policy of the Philippine government by
incorporating heterogeneous characteristics of group of population according to age.
The Multi-Group Susceptible infected recovered model enables to provide epidemi-
ological forecast of the COVID cases that takes into account various factors such
as patterns of mode of transmission of the disease, recovery rate from the disease,
fatality rate based on age, the probability of transmitting the disease based on the
number of contact and hours of contact, and time days of onset to either declared
infected, recovered, or fatal. The result of the study revealed that the mobility of
people has significant contribution to the transmission rate of COVID in the Philip-
pines. Further, the study found that the mobilization of workers in the Philippines,
who have aged 21–59 years old and who are exempted in the implementation of
community quarantine and allowed to go out of home for work and some essential
works and tasking, are the main drivers of fast increase in the transmission of COVID
disease in the Philippines.
Keywords Multi-group susceptible infected recovered model with stage

progression · COVID-19 · Mobility · Community quarantine · Mitigation ·
Heterogeneous-age mixing patterns
R. L. Dizon (B)
Master of Science in Economics, Polytechnic University of the Philippines, Anonas Street, Sta.
Mesa, Manila, Philippines
e-mail: rldizon@pup.edu.ph
860 R. L. Dizon
1 Introduction
The coronaviruses are family viruses that usually caused a mild to moderate human
upper-respiratory illness such as common cold. These coronaviruses also causes
diseases in multiple animal species such as rats, mice, chickens, turkeys, calves,
dogs, cats, rabbits and pigs. The coronaviruses were first identified during 1965 by
Tyrrell and Bynoe with its first name as B814. It was initially found in the human
embryonic trancheal organ cultures which was taken from the human respiratory tract
of a person with a symptom of common cold. Later, the group of virologists lead
by Tyrrell had performed electron microscopy on fluids taken from organ cultures
from people who are infected with B814, and they have found a medium size (80–
150 nm) particles which resembles the infectious bronchitis of chickens. This particle
is morphologically the same as infectious bronchitis virus, transmissible gastroen-
teritis of swine, and mouse hepatitis. The B814 was then latter accepted as a new
genus of viruses called coronavirus. The B814 viruses was renamed as coronavirus
because of its crown-like spikes on their surface features [4, 22].
Before December 2019, the coronaviruses were classified into six strains which
are: (1) 229E (alpha coronavirus); NL63 (alpha coronavirus); (3) OC43 (beta coron-
avires); (4) HKU1 (beta coronavirus); (5) MERS-CoV (beta coronarivurs that causes
Middle East Respiratory Syndrome, or MERS); and (6) SARS-CoV (beta coronavirus
that causes severe acute respiratory syndrome, or SARS).
In December 2019, a new strain of coronavirus had been identified by Chinese
researchers in Wuhan, China. The Chinese researchers had identified this viruses as
a member of β group of coronaviruses. It was first named as Wuhan coronavirus
or 2019 novel coronavirus (2019 nCov). Later, the 2019 novel coronavirus was
renamed as COVID-19 by the International Committee on Taxonomy of Viruses
[4, 13, 25]. The Coronavirus 2019 (COVID-19) is an infectious disease caused by
a new strain of human corona virus that can be transmitted from person to person.
This COVID-19 can be spread through droplets transmission which occurs when a
person is indirect contact with someone who are infected by COVID-19. It can also
be transmitted to human by indirect contact with objects used by the infected person.
The source of COVID-19 is may have been transmitted to people from animal who
have visited the Hunan seafood market in Wuhan city of China [27]. The National
Health Commission of China had found that those patients infected by COVID had
pneumonia, and also found that some individuals contracted the disease even with
no prior record of visiting the seafood market. This COVID-19 had spread rapidly in
China within few weeks and in several other countries, such as United States, Italy,
Germany, and the Philippines, within one month [8].
In the case of the Philippines, the first two confirmed COVID-19 cases were
admitted in national infectious disease referral hospital in Manila. This two confirmed
cases are couple Chinese national who are on vacation in the Philippines. The first
patient is a 39-year-old female who had a symptoms of cough and sore throat. She
was admitted in San Lazaro Hospital in Manila in January 25, 2020, and she was
reported as COVID-19 infected on January 30, 2020 after the initial PCR swab
The Multi-group Susceptible Infected Recovered … 861
test. The second confirmed case of the Philippine is a 44-year-old Chinese male
who had a symptoms of fever, cough, and chills. The first COVID patient in the
Philippines was discharge as her symptoms were resolve. Meanwhile, the second
patient was reported as the first case fatality in the Philippines in February 1, 2020.
The second patient was treated for community-acquired pneumonia and later his
condition become deteriorated.
The first Filipino citizen who was confirmed as positive COVID-19 case is a 48-
year-old male Filipino who had travelled in Japan last February 25, 2020, and upon
returning from Japan he had experienced chills and fever. He was test positive for
COVID-19 on March 5, 2020. Further, the first cases of local transmission of COVID-
19 in the Philippines was recorded on March 5, 2020 who are a husband and wife
without recent travel history. The 62-year-old husband had experienced cought with
phlegm, and he was admitted to hospital due to severe pneumonia. Meanwhile, the
59-year-old wife had experienced cough, and she was admitted to Research Institute
for Tropical Medicine Manila.
As of November 22, 2020, the Philippines has 418,818 confirmed COVID-19
cases. Of these total number of COVID-19 cases, a total of 386,486 had recovered
and 8,123 were fatal. The COVID-19 cases in the Philippines has a share of 0.72% in
the total number of confirmed cases in the world. With the continuos increase in the
number of COVID-19 cases, different countries in the world has been implementing
different forms of locked down system in response to COVID-19. The concept of
locked down system aims to reduce the human to human transmission of COVID by
strictly implementing home quarantine to the household and allowing only people
to move for some essential activities such as buying necessities and attending to
work-related actviities essential in providing neccesity goods. The locked down is
usually coupled on guidelines on maintaining social distancing [20]. The locked down
system has two major objectives which includes: (1) Mitigations which means of
preventing the health care maximum capacity which includes hospitals, quarantine
facilities and Infectious Disease Center; and (2) Suppression which means strategy
on decreasing the number of infected individual by imposing social distancing of
population of areas under locked down, suspension of works and classes in schools
and universities, and prohibiting mass gatherings [20].
In the case of the Philippines, the country has been also implementing the locked
down system in the form of four different levels of community quarantine to prevent
the exponential spread of COVID-19 cases. These four levels of community quaran-
tine includes: (1) Enhanced Community Quarantine (ECQ); (2) Modified Enhanced
Community Quarantine (MECQ); (3) General Community Quarantine (GCQ); and
(4) Modified General Community Quarantine (MGCQ). This community quaran-
tine has serves as a replacement of the China’s health measures called “locked
down system”. The Philippine government had opted to replace the term locked
down system so as not to associate the term into the concept of martial law. The
concept of martial law has caused an intimidation among Filipinos due to its stigma
of overemphasizing the military power.
862 R. L. Dizon
1.1 The Problem and Motivations
The community quarantine serves as the anti-contagion policies of the Philippine

government of prevent the further exponential increase in the COVID-19 cases.
This anti-contagion policy of the has brought controversial issues in the country
since it results to temporary shutting down of operations of most of the businesses,
thereby resulting to massive lay-off of workers and closure of small, medium, and
large enterprises. With this adverse effect, this chapter aims to provide answers to
the following specific problems: (1) What has been the current and future trend of
COVID-19 cases, number recovered and fatal patients in the Philippines; and (2)
What has been the effect of the community quarantine in the number of COVID-19
cases, number recovered and fatal patients in the Philippines.
1.2 Objectives and Contribution of the Chapter
The objective of this chapter is to provide epidemiological forecast of transmission

rate, recovery rate and fatality of COVID-19 cases in the Philippines. The National
Capital Region (NCR) serves as the focus of the discussion of this chapter since it
is considered as the epicenter of COVID-19 transmission. Also, this book chapter
provides an assessment of the effect of the anti-contagion policies of the Philippine
government, specifically community quarantine, to the spread of COVID-19 cases.
This chapter provides additional information on the existing literatures on the
trends of COVID-19 cases in the Philippines. This serves also as an inputs to Philip-
pine Inter-Agency Task Force for Emerging Disease and other Philippine govern-
ment offices on crafting additonal policies in response to the exponential spread of the
COVID-19 cases in the Philippines by forecasting the transmission rate, recovery rate
and fatality and by assessing the effects of different levels of community quarantine
on the spread of COVID-19.
To provide substantial informations to address the specific problem as cited in
portion 1.1, this Chaper is organized into five sections. The Sect. 1 provides intro-
ductions, the problem and motivation, and objectives and contribution of the Chapter.
The Sect. 2 provides review of related literatures and studies. The Sect. 3 provides
the methodology used to forecast the COVID-19 cases and to assess the effects of
community quarantine. The Sect. 4 provides discussion of the case study. The Sect. 5
provides recommendations.
2 Review of Related Literatures and Studies
This section of this book chapter discusses the literatures and studies related to
Philippine COVID-19 cases study. The first portion of this section discusses the
history of mathematical epidemiology. The second portion discusses the evolution

of Susceptible Infected Recovered (SIR) Model. The third portion of this section
discusses the different forecast model of COVID-19.
2.1 The History of Mathematical Epidemiology
2.1.1 The Evolution of Mathematical Epidemiology
The epidemiology is the study of disease occurrence. If there is unusual large, short
term outbreak of any disease it is so called epidemic, and if it persists in the population
it is so called endemic. The rate of spread of infectious diseases is being affected by
various factors such as the characteristics of infectious agent, mode of transmission,
latent period, infectious period, susceptibility and resistance [9]. Also, the rate of
spread of the disease is being affected by social, cultural, demographics, economics
and geographic factors. The spread and transmission of any disease from infected to
susceptible individual can be studied through studying the chain of infection. Since
the transmission interactions among population are very complex, it is important to
develop a mathematical model that contains the pattern of transmission of a disease.
The mathematical model serves as an important tool to analyze the spread and control
of a particular disease. It has both capabilities and limitations that utilizes epidemi-
ological concept and utilizes data to answer specific questions regarding the spread
of disease [10].
The first study of infectious disease was conducted by John Graunt during 1662 in
his book entitled Natural and Political Observations Made Upon the Bills of Mortality.
Graunt have analyzed the different causes of death, and he had developed a model
to estimate a comparative risks of fatality among different diseases. The works of
Graunt was then followed by the first epidemiological model for vaccination against
smallpox by Daniel Bernoulli in 1700–1782. During eighteenth century, the smallpox
was considered as endemic and Bernoulli had developed to calculate the increase in
life expectancy if the smallpox is eliminated as a primary cause of death. In 1800,
William Farr have worked systematically in collecting and analyzing the mortality
statistics of the Britain.
In the mid-1800s John Snow, an anesthesiologist, conducted a series of investiga-
tions in infectious diseases in London that makes him to be considered as the father
of field epidemiology. Snow become popular in 1854 due to his investigation of the
epidemic of cholera by using the spot map. The spot map is a map of residence and
work area of those persons who have cholera. Snow studied the source of cholera
by marking the location of water pumps on his spot map and then he had studied
the relationship between the distribution of households with cases of cholera and
the location of pumps. that among the three pump stations, namely Pump A, Pump
B, and Pump C, he found out that Pump A was the source of cholera since it was
grossly contaminated. He had also found out that there is a brewery with a deep
well on the premises. This deep well serves as the primary source of water for those
864 R. L. Dizon
who have acquired cholera. Since that particular pump was the source of the cholera,
the handle of it was removed so that the residents will no longer obtain water from
the pump. Because of this study, the outbreak was ended in Golden Square London
[2]. In 1906, W. H. Hamer had suggested that in studying the spread of infectious
disease, one must study the number of susceptible individuals and the number of
infected individuals. These suggestions by Hamer became a strong foundations of
the compartmental models approach of epidemiology [1].
2.1.2 The Importance of Mathematical Epidemiology
The interactions in a population are very complex which has caused to difficulty in
understanding the dynamic of the spread of the infectious diseases. With this complex
interaction among population, the mathematical model, particularly epidemiolog-
ical model, enable to provide clear understanding of this complex interaction. The
epidemiological model enables to provide microscopic description to forecast the
macroscopic behavior of transmission of the disease in a certain population. With
the limitations of conducting experiments such incomplete information due to under-
reporting, the mathematical models enable in order to augment the limitations
of conducting experiment by providing simulations. The Epidemiological models
enable to compare the effects of the government’s disease control and prevention
programs. It also leads to a clear statements of the assumptions about the sociological
and biological that affects the disease preventions strategies [10].
Further, the mathematical model serves as an overview of the micro world
consisting of various entities which are behaving according to specific rules of
behavior. The mathematical model is often combine by mathematical analysis and
computer simulation which help us to study the global behavior of infectious diseases.
Thus, the mathematical model serves as a tool for predicting the future spread of infec-
tious diseases by drawing out the global behavior of infectious diseases and making
an assumptions. Also, the mathematical epidemiology can describe the transmission
of the pathogen among hosts which depends on the patterns of contacts among infec-
tious and susceptible individuals, latency period from being infected to becoming
infectious, duration of infectiousness, and the extent of immunity acquired from
infection [12].
With the limitations in conducting an experiments in epidemiology with controls
such as ethical questions involved in withholding treatment from a control group
and difficulty and designing control population, the mathematical modelling enables
to augment the limitations of an experiment by comparing the effects of different
management strategies. It enables to provide understanding the factors that influ-
ences the spread of the diseases, and it suggests control strategies in the process of
formulating a mathematical analysis of the model [1]. In recent years, the epidemi-
ological modelling become an important element of public health decision-making
on examining infectious disease such as, but not limited to, HIV/AIDS epidemics,
pandemic influenza or multi-resistant infections in a hospital [25]. Also, the mathe-

matical modelling has addressed the key issues of resistance in antibiotic that would
led to an analysis of treatment protocols for resistance prevention [24, 26].
The mathematical model also serves as an importance role on assessing the
potentials effects of Non Pharmaceutical Intervention (NPI) against the COVID-
19. The mathematical model has been used to investigate the epidemic development
of COVID-19 in different countries such as China, Philippines, and United States.
The Susceptible-Infected-Removed (SIR) Model is the basic epidemiological model
which are commonly used in assessing the effects of NPI in controlling the spread
of COVID-19. The SIR Model enable to predict the magnitude and timing of the
epidemic peak and the final epidemic size after NPIs [28].
2.2 Different Mathematical Models for COVID-19
2.2.1 The Susceptible-Infected-Removed Model
According to Hethcote [10], there are three basic types of epidemiological models
which are composed of: (1) The SIS model; (2) The SIS Model Without Vital
Dynamics; and (3) the SIR Model with Vital Dynamics. The SIS model is a model
for disease for which infection does not assume immunity. Under the SIS model, the
individual will return to susceptible class once they were recovered from the infec-
tion. This model is appropriate to be used for some bacterial agent diseases such as
meningitis, gonorrhea, and streptococcal sore throat. The SIS model, as represented
in Fig. 1, includes naturally occurring births and deaths and the behavior of solutions
is homogenous when dynamics are not included.
Figure 1 depicts the number of births is added in the total number of susceptible
individuals (NS Susceptible), while the number of Deaths is removed from the total
number of susceptible individuals. The represents the birth rate, N is the total
number of population, and μ is the death rate. The number of cases per unit of time
(λSNI) contributes in the prevalence of the disease (number of cases of a disease at
Fig. 1 The compartmental diagram for the SIS model

866 R. L. Dizon
Fig. 2 The compartmental diagram for the SIR model without vital dynamics
a given time represented by NI). Once the infected individual per unit of time has
been recovered (USNI), one may be form part of the total number of susceptible
population. If the infected individual become death, it will be removed in the total
number of individual who will experience of relapse of infection.
The second model is the SIR Model without vital dynamics for which consider
immunity after recovery from infectious diseases. Figure 2 show the compartmental
diagram for the SIR model without dynamics. The model does not include births and
death as vital dynamics. The SIR model postulates that the infections stop during
the epidemic because the Susceptible individuals decreases due to immunity in the
disease.
The third model is the SIR Model with vital dynamics (Fig. 3). Under this model,
the disease behavior become endemic in the population which stays over a long time
period time for more than 10 or 20 years. The SIR model with vital dynamics postu-
lates that the number of infected individual is determine by the contact rate λ. Mean-
while, the number of removed individuals are affected by the removal rate U. If the
number of contact decreases with less than one, the number of infective individuals
also decreases then the disease dies out. Moreover, the model also emphasized that
as everyone in the population become susceptible when the disease has disappeared
and those immune individual have died.
Several research works have adopted the SIR model to investigate the spread
of COVID-19 in various countries. The SIR model can provide valuable insights
and predictions of the spread of COVID-19 in communities. According to epidemic
model, the infectious disease can be transmitted in two different ways: (1) hori-
zontal transmission which occurs by direct contact between infected and susceptible
individuals [13, 18]; and (2) vertical transmission occurs by direct contact between
Fig. 3 The compartmental diagram for the SIR model with vital dynamics
infected materials and susceptible individuals through a sneeze, cough, skin-skin

contact, or exchange of body fluids [11, 20].
The evolution of the SIR model was trace in the early twentieth century when
Dr. Ronald Ross had developed a simple compartmental model of dynamic trans-
mission of malaria between mosquitoes and humans which popularly known as
SIR (Susceptible-Infected-Removed) model. Dr. Ross was the first to introduce the
concept of basic reproduction number. The model of Dr. Ross had been supported
by the proposition of W.H. Hamer who had emphasized that the infection should be
dependent on the number of individuals who are susceptible and number of infected
individuals. The SIR is composed of a system of three coupled non-linear equations
with the following assumptions: (1) The population is fixed; (2) The only way for
an individual to leave the susceptible group of population is to become infected; (3)
The only way a person can leave the infected group is to recover from the disease
and become immune once the individual has recovered; (4) Age, sex, social status,
and race do not affect the probability of being infected by the disease; (5) There is
no inherited immunity; and (6) The member of the population mix homogenously
which manifest the same contact and degree of interactions among other member of
the population.
The SIR model partition the group of population into three categories which are:
(1) S(t))—Susceptible individuals individual at time t; (2) I(t)—Infected Individuals
at time t; and (3) R(t)—Recovered individuals at time t. The SIR model has been
developed to incorporate different characteristics of population. One of the signif-
icant contribution in the development of the SIR model is the work of Kermack
and Mckendrick. The model intends to describe the pattern of transmission of infec-
tious diseases [16]. The Kermack-McKendrick epidemic model is represented by the
following equations:
vt = −x (t) (1)
⎡ t ⎤

x (t) = −x(t)⎣ A(s)v(t − s)ds + A(t)y0 ⎦ (2)
0
t
Z (t) = C(s)v(t − s)ds + C(t)y0 (3)
0
t
y(t) = B(s)v(t − s)ds + B(t)y0 (4)
0
where, x(t) is the number of susceptible individual, y(t) is the number of infected
individuals, Z(t) is the number of recovered individuals(s) is the rate of recovery at
population age group, ψ(s) is the rate of recovery at certain population age
868 R. L. Dizon
t
B(s) = e − ψ(s)ds, A(s) = ϕ(s)B(s) (5)
0
Since the assumption of the model is that there is no fatality, the total population
would not be reduced. The final size relation is:
∞
1 − yN0
log = pN A(s)ds (6)
1− p
0
where N is the total population size and p is the attack ratio

x∞
p =1− (7)
N
The reduced form of Kermack-McKendrick epidemic model includes the depen-
dence on age of infection which is represented by the three nonlinear ordinary
differntial equations:
d S = −β S I (8)
dI
= βSI − γ I (9)
dt
dR
=γI (10)
dt
where t refers to time, S(t) refers to the number susceptible individual, I(t) is the
number infected individual, R(t) is the number of people who have recovered and
developed immunity to the infection, β is the infection rate or the average number
of transmission from infected person in a time period (β, is greater or equal to zero)
and γ is the recovery rate (γ is greater or equal to zero). The Eq. 8 emphasizes that
the susceptible group will decrease over time and approach to zero. Meanwhile, the
Eq. 10 shows that the recovered group increases and will approach the N over time.
The rate of change of infected group is strictly positive or zero which depends on
the rate of recovery (γ ), transmission rate (β), and number of susceptible individual
S(t). If βS(t) is less than recovery rate γ then the rate of change for the infected group
is negative. If βS(t) is greater than k then the rate of change for infected group is
positive. Then if βS(t) is equal to k then the rate of change for infected group is zero.
Another development in the SIR model is the inclusion of dynamic time model.
The dynamic formula of the SIR model is derived using the Euler’s method of system,
then the equation is represented by:
Sn+1 = Sn − β Sn In t (11)
In+1 = In (1 + β Sn − k)t (12)
Rn+1 = Rn + k In t (13)
where Sn+1 , In+1 , and Rn+1 are the number of susceptible, infected, and recovered
individual at time (n + 1).
The group of population who recovered from disease includes people who receive
life-time immunity, however in the Eq. 10 does not specify whether alive with immu-
nity or fatal. Then to distinguish the difference between the individual who are alive
with immunity or fatal, the Eq. 10 replaces by the Eqs. 14 and 15.
dV
= k V I (t) (14)
dt
dD
= k D I (t) (15)
dt
where V refers to immunity, D is the fatal individual, kV is the recovery rate for those
living individual, and kD is the fatality rate. Expanding the equation using the Euler’s
method to determine the number of individual who recovered and become immune
and those individual who become fatal at time (n + 1) then the new equation would
be represented by:
Vn+1 = Vn + k In t (16)
Dn+1 = Dn + (1 − k)It t (17)
2.2.2 The Basic Reproductive Number
Ross and Kermack and McKendrick have developed an epidemiological threshold

quantity which so called basic reproduction number denoted as R0 . The R0 is the basic
reproduction number that is expected number cases produced by a certain disease. It
measure the transmission potential of a disease. It is the average number of secondary
infections caused by single primary infection or the number of infected by contact
with a single infected person before his death or recovery. The R0 is represented by
the equation:
βS
R0 = (18)
γ
870 R. L. Dizon
where the R0 is denoted as the ratio of infection rate and recovery rate. If R < 1,
each infected individual may infect fewer than one person before his/her recovery or
death. If R > 1 each infected person will infect more than one person so that epidemic
will spread.
2.2.3 The Effective Reproductive Number (R)
In real world, the whole population maybe rarely susceptible to an infection, and some
contacts will be immune due to prior infection which resulted to life-long immunity
or as a result of vaccinition, and then it is worth nothing the effective reproduc-
tive number. The Effective Reproductive Number (R) is then average number of
secondary cases per infectious disease that a papulation is composed of both suscep-
tible and non-susceptible hosts. It can be estimated by the product of basic reproduc-
tive number and the fraction of the host population that is susceptible (x). The R is
represented by the following equation:
R = R0 x (19)
If the R > the number of cases will increase, and if the R < 1 then the number
of cases will decline. Meanwhile, if R = 1 then the disease is endemic. In order to
successfully eliminate a disease from a population, R need to be less than 1.
2.2.4 The Multi-group Susceptible Recovered Model Specification
A realistic epidemiological model to forecast the spread of infectious disease must

include the mechanism of transmission of disease, pattern of mixing among group
of population, the population’s susceptibility, the severity of the infection, the prob-
ability of transmission per contact, and the changes in behavior in the infected group
of population.
The conventional SIR model assumes homogenous mixing population which only
provides a sufficient general insight, however, there can be significant difference in
the early stage of epidemic and the final stage of epidemic. This may cause an
overestimation of the spread of the disease.
The multi-group susceptible-infected-recovered (SIR) model with staged
progression or otherwise known heterogeneous age-mixing model enable to account
the differences in the pattern of transmission of disease, recovery, and fatality (Del
Valle, et al., 2020). The multi-group SIR model classify the population into three
epidemiological classes which are: (1) Susceptible—those populations who are
disease free; (2) Infected—those populations who are infected by certain disease;
and (3) Recovered—those populations who recovered by certain disease.
The three epidemiological classes are further subdivided into age groups with
pattern of mixing, different rate of susceptibility, and rate of infection per age group.
Fig. 4 The schematic diagram of multi-group SIR model
The infected individual is further subdivided into incubation period, prodromal

period, and symptomatic or infectious period.
Figure 4 depicts the schematic diagram of multi-group susceptible-infected-
recovered model with stage progression classified into age group, three infection
stages. S1,S2…..Sn refers to susceptible population at given age, I11,I21…….In1 is
the infected individual at incubation period at different age group, I12,I22…….In2
is the infected individual at prodromal period, I13,I23…….In3 is the infected
individual at infectious period. Meanwhile, λ1,λ2,……….λn is the infection
rate,ω11,ω21………ωn is the stage rate of progression, μ11,μ21,…..μn1 is the
fatality rate.
The mathematical representation of derivation of those who are Susceptible (S),
Infected (I), and Recovered (R) which are measured in days are as follows (Del Valle
et al., 2014):
i(t) = λi (t)Si (t) − (wi + μi1 )Ii1 (ti ) (20)
s(t) = −λi (t)Si (t) (21)
r (t) = wi Iim (22)
The i(t) is the change in number of infected individual which is derive by

substracting the proportion of susceptible who are infected λi (t)Si (t) and propor-
tion of infected who were expired as represented by (wi + μi1 )Ii1 (ti ). The s(t) is
the change in the number susceptible individuals which is derive by determining the
proportion of population who are susceptible −λi (t)Si (t). The r(t) is the change in
the number of recovered individual from the disease which is determine by deriving
the proportion of population who have recovered from disease. The λi (t) is the trans-
mission rate from infected people in the same age group or other age group. It is
872 R. L. Dizon
derived using the following formula:

Ijk (t)
λijk (t) = γij (t) αi ξjk Pij (23)
Nj (t)
where, λijk is the rate at which susceptible individual progresses at particular age
group and infection stage. It is a product of number of contacts per unit γij (t) ,
probability of disease transmission per contact per unit of time of infected individual
at particular age group to susceptible individual at particular age group ( the product
of susceptability (αi ),infectivity (ξ) and the probability of transmission (Pij ), the
I (t)
proportion of contacts that are infected Njkj (t) . Further, the probability of disease trans-
mission per day (Pij ) is derive by using Poisson Distribution which is given by the
formula:
Pi j = 1 − e−ς Ti j (24)
where Tij is the duration of a contact of an susceptible individual to infected indivi-

udal. The ς is the contact patterns which may either be normal, reduced, proportional,
and segregate mixing pattern.
2.3 Various Studies that Have Used SIR Model
Cooper et al. [3] had used the SIR model to investigate the effect of NPI in controlling
the spread of COVID-19 in different countries such as China, South Korea, India,
Australia, USA, Italy and state Texas in the USA. Their study had found that NPIs
implemented by China such as quarantine of confirmed COVID patients, restriction
in the movement of citizen, imposing social distancing, and wearing of face masks has
resulted to a decrease in the number of COVID cases more than the predicted cases
of SIR model. In the case of South Korea, the study had found that the country has
recorded a bullish drop in the number of susceptible population due to implementation
of extensive COVID testing program. South Korea has aldo chieved a low fatality rate
without imposing the draconian lock down system imposed by China. Meanwhile,
the study had included the new surge periods to predict the COVID-19 cases in
India using the SIR model. The India’s SIR model provides rough estimate of future
infections and deaths, and this model was used to evaluate which time the restriction in
the movement of population will be eased. Further, the action taken by the government
of Australia such as testing, contact tracing, social distancing, staying at home policy,
closure of business and encouraging people to work from home were considered
as successful. The rate of success of the Australian government intervention was
reflected in the decline in the number of infections in comparison to the model
predictions. The SIR model has also predicted that the COVID-19 cases in the USA
are keep on increasing, while the spread of the said virus in Texas was slow down
due to government interventions. Further, the SIR model has also suggested that the
spread of Italy’s COVID-19 cases has been contained and the number of active cases
is rapidly declining.
Nguemdjo et al. [19] had used the SIR models to analyze the evolution of COVID-
19 in Cameroon covering the period March 6- April 2020. The result of the study
had revealed that the reproduction number of COVID-19 in Cameroon is about 1.5,
and the peak of transmission of the said virus have occurred at the end of May 2020.
Moreover, the anti-contagion policies implemented by the government of Cameroon
had helped to flatten the curve of transmission of the COVID-19.
Mackolil and Mahanthesh [17] had also investigated the spread of COVID-19 in
India using the SIR framework. The study had used the three states of India such as
Karnataka, Kerala, and Maharashtra to observe the pattern of spread of the disease.
Using the SIR model, the study had predicted that Kerala had attained flattening
of curve of the spread of COVID-19, while Karnataka and Maharashtra states have
shown a continues increase in infection rates.
Talukder [23] had used the SIR model to forecast the outbreak of COVID-19 in
Bangladesh. Based on the result of the study, the individual can be recovered from
COVID-19 infections in a specific period at the rate of 0.2366. Moreover, the study
also found that the average number of infected individual is more seven, as reflected
in R0 of 7.14.
3 Methodology
3.1 The Multi-group Susceptible Infected Recovered Model

with Stage Progression Model to Forecast COVID Cases
in the Philippines
In order to forecast the COVID cases in the Philippines, the Multi-group Age Mixing
Model with stage progression was used. Several theoretical and empirical studies
have developed mathematical models using the SIR to forecast the COVID-19 cases;
however, none of the existing literatures have used the Multi- group Age Mixing
Model to forecast the COVID-19 cases. This extension of SIR model has divided the
population into arbitrary number of subgroups of population. Since the population
is divided into subgroup of population, this model enables to account the differences
in the rate of infection, recovery, and fatality in age sub-group of population. The
model also accounts the differences in contacts and mixing patterns between age
groups with different activity levels. The determination of the differences in contact
and mixing patterns plays an important role in determining the behavior of the spread
of COVID-19 for each group of population. For instance, the working population
group who have ages from 21–65 years old have different levels of activity from
those senior citizen population (ages 65 years old and above) and from those those
874 R. L. Dizon
young population (below 21 years old). Further, the model has the capability to assess
the effectiveness of the NPI being implemented by the Philippine government in the
form of community quarantine in order to prevent the spread of COVID-19.
To implement the multi-group SIR age mixing model, this study had sub-divided
the population into three epidemiological classes which are: (1) Susceptible, (2)
Infected, and (3) Recovered. In line with the community quarantine guidelines
released by the Philippine IATF for COVID-19 to prevent the spread of the COVID-
19, the epidemiological classes are further subdivided into three age sub-group of
population which composed of: (1) Mobile Workers—those who are exempted in
the community quarantine who have aged 21–59 years old, and who are allowed
to work and do some important activities outside their respective home;(2) Senior
Citizen- those population ages 60 years old and above who are under strict quarantine
since they are considered as most vulnerable age group; and (3) Young—those popu-
lation ages less than 21 years old who are under quarantine since they are considered
either super spreader of the COVID and maybe considered as also vulnerable. This
Multi-group SIR with stage progression model of the Philippines has the following
assumptions and limitations: (1) senior citizen will not be allowed to leave the house
for work or to buy necessities since they are more susceptible in the pandemic disease;
(2) people who recovered from the infection become immune and cannot become
infected the second time around;(3) no available vaccines has been developed all
around the word, since experiment to create vaccine is still ongoing or vaccines to
treat the Covid-19; and (4) in view of data limitations, the chances of transmission
to persons who are immunocompromised and with underlying medical conditions
with co-morbidities cannot be estimated using the model. The objective of using the
Multi-group SIR with stage progression model is to determine how each infected
individual is able to transmit the COVID from working population group to other
working population group, to senior citizen, and to young individual. It is assumed
that the transmission of disease originated from workers group of population since
they are exempted on community quarantine under the Inter Agency Task Force
(IATF) guidelines. The workers group of population are those populations who have
a task to do some important activities such as buying food, necessities, and medicines
despite of community quarantine. The mathematical model of multi-group SIR model
is represented by the following transfer diagram in Fig. 5.
Figure 5 shows the schematic diagram to implement the multi-group SIR Model in
forecasting the COVID cases in the Philippines. Since the working population group
who have aged 21–59 years old are allowed to go out of home for work or other
essential activities such as buying necessities and food, they serve as the spreader
of COVID-19. Once the working population became infected, they can transmit
the disease to those other sub-group of population who are under the strict home
quarantine, specifically senior citizen age group (60 years old and above) and young
age group (below 21 years old).
The working age group who are infected may transmit the disease into the suscep-
tible population in the same age group (workers) who may be recovered, fatal, or
remain active cases in certain period. The mathematical notation for the multi-group
SIR model in the Philippines is represented by the following equations:
Recovered
(Senior)
Susceptible Infected
Individual Fatal
(Senior)
(Senior) (Senior)
Active
Cases
(Senior)
Recovered
(Working)
Susceptible Infected Fatal

Infected
(Working) (Working) (Working) (Working)
Active
(Working)
Recovered
(Young)
Susceptible Infected Fatal

(Young) (Young) (Young)
Active
(Young)
Fig. 5 The schematic diagram of multi-group SIR model applied in the philippines
i(t) = i y + i w + i s (26)
s(t) = s y + sw + ss (27)
r (t) = r y + rw + rs (28)
f (t) = f y + f w + f s (29)
where, (t) is the number of infected individuals in the Philippine at particular time
(t). The number of infected individuals is the aggregation of infected young age
group (iy), infected workers (iw), and infected senior citizen (is). Meanwhile, the s(t)
represents the total number of susceptible individuals which are composed of young
age group (sy), working age group (sw), and senior citizen age group (ss). The r(t)
is the number of recovered individual at particular time which are also composed of
876 R. L. Dizon
of young age group (ry), working age group (rw), and senior citizen age group (rs).
Finally, the f(t) is the number of fatal individual which are also composed of young
age group (fy), working age group (fw), and senior citizen age group (fs).
Each infected group of population is computed following the formula of Del Valle
et. al (2013) with a modification to tailored in the Philippine COVID cases situation
which is represented by equation:
In+1 = In + wi j λi (t)Si (t) (30)

Ijk (t)
where : λijk (t) = γij (t) αi ξjk Pij (31)
Nj (t)
where, In+1 is the number of cumulative cases in the Philippines, In is the number
infected individual at previous time, wi j is the relative rate of disease progression, S(t)
is the number of susceptible to COVID, λijk is the rate at which susceptible individual
progresses at particular age group (young, workers, senior citizen) and infection
stage. It is a product of number of contacts per unit γij (t) , probability of disease
transmission per contact per unit of time of infected individual at particular age
group to susceptible individual at particular age group (the product of susceptability
(αi ),infectivity (ξ) and the probability of transmission (Pij ), the proportion of contacts
I (t)
that are infected Njkj (t) .
The rate of contacts of working population to other sub-group of population used in
the model is 50%. This represents the reduced mobility of the people due to commu-
nity quarantine where those senior and young age sub-group of population were not
allowed to go outside their respective houses. The rate of contact that has been used
includes areas which are placed under the community quarantine. The assumption
of rate of contact were based on the Philippine IATF’s guidelines on implementing
the community quarantine to observe minimum health standard in preventing the
spread COVID-19. Under this guidelines, those public and private institution, who
are allowed to operate under the different levels of community quarantine such as
General Community Quarantine, Enhanced Community Quarantine, and Modified
General Community Quarantine, should observe skeletal forces (reduce work force)
and the remaining work forces should work- from-home.
Further, the probability of disease transmission per day (Pij ) is derive by using
Poisson Distribution which is given by the formula:
Pi j = 1 − e−ς Ti j (32)
where Tij is the duration of a contact of an susceptible individual to infected indi-

vidual. The ς is the contact patterns used in the Philippine epidemiological model
is a combination of reduced and proportional mixing pattern. The reduced mixing
pattern was used to determine contact of worker to worker age group. Meanwhile, the
proportional mixing pattern was used to determine the contact of working age group
to either senior citizen and/or young age group. The number of daily contact hours
used between working age group to other working age group is 13 h which represent
the daily working hours and the average travel time from home to working station in
the Philippines. Meanwhile, the number of daily contact hours used between working
age group to young age group and senior citizen age group is 11 h which represents
the time the working age group stayed at home. The proportion of contacts that are
infected is computed by the proportion of 50% of the population of areas which
have recorded COVID infection who are infected. The proportion of contacts that
are infected is computed by by the proportion of 50% of the population of areas
which have recorded COVID infection who are infected.
The number of susceptible individual per age group is computed using the Eq. 32.
Sn+1 = Sn − β Sn In t (33)
where, the number of aggregate number of susceptible individual at time t is repre-

sented by the term Sn + 1. It was derived by subtracting number of Susceptible in
base period to the number of infected individuals Sn In t.
Meanwhile, the total number of recovered and fatal is computed as follows:
Rn+1 = Rn + k In t (34)
Fn+1 = Fn + (1 − k)It t (35)
where, the total number of recovered individual Rn + 1 is determine by the number of

recovered in base period Rn plus the number of newly recovered individual determine
by the recovery rate and time of progression between confirmed infected to recovered
date. Meanwhile, the total number of fatal individual Fn + 1 is determine by the
number of fatal in base period Fn plus the number of new case of fatality individual
determine by the fatality rate (k) and time of progression between confirmed infected
to date of death.
The number of active COVID cases in the Philippines is derived using the
following formula:
Aci = Ii − Ri − Fi (36)
where Aci is the number of active case per age group is derive by subtracting the
number of recovered in particular age group Ri and the number of fatal in particular
age group Fi to the number of infected individual at particular age group Ii. The
data used such as daily number of infected, recovered, and fatal were taken from the
Philippine Department of Health. Meanwhile, the number of population was culled
from the Philippine Statistical Authority [25].
878 R. L. Dizon
3.2 The Periods of Disease
A pandemic disease has five periods which are: (1) incubation; (2) prodromal period;
(3) period of illness; (4) period of decline; and (5) period of convalescence. The
incubation period is the time where the initial entry of disease into the host (patient)
and the time where it begins multiplying. The incubation period used in the model
is 11 days [2]. The prodromal period occurs after the incubation period where the
disease continues to multiply and the patients begins to experience general signs
and symptoms of illness such as fever, pain, swelling and inflammation. Meanwhile,
the period of illness is the time where the symptoms of disease are most obvious
and severe. The period of decline is the time where the disease begins to decrease.
The period of convalescence is a period where patients generally return to normal
functions.
In order to forecast the infection rate, recovery rate and fatality rate, this Multi-
group SIR model of COVID cases in the Philippines have used different period of
disease. The period of disease determines the length of period of exposure to the time
the individual is being reported as positive case, recovered, or fatal. The study has use
16 days as the progression period from prodromal to convalescence. This is based on
the median difference between the prodromal period and the date of discharged of 49
recorded recovered Covid- 19 patients as of September 29, 2020 in the Philippines.
Meanwhile, the median period between the fatality and the prodromal is at 13 days.
4 Discussion
4.1 The Different Measures of Philippine Government

to Prevent the Spread of COVID in the Philippines
The first government measures in response to prevent the spread COVID in the
Philippines is the imposition of travel ban last January 31, 2020 for those non-
Filipino citizen travelling from China, Macau Special Administrative Region, and
Hong Kong. The travel ban was then extended last February 11, 2020 to cover those
Non-Filipino citizen travelling to Philippines from Taiwan since this country was
being used to transit passengers from mainland China.
Due to surging increase in the number of infected individual in South Korea,
the IATF has issued Resolution No. 08 series of 2020 last February 26, 2020
which contains guidelines specifying the suspension of temporary entry of foreigners
coming from the North Gyeongsang Province of South Korea, and exit of Filipinos
to South Korea [7].
On March 7, 2020, the first local case of COVID-19 transmission in the Philippines
was confirmed by the Department of Health, and it has reached to 24 positive cases in
March 9, 2020 [6]. This posed the Philippine government to impose Social Distancing
Measures in the National Capital Region by the virtue of IATF Resolution No. 10
Series of 2020 mandating the following: (1) Suspension of Classes in all levels in
Metro Manila from March 10 to March 14, 2020; (2) Prohibited the mass gathering
which is defined as planned or spontaneous event where this gathering could strain the
planning and response resource of the community; and (3) Encouraging the private
and public sector to implement alternative working arrangements to impose social
distancing between and among employees.
Due to the pronouncement of the World Health Organization and the continues
increase in infected cases in the Philippines, the IATF has issued Resolution No.11
which further expand the IATF Resolution 10. The IATF Resolution No.11 mandates
the imposition of community quarantine in the entire Metro Manila. The resolution
has further mandates the following measures: (1) a barangay-wide quarantine is
advised when there are at least two positive COVID cases belonging to different
household in the same barangay; (2) municipality-wide quarantine is advised when
there are at least two positive COVID belonging to different barangays in the same
municipality; (3) province-wide quarantine is advised when there are at least two
positive COVID cases belonging to different municipalities, component cities or
independent component cities in the same province; (4) work in executive branch
was suspended; (5) flexible work arrangement was encourage in private sector; (6)
strict social distancing in public transports; (7) Suspension of land, domestic air,
domestic sea travel to and from Metro Manila beginning March 15, 2020 to April
14, 2020.
On March 16, 2020, the imposition of community quarantine was upgraded from
the GCQ to a stricter ECQ covering the entire province of Luzon. The ECQ mandates
the following: (1) suspension of work in public and private offices except for the front
liners in the government, military personnel, health workers, banking institutions,
manufacturing sector, and business process outsourcing; (2) imposed strict home
quarantine measures in all households; and (3) suspension of land, air, and water
transportations in the entire Luzon.
Table 1 depicts the different levels of community quarantine being implemented
by the Philippine government based on the guidelines released by the IATF. The
community quarantine in the Philippines are composed of four levels: (1) Enhanced
Community Quarantine; (2) Modified Enhanced Community Quarantine; (3) General
Community Quarantine; and (4) Modified General Community Quarantine. The
Enhanced Community Quarantine and Modified Enhanced Community Quarantine
are the stricter community quarantine in the Philippines. These two types of commu-
nity quarantine mandated the limited movement of population into essential works,
suspension of public transportation, adapting skeletal in government offices, and
implementing strict home quarantine for those vulnerable who have aged 61 years
old and above and transmitter below 21 years old.
The IATF through Memorandum dated March 16 2020 has issued guidelines on
certain sector who was allowed to operate under the Enhanced Community Quaran-
tine which are as follows: (1) Members of Congress and their Chiefs of Staff; (2)
Secretaries, Undersecretaries, Assistant Secretaries and Bureau Directors of different
government agencies under Executive Branch; (3) Ombudsman and their Deputy
Ombudsman; (4) Justices of the Supreme Court, Court of Appeals, Court of Tax
880 R. L. Dizon
Table 1 The different levels of community quarantine in the Philippines

Enhanced Modified enhanced General community Modified general
community community quarantine community
quarantine quarantine quarantine
Population 100% stay at 10% stay at home Stay at home New normal
home Vulnerable (Elderly (Permissive
60 years old and socio-economic
above) activities with
Transmitter (youth; minimum public
below 21 years old) health standards
Exercise Not allowed Limited outdoor Limited contact
exercise allowed sports
(e.g. outdoor walk,
jog/run, and bike)
with safety
protocols (i.e.
masks and 2 m
distancing
Gatherings Not allowed Highly restricted Restricted
(maximum of 5) (Maximum of 10)
Travel No public No public transport Public transport
transport flights; Flights: no with strict safe
no domestic, domestic, distancing
limited limited Inter-island with
international international strict distancing
Controlled inbound (GCQ to GCQ)
travel
No inter-island
travel
Schools School premises School premises Skeletal workforce
closed closed to process
requirements from
students, and to
prepare for
graduation and next
semester
Government Skeletal onsite Skeletal onsite Alternative work
Others work Others work from arrangements (e.g.
from home home 40 h 4-day work
week
Appeals and the Sandiganbayan; (5) Judges of Regional, Metropolitan, and Munic-
ipal Circuit Trial Courts and Prosecutor; (6) Local Chief Executives; (7) personnel
operating cargo vehicles and delivery service for food, drinking water, medicine, and
other basic necessities, (8) employees of manufacturing and processing plants of basic
food products, essential products, medicine and medical supplies; (9) employees of
retails establishments such as groceries, supermarkets, hypermarkets, convenience
store, public markets, pharmacies and drug stores; (10) logistics service provides
such as cargo handling, warehousing, trucking, freight forwarding and shipping line;
(11) hospitals and medical clinics; (12) food preparation and water refilling stations;
(13) delivery of services transporting food, water, medicine or other basic necessities;
(14) banks and capital markets; (15) power, energy, water, IT and Telecommunica-
tions Supplies and Facilities, Waste Disposal Services; (16) export and Business
Process Outsourcing; (17) airline and aircraft maintenance employees; (18) media
establishments; (19) hotels that have booking as of March 17 2020; (20) energy
companies and their third- party contractors including such employees involved in
electric transmission and distribution, electric power plant and line maintenance,
exploration, operation, trading and delivery of coal, oil, or any kind of fuel used to
produce electricity; (21) telecommunication utilities; (22) pastor, priest, imams or
such other religious ministers whose movement was related to conduct of neuro-
logical or funeral rites; and (23) heads of mission or designated foreign mission
representatives.
On the 28th IATF meeting the Resolution No. 29 series of 2020 dated April 27,
2020, the Enhanced Community Quarantine was extended until May 15, 2020 to
certain high-risk regions such as National Capital Region, Region III, Region IV-A
(CALBARZON), The Province of Pangasinan, The Province of Benguet, Baguio
City, The Province of Iloilo, The Province of Cebu, and Davao City. Meanwhile, the
General Community Quarantine has been imposed in certain areas with low-risk and
moderate-risk in Luzon, Visayas, and Mindanao.
On May 15, 2020, the Philippine IATF through Resolution No. 35 partially relaxed
the implementation of community quarantine by imposing Modified Enhanced
Community Quarantine in Laguna, National Capital Region, Pateros, and Cebu
City. Meanwhile, the General Community Quarantine (GCQ) has been adopted in
Cordillera Administrative Region, Region II, Region III, Region IV-A, Region VII,
Region IX, and Region XIII. The community quarantine in regions I, IV-B, V, VI,
VIII, X, XII, Bangsamoro Autonous Region in Muslim Mindanao were lifted. On
June 1, 2020 to August 04 2020, the National Capital Region and the Municipality
of Pateros which are considered as epicenter of the spread of COVID in the Philip-
pine has place into the GCQ. Meanwhile, the Cebu City was placed under Modi-
fied Enhanced Community Quarantine until June 15, 2020 with localized Enhanced
Community Quarantine. The Baguio City, Pangasinan, Region II, Region III, Region
IV-A, Albay, Iloilo City, Region VII, Zamboanga, and Davao City has been also
placed into General Community Quarantine from June 1 to June 15, 2020. The other
places with low-risk infection such as Cordillera Administrative Region, Region I,
Region IV-B, Region V, Region VI, Region VIII, Region IX, Region X, Region
XI, Region XII, Region XIII, and Bangsamoro Autonomous Region in Muslim
Mindanao has been placed into Modified General Community Quarantine. Starting
June 15, 2020, the Philippine had gradually re-open the economy by increasing the
operational capacity of the company by 30% on areas under General Community
Quarantine.
On August 04, 2020 until August 18, 2020, the Philippine IATF has decided to put
the National Capital Region and the provinces of Laguna, Cavite, Rizal, and Bulacan
into Modified Enhanced Community Quarantine. The decision to revert the stricter
882 R. L. Dizon
community quarantine in National Capital Region and the province of Laguna is

due to the petition of the health sector amid the impending full utilization of the
capacity of the hospitals to cater COVID patients. Starting August 18, 2020 until
September 30, 2020, the National Capital Region, Bulacan and Batangas, Bacolod
City and Tacloban has been placed to General Community Quarantine. Meanwhile,
the Iligan City was placed under the Modified Enhanced Community Quarantine,
and the rest of the regions such as CAR, Region I, Region II, Region III, Region IV-A,
Region IV-B, Region V, Region VI, Region VII, Region VIII, Region IX, Region X,
Region XI, Region XII, Region XIII, Bangsamoro Autonomous Region in Muslim
Mindanao were placed under the Modified General Community Quarantine.
4.2 The COVID Cases in the Philippines
As of September 29, 2020, the number of confirmed COVID cases in the Philip-
pines has reached to 309,303 individuals. The highest monthly aggregated number
of COVID cases in the Philippines was posted during August 2020 with 128,060
individuals. Meanwhile, the country had recorded the highest monthly growth in the
number of confirmed cases in April 2020 posting 207% average rate of increase. Due
to the imposition of stricter community quarantine in the Philippines in the form of
Enhanced Community Quarantine, the growth in the number of confirmed cases had
decreased to 49%. Further, the growth of COVID cases in the Philippines recorded
a decrease by 31% in September 2020 from 128,060 in August 2020 to 88,891 in
September 2020.
Of the total number of recorded COVID cases in the Philippines as of September
29, 2020, 81.77% (252,930 individuals) had recovered from the disease, 1.76% (5,448
fatal), and 16.47% (50,925 individuals) remain as active cases (Table 2).
In order to forecast the infection rate, recovery rate and fatality rate, this Multi-
group SIR model of COVID cases in the Philippines have used different period of
disease. The period of disease determine the length of period of exposure to the time
the individual is being reported as positive case, recovered, or fatal. The study have
use 16 days as the progression period from prodromal to convalescence. This is based
on the median difference between the prodromal period and the date of discharged
of 49 recorded recovered Covid-19 patients as of September 29, 2020 in the Philip-
pines. Meanwhile, the median period between the fatality and the prodromal is at
13 days (Fig. 6). As of September 29, 2020, the number of confirmed COVID cases
Table 2 The distribution of

Health status Number of individuals Percent (%)
COVID cases in the
Philippines per health status Active cases 50,925 16.47
Recovered 252,930 81.77
Fatal 5448 1.76
Total cases 309,303 100
Fig. 6 The progression period of the disease
in the Philippines has reached to 309,303 individuals. The highest monthly aggre-
gated number of COVID cases in the Philippines was posted during August 2020
with 128,060 individuals. Meanwhile, the country had recorded the highest monthly
growth in the number of confirmed cases in April 2020 posting 207% average rate
of increase. Due to the imposition of stricter community quarantine in the Philip-
pines in the form of Enhanced Community Quarantine, the growth in the number of
confirmed cases had decreased to 49%. Further, the growth of COVID cases in the
Philippines recorded a decrease by 31% in September 2020 from 128,060 in August
2020 to 88,891 in September 2020 (Fig. 7). Of the total number of confirmed COVID
cases in the Philippines, the workers age group aged 21 years old to 59 years old
had the highest percentage share of 78.93% of the total cases. It was then followed
by senior citizen age group aged 61 years old and above with a share of 11.85%.
Meanwhile, the young age group aged below 21 years old had a share of 9.22% in
the total number of confirmed cases (Fig. 8). The large percentage share of working
population to the total number of confirmed cases in the Philippines is due to the
Fig. 7 The monthly number of confirmed COVID cases in the Philippines

884 R. L. Dizon
Fig. 8 Percentage distribution of COVID cases in the Philippines according to age group
mobility of this group of individuals where under the guidelines of different commu-
nity quarantine such as ECQ, MECQ, GCQ, MGCG they are allowed to mobile for
work-related activities and other essential works.
The regional distribution of COVID cases in the Philippines is shown in Fig. 9.
The National Capital Region (NCR) accounts a total of 56% of the total COVID
cases in the Philippines posting 162,902 confirmed cases. This was then followed by
CALARZON (18.48%; 53,476 confirmed cases), Central Visayas (7.64%; 22,105
confirmed cases), Central Luzon (5.64%; 16,346 confirmed cases), and Western
Visayas ( 4.08%; 11,824 confirmed cases).
Figure 10a–e depicts the regional daily COVID cases in the Philippines. Based
on the figure, the National Capital had the highest number of confirmed cases. This
was then followed by Region 4-A, Region 3, and Region 6. It is worth nothing that
Fig. 9 Regional distribution of confirmed cases in the Philippines

200
400
600
800
500
0
0
1000
1200
3000
1000
1500
2000
2500
3500
4000
4500
30/01/2020 30/01/2020
07/03/2020 07/03/2020
11/03/2020 11/03/2020
15/03/2020 15/03/2020
19/03/2020 19/03/2020
23/03/2020 23/03/2020
27/03/2020 27/03/2020
31/03/2020 31/03/2020
04/04/2020 04/04/2020
08/04/2020 08/04/2020
12/04/2020 12/04/2020
16/04/2020 16/04/2020
20/04/2020 20/04/2020
24/04/2020 24/04/2020
28/04/2020 28/04/2020
02/05/2020 02/05/2020
06/05/2020 06/05/2020
10/05/2020 10/05/2020
14/05/2020 14/05/2020
Region 7
18/05/2020 18/05/2020
22/05/2020 22/05/2020
26/05/2020 26/05/2020
NCR
30/05/2020 30/05/2020
03/06/2020 03/06/2020
07/06/2020 07/06/2020
11/06/2020 11/06/2020
The Multi-group Susceptible Infected Recovered …
15/06/2020 15/06/2020
19/06/2020 19/06/2020
Region 3
23/06/2020 23/06/2020
(a)
(b)
27/06/2020 27/06/2020
01/07/2020 01/07/2020
05/07/2020 05/07/2020
Region 4-A
09/07/2020 09/07/2020
13/07/2020 13/07/2020
17/07/2020 17/07/2020
21/07/2020 21/07/2020
25/07/2020 25/07/2020
Region 6
29/07/2020 29/07/2020
02/08/2020 02/08/2020
06/08/2020 06/08/2020
10/08/2020 10/08/2020
14/08/2020 14/08/2020
18/08/2020 18/08/2020
22/08/2020 22/08/2020
26/08/2020 26/08/2020
30/08/2020 30/08/2020
03/09/2020 03/09/2020
07/09/2020 07/09/2020
11/09/2020 11/09/2020
15/09/2020 15/09/2020
19/09/2020 19/09/2020
23/09/2020 23/09/2020
27/09/2020 27/09/2020
region. e The daily covid cases in region 11, region 12, CARAGA, CAR and BARMM, Philippines
Philippines per Region. d The daily covid cases in region 2, region 4-B and region 5, Philippines per
region 7, region 3, region 6 Philippines. c The Daily Covid Cases in Region 8, Region 10, Region 1,
885
Fig. 10 The daily covid cases in the NCR and region 4-A, Philippines. b The daily covid cases in
886
100
120
20
40
60
80
100
150
200
250
50
0
0
30/01/2020 30/01/2020
07/03/2020
10/03/2020 11/03/2020
15/03/2020
17/03/2020 19/03/2020
23/03/2020
24/03/2020 27/03/2020
31/03/2020 31/03/2020
Fig. 10 (continued)
04/04/2020
07/04/2020 08/04/2020
12/04/2020
14/04/2020 16/04/2020
20/04/2020
21/04/2020 24/04/2020
28/04/2020 28/04/2020
02/05/2020
05/05/2020 06/05/2020
10/05/2020
12/05/2020 14/05/2020
Region 2
Region 8
18/05/2020
19/05/2020 22/05/2020
26/05/2020 26/05/2020
30/05/2020
02/06/2020 03/06/2020
07/06/2020
09/06/2020 11/06/2020
16/06/2020 15/06/2020
(c)
(d)
19/06/2020
23/06/2020 23/06/2020
Region 10
Region 4-B
27/06/2020
30/06/2020 01/07/2020
05/07/2020
07/07/2020 09/07/2020
14/07/2020 13/07/2020
17/07/2020
21/07/2020 21/07/2020
25/07/2020
Region 1
28/07/2020 29/07/2020
Region 5
02/08/2020
04/08/2020 06/08/2020
11/08/2020 10/08/2020
14/08/2020
18/08/2020 18/08/2020
22/08/2020
25/08/2020 26/08/2020
30/08/2020
01/09/2020 03/09/2020
08/09/2020 07/09/2020
11/09/2020
15/09/2020 15/09/2020
19/09/2020
22/09/2020 23/09/2020
27/09/2020
29/09/2020
R. L. Dizon
90
80
70
60
50
40
30
20
10
0
30/01/2020
07/03/2020
11/03/2020
15/03/2020
19/03/2020
23/03/2020
27/03/2020
31/03/2020
04/04/2020
08/04/2020
12/04/2020
16/04/2020
20/04/2020
24/04/2020
28/04/2020
02/05/2020
06/05/2020
10/05/2020
14/05/2020
18/05/2020
22/05/2020
26/05/2020
30/05/2020
03/06/2020
07/06/2020
11/06/2020
15/06/2020
19/06/2020
23/06/2020
27/06/2020
01/07/2020
05/07/2020
09/07/2020
13/07/2020
17/07/2020
21/07/2020
25/07/2020
29/07/2020
02/08/2020
06/08/2020
10/08/2020
14/08/2020
18/08/2020
22/08/2020
26/08/2020
30/08/2020
03/09/2020
07/09/2020
11/09/2020
15/09/2020
19/09/2020
23/09/2020
27/09/2020
Region 11 Region 12 CARAGA CAR BARMM
(e)
Fig. 10 (continued)
the daily COVID cases in the the regions NCR, region 4-A, Region 7, Region 8,
and Region 5 shows significant decreasease overtime due to the implementation of
community quarantine. Meanwhile, other regions in the Philippines such as Region
1, Region 2, Region 3, Region 4-B, Region 6, Region 9, Region 10, Region 11,
Region 12, CARAGA, CAR, and BARMM shows an increasing daily COVID cases.
4.3 The Assessment of Philippine Government Non-

Pharmaceutical Intervention Using the SIR Model
In order to assess the effectiveness of the NPIs being implemented by the Philippine
government, the Multi-Group SIR Model with stage progression was utilized. This
chapter have used the National Capital Region as case study since it serves as the
epicenter of COVID-19 transmssion in the Philippines.
The first step in constructing Multi-Group SIR Model with stage progression is
to determine the probability of disease transmission from workers to other workers,
from workers to senior citizen, and workers to young. This probability of transmis-
sion serves as parameters in determining the rate of transmission of COVID-19 and
in forecasting the number of infected individuals. It is computed using parameters
such as duration of a contact of a susceptible individual to infected individual, contact
patterns, and the proportion of contact that are infected by employing the Poisson
Distribution as presented in Eq. 32. The probability of transmission were catego-
rized based on the time period incorporating the government NPIs compartalized as
before, during, and after the Enhanced Community Quarantine (stricter community
quarantine). The result of the computation were presented in Fig. 11.
888 R. L. Dizon
Fig. 11 a The probability of COVID-19 transmission from mobile workers to other workers under
ECQ. b The probability of COVID-19 transmission from mobile workers to senior citizen. c The
probability of transmitting the COVID-19 disease from mobile workers to young
Figure 12a–c shows that in the absence of the implementation of ECQ the prob-
ability of transmitting COVID-19 in NCR across workers is at 100%, from workers
to senior citizen is 99.49% and to the young group is 64.01%. During the imple-
mentation of ECQ, the probability of COVID-19 transmission from mobile workers
to other workers had decreased to an average of 0.39%, to an average of 4.50% for
senior citizen, and to an average of 0.8% for the young age group.
Fig. 12 a COVID-19The actual and forecast COVID cases, recovery & fatality for working froup
in NCR using multi-group SIR model. b The actual and forecast COVID cases, recovery & fatality
for senior citizen group in NCR using multi-group SIR model. c The actual and forecast COVID
cases, recovery & fatality for young group in NCR using multi-group SIR model
890 R. L. Dizon
The probability of transmission serves as an inputs parameter in determining

the infection rate per group of population. The actual number of infection due to
COVID-19 for workers, senior, and young age group have slow down during the
implementation of ECQ in March 17 to May 14, 2020 and MECQ in March 15, 2020
to May 30, 2020. From June 1 to August 04, 2020, the actual number of infected indi-
viduals for workers, senior, and young age group had increased significantly from an
average of 100 daily infected individuals to an average of 200 daily infected individ-
uals. This significant increase is due to the downgrading of Philippine’s government
health protocols from stricter community quarantine (ECQ) to less strict community
quarantine (GCQ). Using the Multi-Group SIR model, this study had determined
that the number of infected individual will reach up to more than 116 thousand cases
for workers, more than 2641 cases for senior, and more than 16,000 cases for young
age group in December 2020.
Meanwhile, the number of fatality and recovered from COVID-19 was also deter-
mine using the Multi-Group SIR Model. Based on the result of the study, the number
of recovered individuals will have reached up to more than 153,000 individuals in
December 2020. Of the total number of forecasted recovered individuals, the working
individuals will have the largest share recording a total of 115,000 recovered individ-
uals. It was then followed by senior citizen age group with total number of recovered
individuals of 21,000 seniors, and the young age group with 16,000 number of recov-
ered individuals. Meanwhile, the number of fatal cases will have reached up to more
than 3,400 in the end December 2020 (Fig. 12a–c). Figure 12a–c depicts the actual
and forecasted COVID cases, recovery and fatality in NCR, Philippines using the
Multi- Group SIR Model. Analyzing the pattern of the number of COVID-19 cases
per group classification, this study had observed that the curve for mobile workers
are expected to flatten first, and then followed by the simultaneous flattening of the
curves of senior citizens and the young age group. Interestingly, the curve for COVID
cases in the NCR as epicenter of the disease in the Philippine will be flattened at the
end of December 2020.
After the period of a flattened curve, there is the recovery period which ranges
from the shortest of 7 days for workers and the young age group to a maximum of
45 days for the senior citizens group. Factoring this recovery period, the NCR that
attained a flattening of the curve by at the end of December 2020 will reach a state
of equilibrium (i.e., the state of zero transmission rate and that the number of cases
coincides with the number of recovered cases and number of deaths) in the January
2020.
Meanwhile, Fig. 13a–c shows the transmission rate, fatality rate, and recovery
rate in the NCR using the Multi-group SIR Model with stage progression. It can be
observed that the recovery rate for working group population in the NCR will reached
to more than 90%, while the fatality reach would have reached up to 0.736% only.
In the case of Senior Citizen Group, the recovery rate would have reached upto 88%
while fatality rate is about 8%. Further, the young age group would have almost 98%
recovery rate with fatality rate of 0.273%. It is worth noting that the case fatality rate
among workers is 7 times deadlier compared to seasonal flu, while the case fatality
Fig. 13 a The actual and forecast transmission rate, recovery rate and fatality rate in workers group
in NCR using multi-group SIR model. b The actual and forecast transmission rate, recovery rate
and fatality rate in senior citizen group in NCR using multi-group SIR model. c The actual and
forecast transmission rate, recovery rate and fatality rate in young group in NCR using multi-group
SIR model
892 R. L. Dizon
Table 3 The summary of actual and forecasted number of infected, recovered, fatal and active
cases in NCR, Philippines
Date Infected Recovered Fatal Active
Sep 7 125,959 105,071 1906 1785
Sep.30 147,985 132,552 2596 1615
Oct31 156,889 152,610 3311 429
Nov 30 156,895 153,332 3446 117
Dec 15 156,895 153,449 3446 0
rate among senior citizen is 80 times deadlier compared to seasonal flu, and the case
fatality rate among young is almost 2 times deadlier compared to seasonal flu.
The state of equilibrium of COVID-19 cases is the point where the recorded
number of infected individual is equal to the sum of recovered and fatal individuals.
Using the Multi-group SIR model, it is anticipated that the NCR would reached
the equalibrium point at the second week of December where the number of active
cases is equal to zero that depicts a disease free situation (Table 3). This further
indicates that even without vaccine, the Philippine could still achieve the COVID-19
disease free situation if health protocol will be observe by diligently maintaining
minimum health protocols such as social distancing, wearing of face masks, and
strict implementation of community quarantine in the Philippines.
5 Conclusions and Recommendations
Based on these findings, this study had found out the transmission rate of COVID-19
cases in National Capital Region is continuing to decline due to government interven-
tion by imposing minimum health standards such as different levels of community
quarantine, implementing social distancing, and requiring Filipino citizen to wear
face shield and face masks. Moreover, the recovery rate is continuesly increasing
while the fatality is continuesly declining dues to the effort of health care workers to
cure those who are infected. Further, this study concluded that the implementation of
Non-Pharmaceutical Intervention in the Philippines in the form of community quar-
antine had contributed in the preventing the exponential spread COVID-19 cases in
the Philippines.
In view of the findings of the study, this study recommends that the government
should continue limiting the mobilization of the workers and household and as much
as possible lower the mobilization rate in NCR by 1%. This policy would be able to
further suppress the exponential transmission of Covid-19 in shorter period of time.
Also, this study recommends to limit the mobilization of household heads into every
three days for a maximum of three hours and observing schedule per hour. This is
to avoid too much number of household heads who will buy necessity at one point
in time and in the same places. Further, it also recommended that the Philippine
government may consider extending the General Community Quarantine until the
end of December 2020 in NCR.
Further, it is also recommended that the government have to create ad-hoc team
specifically dedicated for contact tracing which may be composed of Department
of Information and Communication Technology, Department of Health, and other
agencies. The spread of COVID-19 may further limit by developing an integrated
system of contact tracing effort of business, household and government entities.
This could be done by linking the health declaration form of each institutions and
businesses located into one repository of health data and requiring each firm to submit
a copy of health declaration form in different Local Government Units offices for
planning purposes and contact tracing.
This study also recommend that the government may revisit the minimum social
distancing of 3 ft, and may adopt the minimum social distancing of 6 ft as imple-
mented by other countries such as Thailand and Japan. It is recommended to
discourage walk in customer/passenger in MRT/LRT but instead an advanced online
booking should be observed in order to contain the passenger, can properly implement
social distancing, and avoid long queuing of the passengers.
In view of the significant increase in the transmission rate among young age
group, the government may craft strategies to further limit the transmission rate in
this particular group of population and consider further investigating the fast increase
in transmission rate in young age group of population in NCR.
References
1. Brauer, F.: Mathematical epidemiology is not an oxymoron. BMC Public Health, 9 (1) (2009).
Retrieved from Mathematical epidemiology is not an oxymoron (nih.gov) Last 21 Nov 2020
2. Center for Disease Control and Prevention. Retrieved from Principles of Epidemiology | Lesson
1—Section 2 (cdc.gov). Last 28 Nov 2020 (2020)
3. Cooper, I., Mondal, A., Antonopoulos.: A SIR model assumption for the spread of COVID-19
in different communities. Chaos Solitons Fractals. Retrieved from a SIR model assumption for
the spread of COVID-19 in different communities (nih.gov) Last 25 Nov 2020 (2020)
4. Das, A., Gopalan S.: Epidemiology of COVID-19 and predictors of recovery in the Republic of
Korea. Retrieved from a epidemiology of COVID-19 and predictors of recovery in the Republic
of Korea (nih.gov) Last 20 Nov 2020 (2020)
5. Del Valle, S.Y., Hyman, J.M., Chitnis, N.: Mathematical models of contact patterns between
age groups for predicting the spread of infectious diseases. Math. Biosci. Eng.: MBE 10(5–6),
1475–1497 (2013). https://doi.org/10.3934/mbe.2013.10.1475
6. Department of Health. Retrived from https://ncovtracker.doh.gov.ph/. Last 24 Mar 2020 (2020)
7. Department of Health. DOH Confirms Local Transmission of COVID-19 in PH; Reports 6th
Case. Retrieved from https://www.doh.gov.ph/doh-press-release/doh-confirms-local-transmiss
ion-of-covid-19-in-ph Last 27 Nov 2020 (2020)
8. Fan, L., et al.: Progress and prospect on imaging diagnosis of COVID-19. Nature Public Health
Emergency Collection, pp. 1–10 (2020)
9. Guo, Y., Qing-Dong, C., Hong, Z., Tan, Y., Chen, S., Jin, H. Tan, K., Wang, D., Yan, Y.: The
origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-
an update on the status. Military Medical Research 7, 11(2020). Retrieved from https://doi.org/
10.1186/s40779-020-00240-0#citeas Last 23, March 2020 (2020)
894 R. L. Dizon
10. Hethcote, H.W.: Three basic epidemiological models. In: Levin, S.A., Hallam, T.G., Gross, L.J.
(eds) Applied Mathematical Ecology. Biomathematics, vol. 18. Springer, Berlin, Heidelberg
(1989). https://doi.org/10.1007/978-3-642-61317-3_5
11. Hilker, F., Langlais, M., Machow, H.: The allee effect and infectious diseases: extinct, musta-
bility, and the (Dis-) appearance of oscillations. Am. Naturalist, 173(1). United State of
America: The University of Chicago (2009)
12. Huppert, A., Katriel, G.: Mathematical modelling and prediction in infectious disease epidemi-
ology. Clinical Microbiol. Infect. 19(11), 999–1005 (2013). https://doi.org/10.1111/1469-0691.
12308
13. Kang, Y., Catillo-Chavez, C.: Dynamics of SI models with both horizontal and vertical
transmissions as well as allee effects. Math Biosci. https://doi.org/10.1016/j.mbs.2013.12.006
14. Khan, J., McIntosh, K.: History and recent advances in corona discovery. Pediatr. Infect. Dis.
J. 24(11) (2005). https://doi.org/10.1097/01.inf.0000188166.17324.60
15. Klepac, P.: What we scientist have discovered about how each group spreads Covid-19.
The Guardian. https://www.theguardian.com/commentisfree/2020/mar/17/scientists-age-gro
ups-covid-19-workplaces-shops-restaurants
16. Lauer, S., Gratz, K., Qifang B., Jones, F., Zheng, Q, Meredith, H., Azman, A., Reich, N.,
Lessler, J.: The incubation period of corona disease 2019 (COVID 2019) from publicly reported
confirmed cases: estimation and application. Ann. Internal Med. (2019). https://www.ncbi.nlm.
nih.gov/pubmed/32150748
17. Mackolil, J., Mahanthesh, B.: Mathematical modelling of corona virus disease (COVID-19)
outbreak in India using logistic growth and SIR models. Retrieved from https://www.researchs
quare.com/article/rs-32142/v1 last November 26, 2020
18. Naji, R., Hussien, R.: The dynamic of epidemic model with two type of infectious diseases and
vertical transmission. J. Appl. Math. 16(16) (2016)
19. Nguemdjo, U. Meno, F., Dongfack, A., Ventelou, B.: Simulating the progression of the COVID-
19 disease in cameroon using sir models. Plos One Collection of Infectious Disease Epidemi-
ology. Retrieved from Simulating the progression of the COVID-19 disease in Cameroon using
SIR models (plos.org) last November 25, 2020
20. Pellis, Ferguson, N., Frase, C.: Threshold parameters for a model of epidemic spread among
household and workplaces. J. Royal Soc. Interface 6(4) (2020). https://doi.org/10.1098/rsif.
2008.0493
21. Philippine Statistical Authority. Retrieved from https://psa.gov.ph/content/2017-annual-
survey-philippine-business-and-industry-aspbi-financial-and-insurance-0 last Sept 24,2020
(2020)
22. Shereen, M., Khan, S., Kazmi, A. Bashir, N., Siddique, R.: COVID-19 Infection: origin, trans-
mission, and characteristics of human coronaviruses. J. Adv. Res. 24(1), 91–98. https://doi.
org/10.1016/j.jare.2020.03.005
23. Talukder, A.: Susceptible-infectious-recovered (SIR) model-based forecasting of COVID-
19 outbreak in Bangladesh. Int. J. Clin. Pract. Retrieved from https://onlinelibrary.wiley.
comhttps://doi.org/10.1111/ijcp.13648 last November 27, 2020. (2020)
24. Temime, L., Hejblum, G., Setbon, M., Valleron, A.J.: The rising impact of mathematical
modelling in epidemiology: antibiotic resistance research as a case study. J. Epidemiol.
Infection 136(3), 289–298. Retrieved from The rising impact of mathematical modelling in
epidemiology: antibiotic resistance research as a case study (nih.gov) last November 25, 2020.
(2008)
25. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases
(COVID-19) —China, 2020 The Novel Coronavirus Pneumonia Emergency Response
Epidemiology Team. Retrieved from http://weekly.chinacdc.cn/fileCCDCW/journal/article/
ccdcw/2020/8/PDF/COVID-19.pdf
26. Thompson, R.: Epidemiological models are important tools for guiding COVID-19 interven-
tions. BMC Medicine. Retrieved from https://bmcmedicine.biomedcentral.com/articleshttps://
doi.org/10.1186/s12916-020-01628-4 Last November 25 (2020)
27. Wu, J., Leung, K., Leung, G.M.: Nowcasting and forecasting the potential domestic and inter-
national spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study.
The Lancet (31 Jan 2020). https://doi.org/10.1016/S0140-6736(20)30260-9
28. Zeng, W., Guohong, L., Turbat, V., Hu, G, Ahn, H.: Optimizing preventive medicine to bridge
the gap between clinical medicine and public health for disease control in China: a lesson from
COVID-19. Preventive Med (2020). https://doi.org/10.1016/j.ypmed.2020.106324
Telehealth and Pharmacological
Strategies of COVID-19 Prevention:
Current and Future Developments
Gopi Battineni, Giulio Nittari, Graziano Pallotta, Getu Gamo Sagaro,

Nalini Chintalapudi, and Francesco Amenta
Abstract After the identification of SARS-CoV-2 virus in China, it has spread

worldwide at a rapid pace. To control novel coronavirus disease (COVID-19), there
is no particular treatments/immunizations are available yet. However, to avoid the
risk of immediate spreading between infected individuals, and healthcare workers,
most organizations adopting virtual media devices in order asses the symptomatic
behaviour of patient and these services are well known for telehealth services. On
other hand, repositioning of drugs can offer a controlling strategy, and several drugs
including remdesivir, lopinavir/ritonavir, hydroxychloroquine (HCQ), and favipi-
ravir were repurposed. The availability of an authenticated vaccine against COVID19
will be hard to produce in the coming days, therefore it is important to propose a phar-
macological strategy to combat this disease. In this chapter, the authors present the
investigation of controlling and preventing methods by telemedical services during
a novel coronavirus outbreak. Besides, it can also report the current drug avail-
able information and future developments that need to present new strategies for
developing pharmacy facilities.
Keywords COVID-19 · Pharmacy services · Drug development · Telehealth · Tele

pharmaceutical services
1 Introduction
Coronavirus disease is an infectious disease caused by severe accurate respiratory

syndrome coronavirus 2 (SARS-CoV-2) and is well known for COVID-19 disease
[22]. The abbreviation COVID-19: “CO” stands for corona, “VI” for the virus, and
“D” stands for the disease. The name Coronavirus derives from the Latin corona,
which means “crown” or “halo,” due to its distinct surface under two-dimensional
G. Battineni (B) · G. Nittari · G. Pallotta · G. G. Sagaro · N. Chintalapudi · F. Amenta

Telemedicine and Tele Pharmacy Center, School of Health Sciences and Medical Products,
University of Camerino, 62032 Camerino, Italy
e-mail: gopi.l@unicam.it
898 G. Battineni et al.
transmission electron microscopy [33]. COVID-19 was announced as a pandemic

by the World Health Organization (WHO) on 11th March 2020.
Coronaviruses are positive-sense enveloped RNA viruses with a diameter from
60- 140 nm with tips projections on its surface that give it a crown-like appearance at
the electron microscope; thus, the name coronavirus [11]. COVID-19 is originated
from the ‘Wet markets’ in South china from wild animals. On 31st December 2019,
china notified the epidemic to the WHO, and the human seafood market was closed
on 1st January 2020. The virus was confirmed as a coronavirus on 07th January
2020, which has more than 90% of homology with the bat coronavirus and over
70% of similarity with the SARS-CoV [97]. The environmental samples from the
human seafood were also tested, and the result was positive which confirmed the
virus has originated from Wuhan city, the capital of Hubei, China [112]. Because of
this, significant morbidity and mortality are caused in China.
Some procedures like dental are risky for transmission due to face to face commu-
nication and the presence of contamination by blood, saliva, use of sharp tools, and
other body fluids. Another means of transmission is equipment and personal items in
the immediate environment around the infected person. In general, COVID-19 can be
transmitted via direct contact with an infected person as well as indirectly through the
surface or objects contaminated by an infected person or environment [39]. The WHO
suggested some preventive measures like mask-wearing in big gatherings, covering
mouth and nose when sniffling, constant handwashing or hand sanitizer containing
in any event 60% of liquor, avoiding close contact with others, and keeping genuine
social separation, and exclusion contact of unwashed hands with eyes, nose, and
mouth [60].
Meanwhile, to control the quantity of the individuals who approach the nearest
medical centres or healthcare workers can contact patients through virtual media
devices for measuring, treating, and understand the patient symptoms called tele-
health services [74]. Telehealth systems are defined as “the provision of health
services, where distance is a critical factor, by health professionals who use infor-
mation and communication technologies (ICT) for exchange of information. This
can be useful for the diagnosis, treatment, disease prevention, research, and training
of health workers, in the interest of improving the health of individuals and their
communities [6].
Telehealth was turn into an essential requirement for the general public, medical
services suppliers, and patients with Coronavirus, particularly when individuals
are isolated, also empowering patients progressively through contact with medical
services suppliers. The use of telemedical systems makes it possible to evaluate and
monitor patients efficiently, protecting the patients themselves, the healthcare staff,
and the entire community from the risks of exposure to contagion.
One of the advantages of telemedicine can be the daily monitoring of some clinical
parameters and symptoms which, for example through an app, can be measured or
reported by patients [68, 70]. Telemedicine also allows access od patient visits who
struggle to go to the hospital or live in areas poorly connected to the treatment centers.
Furthermore, remote consultations (and also some tests) have proved essential in this
Telehealth and Pharmacological Strategies of COVID-19 … 899
period of a health emergency, to be able to carry out clinical trials that otherwise they
would have been redundant [57].
On the other side, Tele pharmacy is the conveyance of conventional drug stores
that incorporates administering of medications and giving patients guidelines by
employing telecommunications in rural or low network areas where they might not
have nearby admittance of pharmacists. A pharmacist at the distant site prepares the
professionally prescribed medication, and the drug specialist at the remote site under-
stands the patient’s profile and plays out the clinical check of the diagnosis prescrip-
tion, like concern information with patients for medicine guiding through video
conferencing technologies. But, the optimum situations for operating telemedicine
and tele pharmacy are unknown yet. In particular, when pandemics like COVID-19
the potential factors of those services and its cost-effective approaches has not been
clearly addressed.
Therefore, this chapter elaborates the issues associated with telemedicine and
tele pharmacy along recent approaches of telehealth (including Telemedicine and
Tele pharmacy) benefits in forestalling, diagnosing, treating, and disease controlling
during an outbreak of COVID-19. In addition, authors reviewed some possible drug
treatments that can work to treat the novel coronavirus infection.
2 Related Works
2.1 Telehealth Approaches in COVID-19 Control
A progression of systems has been proposed for Infection Prevention and Control
(IPC) that may reduce the COVID-19 risk. Telehealth with the utilization of live
video conferencing or a basic useful call permit medical services expert to pose
unique inquiries and gather required data, patient emergency, and flexibly counsel.
It can also be applied for patient symptom registration like respiratory, pulse, and
oxygen level rates from the home [81].
During the COVID-19 outbreak in China, online mental health check-ups with
correspondence programs such as Weibo, WeChat, and Tik-Tok have empowered
mental health experts and medical experts to deliver secured mental health super-
vision via web-based systems [65]. Chinese government authorities dispatched
a distant counsel network that had done through web or phone interviews in a
protected environment to guarantee the continuous monitoring of mental health
benefits and diminish the risk of cross contaminations [54]. Similarly, the National
medical commission of China has distributed a few online rules and free electronic
books about COVID-19 with the point of helping the advancement of Chinese indi-
vidual’s emergency mediations, security, improving the quality and adequacy of crisis
interventions [64].
Furthermore, telehealth can give mental online health systems in the setting of
patient privacy by decreasing the emotional health trouble from COVID-19 and
sharing data about the side effects of stress, discouragement, and nervousness [119].
Greenhawt et al. highlighted telehealth has a few benefits in giving an understanding
of immunology directions such as restricting the introduction of medical experts to
conceivably stained patients and admittance to the fast assessment for COVID-19
contamination [92].
According to Yang [114], considering activities for the security of healthcare,
hospital staff, and patients should need to adopt the virtual systems to create staff
timelines and do charging for medical care administrations. Besides, The study results
of Zhai et al. [116] also shown that to supervise COVID-19, there are some simple
to-set-up possibilities in live video counselling. Because, live video conferencing
can prompt the maintaining of a strategic distance from direct physical contact, also
reduce the danger of presentation to respiratory releases and forecasting the expected
transmission of contamination to doctors and other medical service suppliers [116].
Additionally, the live video could be helpful for patients who looking for a COVID-
19 treatment, also for individuals with high anxiety, rather than in-person visits, some
prescription checks, and emergency when there is no phone [55].
In request to control the COVID-19 disease spread, video meetings, and phone
follow-up is conceivable in different disease settings including lung, endometrial,
colorectal, and prostate [96]. According to the research conducted in the USA Elec-
tronic Health Records (EHR) can encourage screening or patient treatment without
the requirement of in-person visits and improve the dynamic cycle among medical
service groups in mobile and critical care [84]. Generally, the effect of telehealth
during the Coronavirus pandemic in routine prediction and detecting infected people
from high-risk areas, also old people can access the medical services by utilizing
electronic gadgets [78].
Nowadays, a reasonable variation of neighbourhood frameworks with changes
in regards to instalment and coordination of organizations are significant barriers
for the large-scale utilization of telehealth for management of COVID-19 infection
[52]. Therefore, we expect the reality of forecasting and disease controlling through
further preparation of medical agents and patients on the best way to capitalize on
telehealth instruments, returning to conventional meanings of clinical practice.
According to Cascella et al. [18], telehealth procedures gives early care to patients
by possible COVID-19 that demonstrates simple to convince. After the clinical group
recognized all conceivable and affirmed cases with treatment reviews, the COVID-
19 treatment group-administered to thought of utilizing the preventive measure. A
reliable cycle followed by a dedicated group permitted consistency, which prompts
productivity.
Telehealth procedures can be more counteraction centred while the patient is
encountering moderately suitable health with objectives to expand quality and contin-
uation before the disease cycle advances to the basic sickness. Exum et al. [40]
highlighted that as COVID-19 progressing, treatment can help to ease potential
complexities related to delayed Intensive Care Unit (ICU) stay and management of
ventilators. These treatment mediations can address the deconditioning, dyspnoea,
and passionate trouble patients are encountering as a direct result of this condition.
Early medication is basic while thinking about every patient’s long-haul standpoint
and extended-release sensation.
Coronavirus isn’t just a strong respiratory disease like Acute Respiratory Disease
Syndrome (ARDS) yet exceptionally infectious and dangerous for medical care
suppliers. It is generally connected with pneumonia and moderate respiratory trouble
grouped by the respiratory rate of ≤ 30 bpm, Pao2/Fio2 (division of motivated
oxygen) proportion under 300, and lung penetrates of over half inside 24–48 h.
In most serious cases, this infection has been related to septic stun and multiorgan
failure. Therefore, Owusu-Akyaw et al. [82] mention that therapists ordinarily treat
patients with basic clinical qualities with situating, breathing procedures, reme-
dial exercise, action alteration, and user flexibility preparation. These are similar
instruments used to treat patients with COVID-19. Using different virtual media can
encourage self-controlled assessment while control disease spreading can give exact
calculated information and reduce the danger of medical service providers.
The Iranian researchers developed a treatment strategy and novel screening with
teleconsultation service during the COVID-19 outbreak [34]. They deliberately
actualized social media platforms to associate volunteer subspecialists from North
America and the Iranian capital with undertrained clinicians all through Iran for
teleradiology interview. Also, portray the utilization of these teleradiology admin-
istrations conveyed through an online media stage to give demonstrative mastery to
Coronavirus in Iran. Administrations for teleradiology and teleconsultation for the
emergency of COVID-19 disease through a web-based media massager conveyed by
the Iranian Society of Radiology (ISR) to react to the lack of on-location thoracic
radiologists during the COVID-19 pandemic.
Hollander et al. [52] also raised the necessity of telehealth services for COVID-19.
As opposed to expecting all outpatient practices to stay aware of quickly developing
proposals concerning COVID-19, medical frameworks have created computerized
rationale streams (bots) that allude moderate to-highhazard patients to nurture emer-
gency lines but on the other hand are allowing patients to plan video visits with set up
or on-request suppliers, to escape travel to personal care sites [9]. Jefferson Health’s
telemedical frameworks have been effectively sent to assessment, also treat patients
without referring them to physical visits. When testing is required, this methodology
requires unified coordination with training faculty also as government and neighbour-
hood testing organizations. It is important that practices not regularly refer patients
to emergency doctors, critical consideration communities, or workplaces, which risk
introduction to different patients and medical services suppliers.
2.2 Tele Pharmacy in Control of COVID-19
Tele pharmacy is part of telehealth that refers to the remote delivery of pharmaco-
logical care and services via Information and Communication Technologies (ICT).
According to Brent and Joshua [14], tele pharmacy explores healthcare services espe-
cially in remote and medically backward areas, to overcome the challenges to patient
care and enhance patient outcomes. They also mentioned tele pharmacy benefits for
patients, pharmacists, and pharmacy delivery persons during the current pandemic
can avoid the face to face contact, accordingly reduce the risk of infection spread and
helps to ‘flatten the COVID-19 curve’. It empowers a patient’s safe admittance to
their drug specialist, while likewise shielding pharmacists and drug store staff from
the disease.
In the report of Bonner [13], it is highlighted that as like telemedicine, tele phar-
macy is also essential in the COVID-19 crisis. Because pharmacy people are tremen-
dous support for COVID-19 infected patients. So, Tele pharmacy can allow them to
have communication in a safer mode without having a face to face patient contact.
Another cross-sectional study by Ellen et al. [59] highlighted understanding the
COVID-19 epidemic impact on the delivery of pharmacy services in the Netherlands.
Results mentioned that 55.8% of pharmacists not directing any drug reviews, 47%
were interested to deliver medication from home, and 22.3% performing breathing
instructions through telephone. It is proven that the COVID-19 outbreak produces a
large impact on both pharmacy deliveries and patient services regarding counselling
and education. Therefore, it is the urgency of adopting tele pharmacy services to
provide optimal support for virus-infected patients.
Because of the significant vulnerability and threat following the COVID-19
outbreak, all the possibilities need to be accumulated to support patients and care-
takers in dealing of the pandemic emergency. Presently, the most demonstrative trial
of COVID-19 has regularly expecting patients to a long stay at home for results. At
the point when the outcomes become accessible, tested individuals may counsel a
pharmacist on the telephone or through video conferencing platforms (like What-
sApp, google meet, Skype, and so on) [3]. As of now, all consultation is occurring
from home in the arrangement of COVID-19 tests. If these tests become normal, tele
pharmacy administrations could empower drug specialists to give far off guidelines
to the patients in managing of their tests.
At the same time, Mohiuddin [71] described tele pharmacy can help patients with
COVID-19 in remote areas. Tele pharmacy is the latest approach taken for preparing
medical services suppliers to convey high-quality medical advice to treat COVID-
19. The drug specialists need to recognize and report hostile drug impacts. Further,
discharge consultation gave by drug specialists improves drug promotion adher-
ence and decreases side effects [2]. It is also reported that the drug specialist may
give a discussion on diet, self-assurance, and prescription directions after discharge,
medical services improvement, follow-up of ailment, and information required by
COVID-19 patients [62]. The innovative pharmacy services and medical pharma-
cists’ role in dealing with COVID-19 has presented in Fig. 1. In addition, the utiliza-
tion of tele pharmacy can anticipate the unintended drug issues and mistakes by drug
specialists and doctors. Thus, it can diminish the expenses for patients and medical
care suppliers.
Fig. 1 Innovative pharmacy

services [62]
3 Telemedical Approaches During COVID-19
Television, telemonitoring systems, and digital health tools have been used to acti-
vate triage systems (through chatbots and virtual assistants that evaluate the symp-
toms manifested by an individual to identify subjects at risk of COVID-19), contact
tracing systems for identifying, based on proximity (measured via Bluetooth or GPS)
between two subjects equipped with smartphones and the same app, any contacts
of individuals who have tested positive for COVID-19, and epidemiological surveil-
lance systems capable of monitoring the epidemic, identify new outbreaks on which
to intervene and provide useful information to health policymakers of individual
countries [88].
Artificial intelligence (AI) and machine learning have also made an important
contribution to the management of some aspects of the pandemic by providing predic-
tive models on how and where the disease would spread in the world and within
individual countries [25], proposing diagnostic systems to detect pneumonia caused
by COVID-19 starting from chest Xrays and identifying drugs already existing but
registered with other indications that could also be useful against COVID-19 [57].
In emergencies such as that imposed by the COVID-19 pandemic, telemedicine can
allow hospitals to continue to provide a certain level of care by minimizing the risks
for patients, doctors, and nurses, and by lightening the burden on already tried and
tested health systems. But why think about this type of technology also in the future,
once the emergency is over? The answers to this question vary according to the
pathologies and social contexts in which one operates [106].
Another valuable tool for dealing with a rapidly spreading infection like COVID19
is the “virtual cure”, sometimes referred to as telehealth. With the large number
of patients involved and the risk of infecting other patients and healthcare profes-
sionals in person, online consultations can provide invaluable help to the health-
care system [35]. This solution aims to prevent unnecessary visits to general practi-
tioners and hospitals by remotely monitoring the vast majority of COVID-19 patients
who are quarantined at home. Patients infected with COVID19 can be monitored
remotely through intelligent questionnaires about their home situation and health
status, identifying if intervention is needed [89].
In the current situation, where COVID-19 can escalate into severe lungs, there
will be an increasing number of patients requiring acute care in Intensive Care Unit
(ICU). The numbers that grow to unmanageable proportions are already occurring
in many countries and continue to be a real concern for health authorities around
the world, not only because of the limited number of ICU beds and ventilators
but also the lack of personnel care. ICU doctors and nurses are already few and
far between, and repeated exposure to infected patients will increase their risk of
contracting the virus. A Telemedical ICU (tele-ICU) or e-ICU allows a team of ICU
clinicians and nurses to remote monitoring of ICU patients regardless of patient
location. Healthcare staff based in an e-ICU hub are supported by high definition
cameras, telemetry, predictive analytics, data visualization, and advanced reporting
capabilities to support their frontline doctors.
AI Algorithms warn of patient signs of deterioration or improvement [7]. They
help staff to proactively intervene in a phase before the adverse event or to decide
which patients have stabilized and can be transferred. This will allow intensive care
beds to be assigned to do more acute patients. The tele-ICU can be integrated into
a larger clinical and operational center that prioritizes patients based on perception
and optimizes patient flow and logistics [102]. Solutions like these can allow more
COVID-19 patients to receive treatment.
Advanced telemetry and related technologies offer the ability to monitor acute
patients on a large scale. In the near future, image analysis software can be expected
to measure the temperature, heart rate, and respiratory rate of an ICU patient from a
distance of several meters. Using existing patient monitoring solutions, AI is already
able to use the acquired data to predict when a patient’s condition is about to worsen,
hours before a doctor arrival [87].
When there are staff shortages, such as reduced availability of staff on the night
shift, monitoring can be carried out from remote locations, even in the other half
of the world where people are awake. The remote monitoring approach can also
be extended to the home, with smart wearable devices that track patients who are
infected or at risk of infection. These wearable devices, such as a smart patch, can
measure body temperature, respiratory rate, and heart rate, monitor sleep, and detect
falls. All of these measurements can be combined with contextual and behavioral
information about the patient to keep them as safe as possible. Telemedicine has
all the potential to become a new standard, a powerful and innovative tool to take
the health sector to the next level and better protect the health of people around the
world.
4 Are Digital Health Instruments Prerequisites

of Pandemic Control?
This new coronavirus pandemic in a very short time has put a strain on the health
systems of the world’s major nations, many of which have been caught unprepared,
without sufficient tools, personnel, and infrastructure to guarantee adequate and effec-
tive assistance, both about emergencies than to ordinary territorial needs. Further-
more, considering that the care models of Western countries are mostly traditionally
structured, in the ways of providing care services, on the direct interaction between
doctor and patient [38]. As a further critical element, the spread of the virus had to
be addressed not only among patients but also among health professionals who carry
out the assessments, and this has contributed to the increase in infections within the
community [76]. The COVID-19 emergency requires urgent action to transform the
provision of health care by freeing the power of digital technologies; a clinical prac-
tice increasingly mediated by technology, essential in decision-making and treatment
processes in high-risk conditions.
After the declaration of COVID-19 as a deadly pandemic, the medical doctors face
a great emergency due to the sudden spread of the infection [10]. Healthcare profes-
sionals have been working continuously since the early stages of the outbreak, even
without effective protection measures, and sometimes without specialized training.
At the same time, the struggle against the virus took place in the hospitals, with
limited intensive care beds available and the health personnel were forced to over-
work ridiculously long hours. Very often have medical and health personnel have
been stuck in hospitals with heavy work shifts due to the lack of other colleagues to
take over, and many doctors and nurses have been infected and dead [61].
On 25 June, WHO held a press conference during which Dr. Hans Henri P. Kluge,
regional director for Europe, highlighted the potential of digital health tools, AI,
and digital technologies in performing contact tracing of patients with COVID-19
[107]. According to the WHO, however, great attention must be paid to the use of
these solutions because of the issues they raise, starting with the data protection and
privacy. Aware of the fact that digital technology can help health systems to cope
up with essential health care, especially during emergencies, there are three crucial
points on which WHO insists.
The first concerns the integration of digital health with the tools currently in use,
which must be done with care and, above all, in collaboration with those representing
citizens and patients. The second has to do with the concept of trust. The use of digital
tools is based on the public’s trust in them and therefore the proposed solutions must
take into account the privacy and security of people and their data [107]. The third
point concerns the “digital divide". Not all social groups are equally capable of
connecting the potential of digital technologies to fight with the virus. In Europe, for
example, households’ access to the Internet varies from 74 to 87%, with significant
inhomogeneities within individual countries and between population groups. The
invitation is, therefore, to work at a national level so that the technological difference
does not add to the social and economic gap in the population [91].
This ongoing global crisis has forced health institutions and regulatory bodies to
resort to alternative ways of providing health care with unique goal of limit exposure
to the virus. Telemedicine is proving to be the ideal solution to those problems by
limiting the patient movement to hospitals, allocating hospital capacity for the most
important cases, and the containment of the spread of the disease. Therefore, no
coincidence that the scientific world begins to raise the request to take advantage of
this period and widespread use of telemedicine systems to activate clinical studies
and to study their impact on the doctor-patient relationship.
Electronic prescriptions, Tele counseling, remote management of symptoms,
measurement of functional parameters, therapies, and follow-ups have attained a
prevalence on bed-side treatments, which can be implemented, but only in guaranteed
safety conditions (use of personal protective equipment or PPE) [5]. Implementing
telemedicine systems focused on monitoring asymptomatic patients or with mild
symptoms, can reduce hospital overcrowding, and therefore the chance of creating
aggregation areas with an increased risk of contagion of both patients and health
personnel engaged in the facility.
Telemedicine and telemonitoring solutions could be used to check the health of
people suffering from pre-existing and/or chronic diseases, reducing the number of
frontal visits in clinics and hospitals. A digitized care strategy should be applied
in situations of lockdown and limitation of movements, especially in those areas
where healthcare facilities are not in close vicinity, or for those patients whose
mobility is reduced. The validity of e-Health solutions is confirmed by the example
of some remote areas of China, where coronavirus mortality was significantly higher
than in more populated ones and with more health care facilities and telemonitoring
systems [45].
The above-mentioned telemedical solutions should include the specialist care of
hospitalized patients through tested telemonitoring devices and systems where the
patient can communicate through a telephone or computer. Apparently, this would
eliminate any risk of infection for both [109]. This telemedical system will be based
on equipment capable of allowing high-quality video calls as a crucial feature at

this point (smartphone, pc, and/or tablet). Therefore, everything will be supported
by a system of medical devices that will automatically communicate the essential
data, in real-time. The entire system will be managed by specially designed software,
which guarantees stable connections, maximum security of information flows, and
respect for privacy. The devices must be able to communicate automatically with the
application and let the doctor know about the results, without the patient having to
enter them manually due to the risk of errors.
The sick patient in home isolation can be video-monitored and have basic anal-
ysis devices, such as a thermometer and wireless pulse-oximeter. Sick patients also
affected by chronic diseases should get even more attention; therefore, it will be
up to the designed physician to decide what equipment to combine with the above
mentioned, if necessary (e.g. glucometer for diabetics). The application will also
have an “emergency” function the patient can use to contact the doctor or nurse
immediately for a speedy request for help. Video communication is a fundamental
part of the whole system, as it allows the doctor to guide the patient in the measure-
ment operation, monitor his condition, speak and listen to his problems, playing the
role of an empathic figure. The practice of medicine is an essentially moral activity,
founded on a “promise of trust” between patient and doctor and it must be remaining
the same, even in the digitalized context of telemedicine.
Worldwide, there are still several challenges that telemedicine is still going to face,
especially of legal, regulatory, and ethical nature [80], before it can finally become
an ordinary integrated assistance system. The new coronavirus pandemic has pushed
some authorities in one direction, that of promoting the use of digital technologies,
so far way too neglected and underestimated.
5 Current Pharmacological Strategies Applying to Control

COVID-19
In this section, authors present current possible drug therapies in controlling the
present deadly disease. The race towards the discovery of effective drugs against the
novel coronavirus has led to the off-label experimentation of medicines that, based
on the recent shreds of evidence from clinical trials, could have some effectiveness
[79]. Although there are currently no drugs that are declared effective for COVID-19,
some drugs investigated (or under investigation) have shown some efficacy, especially
in certain categories of patients. For these medicines, research continues providing
new and updated information, supported by precise guidelines for treating physicians
[90]. Figure 2 depicts the life cycle of COVID-19 including some drug therapies.
Fig. 2 COVID-19 lifecycle plus possible drug therapies [79]
5.1 Low Molecular Weight Heparins
Low molecular weight heparins (LMWH) are glycosaminoglycans obtained by frac-

tionation of heparin. They are used in the prophylaxis of post-surgical venous throm-
boembolism and venous thromboembolism in NON-surgical patients suffering from
an acute disease (such as acute heart failure, respiratory failure, severe infections, or
rheumatic diseases) and reduced mobility at an increased risk of venous thromboem-

bolism. They are also used in the treatment of deep vein thrombosis and pulmonary
embolism and acute coronary syndromes [12, 100].
Only enoxaparin is indicated in the prophylaxis of venous thromboembolism of
non-surgical patients; the recommended dose in CPR is 40 mg (4,000 U) per day for
at least 6–14 days.
The clinical course of COVID-19 is increasingly clearly delineating the existence
of 3 distinct clinical phases of the disease:
1. An initial phase in which the virus replicates within the host’s cells. This phase
is clinically characterized by the presence of general malaise, fever, and dry
cough. The cases in which it is possible to stop the infection at this stage have
a benign course.
2. The disease can then evolve into a second phase characterized by morpho func-
tional alterations in the lungs caused both by the direct effects of the virus
and by the host’s immune response. This phase is characterized by a very often
bilateral pattern of interstitial pneumonia associated with respiratory symptoma-
tology which in the early phase is stable and without hypoxemia, but which can
subsequently lead to progressive clinical instability.
3. This scenario, in a limited number of people, can evolve towards a wors-
ening clinical picture dominated by the cytokine storm and the consequent
hyperinflammatory state which determines local and systemic consequences
and represents a negative prognostic factor producing, in the lung, pictures of
vascular disease, arterial and venous with a thrombus of small vessels and evolu-
tion towards severe and sometimes permanent pulmonary lesions (pulmonary
fibrosis).
The final stages of this very serious clinical picture lead to severe ARD and
in some cases DIC. In this phase, a progressive alteration of some inflammatory
parameters such as PCR, ferritin, and pro-inflammatory cytokines (IL2, IL6, IL7,
IL10, GSCF, IP10, MCP1, MIP1A, and TNFα) and coagulation such as increased
levels were observed fragments of fibrin degradation such as D-dimer, consump-
tion of coagulation factors, thrombocytopenia, etc. This picture, both clinically and
from the hematochemical point of view, is similar to that of hemophagocytic lymph
histiocytosis (rare clinical picture often triggered by a viral infection) [12].
While the therapeutic choices of the first phase and the second initial phase should
aim at the containment of viral growth, in the second advanced phase and in the third
phase of the disease the goal should be the containment of hyper inflammation and its
consequences using biological drugs that block the cytokine cascade and probably
also cortisone, LMWH or unfractionated heparins at therapeutic doses by exploiting
their anticoagulant properties and more. It has been shown that timely therapeutic
choices can improve the clinical outcome.
Within this complex situation, the LMWHs may act:
• in the initial phase of the disease when pneumonia is present and hypomobility
of the bedridden patient occurs. In this phase, the EBPM must be used at a
prophylactic dose to prevent venous thromboembolism.
• in the most advanced stage, in patients hospitalized to contain the thrombotic
phenomena starting from the pulmonary circulation as a result of hyperinflam-
mation.
• In the latter case, LMWHs must be used at therapeutic doses [12].
In the most advanced stages of the disease, the enoxaparin dosage used in China
was 40–60 mg per day, but considering the greater sensitivity found in the Asian
population, in European patients, the dose could approach those used for therapeutic
purposes (80–100 mg per day corresponding to 8,000–10,000 IU / day), but this
intake has not been verified in clinical studies [79].
5.2 Azithromycin
Azithromycin (500 mg tablets or powder for oral suspension at a concentration of

200 mg / 5 ml) is an antibiotic of the macrolide family, authorized for the treatment of
upper and lower respiratory tract infections, odonto-stomatological infections, skin
infections and soft tissue, non-gonococcal urethritis, soft ulcers [104]. The indicated
dosage is 500 mg per day for 3 consecutive days.
The antibacterial property of macrolides derives from their interaction with the
ribosoma bacterial and the consequent inhibition of protein synthesis. There is
evidence that macrolides exert beneficial effects in patients with inflammatory lung
diseases in addition to their ability to inhibit the replication of pathogenic bacteria
[47, 75, 104].
In vitro and in vivo studies have shown that macrolides mitigate inflammation
and modulate the immune system; in particular, they have been shown to cause
the downregulation of cell surface adhesion molecules, reduce the production of
proinflammatory cytokines, stimulate phagocytosis by alveolar macrophages and
inhibit the activation and mobilization of neutrophils. The mechanism by which
macrolides exert these anti-inflammatory and immunomodulatory effects is not well
known [47].
The lack of a solid rationale and the absence of evidence of efficacy in the treatment
of COVID-19 patients does not allow to recommend the use of azithromycin, alone
or combined with other drugs with particular reference to hydroxychloroquine, apart
from out of any bacterial overlaps. The use of azithromycin for indications other
than those registered can only be considered in the context of randomized clinical
trials. Uses not covered by the authorized and not recommended indications remain
the responsibility of the prescriber [79].
5.3 Darunavir/cobicistat
In the early stages of the epidemic, the off-label use of darunavir/cobicistat was
permitted, as an alternative to lopinavir/ritonavir, based on the preliminary data avail-
able for the latter, only in the context of the national management of the COVID-19
emergency [69].
Its efficacy against COVID-19 is not proven. A small study on darunavir/cobicistat
is underway in China. Its currently identified clinical advantage is its greater intestinal
tolerability compared to lopinavir/ritonavir. In this emergency phase, considering
the premises described above, the therapeutic use of darunavir/cobicistat can be
considered as an alternative to lopinavir/ritonavir (in the same patient setting, i.e.
exclusively within clinical trials) when the latter is not tolerated due to diarrhea
[69, 115].
According to current evidence in the literature, similarly to what was established
for lopinavir/ritonavir, the Italian Medicines Agency (AIFA) has decided to suspend
the authorization for the off-label use of the drug outside of clinical trials.
5.4 Lopinavir/ritonavir
In the early stages of the epidemic, the off-label use of lopinavir/ritonavir was
permitted, based on preliminary data available, only within the context of the
national COVID-19 emergency management plan [79]. It is a ritonavir-boosted
protease inhibitor. Ritonavir improves its pharmacokinetic profile and by inhibiting
cytochrome P450, isoenzyme 3A4 slows the metabolism of lopinavir and increases
its pharmacological exposure. The association has proven effective in the context of
ART for the treatment of HIV [31].
Several protease inhibitors currently used for HIV therapy (lopinavir- LPV - da-
runavir - DRV - atazanavir, - ATV-) can inhibit viral replication by inactivating
the 3CLpro and PL2pro proteases; the 3CLpro protease is an essential molecular
target also for the replication of coronaviruses [15, 94, 108].
Animal models suggest that inhibition of the 3CLpro protease in critically
ill animals is associated with improvement. Finally, previous experiences with
SARSCoV-1 and MERS infection suggest that lopinavir can improve some clinical
parameters of patients [20].
Clinical experience with HIV has shown that in the authorized indications these
drugs tend to be safe, even if variously tolerated and with numerous drug interactions
[31].
Currently, the set of efficacy evidence indicates that the administration of
lopinavir/ritonavir is not associated with a clinical benefit compared to ordinary
therapy. While not excluding the possible existence of specific subpopulations of
patients who may in some way benefit from this treatment, the current frame-
work of uncertainty suggests waiting for further results before recommending its
use outside an experimental context. In the current state of knowledge, the combi-
nation of lopinavir/ritonavir with hydroxychloroquine or the possible addition of
azithromycin is not recommended [79].
This is supported by currently available safety data which further calls for caution
in the case of association with drugs that could potentially lead to toxicity in the
absence of clear evidence of an improvement in efficacy following the combination.
There is no evidence that the further addition of antibiotics (like azithromycin) is
safe and improves the evolution of the disease. Further randomized clinical trials are
needed to evaluate the efficacy of the drug in the various levels of severity of the
disease [17, 94].
5.5 Hydroxychloroquine (HCQ)
Hydroxychloroquine (Plaquenil® cp of 200 mg or generic equivalent) is a chemically

very similar analog of chloroquine and which shares its mechanism of action. It is
an antimalarial, currently used in our country in the rheumatology field at a dose of
200 mg × 2 even for very long periods; therefore, there is ample clinical experience
(superior to chloroquine) regarding its tolerability [79].
Hydroxychloroquine (HCQ) and chloroquine (CQ) (and their active metabolites)
have been shown in vitro or in animal models to have an antiviral effect through
the alteration (increase) of the endosomal pH which is crucial for virus-cell fusion.
These drugs also interfere with the glycosylation of cellular SARS-COV-2 receptors
[23, 26, 85].
In vitro data report that C can block the viral replication of SARS-COV-2 at
doses used in clinical practice. In addition to the antiviral action, both drugs have
an immunomodulatory activity that could synergistically enhance the antiviral effect
in vivo. It also appears from in vitro studies that the effects on cells are observable both
when the drug is present before and when it is present after viral inoculation. CQ and
HCQ are distributed throughout the body including the lung where they appear to be
concentrated. The choice of HCQ derives from a greater efficacy in vitro; according
to a recent study, HCQ could be active against SARS-COV-2 at lower concentrations
than CQ [79]. The use of high doses of HCQ increases the risk of adverse events.
For this reason, even in the context of any clinical studies, it is recommended to use
the lowest dosage and for the shortest possible time (5–7 days) [79].
On April 24, the European Agency (EMA) drew attention to the risks of adverse
reactions, even serious ones, associated with the use of HCQ and CQ. In particular,
while adverse events can occur even at therapeutic dosages, higher doses can further
increase the problems associated with altered heart rhythms (long QT). The EMA is
aware of the current use of HCQ in the context of the COVID19 pandemic and invites
prescribers to pay particular attention to it as well as soliciting clinical studies on
the efficacy of the drug in COVID19. On May 29, the EMA announced that, in light
of new evidence regarding the safety of hydroxychloroquine and chloroquine, these
medicines should only be used in clinical trials or national emergency management

programs only in patients. hospitalized under close monitoring [29].
On March 28, 2020, the FDA issued an emergency use authorization (EUA) in
cases where it was not possible to perform clinical trials. On April 24, the same agency
warns that it is aware of reports of serious heart rhythm problems in patients (hospital-
ized and otherwise) with COVID-19 treated with HCQ or CQ, often in combination
with azithromycin and other drugs that prolong QT, especially in patients with renal
insufficiency. Such reports of adverse reactions include ventricular tachycardia or
fibrillation and include some fatal cases. The recommendation is to maintain the use
of HCQ within clinical trials or in a hospital context that provides for close moni-
toring. On 15/06/2020 the FDA revoked the previously granted EUA (Emergency
Use Authorization) [42].
5.6 Ivermectin
Ivermectin has been studied since 1946 against avid diphtheria when it was consid-
ered as an enigmatic multifaceted (but still effective) drug in 2017 [32]. It has also
been used as an anti-parasite and against HIV, Zika, Dengue, and Influenza viruses
[103].
Its mechanism of action involves the nuclear transport of viral proteins [16]. This
transport is fundamental for the replication of the virus, and therefore drugs that act on
this mechanism could be valid therapeutic opportunities against RNA viruses [113].
Ivermectin is currently under study in COVID-19 patients. The commonly studied
dosage is 12 mg/week. In some studies, it is paired with hydroxychloroquine. Recent
studies report mixed results. Consequently, further studies are needed to determine
if Ivermectin could be efficient and safe in the treatment of COVID-19 [79].
5.7 Corticosteroids
Corticosteroids were among the first drugs to be considered unsuitable for COVID19
therapy. This because they tend to reduce the virus clearance [86].
Several studies have shown that corticosteroids can cause reduced viral elimi-
nation, especially in the respiratory tract. This has led to numerous complications,
including indirect ones, such as psychosis and hyperglycemia [4, 99]. They can also
increase the risk of getting secondary infections [77]. Despite this, many studies
are evaluating the safety and efficacy of corticosteroids against SARS-CoV-2. The
reason lies in the fact that these drugs can reduce the proliferation of T lymphocytes,
and therefore the release of pro-inflammatory cytokines that can cause an excessive
response in the host. To date, the limited information available does not suggest the
use of corticosteroids in the therapy of COVID-19 [79].
5.8 Hyperimmune Plasma
The administration of plasma polyclonal antibodies is being tested in numerous

clinical trials [79]. According to the literature, antibodies could lead to increased
chances of survival in patients suffering from acute respiratory diseases with viral
etiology, thanks to immediate immunity [67]. Some preliminary studies have reported
promising results from Convalescent Plasma Transfusion (CPT) [118].
It is important to investigate suitable dosages to ensure an optimal benefit/safety
ratio. Currently, most studies are analyzing single doses of 200-2400 ml of plasma
[37, 117]. Further detailed and double-blind trials are needed to understand the
therapeutic possibilities of hyperimmune plasma.
5.9 Recombinant Human Angiotensin-Converting Enzyme 2

(APN01)
The recombinant human angiotensin-converting enzyme 2 (rhACE2) could inhibit

the entry of SARS-CoV-2 into host cells by blocking the protein S, responsible
for the interaction between the virus and host’s Angiotensin-Converting Enzyme- 2
(ACE2). Administration of rhACE2 may reduce Angiotensin II levels, subtracting
the substrate of the viral protein S. This could ensure the integrity of the pulmonary
vessels and a reduction of the risk of respiratory failure [58]. Several studies are
testing rhACE2 and should be completed by the end of 2020, potentially providing
useful information in the fight against COVID-19.
5.10 Remdesivir
Remdesivir is a relatively recent drug used in the fight against Ebola and other
emerging viruses [95]. It was among the first drugs used in the fight against COVID-
19, as it proved effective in the fight against SARS-CoV and MERS-CoV [1, 93].
Many in vivo studies have shown inhibitory activity of the drug against SARS-CoV-2
[105].
Remdesivir is a prodrug that is structurally similar to adenosine [95]. It acts by
incorporation into the nascent viral RNA, and inhibits the RNA-dependent RNA
polymerase, stopping the replication of the viral RNA [72].
Doses being tested range from 200 to 400 mg as a loading dose, followed by lower
doses for a period of 5 to 10 days [80]. During the pandemic, the FDA approves the
emergency use of remdesivir, now widely used as a potentially anti-COVID-19 drug
[41, 80].
5.11 Favipiravir
Favipiravir has shown strong inhibitory activity against influenza viruses, and
according to preliminary studies, it has possible activity as a viral RNA polymerase
inhibitor [43]. Similar to remdesivir, favipiravir acts as an RNA- dependent RNA
polymerase inhibitor and this inhibition could reduce viral replication [44].
High doses of the drug are being studied for the treatment of COVID-19. Generally,
an attack dose of 1800-2400 mg is provided, followed by maintenance doses of 300-
1800 mg [98]. It is a generally well-tolerated drug, although the dosages tested in
the treatment of COVID-19 are higher than those for which the drug is commonly
used [36].
We currently do not have much information about the effectiveness of this drug
against the novel coronavirus. But preliminary trials seem to support the emergency
use of favipiravir for COVID-19. As evidence, as early as March 2020, favipiravir
was approved by the National Medical Products Administration of China as the first
anti-COVID-19 drug in China.
5.12 Recently Authorized Clinical Trials
Other clinical studies on drugs for the treatment of the COVID-19 disease have
concluded the authorization process by regulatory bodies such as EMA and AIFA.
The first is a Phase III, randomized, double-blind, placebo-controlled, multicenter,
study to evaluate the efficacy and safety of the use of Ruxolitinib in patients with
COVID-19 associated with a cytokine storm. Ruxolitinib is a selective inhibitor of
Janus Associated Kinases (JAKs) JAK1 and JAK2, already authorized in Europe for
other therapeutic indications [28].
The second authorized study is an open-label single-arm Phase 2/3 study aimed
at evaluating the safety, tolerability, pharmacokinetics, and efficacy of remdesivir
in participants from birth to < 18 years of age with COVID. -19. Remdesivir is an
antiviral drug that last June received the recommendation for conditional authoriza-
tion from the EMA for the “treatment of coronavirus disease 2019 (COVID-19) in
adults and adolescents (aged 12 years and over) and weighing at least 40 kg) with
pneumonia that requires supplementary oxygen therapy".
The third is a phase 2, randomized, double-blind versus placebo study using
Opaganib in hospitalized adults with SARS-CoV-2 pneumonia. Opaganib is an
inhibitor of the enzyme sphingosine kinase-2 (SK2), still in the clinical trial phase
for multiple oncological indications.
The fourth is a phase III, randomized, double-blind, placebo-controlled, multi-
center, study to evaluate the efficacy and safety of the use of baricitinib in patients
with COVID-19. Baricitinb is an inhibitor of Janus Associated Kinases (JAKs) JAK1
and JAK2 authorized in Italy for the treatment of rheumatoid arthritis. The results of
these new studies could lead to new hypotheses of effective treatment for COVID-19.
6 Discussion
Different studies have reported as the cases continued to increase exponentially, and
modeling studies also revealed an epidemic was doubling time of 1.8 days. As of
05th March 2020, 96 thousand COVID-19 cases worldwide. Of these number, 88,
000 cases in China, 87 other countries, and 696 cases in Diamond Princess cruise
ship, Japan. The number of new cases reduced in china lately and increased expo-
nentially in other countries, including Iran, Italy, Spain, and South Korea. Currently,
COVID-19 rapidly transmitted to more than 190 countries worldwide and attributed
to different crises such as economic, social, and political challenges throughout the
world. Globally, until 22nd September 2020, it has affected more than 31 million
people and caused more than 969 thousand deaths [28]. Next to China, Italy, France,
Spain, the USA, Brazil, India, and Russia are the most affected countries by this
pandemic. The strain of COVID-19 is genetically related to SARS-CoV (Severe
Acute Respiratory Syndromes Coronavirus) and MERS- CoV (the Middle East
Respiratory Syndrome Coronavirus). The epidemiology of COVID-19 is almost
similar to the SARS-CoV and may manifest either as an asymptomatic infection
or a mild to severe pneumonia [56].
Studies revealed that bat was the natural host of COVID-19 due to over 96 percent
of whole-genome similarity with the BatCoV-RaTG13 genome [49]. SARS-CoV and
MERS-CoV need intermediate has such as palm civets and camels, respectively, to
transmit from an animal to a human. The common mode of transmission of COVID-
19 is the inhalation of infectious aerosols. Also, the virus may present in the large
respiratory droplets, stool, and urine of affected patients with diarrheal symptoms.
Infected droplets can spread from one to two meters and settle on surfaces. The
coronavirus can remain viable on surfaces for days in favourable weather conditions.
However, it can be destroyed in less than a minute by common disinfectants such as
sodium hypochlorite, hydrogen peroxide, and other disinfectants. Hence, infection
is attained by inhaling these droplets or touching surfaces contaminated with the
infected droplets, then touching the nose, mouth, and eyes.
The incubation periods are approximately 3 to 14 days, with an estimated
median incubation period of 5.1 days, and the transmission can also occur during
the presymptomatic stage [46, 56]. The basic reproduction number (R0) has been
reported to be between 2.13 and 4.82, similar to SARS-CoV [24]. All ages are
prone to COVID-19, but elderly patients, especially with chronic medical conditions
such as diabetes, hypertension, cardiovascular diseases, and individuals with primary
and secondary immunodeficiency, have higher death rates [104]. Different studies
revealed that large proportions of severe COVID-19 cases occur in adults greater
than or equal to 60 years of age [104, 63]. Several studies have reported that a higher
viral load in the nasal cavity than in the throat.
Besides, there was no difference between symptomatic and asymptomatic
COVID- 19 patients in throat viral load. It may cause diseases ranging from asymp-
tomatic to fatal diseases. In the elderly and patients with other pre-condition cases,
it infects the lower respiratory tract with the potential of leading to fatal pneumonia.
Fever, cough, shortness of breath, fatigue, sore throat, headache, myalgia, anosmia,
conjunctivitis, diarrhoea, and sputum production are the common clinical manifes-
tation of COVID-19 [46, 56]. Patients in the second week of infection may require
mechanical ventilation in the Intensive care unit (ICU) with quarantine facilities
[56]. Patients with mild or moderate symptoms can manage them at home without
the need for hospitalization. Simultaneously, patients with serious symptoms such as
shortness of breathing, chest pain, and loose speech need urgent medical attention.
Studies reported that COVID19 during pregnancy did not cause worse symptoms than
non-pregnant women, and no evidence of intrauterine infection caused by vertical
transmission [50].
The lungs are the primary site for COVID-19 infection. Studies on the biopsy
samples of lung, liver, and heart obtained from dead COVID-19 patients reported
that the lung was the main affected tissue with pathological changes [101]. Acute lung
infections, ARDS, shock, and acute kidney infections are among the complications.
By the second or third week of infection, recovery began and the median length of
hospital stay for those who recovered was ten days. The overall death rate of cases is
estimated to be between 2 and 3% [28, 97]. Children are unlikely to be infected or,
if infected, have milder symptoms than adults,therefore, their parents will not seek
treatment that will underestimate the incidence of COVID-19 in children [50].
Quarantine and isolation measures and appropriate clinical management of
patients are an important effort to control the transmission of COVID-19 infec-
tion [25]. On 31st January 2020, the WHO released the COVID-19 Case Surveil-
lance guideline [110]. On the guideline, the WHO recommended different screening
criteria and for a person who meets the criteria, initially screening for common causes
of respiratory diseases [110]. If the result is negative, the sample should be sent to
the laboratory for the detection of SARS-CoV-2.
According to the WHO COVID-19 case definition, suspected cases are subjects
with a severe acute respiratory infection, with no other aetiology that thoroughly
explains the clinical presentation and a history of travel or residence in a country or
a place affected by COVID-19 infection for 14 days before symptoms onset.
Another option for identifying suspected cases, a person with respiratory infec-
tion who is in contact with a confirmed or probable case of SARS-CoV-2 infection
or who has worked or attended a healthcare facility where patients with confirmed or
probable SARS-CoV-2 acute respiratory illnesses were treated in the 14 days before
symptom onset. As for probable cases, a patient who is positive for SARS-CoV-2 by a
pan-coronavirus test and without laboratory evidence of other respiratory pathogens.
Another case definition is confirmed cases, a patient with laboratory confirmation
of SARS-CoV-2 infection, regardless of clinical signs and symptoms. For patients
who are in line with the diagnostic criteria for SARS-CoV-2, the Centres for Disease
Control and Prevention (CDC) recommends collecting nasopharyngeal and oropha-
ryngeal (upper respiratory tract) swab specimens and, if possible, also lower respi-
ratory tract specimens included sputum, tracheal aspirate, or bronchoalveolar lavage
[83].
In general, two types of tests have been applied in the laboratory to detect
COVID19, including PCR tests and serological tests. PCR tests as a molecular diag-
nostic technique upon viral genetic materials, which identify the active COVID-19
infection. Early detection through PCR depends on the presence of enough viral
genome in a patient sample and the sensitivity of the RT–PCR assay [27, 66].
Regarding the serological test type, it can identify the people who have developed
adaptive immune responses to the virus as part of active or prior infection. In this test,
three types of antibodies, including IgG, IgM, and IgA can be detected in response to
the virus. Even though the serological test, along with PCR, increase the sensitivity
or accuracy, immune tests do not help diagnose and screen in early infection due to
the window period. To detect the antibodies, it may take more than two weeks after
infection with COVID-19.
Consequently, molecular tests are more sensitive than immune and serological
tests in diagnosing primary infection and may speed up early detection by directly
identifying viral RNA, even during the incubation period COVID-19 [39]. It is
possible to identify by radiological examination, although the results may vary
patients’ age, disease severity, and comorbidity, and immunity status. Radiolog-
ical examination is an important test for the early detection of CVID-19 cases. For
example, the study conducted on 41 subjects with the initial cases of COVID19
infection reported that all 41 individuals had pneumonia with abnormal findings on
chest computed tomography (CT-scan) [53].
There is still under investigation the specific antiviral treatment for COVID-19,
like to MERS-CoV and SARS-CoV, no specific treatment is declared. However, isola-
tion and supportive care, including oxygen therapy, fluid management, and antibi-
otic treatment for secondary bacterial infections, are recommended [48]. Common
treatments are maintaining hydration, nutrition, and managing fever and cough. In
hypoxic patients, oxygen via a nasal prong, face mask, and non-invasive ventila-
tion is recommended. Maybe antibiotics and antiviral drugs are needed when the
co-infections are suspected.
According to the Chinese COVID-19 treatment guideline, short-term therapy with
a low to moderate dose of corticosteroids was recommended. The routine uses of
some antibiotics and antiviral such as oseltamivir are not recommended. However,
several studies confirmed that chloroquine sulphate and hydroxychloroquine sulphate
drugs are used as first-line treatment drugs in different countries [47, 73]. Chloroquine
is a malaria treatment and regarding cost, inexpensive, and safe for elderly patients.
Although these two drugs were used as a first-line treatment, there are maybe some
negative effects such as cardiac arrhythmias, the risk for gastrointestinal responses,
and retinal damage when long time use. Some drugs are still under investigation. For
example, Remdesivir drug is a new antiviral agent and currently under examination,
which inhibits viral replications via premature termination of RNA transcriptions.
Also, some anti-influenza drugs such as umifenovir, oseltamivir, and other drugs that
treated SARS and MERS are under examination [73].
In the current situation, public health efforts are a good approach to prevent the
transmission of COVID-19. Unfortunately, the health care facilities are currently the
sources of viral transmission. Hence, various strategies should be implemented in
health care settings to prevent the spreading of COVID-19 infection [50]. Strategies
such as applying triage, case isolation, quarantine for suspects, and contact tracing
are essential strategies for limiting further transmission of the virus in a healthcare
facility, clinics, and community. A person presents with the symptom of respiratory
infection like runny nose, fever, and the cough must wear a face mask and undergo
triage procedure to contain the virus. Those persons who have the symptoms of
respiratory infection must not be permitted to wait with other clients seeking medical
care at health facilities, and they should be treated separately. The confirmed COVID-
19 cases should be isolated and provided care based on the severity of the cases. If
individuals with mild to moderate illness, home-based care are recommended, but
the condition is severe or getting severe, hospitalization is required. For patients with
mild to moderate illness, ventilation with sunlight is good to destruct the virus and
reduce the severity of the conditions. Patients infected with the virus should be asked
to wear a face mask, especially during sneezing and coughing; they should cover the
mouth and nose properly. Healthcare workers are more prone to COVID-19.
During the SARS outbreak, 21% of infected cases were healthcare workers [21].
More than 570,000 healthcare workers were infected, and 2500 died as of 02nd
September 2020, in the United States [30]. Globally, over 1.4 million infections of
COVID-19 are accounted for the health workers [111]. Hence, medical personals who
are entering the room in which the patients admitted must wear personal protective
equipment (PPE) such as eye protection, disposable N95 mask, gowns, surgical
gloves, etc. The patient admitted the room should be properly clean, especially after
the patient is discharged. The room should be disinfected, and a person who enters
the room should wear PPE. All contacts, including health professionals, should be
screened for developing symptoms. Certain procedures, such as setting temperature
checks or scanning at airports and borders to identify suspicious cases, maybe the
best approach to prevent transmission of the virus.
Telemedicine has already been proved to be effective in the past, during SARS-
CoV (Severe Acute Respiratory Syndrome-Associated Coronavirus) and MERS-
CoV (Middle East Respiratory Syndrome Coronavirus) emergencies, as well as Ebola
and Zika [81]. A proposed framework of the application of telemedicine and tele-
monitoring is summarized in Fig. 3. This integrated system may guarantee controlled
management not only of positive patients but also of asymptomatic and chronically
ill patients, in the new coronavirus outbreak and/or in similar emergencies.
Healthcare systems have had to change the way they triage, evaluate, and care
for patients using methods that reduce contact in-person services [8]. Pharmacists
are among the most trusted and accessible healthcare professionals with established
relationships with their patients. Countries like the U.S have authorized community
pharmacists to carryout COVID-19 testing during the pandemic [51]. That proximity
reduces travel to testing locations and results can be communicated to patients and
their medical providers as this will allow for treatment initiation where necessary,
which is an important measure to curtail the spread of the virus. Pharmacists also
have strong relationships with medical practitioners to appropriately refer patients
when necessary. As such, residents have to either seek healthcare from the nearest
community.
Fig. 3 Proposed telemedicine framework for the COVID-19 emergency
Pharmacy or use mail order or online services to fill their prescriptions, which is
a particular concern for the elderly who have a much higher risk of infection and
limited support or without internet connection/low competence in the use of modern
technology. This could lead to an increase in COVID-19 cases. Tele-pharmacy, as
defined by the National Association of Boards of Pharmacy “is the provision of
pharmaceutical care through the use of telecommunications and information tech-

nologies to patients at a distance,” tele-pharmacy is an inpatient or retail/outpatient
pharmacy where the pharmacist counsels and verifies prescriptions via a software
platform from another physical location [19].
Individuals seek healthcare advice via telephone calls with trained pharmacists,
who provide counselling, education, and pharmaceutical care. These innovative
pharmacy practices not only reduce the number of individuals in hospitals seeking
healthcare, but they also reduce nosocomial infections. Using a smartphone-based
tele-pharmacy app that allows pharmacists to review medication orders and counsel
patients. In several facilities in different locations at once and in real-time, could
increase access to pharmaceutical care, adherence to therapy, reducing the risk of
contracting an infectious disease such as that caused by COVID-19. Tele-pharmacy
is still a relatively new idea, and there is a delay in the implementation of new laws
by administrations and States.
7 Conclusions
The latest pandemic caused by COVID-19 disease shows significant challenges to

global public health. In this chapter, we presented the possible solutions including
telehealth and drug therapeutic choices at present under review and future perceptions
of this virus. However, there is no verified vaccine or drug available to control this
disease, prevention through available technological solutions is the only option. Up
to date, drug therapy is the standalone method to have an immediate response to
the coronavirus. Some mentioned drugs conducted by preliminary studies are have
already displayed reliable responses and approved for extensive use. Although there
is no standard or effective drug solution has been discovered yet. Therefore, to find
an effective and safe solution at a rapid pace to control this deadly virus, a worldwide
collaboration between research centres and healthcare authorities is mandatory.
References
1. Agostini, M. L. et al. (2018) ‘Coronavirus susceptibility to the antiviral remdesivir (GS-5734)

is mediated by the viral polymerase and the proofreading exoribonuclease’, mBio. doi: https://
doi.org/10.1128/mBio.00221-18.
2. Ameri, A. et al. (2020) ‘Investigating Pharmacists’ Views on Telepharmacy: Prioritizing Key
Relationships, Barriers, and Benefits’, Journal of Pharmacy Technology. doi: https://doi.org/
10.1177/8755122520931442.
3. Ameri, A., Salmanizadeh, F., Bahaadinbeigy, K.: Tele-pharmacy: A new opportunity for
consultation during the COVID-19 pandemic. Health Policy and Technology (2020). https://
doi.org/10.1016/j.hlpt.2020.06.005
4. Arabi, Y.M., et al.: Corticosteroid therapy for critically ill patients with middle east respira-
tory syndrome. Am. J. Respir. Crit. Care Med. (2018). https://doi.org/10.1164/rccm.201706-
1172OC
5. Bashshur, R., et al.: Telemedicine and the COVID-19 pandemic, lessons for the future.
Telemedicine and e-Health (2020). https://doi.org/10.1089/tmj.2020.29040.rb
6. Battineni, G., et al.: Report on market analysis and preventions need to provide medications for
rural patients of Italy using ICT technologies. International Journal of Innovative Technology
and Exploring Engineering (2019). https://doi.org/10.35940/ijitee.A4025.119119
7. Battineni, G., Sagaro, G.G., et al.: Applications of machine learning predictive models in the
chronic disease diagnosis. Journal of Personalized Medicine (2020). https://doi.org/10.3390/
jpm10020021
8. Battineni, G., Mittal, M., et al.: Cloud-based framework to mitigate the impact of COVID-19
on seafarers’ mental health. Int. Marit. Health 71(3), 213–214 (2020). https://doi.org/10.5603/
IMH.2020.0038
9. Battineni, G., Chintalapudi, N., Amenta, F.: AI Chatbot Design during an Epidemic like the
Novel Coronavirus. Healthcare (2020). https://doi.org/10.3390/healthcare8020154
10. Battineni, G., Chintalapudi, N. and Amenta, F. (2020b) ‘SARS-CoV-2 epidemic calcula-
tion in Italy by SEIR compartmental models’, Applied Computing and Informatics. Emerald
Publishing Limited, ahead-of-p(ahead-of-print). doi: https://doi.org/10.1108/ACI-09-2020-
0060.
11. Battineni, G., Chintalapudi, N., Amenta, F.: Tropical Conditions and Outbreak of COVID-19.
Pharmaceutical and Biomedical Research. Knowledge E 6(1), 9–16 (2020). https://doi.org/
10.18502/pbr.v6i(s1).4396
12. Belen-Apak, F.B., Sarialioglu, F.: The old but new: Can unfractioned heparin and low molec-
ular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2
by inhibition of host cell proteases? Med. Hypotheses (2020). https://doi.org/10.1016/j.mehy.
2020.109743
13. Bonner, L. (2020) Telehealth basics for pharmacists during COVID-19 and beyond. doi:
https://doi.org/10.1016/j.ptdy.2020.05.013.
14. Brent I. Fox, J. C. H. (no date) Telepharmacy During the COVID-19 Pandemic and
Beyond|ComputerTalkForThePharmacist.Availableat: https://www.computertalk.com/teleph
armacy-during-the-covid-19-pandemic-and- beyond/ (Accessed: 24 September 2020).
15. Cai, Q., et al.: Experimental Treatment with Favipiravir for COVID- 19: An Open-Label
Control Study. Engineering (2020). https://doi.org/10.1016/j.eng.2020.03.007
16. Caly, L., Wagstaff, K.M., Jans, D.A.: Nuclear trafficking of proteins from RNA viruses:
Potential target for antivirals? Antiviral Res. (2012). https://doi.org/10.1016/j.antiviral.2012.
06.008
17. Cao, B., et al.: A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.
N. Engl. J. Med. (2020). https://doi.org/10.1056/NEJMoa2001282
18. Cascella, M. et al. (2020) Features, Evaluation and Treatment Coronavirus (COVID-19),
StatPearls.
19. Casey, M.M., et al.: Current practices and state regulations regarding telepharmacy in rural
hospitals. Am. J. Health Syst. Pharm. (2010). https://doi.org/10.2146/ajhp090531
20. Chan, J.F.W., et al.: Treatment with lopinavir/ritonavir or interferon-β1b improves outcome
of MERSCoV infection in a nonhuman primate model of common marmoset. J. Infect. Dis.
(2015). https://doi.org/10.1093/infdis/jiv392
21. Chang, D., et al.: Protecting health-care workers from subclinical coronavirus infection. The
Lancet Respiratory Medicine. Elsevier Ltd 8(3), e13 (2020). https://doi.org/10.1016/S2213-
2600(20)30066-7
22. Chawla, S., et al.: Corona Virus - SARS-CoV-2: An Insight to Another way of Natural Disaster.
EAI Endorsed Transactions on Pervasive Health and Technology (2020). https://doi.org/10.
4108/eai.28-5-2020.164823
23. Chen, J., et al.: A pilot study of hydroxychloroquine in treatment of patients with common
coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 49(February), 1–10 (2020).
https://doi.org/10.3785/j.issn.1008-9292.2020.03.03
24. Chintalapudi, N., et al.: ‘COVID-19 outbreak reproduction number estimations and fore-
casting in Marche. Italy’, International Journal of Infectious Diseases. (2020). https://doi.org/
10.1016/j.ijid.2020.05.029
25. Chintalapudi, N., Battineni, G. and Amenta, F. (2020) ‘COVID-19 virus outbreak forecasting
of registered and recovered cases after sixty day lockdown in Italy: A data driven model
approach’, Journal of Microbiology, Immunology and Infection. Elsevier Ltd. doi: https://
doi.org/10.1016/j.jmii.2020.04.004.
26. Colson, P., et al.: Chloroquine and hydroxychloroquine as available weapons to fight COVID-
19. Int. J. Antimicrob. Agents (2020). https://doi.org/10.1016/j.ijantimicag.2020.105932
27. Corman, V.M., et al.: Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-
PCR. Eurosurveillance 25(3), 1–8 (2020). https://doi.org/10.2807/1560-7917.ES.2020.25.3.
2000045
28. Coronavirus outbreak (2020) Worldometer. doi: https://doi.org/10.1101/2020.01.23.200185
49V2. COVID-19: Nuovi studi clinici autorizzati (2020) Agenzia Italiana del Farmaco.
29. COVID-19: reminder of risk of serious side ef-fects with chloroquine and hydroxychloroquine
(2020) European Medicine Agency (EMA).
30. COVID-19 has infected some 570,000 health workers and killed 2,500 in the Americas, PAHO
Director says - PAHO/WHO | Pan American Health Organization (no date).
31. Croxtall, J.D., Perry, C.M.: LopinavirRitonavir: A review of its use in the management of
HIV-1 infection. Drugs (2010). https://doi.org/10.2165/11204950-000000000-00000
32. Crump, A.: Ivermectin: Enigmatic multifaceted “wonder” drug continues to surprise and
exceed expectations. J. Antibiot. (2017). https://doi.org/10.1038/ja.2017.11
33. Damian N. Valencia (2020) ‘Brief Review on COVID-19: The 2020 Pandemic Caused by
SARS-CoV-2’, Cureus, 12(3). doi: https://doi.org/10.7759/cureus.7386.
34. Davarpanah, A.H., et al.: Novel Screening and Triage Strategy in Iran During Deadly Coron-
avirus Disease 2019 (COVID-19) Epidemic: Value of Humanitarian Teleconsultation Service.
J. Am. Coll. Radiol. (2020). https://doi.org/10.1016/j.jacr.2020.03.015
35. Dedeilia, A., et al.: Medical and surgical education challenges and innovations in the COVID-
19 era: A systematic review. Vivo (2020). https://doi.org/10.21873/invivo.11950
Drug Discoveries & Therapeutics (2020). https://doi.org/10.5582/ddt.2020.01012
37. Duan, K., et al.: Effectiveness of convalescent plasma therapy in severe COVID-19 patients.
Proc. Natl. Acad. Sci. (2020). https://doi.org/10.1073/pnas.2004168117
38. Duffy, S., Lee, T.H.: In-person health care as option B. N. Engl. J. Med. (2018). https://doi.
org/10.1056/NEJMp1710735
39. Esakandari, H., et al.: A comprehensive review of COVID-19 characteristics. Biological
Procedures Online. Biological Procedures Online 22(1), 1–10 (2020). https://doi.org/10.1186/
s12575-020-00128-2
40. Exum, E., et al.: Applying Telehealth Technologies and Strategies to Provide Acute Care
Consultation and Treatment of Patients With Confirmed or Possible COVID-19. Journal of
Acute Care Physical Therapy (2020). https://doi.org/10.1097/jat.0000000000000143
41. FDA Allows For ‘Emergency Use’ of Remdesivir, Experimental Coronavirus Drug (2020)
TIME.
42. FDA Drug Safety Communication (2020) Food and Drug Administration (FDA).
43. Furuta, Y., et al.: Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res.
(2013). https://doi.org/10.1016/j.antiviral.2013.09.015
44. Furuta, Y., Komeno, T. and Nakamura, T. (2017) ‘Favipiravir (T-705), a broad spectrum
inhibitor of viral RNA polymerase’, Proceedings of the Japan Academy Series B: Physical
and Biological Sciences. doi: https://doi.org/10.2183/pjab.93.027.
45. Gadzinski, A.J., et al.: Implementing Telemedicine in Response to the COVID-19 Pandemic.
J. Urol. (2020). https://doi.org/10.1097/JU.0000000000001033
46. Galluccio, F., et al.: Treatment algorithm for COVID-19: a multidisciplinary point of view.
Clinical Rheumatology. Clinical Rheumatology 39(7), 2077–2084 (2020). https://doi.org/10.
1007/s10067-020-05179-0
47. Gautret, P., et al.: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results
of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents (2020). https://doi.
org/10.1016/j.ijantimicag.2020.105949
48. Habibzadeh, P., Stoneman, E.K.: The novel coronavirus: A bird’s eye view. International
Journal of Occupational and Environmental Medicine 11(2), 65–71 (2020). https://doi.org/
10.15171/ijoem.2020.1921
49. Han, Y. et al. (2019) ‘Identification of diverse bat alphacoronaviruses and betacoronaviruses
in china provides new insights into the evolution and origin of coronavirus-related diseases’,
Frontiers in Microbiology, 10(AUG). doi: https://doi.org/10.3389/fmicb.2019.01900.
50. Harapan, H., et al.: Coronavirus disease 2019 (COVID-19): A literature review. J. Infect.
Public Health 13(5), 667–673 (2020). https://doi.org/10.1016/j.jiph.2020.03.019
51. HHS Statements on Authorizing Licensed Pharmacists to Order and Administer COVID-
19Tests|HHS.gov(nodate).Availableat: https://www.hhs.gov/about/news/2020/04/08/hhs-sta
tements-on-authorizing- licensed-pharmacists-to-order-and-administer-covid-19-tests.html
(Accessed: 14 September 2020).
52. Hollander, J.E., Carr, B.G.: Virtually perfect? Telemedicine for covid- 19. N. Engl. J. Med.
(2020). https://doi.org/10.1056/NEJMp2003539
53. Huang, C., et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan,
China. The Lancet 395(10223), 497–506 (2020). https://doi.org/10.1016/S0140-6736(20)301
83-5
54. Jiang, X., et al.: Psychological crisis intervention during the outbreak period of new coron-
avirus pneumonia from experience in Shanghai. Psychiatry Res. (2020). https://doi.org/10.
1016/j.psychres.2020.112903
55. Jiménez-Rodríguez, D., et al.: Increase in video consultations during the COVID19 pandemic:
Healthcare professionals’ perceptions about their implementation and adequate management.
Int. J. Environ. Res. Public Health (2020). https://doi.org/10.3390/ijerph17145112
56. Kannan, S., et al.: COVID-19 (Novel Coronavirus) - Recent trends. Eur Rev Med Pharmacol
Sci 24, 2006–2011 (2020)
57. Keesara, S., Jonas, A., Schulman, K.: Covid-19 and health care’s digital revolution. N. Engl.
J. Med. (2020). https://doi.org/10.1056/NEJMp2005835
58. Khan, A., et al.: A pilot clinical trial of recombinant human angiotensin- converting enzyme
2 in acute respiratory distress syndrome. Crit. Care (2017). https://doi.org/10.1186/s13054-
017-1823-x
59. Koster, E.S., Philbert, D., Bouvy, M.L.: Impact of the COVID-19 epidemic on the provision
of pharmaceutical care in community pharmacies. Res. Social Adm. Pharm. (2020). https://
doi.org/10.1016/j.sapharm.2020.07.001
60. Kucharski, A.J., et al.: Early dynamics of transmission and control of COVID-19: a mathemat-
ical modelling study. Lancet. Infect. Dis (2020). https://doi.org/10.1016/S1473-3099(20)301
44-4
61. Lazzerini, M., Putoto, G.: COVID-19 in Italy: momentous decisions and many uncertainties.
Lancet Glob. Health (2020). https://doi.org/10.1016/S2214-109X(20)30110-8
62. Li, H., et al.: Fighting against COVID-19: Innovative strategies for clinical pharmacists. Res.
Social Adm. Pharm. (2020). https://doi.org/10.1016/j.sapharm.2020.04.003
63. Li, Q., et al.: Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected
Pneumonia. N. Engl. J. Med. (2020). https://doi.org/10.1056/NEJMoa2001316
64. Li, W., et al.: Progression of mental health services during the COVID-19 outbreak in China.
Int. J. Biol. Sci. (2020). https://doi.org/10.7150/ijbs.45120
65. Liu, S., et al.: Online mental health services in China during the COVID-19 outbreak. The
Lancet Psychiatry (2020). https://doi.org/10.1016/S2215-0366(20)30077-8
66. Lu, R. et al. (2020) ‘Genomic characterisation and epidemiology of 2019 novel coronavirus:
implications for virus origins and receptor binding’, (January), pp. 19– 21.
67. Mair-Jenkins, J., et al.: The effectiveness of convalescent plasma and hyperimmune
immunoglobulin for the treatment of severe acute respiratory infections of viral etiology:
A systematic review and exploratory meta-analysis. J. Infect. Dis. (2015). https://doi.org/10.
1093/infdis/jiu396
68. Masoud Mirmoeini, S., et al.: Telepediatric assistance in Iran: Specialist and subspecialty chal-
lenges. EAI Endorsed Transactions on Pervasive Health and Technology 6(22), 1–8 (2020).
https://doi.org/10.4108/eai.22-9-2020.166356
69. De Meyer, S., et al.: Lack of antiviral activity of darunavir against SARS- CoV-2. Int. J. Infect.
Dis. (2020). https://doi.org/10.1016/j.ijid.2020.05.085
70. Mirmoeini, S.M., et al.: Policies and challenges on the distribution of specialists and subspe-
cialists in rural areas of Iran. Medicina (Lithuania) (2019). https://doi.org/10.3390/medicina5
5120783
71. Mohiuddin, A. K. (2020) ‘Prospect of Tele-Pharmacists in Pandemic Situations: Bangladesh
Perspective’, Journal of Health Care and Research.
72. Mulangu, S., et al.: A randomized, controlled trial of Ebola virus disease therapeutics. N.
Engl. J. Med. (2019). https://doi.org/10.1056/NEJMoa1910993
73. Naserghandi, A., Allameh, S.F., Saffarpour, R.: ‘All about COVID-19 in brief’, New Microbes
and New Infections. Elsevier Ltd 35, 100678 (2020). https://doi.org/10.1016/j.nmni.2020.
100678
74. National Center for Immunization and Respiratory Diseases and Division of Viral Diseases
(2020) ‘Interim Infection Prevention and Control Recommendations for Patients with
Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings’,
Cdc.
75. NCT04339816 (2020) ‘Azithromycin Added to Hydrochloroquine in Patients Admitted to
Intensive Care With COVID-19: randomised Controlled Trial’, https://clinicaltrials.gov/show/
NCT04339816.
76. Ng, K., et al.: COVID-19 and the Risk to Health Care Workers: A Case Report. Ann. Intern.
Med. (2020). https://doi.org/10.7326/L20-0175
77. Ni, Y.N., et al.: The effect of corticosteroids on mortality of patients with influenza pneumonia:
A systematic review and meta-analysis. Crit. Care (2019). https://doi.org/10.1186/s13054-
019-2395-8
78. Nicol, G.E., et al.: Action at a Distance: Geriatric Research during a Pandemic. J. Am. Geriatr.
Soc. (2020). https://doi.org/10.1111/jgs.16443
79. Nittari, G., Pallotta, G., et al.: Current pharmacological treatments for SARS-COV-2: A
narrative review. Eur. J. Pharmacol. (2020). https://doi.org/10.1016/j.ejphar.2020.173328
80. Nittari, G., Khuman, R., et al.: Telemedicine Practice: Review of the Current Ethical and
Legal Challenges. Telemedicine and e-Health (2020). https://doi.org/10.1089/tmj.2019.0158
81. Ohannessian, R., Duong, T.A., Odone, A.: Global Telemedicine Implementation and Integra-
tion Within Health Systems to Fight the COVID-19 Pandemic: A Call to Action. JMIR Public
Health Surveill. (2020). https://doi.org/10.2196/18810
82. Owusu-Akyaw, K.A., et al.: Concurrent validity of a patient self- administered examination
and a clinical examination for femoroacetabular impingement syndrome. BMJ Open Sport
Exerc. Med. (2019). https://doi.org/10.1136/bmjsem-2019-000574
83. Patel, A. and Jernigan, D. B. (2020) ‘Initial Public Health Response and Interim Clinical
Guidance for the 2019 Novel Coronavirus Outbreak — United States ’, US Department of
Health and Human Services/Centers for Disease Control and Prevention, 69(5), pp. 140–146.
84. Reeves, J.J., et al.: Rapid response to COVID-19: Health informatics support for outbreak
management in an academic health system. J. Am. Med. Inform. Assoc. (2020). https://doi.
org/10.1093/jamia/ocaa037
85. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment
of COVID-19: a multinational registry analysis (2020) The Lancet.
86. Russell, C.D., Millar, J.E., Baillie, J.K.: Clinical evidence does not support corticosteroid
treatment for 2019-nCoV lung injury. The Lancet (2020). https://doi.org/10.1016/S0140-673
6(20)30317-2
87. Samareh, A., et al.: Artificial intelligence methods for surgical site infection: Impacts on
detection, monitoring, and decision making. Surg. Infect. (2019). https://doi.org/10.1089/sur.
2019.150
88. Santoro, E. (2020) ‘Information technology and digital health to support health in the time of
CoViD-19’, Recenti Progressi in Medicina. Il Pensiero Scientifico Editore s.r.l., pp. 393–397.
doi: https://doi.org/10.1701/3407.33919.
89. Scott, B.K., et al.: Advanced Digital Health Technologies for COVID-19 and Future
Emergencies. Telemedicine and e-Health (2020). https://doi.org/10.1089/tmj.2020.0140
90. Selkoe, D.J.: The therapeutics of Alzheimer’s disease: where we stand and where we are
heading. Ann. Neurol. (2013). https://doi.org/10.1002/ana.24001
91. Shachar, C., Engel, J., Elwyn, G.: Implications for Telehealth in a Postpandemic Future:
Regulatory and Privacy Issues. JAMA - Journal of the American Medical Association (2020).
https://doi.org/10.1001/jama.2020.7943
92. Shaker, M. S. et al. (2020) ‘COVID-19: Pandemic Contingency Planning for the Allergy and
Immunology Clinic’, Journal of Allergy and Clinical Immunology: In Practice. doi: https://
doi.org/10.1016/j.jaip.2020.03.012.
93. Sheahan, T.P., et al.: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic
coronaviruses. Science Translational Medicine (2017). https://doi.org/10.1126/scitranslmed.
aal3653
94. Sheahan, T.P., et al.: Comparative therapeutic efficacy of remdesivir and combination
lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. (2020). https://
doi.org/10.1038/s41467-019-13940-6
95. Siegel, D., et al.: Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-
f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and
Emerging Viruses. J. Med. Chem. (2017). https://doi.org/10.1021/acs.jmedchem.6b01594
96. Simcock, R., et al.: COVID-19: Global radiation oncology’s targeted response for pandemic
preparedness. Clinical and Translational Radiation Oncology (2020). https://doi.org/10.1016/
j.ctro.2020.03.009
97. Singhal, T.: ‘Review on COVID19 disease so far’, The Indian Journal of Pediatrics. The Indian
Journal of Pediatrics 87(April), 281–286 (2020)
98. Sissoko, D., et al.: ‘Experimental Treatment with Favipiravir for Ebola Virus Disease (the
JIKI Trial): A Historically Controlled. Single-Arm Proof-of-Concept Trial in Guinea’, PLoS
Medicine. (2016). https://doi.org/10.1371/journal.pmed.1001967
99. Stockman, L.J., Bellamy, R., Garner, P.: SARS: Systematic review of treatment effects. PLoS
Med. (2006). https://doi.org/10.1371/journal.pmed.0030343
100. Tang, N., et al.: Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 patients with coagulopathy. J. Thromb. Haemost. (2020). https://
doi.org/10.1111/jth.14817
101. Tian, S., et al.: ‘Pathological study of the 2019 novel coronavirus disease (COVID-19) through
postmortem core biopsies’, Modern Pathology. Springer, US 33(6), 1007–1014 (2020). https://
doi.org/10.1038/s41379-020-0536-x
102. Udeh, C., et al.: Telemedicine/Virtual ICU: Where Are We and Where Are We Going?
Methodist Debakey Cardiovasc. J. (2018). https://doi.org/10.14797/mdcj-14-2-126
103. Wagstaff, K.M., et al.: Ivermectin is a specific inhibitor of importin α/β- mediated nuclear
import able to inhibit replication of HIV-1 and dengue virus. Biochemical Journal (2012).
https://doi.org/10.1042/BJ20120150
104. Wang, D., et al.: ‘Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel
Coronavirus-Infected Pneumonia in Wuhan. China’, JAMA - Journal of the American Medical
Association. (2020). https://doi.org/10.1001/jama.2020.1585
105. Wang, M., et al.: Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res. (2020). https://doi.org/10.1038/s41422-020-
0282-0
106. Webster, P.: Virtual health care in the era of COVID-19. The Lancet (2020). https://doi.org/
10.1016/s0140-6736(20)30818-7
107. WHO (2020) ‘Virtual press briefing on COVID-19: digital health opportunities and
risks’.WorldHealthOrganization.Availableat: https://www.euro.who.int/en/media-centre/eve
nts/events/2020/06/virtual-press-briefing-on-covid-19-digital-health-opportunities-and-risks
(Accessed: 25 September 2020).
108. De Wilde, A.H., et al.: Screening of an FDA-approved compound library identifies four
small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in
cell culture. Antimicrob. Agents Chemother. (2014). https://doi.org/10.1128/AAC.03011-14
109. World Health Organization (1998) ‘A Health Telematics Policy in support of WHO´s Health-
for-All Strategy for Global Health Development’, in WHO Group Consultation on Health
Telematics.
110. World Health Organization (2020) ‘Global surveillance for COVID-19 caused by human
infection with COVID-19 virus: interim guidance, 20 March 2020’.
111. World Health Organization (no date) Coronavirus latest: WHO says health workers account
for 10% of global infections.
112. Xinhua (no date) China detects large quantity of novel coronavirus at Wuhan seafood market.
113. Yang, S.N.Y., et al.: The broad spectrum antiviral ivermectin targets the host nuclear transport
importin α/β1 heterodimer. Antiviral Res. (2020). https://doi.org/10.1016/j.antiviral.2020.
104760
114. Yang, Y., et al.: Health services provision of 48 public tertiary dental hospitals during the
COVID-19 epidemic in China. Clin. Oral Invest. (2020). https://doi.org/10.1007/s00784-020-
03267-8
115. Zanon, D., et al.: Data on the stability of darunavir/cobicistat suspension after tablet
manipulation. Data Brief (2020). https://doi.org/10.1016/j.dib.2020.105552
116. Zhai, Y. et al. (no date) ‘From Isolation to Coordination: How Can Telemedicine Help Combat
the COVID-19 Outbreak?’ doi: https://doi.org/10.1101/2020.02.20.20025957
117. Zhang, B., et al.: Treatment With Convalescent Plasma for Critically Ill Patients With SARS-
CoV-2 Infection. Chest (2020). https://doi.org/10.1016/j.chest.2020.03.039
118. Zhang, L., Liu, Y.: Potential interventions for novel coronavirus in China: A systematic review.
J. Med. Virol. (2020). https://doi.org/10.1002/jmv.25707
119. Zhou, X., et al.: The Role of Telehealth in Reducing the Mental Health Burden from COVID-
19. Telemedicine and e-Health (2020). https://doi.org/10.1089/tmj.2020.0068
Forecasting on Global Dynamics
for Coronavirus (COVID-19) Outbreak
Using Time Series Modelling
Soumyadeep Debnath, Subrata Modak, and Dhrubasish Sarkar
Abstract The spreading and Development of COVID-19 have analyzed which was
first officially reported in Wuhan City, in December 2019. Firstly the data have
explored in terms of information and quality and after that, the data have cleaned and
gone through with feature engineering. Analyzed different types of machine learning-
based prediction methods, namely Linear Regression, ARIMA, and SARIMA on
the spread of COVID-19 in different regions all over the world. In the end, It has
been concluded with the best machine learning model among them for COVID-19
spread forecasting based on theoretical and results in analysis. And also we have
discussed that how deep learning can be considered with data limit problem in order
to improve the result more dynamically with combination and comparisons of state-
of-art approaches for time series problems.
Keywords Corona virus outbreak · COVID-2019 · Forecasting · Linear

regression · Time series · ARIMA · SARIMA · Deep learning · Transfer learning
1 Introduction
The Corona Virus Disease (COVID-19) named as SARS-CoV2 was first officially
reported in Wuhan City, in December 2019. Day by day it has been spread all over
the world by the human to human transmission last week of December onward.
As reported many countries COVID-19 highly contagious infections disease and it
spread rapidly World Health Organization (WHO) has announced a global Public
Health Emergency [1]. The world faced smallpox that also a pandemic in 1500, the
S. Debnath
Tata Consultancy Services Limited, Kolkata, India
S. Modak
Maulana Abul Kalam Azad University of Technology, Kalyani West Bengal,, India
D. Sarkar (B)
Amity Institute of Information Technology, Amity University Kolkata, Kolkata, India
e-mail: dhrubasish@inbox.com
930 S. Debnath et al.
mortality rate was 50% [2]. After that cholera pandemic total death was more 1.5
million lives [3].
In 1918, Spanish flu influenza pandemics were seen. This pandemic faced 20
million to 110 million lives. After that many pandemic situations hit human civi-
lization. But COVID-19 is one of the horrible pandemics in the twenty-first century.
Centers for Disease Control and Prevention (CDC) confirmed all three major stages
(from Human Transmission to Community Transmission) of spreading for these
infectious diseases which also can be defined by an Epidemiologic Triad.
With COVID-19 sweeping across the world, and people (particularly Americans)
anxious to get back to work, now more than ever we need models to effectively
forecast the spread of COVID-19. However, at present many models have performed
poorly at estimating the disease spread and the overall impacts of social distancing.
In this chapter, we have firstly reviewed why disease forecasting models are useful,
problems/limitations with the approaches taken by current models, and the benefits
and barriers of using deep learning approaches.
We have tried to forecast the pandemic spread of COVID-19 outbreak all over the
world based on different machine learning-based time series forecasting models and
compared their results depending on evaluation model. Even though this is a very
serious topic, we can conclude with a better prediction approach using Time Series
Forecasting for COVID-19 spread which will be more productive for the future. In
the next section, we have discussed various related research works on this domain
and also similar domains like other outbreak events.
2 Related Work
Previously many research works addressed various mathematical and algorithmic

methods like machine learning models on different data sources to forecast
epidemics. Till now a lot of studies guided the public health officials for aggres-
sive interventions to control the exponential growth of infection. Walters et al. [4]
already did a detailed survey of the uses of mathematical models for the global spread.
Kumar et al. [5] proposed the model to predict some trajectories of COVID-19 in the
near future using the most advanced ARIMA model. Ardabili et al. [6] did a analysis
of machine learning and soft computing models to estimate the COVID-19 spread
and showed promising results with MLP and ANFIS.
Hamer et al. [7] developed an environment for spatial and temporal predictions
based on local data using various deterministic, geostatistical regionalization, and
machine learning algorithms with very high accuracy. Li et al. [8] used machine
learning approaches to predict the COVID-19 epidemic trend in China and across
the world with an estimation of the mortality rate around 4% all over the world.
Batista [9] used the logistic growth regression model for estimating the final size.
Akhtar et al. [10] proposed a dynamic neural network model to estimate the
geographic spread. Caccavo [11] developed a SIRD (Susceptible Infected Recovered
Forecasting on Global Dynamics for Coronavirus (COVID-19) … 931
and Death) compartment for describing and predicting the evolution of the Chinese
and Italian COVID-19 outbreaks.
Zhao et al. [12] introduced a mathematical estimated technique to evaluate the
real value of COVID-19 cases in January 2020. Nishiura et al. [13] introduce a
mathematical estimation model to calculate the infection rate of COVID-19 in the
City of Wuhan, China from 29 to 31 January 2020 using 565 data. Tang et al. [14]
introduced an estimated model to calculate COVID-19 transmission risks. In [15],
the authors proposed a mathematical model for the risk of death estimation from
the COVID-19 dataset. Thompson et al. [16] took only 47 infected patients’ data to
estimate sustained person to person infected of COVID-19.
Munish Kumar, Surbhi Gupta, Krishan Kumar, and Monika Sachdeva. [15], have
used Long Short-Term Memory (LSTM) and Auto-Regressive Integrated Moving
Average (ARIMA) to estimate of the increasing number of COVID-19 cases and
the increasing number of deaths due to COVID-19. Authors have used 80% of data
to build the model and the rest of 20% are applyed to test. For accuracy measurement,
Mean Absolute Percentage Error (MAPE), Akaike Information Criteria (AIC), and
Root Mean Square Error (RMSE) are computed for the model of ARIMA and for the
model of LSTM, Root Mean Squared Error (RMSE) and Mean Absolute Percentage
Error (MAPE) is computed.
Kumar et al. [16] proposed the model to predict some trajectories of COVID-
19 in the near future using the most advanced Auto-Regressive Integrated Moving
Average Model (ARIMA). Their result analysis shows that few countries like Iran,
entire Europe especially Italy, Spain France et. Will go through worsen condition.
As per their analysis the United State of America would become the epicentre for
new cases during the mid-April 2020 while South Korea would get stability and so as
China with more positive recovery. Their study also guides the public health officials
for aggressive interventions to control the exponential growth in rapid infection [16].
Li et al. [17] have used machine learning approaches to predict the COVID-19
epidemic trend in China and across the world using the machine learning approach.
The total number of COVID-19 cases will reach around 89,000 in China and 403,000
across the world during the epidemic. Around 4,000 and 18,300 people will died of
COVID-19 in China and across the world, respectively. The COVID-19 mortality
rate is estimated to be around 4% all over the world. Interpretation: The COVID-
19 outbreak is controllable in the foreseeable future if comprehensive and stringent
control measures are taken [17].
The proposed model of Chae et al. [18] considers big data including social media
data for predicting infectious diseases by optimizing the parameters of various deep
learning algorithms. The have compared the performance of the deep neural network
(DNN) and long-short term memory (LSTM) learning models with the autoregressive
integrated moving average (ARIMA). Their analysis shows that the DNN and LSTM
models perform better than ARIMA. The DNN model performed stably and the LSTM
model was more accurate in predicting the spread of infectious disease [18].
3 Discussion Begore Deep Drive
In this section, we have discussed the purpose and limitations of the solution
approaches with existing limited data for the current problem before going deep
into the forecasting models and their performance evaluation.
3.1 Reasons Behind Forecasting
Before jumping into the problems of current COVID-19 forecasting models, let’s
look at why they are useful:
• Informing policymakers about the impacts of social distancing.
• Identifying specific counties/cities/towns with the highest risks.
• Helping hospitals plan in terms of staffing, beds, and equipment.
• Informing virologists and epidemiologists of what factors to study.
3.2 Major Difficulties in Modeling
Nate Silver in this popular article1 enumerates the many difficulties with modelling
COVID-19. However, many of these difficulties stem from trying to compose exact
mathematical or statistical formulas for forecasting COVID-19. Silver discusses using
variables like the asymptomatic rate and infection rate. This is problematic as in
the classical SEIR model we have to assume certain values for these parameters.
Additionally, models like IMHE, for instance, primarily rely on curve fit. CurveFit 2
utilizes a wide variety of variables to be supplied to the model. First IMHE 3 utilizes
a spline to fit the COVID-19 curve before relying on a number of additional tweaks
to fit data. For those unaware, a spline is a mathematical polynomial formula meant
to draw a smooth curve. This method still requires a lot of manual parameters and
features. A VOX article from April noted some of the many problems related to the
IMHE model.4 Specifically, the article discusses changes to the model’s confidence
intervals and problems with the updating forecasts. For instance, when forecasting
at the daily level there is a lot of noise, differences in reporting and also there are
many different factors that could stop the real data from having such a trajectory.
Models have to be robust enough to determine the noise and thus not make general
assumptions.
1 https://fivethirtyeight.com/features/why-its-so-freaking-hard-to-make-a-good-covid-19-model/
2 https://ihmeuw-msca.github.io/CurveFit/
3 http://www.healthdata.org/covid/updates.
4 https://www.vox.com/future-perfect/2020/5/2/21241261/coronavirus-modeling-us-deaths-ihme-
pandemic.
Table 1 Description of
Parameters Description
parameters of dataset
Id Identifier (unique)
State States of a specific country, e.g. Washington
(US)
Country Country as France
Date Date stamp for the respective row
Confirmed cases Counts of confirmed registered cases
Fatalities Registered deaths counts
Other models, such as the Geneva, GA_Tech, MIT, MOBS, UCLA, UA, and UT,
in making their predictions, assume that social distancing will continue in its current
form. As restrictions ease, their numbers are likely to drastically change as result.
Finally, a large number of models only forecast at the state and national level. This is
an area where deep learning has the most potential, given its ability to learn the many
complex interactions between input features such as seasonality, social distancing,
and geography. Moreover, with sufficient data augmentation techniques and transfer
learning the model should be able to deal with a change in distribution such as the end
of social distancing. However, as we will discuss below, there remain many barriers
to using deep learning for predicting COVID-19.
4 Dataset Description for Machine Learning Models
For this work, we selected a very well-known dataset provided by ‘John Hopkins
CSSE’ which is publicly available in GitHub5 and they update the data very frequently
in a daily manner. The description of the collection process is mentioned in the
README file of this repository.
In order to start working with a static version, we have selected a subset from the
above-mentioned dataset which is also publicly available in GitHub.6 Here, the Train
Set contains 6 parameters (Id, Province_State, Country_Region, Date, Confirmed-
Cases, Fatalities) and the Test Set contains 4 parameters (ForecastId, Province_State,
Country_Region, Date). The description of the parameters is mentioned below
(shown in Table. 1).
Missing values is not present in the dataset (exceptional for ‘province state’
attribute). Overlapping date interval cases have been handled in the next stage of
Feature Engineering.
5 https://github.com/CSSEGISandData/COVID-19.
6 https://github.com/ResearchProjects-codes/ForecastCOVID-19.
5 Feature Engineering for Machine Learning Models
Feature engineering is a very important factor for prediction techniques like time
series analysis. Here, data is prepared in such a way that they can be made for
forecasting using various statistical methods.
5.1 Data for Parameters: Country, State, and Date
Here, we have cleaned up the data and created features. Firstly we have deleted the
data with overlapping time periods from the training dataset. From the Date field,
we have extracted features like day, week, and weekly trends (combing both day and
week).
Additionally, scikit-learn Label Encoder has used for States and Provinces to
assign numbers to every different case.
5.2 Data for Parameters: Confirmed Cases and Fatalities
Here, we have used the concepts of Lags and Trends for features. In time series
analysis, Lags is used for the previous improvement of the aim (e.g. registered cases),
noted as a parameter in the dataset. Trends are used for short-term development for
example (t0 - t1) / t1 is the result of trends between two consecutive points.
6 Machine Learning Models
Here we have discussed our implementations with theoretical advantages and draw-
backs of various machine learning-based time series forecasting models which are
highly applicable for COVID-19 outbreak spread prediction.
Analysis of data over different time interval gives unique problems in mathemat-
ical and statistical modelling. Continuous figure out of daily stock market predic-
tion, monthly unemployment number, and population series such as school college
enrolment, birth and death rates, number of pandemic case over a period of time in
pandemic situation, estimating drug use of hypertension patients and so on can be
observed by using time series analysis.
6.1 Time Series Modelling
Time Series is a set of numerical data points which is sequential in nature and calculate over
time interval.
For example y1, y2, y3, y4… where random variable y1 is first time period and y2
is second time period and so on, where the observation of the time series is realization
of the Stochastic Process. Basically there are two type time series, one is Univariate
when time series based on single variable and Multivariate when the series based on
records of a more than one variable. Trend, Seasonal, Cyclical, and Irregular are the
main four components in time series data observation [19, 20].
Trend describes tendency of the time series to decrease, stagnates or increase
over long interval of time. For example, time series related to population growth,
number of house in a town, epidemics etc. Cyclical describes medium term reflect
in changes in series which repeats in cycles. For example, economic and financial
time series. Seasonal describes the fluctuation within year in running season. For
example, weather condition, ice-cream sales in the summer etc. Irregular describes
the random variation in a time series. This is not repeat in a specific pattern, it may
be caused by incidence; for example flood, strikes etc.
The meaning of stationary of a stochastic process can be think out as a form of
statistical equilibrium [22]. Statistical fundamental properties mean and variance of a
stationary process are independent of time then it is called Stationary of a time series
[21]. There two type of stationary processes one is Strong Stationary and another is
Weakly Stationary.
• Strong Stationary: a process {y(t), t = 0,1,2,..} is called Strong Stationary or
Strictly Stationary, where joint probability distribution function {yt-s, yt-s + 1,…,
yt,…yt + s-1,yt + s} is not dependent of t for all s.
• Weakly stationary: A stochastic process is called Weakly Stationary of order k if
order is depended on time differences.
A Stochastic Process {y(t),t = 0,1,2,..} is 2nd order stationary where covariance
Cov(yt,yt-s) depends on s. trend or season pattern in time series are non-stationary
[21]. Power transformation and differencing is used to ignore the trends and to make
Time series stationary.
6.2 Method 1: Linear Regression
In this stage, we haven’t drawn random samples using common train-test-split func-
tion due to the chronological dependency of data points on each other and have
created their own function in the following way:
a. Firstly, we have trained the algorithm for each country individually and for each
of them separately if there are several states in a country because the prediction
will not be good by training the model with on all data points as the states were
in different stages of the COVID-19.
b. Then lags are calculated for the respective state or country and the accurate
value is computed by using trial and error technique. Here, few lags led to an
over the interpretation of the short-term trend.
c. Now targets and lags have logarithmized. An LR is not good for calculating the
result of exponential trends and logarithms that helps in our method to better
process and interpret the data.
Here, we have used the lags for the first prediction as they were only available for
our training data. After that, we have recalculated the lag, made a new prediction,
and repeated this for each data point. We have trained our data till 31st March which
was the 69th day from 22nd January (the first day in our data set) and observed the
prediction accuracy with actual by varying two parameters;
i. how many lags is applied.
ii. the period of time.
But the limitation for this method is if the countries are without Confirmed Cases
or Fatalities then this prediction will run until at zero. Therefore, we have continued
with the next model, the ARIMA model.
6.3 Method 2: Auto-Regressive Integrated Moving Average

(ARIMA)
In this stage, we have used ARIMA (Auto-Regressive Integrated Moving Average)

model which calculates future data points from the past similarly like linear regression
but only applicable for univariate, non-stationary, non-seasonal time series data as
data value are only extrapolated depends on previous data. It has three important
trend parameters;
(i) AR – Auto-Regressive (p): It is a multiple linear regression form that is used
to predict the future value based on past observation of time series analysis
in a specific interval of time when correlation exists in time value and time
series.
(ii) I - Integrated/Differencing (d): It defines the amount of non-seasonal differ-
encing order. Differencing is used when the available time-series data is not
stationary and contains trends.
(iii) MA - Moving Average (q): It uses the previous forecast error value in the
linear regression model so that random effects can be smoothed.
ARIMA works very well on random disturbances, long term changing trends,
periodic changes in time series. But the limitation for this method is it does not
deal with Seasonal data and does not support stationary multivariate time series.
Therefore, we have continued with the upgraded version of this model, the SARIMA
method.
6.4 Method 3: Seasonal Auto-Regressive Integrated Moving

Average (SARIMA)
In this stage, we have used the SARIMA (Seasonal Auto-Regressive Integrated Moving
Average) model which is an extension model of ARIMA that supports univariate,
seasonal time series data. It has four important seasonal parameters including three
new hyperparameters like Auto Regression (AR), Differencing (I), Moving Average
(MA) for the seasonal variability of the time series and another parameter is the
number of times steps for a single seasonal period (m). Theoretically, this method is
more effective than the previous models for COVID-19 spread forecasting.
7 Result Analysis of Machine Learning Models
In order to validate the result, we have to analyze the closeness between the values
predicted by machine learning models and the actual values. The details of the result
analysis process are elaborated below.
7.1 Evaluation of Forecasting Models
Here, all three machine learning methods (LR, ARIMA, and SARIMA) have been
evaluated using the column-wise Root Mean Squared Logarithmic Error (RMSLE)
method which penalizes an under-predicted estimate greater than an over-predicted
estimate by definition. The mathematical representation is mentioned below.
The RMSLE for a single column is calculated:

n
1
(log( pi + 1) − log(ai + 1))2
n i=1
where, n is observations count, pi is my prediction, ai is the actual value, log(x) is

the natural logarithm of x.
The final evaluated scores have been calculated as the mean of the RMSLE
overall two columns (Confirmed Cases and Fatalities) and those scores for all three
forecasting models are mentioned below (shown in Table. 2).
Based on the final score, the SARIMA model is proved to produce the best results
with the considered datasets.
Table 2 Evaluation scores comparison among forecasting models

Machine learning methods Scores
Linear regression (LR) 0.48503
Automatic regressive integrated moving average (ARIMA) 0.40371
Seasonal automatic regressive integrated moving average (SARIMA) 0.36819
7.2 Geographical Result Analysis with Linear Regression
Here, we have plotted the line graphs (shown in Fig. 1, 2, 3 and 4) highlighting both
the prediction result and official truth for both Confirmed Cases and confirmed death
count (Fatalities) scenarios depends on the outcomes of the LR model for 4 countries
with the different spread from the dataset. And Fig. 5 indicates the color indicators
for all four different classes.
In all the above graphs, parameters in the left Y-axis indicate Confirmed Case,
parameters in right Y-axis indicate death, and parameters in X-axis indicate the Day
from 22nd January to 12th April 2020. And the orange description has identified the
training and testing data separated by the dark vertical line.
Fig. 1 Germany
Fig. 2 Spain
Initially, for Spain and Germany, the forecasting result is good, but there is a
difference between the forecast figure and the actual figures. For Algeria also the
forecast and actual figures are drifting apart as the number of cases is less. For
Andorra, the forecast is odd because there are no cases here so far.
7.3 Geographical Result Analysis with SARIMA
Here, we have plotted the line graphs (shown in Fig. 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18 and 19) highlighting both the prediction result and official truth for
both Confirmed Cases and confirmed death count(fatalities) scenarios based on the
outcomes of the SARIMA model for top 14 countries from the dataset. And Fig. 20
indicates the color indicators for all four different classes.
In all the above graphs, parameters in the left Y-axis indicate Confirmed Case,
parameters in right Y-axis indicate Fatalities and parameters in X-axis indicate the
Date from 1st April to 12th May 2020.
Fig. 3 Algeria
For countries, these forecasts are a reliable overtime period. The data value for
countries with confirmed cases such as Germany can be calculated accurately. But if
the resultant figures are reported unreliably, as in Shanghai, then machine learning-
based all major time series forecasting methods will not predict good results.
8 Details for Deep Learning Model
We have aimed to incorporate the newest research from deep learning for time series
forecasting to address these issues. Although a lot of people remain wary about deep
learning in epidemiology, there are numerous advantages in using it. For instance,
unlike pure statistical models, deep learning models learn from the actual data present.
Deep learning models also have the potential to better integrate all the complex
variables, such as weather and symptom surveys. However, many challenges still
remain with deep learning methods. The most obvious initial challenge with using
deep learning revolves around the lack of training data: right now we still only have
110 time steps, at the most, for many US counties. Moreover, for the majority of
Fig. 4 Andorra
Fig. 5 Color indicators
counties/states, we have less than 90 time steps. Another problem is an imbalance

of time steps with zero new cases. For mobility we have little data to give to the
model before the pandemic begins. Therefore utilizing transfer learning and data
augmentation is essential to achieving good results.
8.1 Meta-Learning/Transfer Learning for Time Series

Forecasting
As already known, limited data is one of the primary barriers to effectively leveraging
machine learning in this context. Normally in these cases, we would turn towards
proven few-shot learning techniques. However, despite the widespread success of
Fig. 6 Iran
transfer learning in NLP and Computer Vision, there is little literature examining its
utility for time series forecasting. TimeNet [23] examined using a pre-trained RNN
and found it improved performance on clinical time series forecasting datasets. Yet,
besides TimeNet, only a few papers have studied the problem. Laptev, Yu et. al. [24],
describe using a reconstruction loss to aid in transfer learning. In addition to the works
on TL, several papers have explored other approaches. Adapting popular algorithms
such as REPTILE and MAML from computer vision is another possible avenue that
could lead to overall better few-shot time series forecasting approaches. In some of
our initial model iterations we did see some positive transfer on select counties (for
instance NYC and Chicago seemed to benefit from pre-training), however we have
not rigorously evaluated these results. This leaves plenty of areas for future research.
8.2 Vertically Data Import
Transfer Learning can be done for a variety of time series forecasting datasets.
However, the most similar data would likely result in the most positive transfer.
Fig. 7 Algeria
Therefore, we have worked to collect data from similar pandemics and viruses.
Collecting data from outbreaks such as SARs, MERs, and Zika can help the model
learn. We have also researched more general transfer learning techniques aiming to
answer a few key questions like;
• Could pre-training on wind/solar data improve performance through general
embedding layers?
• Are there general geo-spatial patterns that could be found from any temporal data?
Our thought process is that even though the data is not related at all, it could serve
as an effective method of transfer learning because it could help the initial layers
extract temporal patterns effectively. Another, and perhaps more effective transfer
method, is to train on each county, state, and country iteratively. These are just some
of the examples of the types of data we have incorporated vertically. Paradoxically
of course, the longer the pandemic goes on, the better our models should get. That’s
why our infrastructure need more efficient to create a framework for continuous
improvement/re-training of the models as more data becomes available.
Fig. 8 Italy
Fig. 9 Spain
Fig. 10 Russia
8.3 Horizontally Data Import
We have integrated a wide of variety of data sources horizontally. Perhaps most

importantly, we have looked at integrating mobility data from Google, Facebook and
other providers. We have also added weather data, such as humidity, temperature,
UV, and wind. We have carefully monitored how each addition to the models affects
the overall performance. For instance, we started with previous cases and day of the
week variables. Now we have incorporated mobility data and weather data. Next we
will consider incorporating demographic data on the number of hospitals in a county,
average distance to a hospital, average age, population density, total population, etc.,
to better forecast admissions and COVID spread. We have also looked at ways to add
patient surveys from Facebook and other data sources. Additionally, more advanced
geo-spatial data could potentially prove valuable.
Initially, when we have added data on the mobility we noticed performance
decrease versus having just new cases from prior days. It was only when we expanded
forecast history that performance seemed to increase. This is likely due to the long
incubation period of COVID-19.
Fig. 11 US - New York
8.4 Data Augmentation and Hybrid Models
There are several ways to generate time series data. TSAug is a library that offers
different methods to augment TS-data. An easy way of creating synthetic data in
TSAug is by using cropping and drifting. Other libraries and techniques exist such as
GANs for creating synthetic time series data as well. Another way we can potentially
augment data is to create more geo-locations. For instance, we can sum together
counties in close proximity. This would have the effect of providing more training
data points for the model.
There are some potential hybrid approaches worth exploring. For instance, we
could integrate deep learning with the SEIR model or the curve fitting approaches
mentioned above. Hybrid models are appealing; e.g., the winning model in the ‘M5
forecasting competition’ used a combination of a RNN and exponential smoothing.
Additionally, the aforementioned Youyang Gu model is a hybrid SEIR/ML approach.
Fig. 12 US – Washington
8.5 Model Creation for Effective Transfer

with Hyperparameters
Part of the difficulty of using transfer learning on time series data is the lack of
uniform dimensions. Different multivariate time series data might not contain all the
same features. Zika data contains information on infections but does not have the
same accompanying mobility data. SARs and MERs are the most similar viruses,
however officials have not tracked them as extensively. Therefore, our models need
to handle a variable number of feature time series. One method for handling this
problem is to actually swap out upper layers. In most transfer learning tasks we
generally swap out the lower layers. However, here we need at least one swappable
upper layer if we want to map multivariate time series data to a common embedding
dimension.
Another disadvantage of our approach revolves around the sheer number of param-
eters. Therefore, we utilize parameter sweeps to help us search for the most effective
combinations.
Fig. 13 South Korea
8.6 Explainability
Another barrier to using deep learning for COVID is related to interpreting and
explaining the findings. Many of the statistical models have garnered negative press
for their lack of transparency. This problem might be exacerbated by DL models
which have a negative reputation for acting as a black box. However, there are poten-
tial remedies to this issue, especially when using transformers and other variants.
We can, for example, easily view with transformers what features the model attends
to with heatmaps. Similarly, various approaches, such as leveraging convolutional
heatmaps or cross dimensionally attending to input features, could help us to under-
stand how the model is learning. Finally, utilizing methods such as bayesian learning
can help the model gauge its own uncertainty and generate intervals. We recently
successfully added confidence intervals to our model outputs and plan on including
them in all future results.
Fig. 14 Germany
8.7 Evaluation
Evaluating a model is complex even when there is a diverse range of data available.
For COVID unfortunately we have very limited temporal data. Therefore evaluation
at best is limited to 40 or so time steps. Originally, we evaluated models on solely
a (held out) one week period in April, however we quickly discovered that our
hyperparameter searches overfit to that one-week test set. As a result, we recently
expanded our evaluation to a two-week period in May. However, this still has the
potential to over-fit. We currently have plans to add code to automatically evaluate on
every two-week permutation in the test set. While not perfect, this does provide more
evaluation data points and lessens the chance of merely tuning the hyper-parameters
to a one two-week period. As more data becomes available over a wider range of
seasons, stages in the pandemic, and locations, we hope to develop even more robust
evaluation methods, including evaluating data on a rolling basis.
Choosing the proper evaluation metric is another difficult decision. In our case
for now we are using Mean Squared Error (MSE). However, MSE does have the
fundamental problem that it is not scale agnostic. Therefore, while it is easy to
compare models on specific counties it is not good across counties. This is where
metrics such as normalized MSE or mean absolute percentage error could work well.
Additionally, Mean Absolute Squared Error (MASE) might be another alternative.
Fig. 15 Andorra
9 Conclusion and Future Scope
In the end, we can summarize that we have analyzed different machine learning
models for time series forecasting on the pandemic spread of COVID-19 outbreak
and compared their performance based on an efficient evaluation model. Finally, we
have tested the results of the highest effective forecasting model (SARIMA) based
on the considered dataset with the official result for the top 14 countries during
approximately 1.5 months duration of time and can conclude by getting positive
results.
As deep learning has the potential to help create better COVID forecasting models
which can, in turn, aid in public policy planning. However, many barriers still exist
to using effectively COVID data. This is why we are currently ramping up efforts to
leverage cutting edge techniques in the machine learning space to overcome these
challenges. We are continuing to look for experts review in transfer learning, meta-
learning, time series forecasting and data engineering.
Fig. 16 South Africa
The outcomes of forecasting techniques can be improved or better depending

on reliable datasets containing different analytical, mathematical, statistical, symp-
tomatic, and asymptomatic parameters. Some of the major significant parameters can
be age, gender, geographical location, report time, previous health history, mobility,
transmission rate, incubation period, daily death count, number of carriers, temper-
ature, humidity, social distance, isolation, quarantine, and many more. Therefore
improvement of training data with better features can be great future work.
Fig. 17 Ghana
Fig. 18 China–Beijing
Fig. 19 China–Shanghai
Fig. 20 Color ındicators
References
1. World Health Organization. (2020). Novel Coronavirus (2019-nCoV): situation report,

3.Available online: https://www.who.int/
2. Diamond, J., Ford, L.E.: Guns, germs, and steel: the fates of human societies. Perspect. Biol.
Med. 43(4), 609 (2000)
3. Frieden, N.M.: The Russian cholera epidemic, 1892–93, and medical professionalization. J.
Soc. Hist. 10(4), 538–559 (1977)
4. Walters, C.E., Meslé, M., Hall, I.M.: Modelling the global spread of diseases: A review of
current practice and capability. Epidemics 25, 1–8 (2018). https://doi.org/10.1016/j.epidem.
2018.05.007
5. Kumar, P., Kalita , H., Patairiya, S., Sharma, Y. D., Nanda, C., Rani, M., Rahmani, J., Bhaga-
vathula, A. S. (2020). Forecasting the dynamics of COVID-19 Pandemic in Top 15 countries in
April 2020: ARIMA Model with Machine Learning Approach, medRxiv preprint doi: https://
doi.org/10.1101/2020.03.30.20046227
6. Ardabili, S., Mosavi, A., Ghamisi, P., Ferdinand, F., Annamária R. V., Reuter, U., Rabczuk, T.
& Atkinson, P. M. COVID-19 Outbreak Prediction with Machine Learning. EasyChair Preprint
no. 3193. (2020).
7. Hamer, W. B., Birr, T., Verreet, J. A., Duttmann, R. & Klink, H. Spatio-Temporal Prediction
of the Epidemic Spread of Dangerous Pathogens Using Machine Learning Methods. ISPRS
International Journal of Geo-Information, 9(1). 44. (2020).
8. Li, M., Zhang, Z., Jiang, S., Liu, Q., Chen, C., Zhang, Y. & Wang, X (2020). Predicting
the epidemic trend of COVID-19 in China and across the world using the machine learning
approach. medRxiv preprint doi: https://doi.org/10.1101/2020.03.18.20038117.
9. Batista, M., Estimation of the final size of the second phase of the coronavirus epidemic by the
logistic model. medRxiv, 2020: p. 2020.03.11.20024901.
10. Akhtar, M., Kraemer, M.U.G., Gardner, L.M.: A dynamic neural network model for predicting
risk of Zika in real-time. BMC Med. 17, 171 (2019)
11. Caccavo, D (2020). Chinese and Italian COVID-19 outbreaks can be correctly described by a
modified SIRD model, medRxiv preprint doi: https://doi.org/10.1101/2020.03.19.20039388.
12. Zhao, S., Musa, S.S., Lin, Q., Ran, J., Yang, G., Wang, W., Wang, M.H., et al.: Estimating
the unreported number of novel coronavirus (2019-nCoV) cases in China in the first half of
January 2020: a data-driven modelling analysis of the early outbreak. J. Clin. Med. 9(2), 388
(2020)
13. Nishiura, H., Kobayashi, T., Yang, Y., Hayashi, K., Miyama, T., Kinoshita, R., ... & Akhmet-
zhanov, A. R. (2020). The rate of underascertainment of novel coronavirus (2019-nCoV)
infection: estimation using Japanese passengers data on evacuation flights.
Med. 9(2), 462 (2020)
15. Munish Kumar, Surbhi Gupta, Krishan Kumar, and Monika Sachdeva. 2020. SPREADING
OF COVID-19 IN INDIA, ITALY, JAPAN, SPAIN, UK, US: A Prediction Using ARIMA and
LSTM Model. Digit. Gov.: Res. Pract. 1, 4, Article 24 (July 2020), 9 pages. DOI: https://doi.
org/10.1145/3411760
16. Kumar, P., Kalita , H., Patairiya, S., Sharma, Y. D., Nanda, C., Rani, M., Rahmani, J., Bhaga-
vathula, A. S. (2020). Forecasting the dynamics of COVID-19 Pandemic in Top 15 countries in
April 2020: ARIMA Model with Machine Learning Approach, medRxiv preprint doi: https://
doi.org/10.1101/2020.03.30.20046227
17. Li, M., Zhang, Z., Jiang, S., Liu, Q., Chen, C., Zhang, Y. & Wang, X. Predicting the epidemic
trend of COVID-19 in China and across the world using the machine learning approach.
medRxiv 2020.03.18.20038117; doi: https://doi.org/10.1101/2020.03.18.20038117
18. Chae, S., Kwon, S., Lee, D.: Predicting Infectious Disease Using Deep Learning and Big Data.
Int. J. Environ. Res. Public Health 15(8), 1596 (2018)
19. Wei, W.W.S.: Time Series Analysis: Univariate and Multivariate Methods. Addison-Wesley
Publishing Company, New York (1994)
20. Shumway, Robert H and Stoffer, David S. Time series analysis and its applications, 2017.
21. Ratnadip Adhikari, R. K. Agrawal, An Introductory Study on Time Series Modeling and
Forecasting, 2013.
22. Hipel, K.W., McLeod, A.I.: Time Series Modelling of Water Resources and Environmental
Systems. Elsevier, Amsterdam (1994)
23. Malhotra, Pankaj, Vishnu TV, Lovekesh Vig, Puneet Agarwal, and Gautam Shroff. “TimeNet:
Pre-trained deep recurrent neural network for time series classification.” arXiv preprint arXiv:
1706.08838 (2017).
24. Laptev, Nikolay, Jiafan Yu, and Ram Rajagopal. “Reconstruction and regression loss for time-
series transfer learning.” In Proceedings of the Special Interest Group on Knowledge Discovery
and Data Mining (SIGKDD) and the 4th Workshop on the Mining and LEarning from Time
Series (MiLeTS), London, UK, vol. 20. 2018.
Some Fractional Mathematical Models
of the COVID-19 Outbreak
H. Mohammadi and Sh. Rezapour
Abstract One of the powerful tools in studying the outbreak of pandemic diseases
and providing the necessary predictions is to provide the mathematical model for the
spread of these diseases. COVID-19 is a global pandemic that has severely affected
the economies of countries and the daily lives of people. Using three mathematical
models that are an extension of the classical SIR model, we model the spread of
COVID-19 and predict the outbreak of this disease. The first model is the fractional
SEIR model in which an exposed group is added to SIR model and we improve this
model by adding daily birth and mortality. Using this model, we present a numerical
simulation for the spread of COVID-19 in Iran and the world. The second model is
a fractional SEIARW model in which we add three groups of exposed and asymp-
tomatic individuals and a virus repository to classic SIR Model. Also to increase
the efficiency of this model in simulating the release of COVID-19, we add to it the
natural birth and death rate. The third model is a fractional SIRD model in which the
group of deaths due to disease is added to the classical SIR model. Using this model,
we simulate the second wave of COVID-19 transmission in Iran, Japan, Romania
and Saudi Arabia. In these models we use the Caputo and Caputo-Fabrizio fractional
order derivatives and we prove the existence of a solution by fixed point theorems
and determine the equilibrium points of the system in each of the models. Also,
we determine the reproduction number and calculate the approximate answer of the
system using the numerical method.
Keywords COVID-19 · Equilibrium point · Fixed point · Fractional

mathematical model · Numerical result
H. Mohammadi
Department of Mathematics, Miandoab Branch,
Islamic Azad University, Miandoab, Iran
Sh. Rezapour (B)
Department of Mathematics, Azarbaijan Shahid Madani University, Tabriz, Iran
e-mail: sh.rezapour@azaruniv.ac.ir
958 H. Mohammadi and Sh. Rezapour
1 Introduction
Coronaviruses are crown viruses that can cause disease in humans and animals. In
humans, several coronaviruses are known to cause respiratory illnesses such as com-
mon cold and more severe illnesses such as acute Middle East Respiratory Syndrome
(SARS) and Severe Acute Respiratory Syndrome (SARS) and recently discovered
disease COVID-19. A coronavirus (Sars-Cov2) that was first identified in the Chi-
nese city of Wuhan in 2019, is a new strain that has not been previously identified in
humans. Snakes or bats have been suspected as a potential source for the outbreak,
though other experts currently consider this as unlikely. Fever, cough, shortness of
breath and breathing difficulties are initial symptoms of this infection. In the next
steps, the infection can cause pneumonia, severe acute respiratory syndrome, kidney
failure and even death.
The study of diseases dynamics is a dominating theme for many biologists and
mathematicians. One of the important tools in studying the dynamics of diseases
is the use of mathematical models that allow the study of the spread of disease at
different time. In this mathematical models, the humans or animals are divided into
categories and the models are named at the base on these categories, such as the SI,
SIR, SEIR, SIRD, SEIRD, SIRS, SIRC, ...model.
The system of integer differential equations is usually used in modeling the spread
of diseases, but this type of derivative does not preserve the internal memory of the
system, and this is one of the weaknesses of this type of modeling. By introducing
the fractional order derivative, some researchers have used the fractional differential
equation system in their models, which has very good results in simulating phenom-
ena and also preserves the system memory (see for example, [1–3]).
The outbreak of COVID-19 prompted researchers to conduct research to simulate
the spread of disease with mathematical models. Depending on how COVID-19 was
published, mathematical models were considered to investigate its prevalence [4,
5]. In recent decades, the use of fractional order derivatives has had good results in
modeling natural phenomena and preserves the historical memory of the system well,
so we use fractional order mathematical models to simulate the release of COVID-19
Tuan et al. [6] and Rezapour et al. [7].
In this chapter, some fractional order mathematical models will introduce to inves-
tigate the release of COVID-19.The content structure is as follows: In Sect. 2 some
basic definitions and concepts of fractional calculus are recalled. The fractional SEIR
model for COVID-19 transmission with numerical simulation is presented in Sect. 3.
In Sect. 4 a fractional SEIARW model for COVID-19 outbreak is presented. The
fractional SIRD model for the transmission of COVID-19 and the numerical results
are presented in Sect. 4. The conclusion is given in Sect. 6.
Some Fractional Mathematical Models of the COVID-19 Outbreak 959
2 Basic Definitions
In this section, we recall some of the fundamental concepts of fractional differential

calculus, which are found in many books and papers (see for example [6, 8–10] and
their references).
Definition 2.1 For a integrable function g, the Caputo derivative of fractional order
υ ∈ (0, 1) is given by
t
υ 1 g (m) (υ)
C
D g(t) = d υ, m = [υ] + 1.
(m − υ) (t − υ)υ−m+1
0
Also, the corresponding fractional integral of order υ with Re(υ) > 0 is given by
t
C υ 1
I g(t) = (t − υ)υ−1 g(υ)d υ.
(υ)
0
Definition 2.2 For g ∈ H 1 (c, d ) and d > c, The Caputo-Fabrizio derivative of frac-
tional order υ ∈ (0, 1) for g is given by
t
υ M (υ) −υ
CF
D g(t) = exp( (t − υ))g (υ)d υ,
(1 − υ) 1−υ
c
where t ≥ 0, M (υ) is a normalization function that depends on υ and M (0) =

M (1) = 1. If g ∈
/ H 1 (c, d ) and 0 < υ < 1, this derivative for g ∈ L1 (−∞, d ) as
given by
d
υ υM (υ) −υ
CF
D g(t) = (g(t) − g(υ)) exp( (t − υ))d υ.
(1 − υ) 1−υ
−∞
Also, the corresponding CF fractional integral is presented by
t
CF υ 2(1 − υ) 2υ
I g(t) = g(t) + g(υ)d υ.
(2 − υ)M (υ) (2 − υ)M (υ)
0
Definition 2.3 Let b > a , g ∈ H 1 (a, b) and 0 < υ < 1 then the fractional Atangana-
Baleanu derivative in Caputo sense is defined by
t
υ B(υ) −υ
ABC
D g(t) = g (s)Eυ ( (t − υ)υ )d υ,
(1 − υ) 1−υ
a
where B(υ) denotes the normalization function satisfying B(0) = B(1) = 1 and Eυ (.)
is the one-parameter Mittag-Leffler function. Also, the Atangana-Baleanu fractional
integral is given as
t
ABC υ 1−υ υ
I g(t) = g(t) + g(υ)(t − υ)υ−1 d υ.
B(υ) B(υ)(υ)
a
The Laplace transform is one of the important tools in the solving of differential
equations that are defined below for two kind of fractional derivative.
Definition 2.4 The Laplace transform of the Caputo fractional differential operator
of order υ is given by

m−1
C υ υ
L[ D g(t)](s) = s Lg(t) − sυ−i−1 g (i) (0), m − 1 < υ ≤ m ∈ N ,
i=0
which can also be obtain in the form

sm L[g(t)] − sm−1 g(0) − sm−1 g (0) − · · · − g (m−1)
L[CDυ g(t)] = .
sm−υ
Definition 2.5 The Laplace transform of the Caputo-Fabrizio fractional differential
operator of order 0 < υ ≤ 1 is defined by
sn+1 L[g(t)] − sn g(0) − sn−1 g (0) − · · · − g (n) (0)

L[CF D(υ+n) g(t)](s) =
s + υ(1 − s)
where M (υ) = 1.
Definition 2.6 Consider the set A = {G : ∃λ, k1 , k2 ≥ 0, |G(t)| < λ exp( ktj ), t ∈
(−1)j × [0, ∞)}. The Sumudu transform of a function g ∈ A, t ≥ 0 is defined by
∞
1
G(u) = ST [g(t); u] = exp(−t/u)g(t)dt [u ∈ (−k1 , k2 )],
u
0
also the inverse Sumudu transform of G(u) is denoted by g(t) = ST −1 [G(u)].

Definition 2.7 The Sumudu transform of the Caputo fractional differential operator
of order υ is given by

m
ST [c Dtυ g(t); u] = u−η [G(u) − uυ−i [c Dυ−i g(t)]t=0 ],
i=0
where (m − 1 < υ ≤ m).
Definition 2.8 The Sumudu transform of the Caputo-Fabrizio fractional differential

operator of order υ is given by
υ M (υ)
ST (CF
0 Dt )(g(t)) = [ST (g(t)) − g(0)].
1 − υ + υu
3 Fractional SEIR Model
In this section, we intend to investigate the spread of COVID-19 disease using the
SEIR mathematical model with the Caputo fractional-order derivative. In viral epi-
demic diseases, mathematical models are very important for predicting the trans-
mission of the virus by considering its behavior in different regions for helping
to manage the disease. According to information published about COVID-19 by the
World Health Organization, there are two types of people with the disease: one group
has no symptoms and the other group has symptoms and both groups transmit the
disease to healthy people, and the sick people either recover or die. In this compart-
mental model, we divide people into 4 groups: susceptible people (S), exposed or
asymptomatic infected people (E), symptomatic infected people (I), recovered peo-
ple (R) including improved people. The diagram for dynamics of COVID-19 disease
model is shown in Fig. 1 as below:
Fig. 1 The diagram for μS μE

proposed model of ω
COVID-19 (β1 E + β2 I)S
S E
λI
δI
τI
I R
μR
μI
Based on the figure above, we consider the SEIR model for COVID-19 as follows:
⎧ dS
⎪ dt = ω − (β1 E + β2 I )S − μS,
⎪
⎪
⎪
⎪
⎪
⎨ dE = (β E + β I )S − (λ + μ)E,
dt 1 2
⎪
⎪ dI
= λE − (τ + μ + δ)I ,
⎪
⎪
⎪
⎪
dt
⎩ dR
dt
= τ I − μR,
where ω = n × N , N is the total number of individuals and n is the birth rate μ :

the death rate of people, β1 : The transmission rate of infection from E to S, β2 : The
transmission rate of infection from I to S, λ : The transmission rate of people from E to
I , δ : The mortality rate due to disease, τ : The rate of recovery of infected people, with
initial conditions S(0) = S0 > 0, E(0) = E0 > 0, I (0) = I0 > 0, R(0) = R0 ≥ 0.
In this section, we moderate the system by substituting the time-derivative by the
Caputo fractional derivative.
The ordinary derivative has inverse second dimension s−1 and the fractional
derivative Dυ has a dimension of s−υ . To solve this problem, we use an auxiliary
parameter θ that has a second dimension s and called the cosmic time. By the param-
eter, from a physical point of view, we will have [θυ−1 CDυ ] = [ dtd ] = s−1 .
According to the explanation presented, the COVID-19 fractional model for t > 0
and υ ∈ (0, 1) is given as follows
⎧ υ−1
⎪
⎪ θ C
Dtυ S(t) = ω − (β1 E(t) + β2 I (t))S(t) − μS(t),
⎨ υ−1
θ C
Dtυ E(t) = (β1 E(ts) + β2 I (t))S(t) − (λ + μ)E(t),
(1)
⎪
⎪ θυ−1 C υ
Dt I (t) = λE(t) − (τ + μ + δ)I (t),
⎩ υ−1 C υ
θ Dt R(t) = τ I (t) − μR(t),
where the initial conditions are S(0) = S0 > 0, E(0) = E0 > 0, I (0) = I0 > 0,
R(0) = R0 ≥ 0.
3.1 Non-negative Solution
Consider ϒ = {(S, E, I , R) ∈ R+ ω
4 : S + E + I + R ≤ μ }, we show that the closed set
ϒ is the region of the feasibility of system (1).
Lemma 3.1 The closed set ϒ is positively invariant with respect to fractional system
(1).
Proof To obtain the fractional derivative of the total population, we add all the
relations in the system (1). So
θυ−1 CDtυ N (t) = ω − μN (t) − δI (t),

≤ ω − μN (t).
where N (t) = S(t) + E(t) + I (t) + R(t). Using the Laplace transform and Theorem
7.2 (and Remark 7.2) in Diethelm [11], we obtain
t
1−υ υ
N (t) ≤ N (0)Eυ (−μθ t )+ ωθ1−υ η υ−1 Eυ,υ (−μθ1−υ η υ )d η,
0
where N (0) is the initial population size. With some calculations, we get
t ∞

1−υ υ (−1)i μi θi(1−υ) η iυ
N (t) ≤ N (0)Eυ (−μθ t )+ ωθ1−υ η υ−1 d η,
i=0
(iυ + υ)
0
ωθ1−υ 1−υ υ ωθ1−υ

= + Eυ (−μθ t )(N (0) − ),
μθ1−υ μθ1−υ
ω ω
= + Eυ (−μθ1−υ t υ )(N (0) − ).
μ μ
thus, if N (0) ≤ ωμ , then for t > 0, N (t) ≤ ωμ . Consequently, the closed set ϒ is pos-
itively invariant with respect to fractional model (1).
3.2 Equilibrium Points
To determine the equilibrium points of the fractional order system (1), we solve the
following equations
C υ
D S(t) =C Dυ E(t) =C Dυ I (t) =C Dυ R(t) = 0.
By solving the algebraic equations we obtain equilibrium points of system (1).

The disease-free equilibrium point is obtained as E0 = ( ωμ , 0, 0, 0, 0, 0). In addi-
tion, if R0 > 1, then the system (1) has a positive endemic equilibrium point
E1 = (S ∗ , E ∗ , I ∗ , R∗ ), so that
(λ + μ)(τ + μ + δ)
S∗ = ,
β1 (τ + μ + δ) + β2 λ
β1 ω(τ + μ + δ) + β2 λω − μ(λ + μ)(τ + μ + δ)

E∗ = ,
(λ + μ)(β1 (τ + μ + δ) + β2 λ)
λ(β1 ω(τ + μ + δ) + β2 λω − μ(λ + μ)(τ + μ + δ))

I∗ = ,
(λ + μ)(β1 (τ + μ + δ) + β2 λ)(τ + μ + δ)
τ λ(β1 ω(τ + μ + δ) + β2 λω − μ(λ + μ)(τ + μ + δ))

R∗ = .
(λ + μ)(β1 (τ + μ + δ) + β2 λ)(τ + μ + δ)μ
Also, R0 is the basic reproduction number and is obtained using the next generation
method. To find R0 , we first consider the system as follows
C υ
D (t) = F((t)) − V ((t)),
where
(β1 E(t) + β2 I (t))S(t)
F((t)) = θ1−υ
0
and
(λ + μ)E(t)
V ((t)) = θ1−υ
−λE(t) + (τ + μ + δ)I (t)
At E 0 , the Jacobian matrix for F and V are obtained as

ω
β1 μ β2 ωμ λ+μ 0
JF (E0 ) = θ1−υ , Jv (E0 ) = θ1−υ
0 0 −λ τ + μ + δ
FV −1 is the next generation matrix for system (1) and the basic reproduction number
is obtained from R0 = ρ(FV −1 ), so we get
β1 ω(τ + μ + δ) + β2 ωλ
R0 = .
μ(λ + μ)(τ + μ + δ)
This basic reproduction number R0 , is an epidemiologic metric used to describe the

contagiousness or transmissibility of infectious agents.
3.3 Stability of Equilibrium Points
In this section we investigate the stability of equilibrium points. The Jacobian matrix
of system (1) is obtained as follows
⎡ ⎤
−(β1 E + β2 I ) − μ −β1 S −β2 S 0
⎢ β1 E + β2 I β1 S − (λ + μ) β2 S 0 ⎥
J = θ1−υ ⎢
⎣
⎥
0 λ −(τ + μ + δ) 0 ⎦
0 0 τ −μ
So, the Jacobian matrix of system at E0 is

⎡ ⎤
−μ −β1 ωμ −β2 ωμ 0
⎢ 0 β1 ω − (λ + μ) β2 ωμ 0 ⎥
J (E0 ) = θ1−υ ⎢
⎣ 0
μ ⎥
λ −(τ + μ + δ) 0 ⎦
0 0 τ −μ
Theorem 3.1 The equilibrium point E0 of system (1) is locally asymptotically stable
if R0 < 1 and E0 is unstable if R0 > 1.
Proof The characteristic equation of the Jacobian matrix at the disease free equilib-
rium point, J (E0 ), is det(J (E0 ) − kI ) = 0. Then we obtain
−θ1−υ (k + μ)2 (k 2 + Ak + B) = 0,
where A = − β1 ω−μ(λ+μ)−μ(τ
μ
+μ+δ)
and B = − β1 ω(τ +μ+δ)−μ(λ+μ)(τ
μ
+μ+δ)+λβ2 ω
. The
eigenvalues of characteristic equation are k = −μ and the roots of the equation
k 2 + Ak + B = 0. (2)
If R0 < 1, since all of the parameters are positive then
β1 ω(τ + μ + δ) + β2 ωλ < μ(λ + μ)(τ + μ + δ),
β1 ω(τ + μ + δ) + β2 ωλ − μ(λ + μ)(τ + μ + δ)

< 0 ⇒ A > 0.
μ
Also, from R0 < 1 we have
−β2 ωλ β1 ω − μ(λ + μ) − μ(τ + μ + δ)

β1 ω − μ(λ + μ) < <0 ⇒ < 0 ⇒ B > 0.
τ +μ+δ μ
Applying the Routh-Hurwitz criteria, E0 is locally asymptotically stable. If R0 > 1

then B < 0 and there is one positive real root for Eq. (3), then E0 will be unstable.
The Jacobian matrix of system (1) at endemic equilibrium point is

⎡ ⎤
−(β1 E ∗ + β2 I ∗ ) − μ −β1 S ∗ −β2 S ∗ 0
⎢ ∗
β1 E + β2 I ∗ ∗
β1 S − (λ + μ) β2 S ∗ 0 ⎥
J (E1 ) = θ1−υ ⎢
⎣
⎥
0 λ −(τ + μ + δ) 0 ⎦
0 0 τ −μ
The characteristic equation of matrix J (E1 ) is obtained as follows
θ1−υ (k + μ)(k + (μ + δ + τ ))(k 2 − A1 k + B1 ) = 0,

where
β2 S ∗ λ
A1 = β1 S ∗ − λ − 2μ + ,
μ+τ +δ
(β1 S ∗ − λ − μ)(μ + τ + δ) + β2 S ∗ λ
B1 = (μ + β1 E ∗ + β2 I ∗ )(λ + μ) + ( ).
μ+τ +δ
The eigenvalues of characteristic equation are k1 = −μ , k2 = −(μ + δ + τ ) and the

roots of the equation
k 2 − A1 k + B1 = 0. (3)
Since k1 , k2 are negative, so E1 is locally asymptotically stable when two roots of

Eq. (32) are negative, so it is enough to have, B1 > 0 and A1 < 0.
3.4 R0 Sensitivity Analysis
To check the R0 sensitivity, we calculate its derivatives as follows
∂R0 ω
= ,
∂β1 μ(λ + μ)
∂R0 ωλ
= ,
∂β2 μ(λ + μ)(τ + μ + δ)
∂R0 β1 (τ + μ + δ) + β2 λ
= ,
∂ω μ(λ + μ)(τ + μ + δ)
∂R0 β2 ω(2λ + μ) − β1 ω(τ + μ + δ)

= ,
∂λ μ(λ + μ)2 (τ + μ + δ)
∂R0 β1 ω(τ + μ + δ)2 − β1 ω(τ + μ + δ) + β2 ωλ

= ,
∂τ μ(λ + μ)(τ + μ + δ)2
∂R0 β1 ω(τ + μ + δ)2 − β1 ω(τ + μ + δ) + β2 ωλ

= ,
∂δ μ(λ + μ)(τ + μ + δ)2
∂R0 β1 ωμ − β1 ω(τ + μ + δ) − β2 ωλ
=
∂μ μ2 (λ + μ)(τ + μ + δ)
β1 ω(τ + μ + δ) + β2 ωλ β1 ω(τ + μ + δ) + β2 ωλ
− − .
μ(λ + μ)2 (τ + μ + δ) μ(λ + μ)(τ + μ + δ)2
Because all parameters are positive, so ∂R 0

∂β1
> 0, ∂R0
∂β2
> 0, ∂R∂ω
0
> 0. Thus R0 is
increasing with β1 , β2 , ω, but about other parameters we cant say any thing at here.
3.5 Existence a Unique Solution
We show that the system has a unique solution. First, we write the system (1) as
follows ⎧ υ−1 C υ
⎪
⎪ θ D S(t) = Q1 (t, S(t)),
⎨ υ−1 C tυ
θ Dt E(t) = Q2 (t, E(t)),
υ−1 C υ
⎪
⎪ θ D I (t) = Q3 (t, I (t)),
⎩ υ−1 C tυ
θ Dt R(t) = Q4 (t, R(t)).
By taking integral form both sides of above equations, we get

⎧
⎪ t
⎪
⎪
⎪ S(t) − S(0) = (υ) Q1 (τ , S)(t − τ )υ−1 d τ ,
θ 1−υ
⎪
⎪
⎪
⎪
⎪
⎪ 0
⎪
⎪ t
⎪
⎪
⎪
⎪ E(t) − E(0) = (υ) Q2 (τ , E)(t − τ )υ−1 d τ ,
θ 1−υ
⎪
⎪
⎨
0
t (4)
⎪
⎪
⎪
⎪
⎪
⎪ I (t) − I (0) = (υ) Q3 (τ , I )(t − τ )υ−1 d τ ,
θ1−υ
⎪
⎪
⎪
⎪
⎪
⎪
0
⎪
⎪ t
⎪
⎪
⎪ A(t) − A(0) = (υ) Q4 (τ , A)(t − τ )υ−1 d τ .
θ 1−υ
⎪
⎩
0
We show that the kernels Qi , i = 1, 2, 3, 4 satisfy the Lipschitz condition and con-
traction.
Theorem 3.2 The kernel Q1 satisfy the Lipchitz condition and contraction if the
inequality given below hold
0 ≤ β1 d2 + β2 d3 + μ < 1.
Proof For S and S1 we have
Q1 (t, S) − Q1 (t, S1 )
=
− (β1 E(t) + β2 I (t))(S(t) − S1 (t)) − μ(S(t) − S1 (t))
,
≤
β1 E(t) + β2 I (t)
S(t) − S1 (t)
+ μ
S(t) − S1 (t)
,
≤ (β1
E(t)
+ β2
I (t))
+ μ)
S(t) − S1 (t)
,
≤ (β1 d2 + β2 d3 + μ)
S(t) − S1 (t)
.
Suppose that h1 = β1 d2 + β2 d3 + μ, where

E(t)
≤ d2 ,
I (t)
≤ d3 , are bounded
functions. So

Q1 (t, S) − Q1 (t, S1 )
≤ h1
(S(t) − S1 (t))
. (5)
Thus, for Q1 the Lipschitz condition is obtained and if 0 ≤ β1 d2 + β2 d3 + μ < 1

then Q1 is a contraction.
At the same way, we can prove that the Qj , j = 2, 3, 4 satisfied at the Lipschitz
condition as follows
⎧
⎨
Q2 (t, E) − Q2 (t, E1 )
≤ h2
(E(t) − E1 (t))
,

Q3 (t, I ) − Q3 (t, I1 )
≤ h3
(I (t) − I1 (t))
,
⎩

Q4 (t, R) − Q4 (t, R1 )
≤ h4
(R(t) − R1 (t))
,
where
S(t)
≤ d1 , and h2 = β1 d1 + λ + μ, h3 = τ + μ + δ, h4 = μ, are bounded
functions. If for j = 2, 3, 4 we have 0 ≤ hj < 1 then Qj are contraction for j = 2, 3, 4.
According to System (4), consider the following recursive forms
t
θ1−υ
ψ1n (t) = Sn (t) − Sn−1 (t) = (Q1 (τ , Sn−1 ) − Q1 (τ , Sn−2 ))(t − τ )υ−1 d τ ,
(υ)
0
t
θ1−υ
ψ2n (t) = En (t) − En−1 (t) = (Q2 (τ , En−1 ) − Q2 (τ , En−2 ))(t − τ )υ−1 d τ ,
(υ)
0
t
θ1−υ
ψ3n (t) = In (t) − In−1 (t) = (Q3 (τ , In−1 ) − Q3 (τ , In−2 ))(t − τ )υ−1 d τ ,
(υ)
0
t
θ1−υ
ψ4n (t) = Rn (t) − Rn−1 (t) = (Q4 (τ , Rn−1 ) − Q4 (τ , Rn−2 ))(t − τ )υ−1 d τ ,
(υ)
0
with initial conditions S0 (t) = S(0) , E0 (t) = E(0),I0 (t) = I (0) and R0 (t) = R(0).
We take the norm of first equation in the above system, then

ψ1n (t)
=
Sn (t) − Sn−1 (t)
,
t
θ1−υ
=
(Q1 (τ , Sn−1 ) − Q1 (τ , Sn−2 ))(t − τ )υ−1 d τ
,
(υ)
0
t
θ1−υ
≤
Q1 (τ , Sn−1 ) − Q1 (τ , Sn−2 ))(t − τ )υ−1
d τ ,
(υ)
0
with Lipschitz condition (5), we have
t
θ1−υ

ψ1n (t)
≤ h1
ψ1(n−1) (τ )
d τ . (6)
(υ)
0
As a similar way, we obtained
t
θ1−υ

ψ2n (t)
≤ h2
ψ2(n−1) (τ )
d τ ,
(υ)
0
t
θ1−υ

ψ3n (t)
≤ h3
ψ3(n−1) (τ )
d τ ,
(υ)
0
t
θ1−υ

ψ4n (t)
≤ h4
ψ4(n−1) (τ )
d τ . (7)
(υ)
0
Thus, we can write that

n
n
n
n
Sn (t) = ψ1i (t), En (t) = ψ2i (t), In (t) = ψ3i (t), Rn (t) = ψ4i (t).
i=1 i=1 i=1 i=1
In the next theorem, we prove the existence of a solution.

Theorem 3.3 A system of solutions given by the fractional COVID-19 SEIR model
(1) exists if there exist t1 such that
θ1−υ
t1 hj < 1.
(υ)
Proof From recursive technique, and Eqs. (6) and (7) we conclude that
θ1−υ

ψ1n (t)
≤
Sn (0)
[ h1 t]n ,
(υ)
θ1−υ

ψ2n (t)
≤
En (0)
[ h2 t]n ,
(υ)
θ1−υ

ψ3n (t)
≤
In (0)
[ h3 t]n ,
(υ)
θ1−υ

ψ4n (t)
≤
Rn (0)
[ h4 t]n .
(υ)
Thus, the system has a solution and also it is continuous. Now we show that the
above functions construct solution for the model (4), we assume that
S(t) − S(0) = Sn (t) − B1n (t),
E(t) − E(0) = En (t) − B2n (t),
I (t) − I (0) = In (t) − B3n (t),
R(t) − R(0) = Rn (t) − B4n (t).
So
t
θ1−υ

B1n (t)
=
(Q1 (τ , S) − Q1 (τ , Sn−1 ))d τ
(υ)
0
t
θ1−υ
≤
Q1 (τ , S) − Q1 (τ , Sn−1 )
d τ
(υ)
0
θ1−υ
≤ h1
S − Sn−1
t.
(υ)
By repeating the method we obtain
θ1−υ n+1 n+1

B1n (t)
≤ [ t] h1 k.
(υ)
At t1 , we get
θ1−υ n+1 n+1

B1n (t)
≤ [ t1 ] h1 k.
(υ)
Taking limit on recent equation as n approaches to ∞, we obtain

B1n (t)
→ 0. As
a same way, we can show that
Bjn (t)
→ 0, j = 2, 3, 4. This complete the proof.
To show the uniqueness of the solution, we suppose that the system has another
solution such as S1 (t) , E1 (t), I1 (t) and R1 (t), then we have
t
θ1−υ
S(t) − S1 (t) = (Q1 (τ , S) − Q1 (τ , S1 ))d τ .
(υ)
0
We take norm from this equation
t
θ1−υ

S(t) − S1 (t)
=
Q1 (τ , S) − Q1 (τ , S1 )
d τ .
(υ)
0
It follows from Lipschitz condition (5) that
θ1−υ

S(t) − S1 (t)
≤ h1 t
S(t) − S1 (t)
.
(υ)
Thus
θ1−υ

S(t) − S1 (t)
(1 − h1 t) ≤ 0. (8)
(υ)
Theorem 3.4 The solution of COVID-19 SEIR model (1) is unique if below condition
hold
θ1−υ
1− h1 t > 0.
(υ)
Proof Suppose that condition (8) hold
θ1−υ

S(t) − S1 (t)
(1 − h1 t) ≤ 0.
(υ)
Then
S(t) − S1 (t)
= 0. So, we obtain S(t) = S1 (t). Similarly we can show the
same equality for E, I , R.
3.6 Numerical Method
Using the fractional Euler method for Caputo derivative, we present the approximate
solutions for fractional-order COVID-19 SEIR model [12]. We present simulations
for predict the COVID-19 transmission in the World. We consider the system (1) in
the compact form as follows
θυ−1 CDtυ w(t) = g(t, w(t)), w(0) = w0 , 0 ≤ t ≤ T < ∞, (9)
where w = (S, E, I , R) ∈ R4+ ,w0 = (S0 , E0 , I0 , R0 ) is the initial vector and g(t) ∈ R
is a continuous vector function satisfying Lipschitz condition

g(w1 (t)) − g(w2 (t))
≤ k
w1 (t) − w2 (t)
, k > 0.
Applying fractional integral operator corresponding Caputo derivative to Eq. (9) we

obtain
w(t) = θ1−υ [w0 + I υ g(w(t))], 0 ≤ t ≤ T < ∞.
Set h = TN−0 and tn = nh, where t ∈ [0, T ] and N is a natural number and n =
0, 1, 2, ..., N . Let wn be the approximation of w(t) at t = tn . Using the fractional
Euler method, we get
hυ n
wn+1 = θ1−υ [w0 + un+1,j g(tj , wj )], j = 0, 1, 2, ..., N − 1, (10)
(υ + 1) j=0
where
un+1,j = (n + 1 − j)υ − (n − j)υ , j = 0, 1, 2, ..., n.
the stability analysis of the obtained scheme has been proved in Theorem (3.1) in
[12].
Thus, the solution of the system (1) is written as follows
hυ n
Sn+1 = θ1−υ [S0 + un+1,j f1 (tj , wj )],
(υ + 1) j=0
hυ n
En+1 = θ1−υ [E0 + un+1,j f2 (tj , wj )],
(υ + 1) j=0
hυ n
In+1 = θ 1−υ
[I0 + un+1,j f3 (tj , wj )],
(υ + 1) j=0
hυ n
Rn+1 = θ1−υ [R0 + un+1,j f4 (tj , wj )],
(υ + 1) j=0
where un+1,j = (n + 1 − j)υ − (n − i)υ , f1 (t, w(t)) = ω − (β1 E(t) + β2 I (t))S(t) −

μS(t), f2 (t, w(t)) = (β1 E(t) + β2 I (t))S(t) − (λ + μ)E(t), f3 (t, w(t)) = λE(t) −
(τ + μ + δ)I (t), f4 (t, w(t)) = τ I (t) − μR(t).
3.7 Simulation
Case I: The world

To provide numerical simulation, we must first determine the value of the parameters
and for this end we use the information of World Health Organization (WHO) and
Worldometer websites. The current birth rate for the world in 2020 is 18.077 births per
1000 people, and the death rate is 7.612 per 1000 people. The world’s population on
4th February was N =7,610,105,452, so ω = n×N 365
= 391,347.066 and μ = 365×1000
7.612
=
−5
2.08547 × 10 and we choose θ = 0.99. Since N (0) = S(0) + E(0) + I (0) + R(0)
and at 4th February we have I (0) = 24,545, R(0) = 907, then we assume E(0) =
80, 000 and S(0) = 7,610,026,000. Also, according to report of WHO the COVID-19
mortality rate is δ = 3.4 × 10−2 . To estimate the other parameters, we use the fitting
curve technique with the real data reported for COVID-19. The fitted curve and the
reported Cumulative number of COVID-19 in 2020 at the world from 4th February
to 12th May are plotted in Fig. 2, so that every part is a week.
Using this method, we obtain the parameters as β1 = 2 × 10−11 , β2 = 2.2 ×
10 , λ = 2.35 × 10−5 , τ = 0.03.
−9
Table 1 compare the absolute and relative errors for I(t) concerning the fractional
and the integer-order models with respect to the reported cases of Infected people.
From this table, you can observe that the Caputo model with υ = 0.97 provides more
realistic results than the classic model with integer-order derivatives.
A comparison between the non-integer order model with υ = 0.97 and integer-
order with υ = 1 and the real data for the Infected cases of the COVID-19 from 4th
February to 12th May is also given in Fig. 3. The obtained results show that the answer
of the fractional-order model corresponds well with the real data and together with
the results of the Table 1 show the advantage of using the fractional-order derivative
instead of the correct order derivative.
In Figs. 4 and 5, we have plotted the results of the model (1) for different
values of υ. In this simulation, the equilibrium point is E1 = (S ∗ , E ∗ , I ∗ , R∗ ) =
(2.5 × 106 , 7.52 × 109 , 2.76 × 106 , 2.9 × 109 ). Figures 4 and 5 show that the results
of the model converge to their equilibrium point for different orders of derivation,
and the results of all orders are stable at the equilibrium points. These figures show
that the obtained plots for different values of υ are different in quantity but they
Fig. 2 The fitted curve and the reported total cases of COVID-19 in the world from 4th February
to 12th May
Table 1 The absolute and relative errors for I (t)

Model υ Absolute error Relative error
Fractional 0.97 7.23451 0.0312
Integer − 9.04562 0.0394
6
3 x 10
Integer order
Fractional order
2.5
Real data
Active cases of COVID−19
1.5
0.5
0
0 20 40 60 80 100 120
t(days)
Fig. 3 Comparison between the results of the integer-order derivative υ = 1 and the fractional-order
derivative υ = 0.97 with real data
9 9
x 10
8 8 x 10
υ=0.95
7 υ=0.9 7
υ=0.85
6 υ=0.8 6
5 5
E (t)
S (t)
4 4
3 3
2 2 υ=0.95
υ=0.9
1 1 υ=0.85
υ=0.8
0 0
0 50 100 150 200 250 300 350 400 450 500 0 50 100 150 200 250 300 350 400 450 500
t(days) t(days)
Fig. 4 Dynamics of S(t) and E(t) for different values of υ = 0.95, 0.9, 0.85, 0.8
6 7
3 x 10 3 x 10
υ=0.95
υ=0.9
2.5 2.5 υ=0.85
υ=0.8
2 2
R(t)
I (t)
1.5 1.5
1 1
υ=0.95
0.5 υ=0.9 0.5
υ=0.85
υ=0.8
0 0
0 50 100 150 200 250 300 350 400 450 500 0 50 100 150 200 250 300 350 400 450 500
t(days) t(days)
Fig. 5 Dynamics of I(t) and R(t) for different values of υ = 0.95, 0.9, 0.85, 0.8
have the same behavior. Also, Fig. 5 shows that approximately 50 days after the 4th
February 2020, the number of active cases is out of the increasing state and becomes
stable in the 2.76 × 106 .
Case II: Iran
In the second case, we provide a numerical simulation using real data for the trans-
mission model of COVID-19 in Iran. According to the report of WHO, the total popu-
lation of Iran in 18-February 2020 was N = 83,392,425, the birth rate for Iran in 2019
was 18.547 births per 1000 people, and the death rate was 4.866 per 1000 people. Thus
for every day, we have ω = n×N 365
= 4237.477 and μ = 0.004866
365
= 0.0000133315.
Similarly, we assumed the mortality rate due to disease in Iran is δ = 3.4 × 10−2
Fig. 6 The fitted curve and the reported cases of COVID-19 in the Iran from 18 February to 12
April 2020
and θ = 0.99. Since N (0) = S(0) + E(0) + I (0) + R(0) and at 18th February we
have I (0) = 61, R(0) = 12, then we assume E(0) = 3000 and S(0) = 83,389,352.
For the fitting, we use the information provided by the World Health Organization
for COVID-19. The fitted curve and the reported cases of COVID-19 in 2020 at
the Iran from 18 February to 12 April 2020 are plotted in Fig. 6, so that every part
is 3 days. Using this method, we obtain the parameters as β1 = 1.1 × 10−4 , β2 =
3.3 × 10−6 , λ = 1.02 × 10−3 , τ = 0.03.
In Figs. 7 and 8, we plotted the results of the system of COVID-19 transmission
(1). As you can see in Figs. 7 and 8, the variables have different results in different
amounts of υ but exhibit the same behavior. Figure 7 shows that two months after
the virus is released, almost the entire population is at risk for the disease. Figure
8 shows that the number of people with COVID-19 increases until 200 days and
then stabilizes. Also, the forecast is that the number of infected people could rise to
280,000. Also, Fig. 8 shows that the number of people who have recovered or died
also increases over time.
4 Fractional SEIARW Model
About the spread of Sars-Cov2, it assumes that the virus transmitted among the bats’
population, and then transmitted to an unknown host (probably be wild animals).
Then hosts were hunted and sent to the seafood market which was defined as the
7 7
9x 10 9 x 10
α=0.95
8 α=0.9 8
α=0.85
7 7
α=0.8
6 6
5 5
S (t)
E (t)
4 4
3 3
α=0.95
2 2
α=0.9
1 1 α=0.85
α=0.8
0 0
0 50 100 150 200 250 300 0 50 100 150 200 250 300
t(days) t(days)
Fig. 7 Plots of S(t) and E(t) for different values of υ = 0.95, 0.9, 0.85, 0.8
5 6
3 x 10 2.5 x 10
α=0.95
α=0.9
2.5
2 α=0.85
α=0.8
2
1.5
R(t)
I (t)
1.5
1
1
α=0.95
α=0.9 0.5
0.5
α=0.85
α=0.8
0 0
0 50 100 150 200 250 300 0 50 100 150 200 250 300
t(days) t(days)
Fig. 8 Plots of I(t) and A(t) for different values of υ = 0.95, 0.9, 0.85, 0.8.
reservoir or the virus. People exposed to the market got the risks of the infection. In
SEIARW model, the people were divided into five groups: susceptible people (S),
exposed people (E), symptomatic infected people (I), asymptomatic infected people
(A), and removed people (R)including recovered and death people. The COVID-19
in the reservoir was denoted as (W). This model was presented as follows
⎧ dS
⎪
⎪ = − mS − βp S(I + κA) − βw SW,
⎪
⎪
dt
dE
= βp S(I + κA) + βw SW − (1 − δ)ωE − δω E − mE,
⎪
⎪
⎨ dI
dt
dt
= (1 − δ)ωE − (γ + m)I ,

⎪
⎪
dA
= δωp E − (γ + m)A,
⎪
⎪
dt
⎪
⎪
dR
= γI + γ A − mR,
⎩ ddtW
dt
= μI + μ A − εW,
where
= n × N , N refer to the total number of people and n is the birth rate,
m : the death rate of people,
βp : The transmission rate from I to S,
κ : The multiple of the transmissible of A to that of I ,
βw : The transmission rate from W to S,
δ : The proportion of asymptomatic infection rate of people
1
ω
: The incubation period of people,
1
ω
: The latent period of people,
1
γ
: The infectious period of symptomatic infection of people,
1
γ
: The infectious period of asymptomatic infection of people,
μ : The shedding coefficients from I to W ,

μ : The shedding coefficients from A to W ,
1
ε
: The lifetime of the virus in W .
Also, initial conditions are S(0) = S0 , E(0) = E0 , I (0) = I0 , A(0) = A0 , W (0) =
W0 .
We moderate the system by substituting the time-derivative by the Caputo-
Fabrizio fractional derivative in Caputo sense. With this change, the right and left
sides will not have the same dimension. To solve this problem, we use an auxil-
iary parameter θ, having the dimension of sec., to change the fractional operator so
that the sides have the same dimension. According to the explanation presented, the
COVID-19 transmission fractional model for t ≥ 0 and υ ∈ (0, 1) is given as follows
⎧ υ−1 CF υ
⎪
⎪ θ Dt S(t) = − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t),
⎪
⎪ θυ−1 CF Dtυ E(t) = βp S(t)(I (t) + κA(t))
⎪
⎪
⎪
⎪ +βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t),
⎨
θυ−1 CF Dtυ I (t) = (1 − δ)ωE(t) − (γ + m)I (t), (11)
⎪
⎪
⎪
⎪ θυ−1 CF Dtυ A(t) = δωp E(t) − (γ + m)A(t),
⎪
⎪
⎪
⎪ θυ−1 CF Dυ R(t) = γI (t) + γ A(t) − mR(t),
⎩ υ−1 CF tυ
θ Dt W (t) = μI (t) + μ A(t) − εW (t),
where initial conditions are S(0) = S0 , E(0) = E0 , I (0) = I0 , A(0) = A0 , W (0) =

W0 . In the next section we investigate the existence and uniqueness of the solution
for system (11) by fixed point theorem.
In this section, we show that the system has a unique solution. For this purpose,
employing the fractional integral operator due to Nieto and Losada [10] on the system
(11), we obtain
⎧
⎪
⎪ S(t) − S(0) = (θ1−υ ) CF Itυ [ − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t)],
⎪
⎪ E(t) − E(0) = (θ1−υ ) CF Itυ [βp S(t)(I (t) + κA(t))
⎪
⎪
⎪
⎪ +βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t)],
⎨
I (t) − I (0) = (θ1−υ ) CF Itυ [(1 − δ)ωE(t) − (γ + m)I (t)],
⎪
⎪
⎪
⎪ A(t) − A(0) = (θ1−υ ) CF Itυ [δωp E(t) − (γ + m)A(t)],
⎪
⎪ υ
⎪
⎪ R(t) − R(0) = (θ ) It [γI (t) + γ A(t) − mR(t)],
1−υ CF
⎩
W (t) − W (0) = (θ1−υ ) CF Itυ [μI (t) + μ A(t) − εW (t)].
Using the definition of Caputo-Fabrizio fractional integral, we obtain
2(1 − υ)θ1−υ
S(t) − S(0) = { − mS(t) − βp S(t)(I (t)
(2 − υ)M (υ)
+κA(t)) − βw S(t)W (t)}
t
2υθ1−υ
+, [ − mS(y) − βp S(y)(I (y) + κA(y)) − βw S(y)W (y)]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
E(t) − E(0) = {βp S(t)(I (t)
(2 − υ)M (υ)

+κA(t)) + βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t)}+,
t
2υθ1−υ
[βp S(y)(I (y) + κA(y)) + βw S(y)W (y) − (1 − δ)ωE(y) − δω E(y) − mE(y)]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
I (t) − I (0) = {(1 − δ)ωE(t) − (γ + m)I (t)}
(2 − υ)M (υ)
t
2υθ1−υ
+ [(1 − δ)ωE(y) − (γ + m)I (y)]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
A(t) − A(0) = {δωp E(t) − (γ + m)A(t)}
(2 − υ)M (υ)
t
2υθ1−υ
+ [δωp E(t) − (γ + m)A(t)]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
R(t) − R(0) = {γI (t) + γ A(t) − mR(t)}
(2 − υ)M (υ)
t
2υθ1−υ
+ [γI (y) + γ A(y) − mR(y)]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
W (t) − W (0) = {μI (t) + μ A(t) − εW (t)}
(2 − υ)M (υ)
t
2υθ1−υ
+ [μI (y) + μ A(y) − εW (y)]dy. (12)
(2 − υ)M (υ)
0
For convenience, we consider

⎧
⎪
⎪ P1 (t, S) = − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t),
⎪
⎪
⎪
⎪ P2 (t, E) = βp S(t)(I (t) + κA(t)) + βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t),
⎪
⎨ P (t, I ) = (1 − δ)ωE(t) − (γ + m)I (t),
3

⎪
⎪ P4 (t, A) = δωp E(t) − (γ + m)A(t),
⎪
⎪
⎪
⎪ P5 (t, R) = γI (t) + γ A(t) − mR(t),
⎪
⎩
P6 (t, W ) = μI (t) + μ A(t) − εW (t).
Theorem 4.1 The kernel P1 satisfy the Lipschitz condition and contraction if the
following inequality holds
0 < m + βp l1 + βw l2 ≤ 1.
Proof Consider functions S(t) and S1 (t), then

P1 (t, S(t)) − P1 (t, S1 (t))
=
− m(S(t) − S1 (t))
−βp I (t)(S(t) − S1 (t)) − βw W (t)(S(t) − S1 (t))
,
≤ m
S(t) − S1 (t)
+ βp
I (t)
S(t) − S1 (t)
+ βw
W (t)
S(t) − S1 (t)
,
≤ (m + βp
I (t)
+ βw
W (t)
)
S(t) − S1 (t)
,
≤ (m + βp l1 + βw l2 )
S(t) − S1 (t)
.
Let λ1 = m + βp l1 + βw l2 where the l1 =

I (t)
and l2 =
W (t)
are bounded func-
tions, then we have

P1 (t, S(t)) − P1 (t, S1 (t))
≤ λ1
S(t) − S1 (t)
.
Thus, Lipschitz’s condition is fulfilled for P1 . In addition, if 0 < m + βp l1 + βw l2 ≤

1, then P1 is a contraction.
Similarly P2 , P3 , P4 , P5 , P6 satisfy the Lipschitz condition, as follows

P2 (t, E(t)) − P2 (t, E1 (t))
≤ λ2
E(t) − E1 (t)
,

P3 (t, I (t)) − P3 (t, I1 (t))
≤ λ3
I (t) − I1 (t)
,

P4 (t, A(t)) − P4 (t, A1 (t))
≤ λ4
A(t) − A1 (t)
,

P5 (t, R(t)) − P5 (t, R1 (t))
≤ λ5
R(t) − R1 (t)
,

P6 (t, W (t)) − P6 (t, W1 (t))
≤ λ6
W (t) − W1 (t)
.
On consideration of P1 , P2 , P3 , P4 , P5 , P6 , we can write Eq. (12) as follows
t
2(1 − υ)θ1−υ 2υθ1−υ
S(t) = S(0) + P1 (t, S) + (P1 (y, S))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
E(t) = E(0) + P2 (t, E) + (P2 (y, E))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
I (t) = I (0) + P3 (t, I ) + (P3 (y, I ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
A(t) = A(0) + P4 (t, A) + (P4 (y, A))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
R(t) = R(0) + P5 (t, R) + (P5 (y, R))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
W (t) = W (0) + P6 (t, W ) + (P6 (y, W ))dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
Thus, consider the following recursive formula:
t
2(1 − υ)θ1−υ 2υθ1−υ
Sn (t) = P1 (t, Sn−1 ) + (P1 (y, Sn−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
En (t) = P2 (t, En−1 ) + (P2 (y, En−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
In (t) = P3 (t, In−1 ) + (P3 (y, In−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
An (t) = P4 (t, An−1 ) + (P4 (y, An−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
Rn (t) = P5 (t, Rn−1 ) + (P5 (y, Rn−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
Wn (t) = P6 (t, Wn−1 ) + (P6 (y, Wn−1 ))dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
Where S0 (t) = S(0), E0 (t) = E(0), I0 (t) = I (0), A0 (t) = A(0), R0 (t) = R(0), W0
(t) = W (0).
Now, we consider
2(1 − υ)θ1−υ
H1n = Sn (t) − Sn−1 (t) = [P1 (t, Sn−1 ) − P1 (t, Sn−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P1 (y, Sn−1 ) − P1 (y, Sn−2 )]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
H2n = En (t) − En−1 (t) = [P2 (t, En−1 ) − P2 (t, En−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P2 (y, En−1 ) − P2 (y, En−2 )]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
H3n = In (t) − In−1 (t) = [P3 (t, In−1 ) − P3 (t, In−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P3 (y, In−1 ) − P3 (y, In−2 )]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
H4n = An (t) − An−1 (t) = [P4 (t, An−1 ) − P4 (t, An−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P4 (y, An−1 ) − P4 (y, An−2 )]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
H5n = Rn (t) − Rn−1 (t) = [P5 (t, Rn−1 ) − P5 (t, Rn−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P5 (y, Rn−1 ) − P5 (y, Rn−2 )]dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
H6n = Wn (t) − Wn−1 (t) = [P6 (t, Wn−1 ) − P6 (t, Wn−2 )],
(2 − υ)M (υ)
t
2υθ1−υ
+ [P6 (y, Wn−1 ) − P6 (y, Wn−2 )]dy.
(2 − υ)M (υ)
0
Given the above equations, one can write

n
n
n
Sn (t) = H1j (t), En (t) = H2j (t), In (t) = H3j (t),
j=0 j=0 j=0

n
n
n
An (t) = H4j (t), Rn (t) = H5j (t), Wn (t) = H6j (t). (13)
j=0 j=0 j=0
According to H1n ’s definition and using triangular inequality, we have

H1n (t)
=
Sn (t) − Sn−1 (t)
,
2(1 − υ)θ1−υ
=
[P1 (t, Sn−1 ) − P1 (t, Sn−2 )]
(2 − υ)M (υ)
t
2υθ1−υ
+ [P1 (y, Sn−1 ) − P1 (y, Sn−2 )]dy
,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
≤
P1 (t, Sn−1 ) − P1 (t, Sn−2 )
(2 − υ)M (υ)
t
2υθ1−υ
+
[P1 (y, Sn−1 ) − P1 (y, Sn−2 )]dy
.
(2 − υ)M (υ)
0
P1 satisfies the Lipschitz condition, therefore
2(1 − υ)θ1−υ

Sn (t) − Sn−1 (t) ≤ λ1
Sn−1 − Sn−2
(2 − υ)M (υ)
t
2υθ1−υ
+ λ1
Sn−1 − Sn−2
dy.
(2 − υ)M (υ)
0
Thus we get
t
2(1 − υ)θ1−υ 2υθ1−υ

H1n (t)
≤ λ1
H1n−1 (t)
+ λ1
H1n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
(14)
It can be shown that similar results are obtained for Hin , i = 2, 3, 4, 5, 6 as follows
t
2(1 − υ)θ1−υ 2υθ1−υ

H2n (t)
≤ λ2
H2n−1 (t)
+ λ2
H2n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ

H3n (t)
≤ λ3
H3n−1 (t)
+ λ3
H3n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ

H4n (t)
≤ λ4
H4n−1 (t)
+ λ4
H4n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ

H5n (t)
≤ λ5
H5n−1 (t)
+ λ5
H5n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ

H6n (t)
≤ λ6
H6n−1 (t)
+ λ6
H6n−1 (y)
dy.
(2 − υ)M (υ) (2 − υ)M (υ)
0
(15)
According the above result, we show that the system (11) has a solution.
Theorem 4.2 The fractional COVID-19 model (11) has a system of solutions if there
exist ti , i = 1, 2, 3, 4, 5, 6, such that
2(1 − υ)θ1−υ 2υθ1−υ

λi + λi ti ≤ 1.
(2 − υ)M (υ) (2 − υ)M (υ)
Proof Assume functions S(t), E(t), I (t), A(t), R(t), W (t) are bounded. We have
shown that kernels Hin , i = 1, 2, 3, 4, 5, 6 satisfy the Lipschitz condition. By using
the recursive method and the results of (14) and (15), we obtain
2(1 − υ)θ1−υ 2υθ1−υ

H1n (t)
≤
S(0)
[ λ1 + λ1 t]n ,
(2 − υ)M (υ) (2 − υ)M (υ)
2(1 − υ)θ1−υ 2υθ1−υ

H2n (t)
≤
E(0)
[ λ2 + λ2 t]n ,
(2 − υ)M (υ) (2 − υ)M (υ)
2(1 − υ)θ1−υ 2υθ1−υ

H3n (t)
≤
I (0)
[ λ3 + λ3 t]n ,
(2 − υ)M (υ) (2 − υ)M (υ)
2(1 − υ)θ1−υ 2υθ1−υ

H4n (t)
≤
A(0)
[ λ4 + λ4 t]n ,
(2 − υ)M (υ) (2 − υ)M (υ)
2(1 − υ)θ1−υ 2υθ1−υ

H5n (t)
≤
R(0)
[ λ5 + λ5 t]n ,
(2 − υ)M (υ) (2 − υ)M (υ)
2(1 − υ)θ1−υ 2υθ1−υ

H6n (t)
≤
W (0)
[ λ6 + λ6 t]n .
(2 − υ)M (υ) (2 − υ)M (υ)
Thus, the functions (13) exists and is smooth. We claim that the above functions are
the solutions of the system (11), to prove this claim we assume
S(t) − S(0) = H1n (t) − G 1n (t), E(t) − E(0) = H2n (t) − G 2n (t),
I (t) − I (0) = H3n (t) − G 3n (t), A(t) − A(0) = H4n (t) − G 4n (t),
R(t) − R(0) = H5n (t) − G 5n (t), W (t) − W (0) = H6n (t) − G 6n (t).
We have
2(1 − υ)θ1−υ

G 1n (t)
=
[P1 (t, S) − P1 (t, Sn−1 )]
(2 − υ)M (υ)
t
2υθ1−υ
+ [P1 (y, S) − P(y, Sn−1 )]dy
,
(2 − υ)M (υ)
0
2(1 − υ)θ 1−υ
≤
P1 (t, S) − P1 (t, Sn−1 )
(2 − υ)M (υ)
t
2υθ1−υ
+
P1 (y, S) − P(y, Sn−1 )
dy,
(2 − υ)M (υ)
0
2(1 − υ)θ1−υ
≤ λ1
S − Sn−1
(2 − υ)M (υ)
2υθ1−υ
+ λ1
S − Sn−1
t.
(2 − υ)M (υ)
By repeating this process, we obtain
2(1 − υ)θ1−υ 2υθ1−υ

G 1n (t)
≤ [ + t]n+1 λ1n+1 q.
(2 − υ)M (υ) (2 − υ)M (υ)
By taking limit on recent equation as n tends to infinity, we obtain

G 1n (t)
→ 0. By
the same way, we get
G in (t)
→ 0, i = 2, 3, 4, 5, 6, and this complete the proof.
To prove the uniqueness of solution, we assume that the system (11) has another
solution such as S1 , E1 , I1 , A1 , R1 , W1 . then
2(1 − υ)θ1−υ

S(t) − S1 (t)
=
(P1 (t, S) − P1 (t, S1 )
(2 − υ)M (υ)
t
2υθ1−υ
+ (P1 (y, S) − P1 (y, S1 )dy
,
(2 − υ)M (υ)
0
t
2(1 − υ)θ1−υ 2υθ1−υ
≤
P1 (t, S) − P1 (t, S1
+
P1 (y, S) − P1 (y, S1
dy,
(2 − υ)M (υ) (2 − υ)M (υ)
0
According the Lipschitz condition of the S, we get
2(1 − υ)θ1−υ 2υθ1−υ

S(t) − S1 (t)
≤ λ1
S(t) − S1 (t)
+ λ1 t
S(t) − S1 (t)
.
(2 − υ)M (υ) (2 − υ)M (υ)
Thus
2(1 − υ)θ1−υ 2υθ1−υ

S(t) − S1 (t)
(1 − λ1 − λ1 t) ≤ 0. (16)
(2 − υ)M (υ) (2 − υ)M (υ)
Theorem 4.3 The solution of the COVID-19 fractional model (11) is unique if the
following condition holds
2(1 − υ)θ1−υ 2υθ1−υ

(1 − λ1 − λ1 t) ≥ 0. (17)
(2 − υ)M (υ) (2 − υ)M (υ)
Proof From condition (17) and Eq. (16), we conclude that
2(1 − υ)θ1−υ 2υθ1−υ

S(t) − S1 (t)
(1 − λ1 − λ1 t) = 0,
(2 − υ)M (υ) (2 − υ)M (υ)
So
S(t) − S1 (t)
= 0, then S(t) = S1 (t). In the same way, we can show that
E(t) = E1 (t), I (t) = I1 (t), A(t) = A1 (t), R(t) = R1 (t), W (t) = W1 (t).
The proof is complete.
4.2 Stability Analysis by Fixed Point Theory
Using the Sumudu transform, we obtain a special solution to the COVID-19 model
and then prove the stability of the iterative method using fixed point theory. At first,
we apply the Sumudu transform on both sides of equations in model (11), then
⎧
⎪
⎪ ST (θυ−1 CF Dtυ S(t)) = ST ( − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t)),
⎪
⎪ ST (θυ−1 CF Dtυ E(t)) = ST (βp S(t)(I (t) + κA(t))
⎪
⎪
⎪
⎪
⎨ +βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t)),
υ−1 CF υ
ST (θ Dt I (t)) = ST ((1 − δ)ωE(t) − (γ + m)I (t)),
⎪
⎪ υ−1 CF υ
⎪
⎪ ST (θ Dt A(t)) = ST (δωp E(t) − (γ + m)A(t)),
⎪
⎪
⎪
⎪ ST (θυ−1 CF Dtυ R(t)) = ST (γI (t) + γ A(t) − mR(t)),
⎩
ST (θυ−1 CF Dtυ W (t)) = ST (μI (t) + μ A(t) − εW (t)).
We conclude from the Sumudu transform definition of the Caputo-Fabrizio derivative

⎧ M (υ)
⎪
⎪ (ST (S(t)) − S(0)) = θ1−υ ST ( − mS(t) − βp S(t)(I (t)
⎪
⎪
1−υ+υu
⎪
⎪ +κA(t)) − βw S(t)W (t)),
⎪
⎪ M (υ)
⎪ 1−υ+υu
⎪ (ST (E(t)) − E(0)) = θ1−υ ST (βp S(t)(I (t)
⎪
⎪ +κA(t)) + β S(t)W (t) − (1 − δ)ωE(t),
⎪
⎨ w

−δω E(t) − mE(t)),
⎪
⎪ M (υ)
⎪
⎪ (ST (I (t)) − I (0)) = θ1−υ ST ((1 − δ)ωE(t) − (γ + m)I (t)),
⎪
⎪
1−υ+υu
M (υ)
⎪
⎪ (ST (A(t)) − A(0)) = θ1−υ ST (δωp E(t) − (γ + m)A(t)),
⎪
⎪
1−υ+υu
⎪
⎪
M (υ)
(ST (R(t)) − R(0)) = θ1−υ ST (γI (t) + γ A(t) − mR(t)),
⎪ 1−υ+υu
⎩ M (υ)
1−υ+υu
(ST (W (t)) − W (0)) = θ1−υ ST (μI (t) + μ A(t) − εW (t)).
If we rearrange the above inequalities then

⎧
⎪ ST (S(t)) = S(0) + 1−υ+υu θ1−υ ST [ − mS(t) − βp S(t)(I (t)
⎪
⎪ M (υ)
⎪
⎪ +κA(t)) − βw S(t)W (t)],
⎪
⎪
⎪
⎪ ST (E(t)) = E(0) + 1−υ+υu θ1−υ ST [βp S(t)(I (t)
⎪
⎪ M (υ)
⎪ +κA(t)) + βw S(t)W (t) − (1 − δ)ωE(t),
⎪
⎨
−δω E(t) − mE(t)],
⎪
⎪ ST (I (t)) = I (0) + 1−υ+υu θ1−υ ST [(1 − δ)ωE(t) − (γ + m)I (t)],
⎪
⎪ M (υ)
⎪
⎪
⎪
⎪ ST (A(t)) = A(0) + M (υ) θ
1−υ+υu 1−υ
ST [δωp E(t) − (γ + m)A(t)],
⎪
⎪
⎪
⎪ ST (R(t)) = R(0) + 1−υ+υu

θ1−υ ST [γI (t) + γ A(t) − mR(t)],
⎪
⎩ M (υ)

ST (W (t)) = W (0) + 1−υ+υu
M (υ)
θ1−υ ST [μI (t) + μ A(t) − εW (t)].
We obtain
⎧
⎪ S (t) = Sn (0) + ST −1 { 1−υ+υu θ1−υ ST [ − mSn (t) − βp Sn (t)(In (t)
⎪ n+1
⎪ M (υ)
⎪
⎪ +κAn (t)), −βw Sn (t)W−1
⎪
⎪
n (t)]},
⎪
⎪ En+1 (t) = En (0) + ST { 1−υ+υu θ1−υ ST [βp Sn (t)(In (t)
⎪
⎪ M (υ)
⎨ +κA (t)) + β S (t)W (t), −(1 − δ)ωE (t) − δω E (t) − mE (t)]},
n w n n n n n
−1 1−υ+υu 1−υ
⎪
⎪ I n+1 (t) = I n (0) + ST { M (υ)
θ ST [(1 − δ)ωE n (t) − (γ + m)In (t)]},
⎪
⎪ −1 1−υ+υu 1−υ
⎪
⎪ A n+1 (t) = A n (0) + ST { θ ST [δω E
p n (t) − (γ + m)A n (t)]},
⎪
⎪
M (υ)
⎪
⎪
−1 1−υ+υu 1−υ
Rn+1 (t) = Rn (0) + ST { M (υ) θ

ST [γIn (t) + γ An (t) − mRn (t)]},
⎪
⎩
Wn+1 (t) = Wn (0) + ST −1 { 1−υ+υu M (υ)
θ 1−υ
ST [μIn (t) + μ An (t) − εWn (t)]}.
(18)
The approximate solution of the system (11) is as follows
S(t) = lim Sn (t), E(t) = lim En (t), I (t) = lim In (t),

n→∞ n→∞ n→∞
A(t) = lim An (t), R(t) = lim Rn (t), W (t) = lim Wn (t).

n→∞ n→∞ n→∞
4.3 Stability Analysis of Iteration Method
Consider the Banach space (G,

.
), a self-map T on G and recursive method
qn+1 = φ(T , qn ). Assume that ϒ(T ) be the fixed point set of T which ϒ(T ) = ∅
and limn→∞ qn = q ∈ ϒ(T ). Suppose that {tn } ⊂ ϒ and rn =
tn+1 − φ(T , tn )
. if
limn→∞ rn = 0 implies that limn→∞ tn = q, then the recursive procedure qn+1 =
φ(T , qn ) is T -Stable. Suppose that our sequence {tn } has an upper boundary. If Picard
s iteration qn+1 = Tqn is satisfied in all these conditions, then qn+1 = Tqn is T -Stable.
First, we express the following theorem from [9].
Theorem 4.4 Let (G,
.
) be a Banach space and T a self-map of G satisfying

Tx − Ty
≤ B
x − Tx
+ b
x − y
for all x, y ∈ G where B ≥ 0 and 0 ≤ b < 1. Suppose that T is Picard T -Stable.

According to (18), fractional model of COVID-19 (11) is connected with the subse-
quent iterative formula. Now consider the following theorem
Theorem 4.5 Suppose that T be a self-map defined as below
⎧
⎪
⎪ T (Sn (t)) = Sn+1 (t) = Sn (t) + ST −1 { 1−υ+υu M (υ) θ
1−υ ST [ − mS (t),
n
⎪
⎪
⎪
⎪ −β p Sn (t)(I n (t) + κA n (t)) − β w Sn (t)W n (t)]},
⎪
⎪
⎪
⎪
⎪ T (En (t)) = En+1 (t) = En (t) + ST −1 { 1−υ+υu M (υ) θ
1−υ ST [β S (t)(I (t) + κA (t)),
p n n n
⎪
⎪
⎨ +βw Sn (t)Wn (t) − (1 − δ)ωEn (t) − δω En (t) − mEn (t)]},
⎪ T (In (t)) = In+1 (t) = In (t) + ST −1 { 1−υ+υu
M (υ) θ
1−υ ST [(1 − δ)ωE (t) − (γ + m)I (t)]},
n n
⎪
⎪
⎪
⎪ T (An (t)) = An+1 (t) = An (t) + ST { −1 1−υ+υu θ 1−υ ST [δω E (t) − (γ + m)A (t)]},
⎪
⎪ M (υ) p n n
⎪
⎪
⎪ T (Rn (t)) = Rn+1 (t) = Rn (t) + ST −1 { 1−υ+υu
⎪
⎪ (υ) θ1−υ ST [γIn (t) + γ An (t) − mRn (t)]},
⎪
⎩
M
T (Wn (t)) = Wn+1 (t) = Wn (t) + ST −1 { 1−υ+υu 1−υ ST [μI (t) + μ A (t) − εW (t)]}.
M (υ) θ n n n
This iterative recursive is T -stable in L1 (a, b) if following conditions are achieved

⎧
⎪
⎪ (1 − (m + βp M3 + βp M4 + βw M6 )f1 (υ) − βp M1 f2 (υ)
⎪
⎪ −β
⎪
⎪ p κM1 f4 (υ) − βw M1 f4 (υ)) < 1,
⎪
⎪ (1 + βp M1 f5 (υ) + (βp M3 + βp κM4 + βw M6 )f6 (υ)
⎪
⎪
⎪
⎪
⎨ p 1 f7 (υ) + βw M1 f8 (υ),
+β κM
−((1 − δ)m + δω + m)f9 (υ)) < 1,
⎪
⎪ (1 + (1 − δ)ωf10 (υ) − (γ + m)f11 (υ)) < 1,
⎪
⎪
⎪
⎪
⎪
⎪ (1 + δωp f12 (υ) − (γ + m)f13 (υ)) < 1,
⎪
⎪
⎪
⎪ (1 + γf14 (υ) + γ f15 (υ) − mf16 (υ)) < 1,
⎩
(1 + μf17 (υ) + μ f18 (υ) − εf19 (υ)) < 1.
Proof To prove that T has a fixed point, we compute the following inequalities for
(i, j) ∈ N × N .
1 − υ + υu 1−υ
T (Si (t)) − T (Sj (t)) = Si (t) − Sj (t) + ST −1 { θ ST [( − mSi (t),
M (υ)
−βp Si (t)(Ii (t) + κAi (t)) − βw Si (t)Wi (t)) − ( − mSj (t)
−βp Sj (t)(Ij (t) + κAj (t)) − βw Sj (t)Wj (t))]},
= (Si (t) − Sj (t))
1 − υ + υu 1−υ
+ST −1 { θ ST [−(m + βp Ij (t) + βp κAj (t) + βw Wj (t))(Si (t) − Sj (t)),
M (υ)
−βp Si (t)(Ii (t) − Ij (t)) − βp κSi (t)(Ai (t) − Aj (t)) − βw Si (t)(Wi (t) − Wj (t))]}
By apply norm on both sides, we obtain

T (Si (t)) − T (Sj (t))
,
1 − υ + υu 1−υ
=
(Si (t) − Sj (t)) + ST −1 { θ ST [−(m + βp Ij (t)
M (υ)
+βp κAj (t) + βw Wj (t))(Si (t) − Sj (t)),
−βp Si (t)(Ii (t) − Ij (t)) − βp κSi (t)(Ai (t) − Aj (t)) − βw Si (t)(Wi (t) − Wj (t))]}
,
1 − υ + υu 1−υ
≤
Si (t) − Sj (t)
+ ST −1 { θ ST [
− (m + βp Ij (t)
M (υ)
+βp κAj (t) + βw Wj (t))(Si (t) − Sj (t))
,
+
− βp Si (t)(Ii (t) − Ij (t))
+
− βp κSi (t)(Ai (t) − Aj (t))
+
− βw Si (t)(Wi (t) − Wj (t))
]}. (19)
Since the solutions are the same roles, we can consider
Si (t) − Sj (t)
∼
=
Ei (t) − Ej (t)
∼
=
Ii (t) − Ij (t)
∼
=
Ai (t) − Aj (t)
∼
=
Rn (t) − Rm (t)
∼
=
Rn (t) − Rm (t)
. (20)
From Eqs. (19) and (20), we get
T (Si (t)) − T (Sj (t))

,
1 − υ + υu 1−υ
≤
Si (t) − Sj (t)
+ ST −1 { θ ST [
− (m + βp Ij (t)
M (υ)
+ βp κAj (t) + βw Wj (t))(Si (t) − Sj (t))
,
+
− βp Si (t)(Si (t) − Sj (t))
+
− βp κSi (t)(Si (t) − Sj (t))
+
− βw Si (t)(Si (t) − Sj (t))
]}.
(21)
Si , Ei , Ii , Ai , Ri , Wi are bounded, because they are convergent sequence, then for all
t there exist Mi , i = 1, 2, 3, 4, 5, 6 such that
Si
< M1 ,
Ei
< M2 ,
Ii
< M3 ,
Ai
< M4 ,
Ri
< M5 ,
Wi
< M6 , (i, j) ∈ N × N
(22)
From Eqs. (21) and (22), we get

T (Si (t) − T (Sj (t))
,
≤ [1 − (m + βp M3 + βp M4 + βw M6 )f1 (υ) − βp M1 f2 (υ)
−βp κM1 f4 (υ) − βw M1 f4 (υ)]
Si (t) − Sj (t)
. (23)
where fi are functions from ST −1 [ 1−υ+υu

M (υ)
θ1−υ ST [∗]]. Similarly, we will obtain
⎧
⎪
⎪
T (Ei (t) − T (Ej (t))
≤ [1 + βp M1 f5 (υ) + (βp M3 + βp κM4
⎪
⎪ +βw M6 )f6 (υ) + βp κM1 f7 (υ),
⎪
⎪
⎪
⎪
⎨ +βw M1 f8 (υ) − ((1 − δ)m + δω + m)f9 (υ)]
Ei (t) − Ej (t)
,

T (Ii (t) − T (Ij (t))
≤ [1 + (1 − δ)ωf10 (υ) − (γ + m)f11 (υ)]
Ii (t) − Ij (t)
,
⎪
⎪
⎪
T (Ai (t) − T (Aj (t))
≤ [1 + δωp f12 (υ) − (γ + m)f13 (υ)]
Ai (t) − Aj (t)
,
⎪
⎪
⎪
⎪
T (Ri (t) − T (Rj (t))
≤ [1 + γf14 (υ) + γ f15 (υ) − mf16 (υ)]
Ri (t) − Rj (t)
,
⎪
⎩

T (Wi (t) − T (Wj (t))
≤ [1 + μf17 (υ) + μ f18 (υ) − εf19 (υ)]
Wi (t) − Wj (t)
.
(24)
where
⎧
⎪
⎪ (1 − (m + βp M3 + βp M4 + βw M6 )f1 (υ) − βp M1 f2 (υ)
⎪
⎪ −βp κM1 f4 (υ) − βw M1 f4 (υ)) < 1,
⎪
⎪
⎪
⎪ (1 + βp M1 f5 (υ) + (βp M3 + βp κM4 + βw M6 )f6 (υ) + βp κM1 f7 (υ) + βw M1 f8 (υ),
⎪
⎪
⎨ −((1 − δ)m + δω + m)f (υ)) < 1,
9
⎪
⎪ (1 + (1 − δ)ωf10 (υ) − (γ + m)f11 (υ)) < 1,
⎪
⎪
⎪
⎪ (1 + δωp f12 (υ) − (γ + m)f13 (υ)) < 1,
⎪
⎪
⎪
⎪ (1 + γf14 (υ) + γ f15 (υ) − mf16 (υ)) < 1,
⎩
(1 + μf17 (υ) + μ f18 (υ) − εf19 (υ)) < 1.
thus T -self mapping has a fixed point. Also, we show that T satisfies the conditions
in theorem (4.4). Consider (23), (24) hold, we assume
B = (0, 0, 0, 0, 0, 0),
⎧
⎪
⎪ (1 − (m + βp M3 + βp M4 + βw M6 )f1 (υ)
⎪
⎪ −βp M1 f2 (υ) − βp κM1 f4 (υ) − βw M1 f4 (υ)),
⎪
⎪
⎪
⎪
⎪
⎪
⎪
⎪ (1 + βp M1 f5 (υ) + (βp M3 + βp κM4
⎪
⎪
⎪
⎪
⎨ +βw M6 )f6 (υ) + βp κM1 f7 (υ) + βw M1 f8 (υ)
b = −((1 − δ)m + δω + m)f9 (υ)),
⎪
⎪
⎪
⎪
⎪
⎪ (1 + (1 − δ)ωf10 (υ) − (γ + m)f11 (υ)),
⎪
⎪
⎪
⎪
⎪
⎪ (1 + δωp f12 (υ) − (γ + m)f13 (υ)),
⎪
⎪
⎪
⎪ (1 + γf14 (υ) + γ f15 (υ) − mf16 (υ)),
⎩
(1 + μf17 (υ) + μ f18 (υ) − εf19 (υ)).
So, all conditions of theorem (4.4) satisfied and the proof is complete.
In this section, we apply the homotopy analysis transform method (HATM) to

implement the fractional model (11) appropriately. Notice that the HATM is a well-
developed mixture of the standard Laplace transform technique and the homotopy
analysis method (HAM). To solve the model (11) by the HATM, first, we apply the
Laplace transform in the way
⎧
⎪
⎪ L[θυ−1 CF Dtυ S(t)](s) = L[ − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t)],
⎪
⎪ L[θυ−1 CF Dυ E(t)](s) = L[β S(t)(I (t) + κA(t)) + β S(t)W (t) − (1 − δ)ωE(t) − δω E(t)
⎪
⎪ w
⎪
⎪
t p
⎪
⎨ −mE(t)],
L[θυ−1 CF Dtυ I (t)](s) = L[(1 − δ)ωE(t) − (γ + m)I (t)],
⎪
⎪
⎪ L[θυ−1 CF Dtυ A(t)](s) = L[δωp E(t) − (γ + m)A(t)],
⎪
⎪
⎪
⎪
⎪ L[θυ−1 CF Dtυ R(t)](s) = L[γI (t) + γ A(t) − mR(t)],
⎪
⎩
L[θυ−1 CF Dtυ W (t)](s) = L[μI (t) + μ A(t) − εW (t)].
which results
⎧ sL(S)−S(0)
⎪
⎪ = θ1−υ L[ − mS(t) − βp S(t)(I (t) + κA(t)) − βw S(t)W (t)],
⎪ s+υ(1−s)
⎪ sL(E)−E(0)
⎪
⎪ = θ1−υ L[βp S(t)(I (t)
⎪
⎪ s+υ(1−s)
⎪
⎪

⎨ +κA(t)) + βw S(t)W (t) − (1 − δ)ωE(t) − δω E(t) − mE(t)],
sL(I )−I (0)
= θ1−υ L[(1 − δ)ωE(t) − (γ + m)I (t)],
⎪
⎪
s+υ(1−s)

⎪
⎪ s+υ(1−s) = θ L[δωp E(t) − (γ + m)A(t)],
sL(A)−A(0) 1−υ
⎪
⎪
⎪
⎪ s+υ(1−s) = θ1−υ L[γI (t) + γ A(t) − mR(t)],
sL(R)−R(0)
⎪
⎪
⎩ sL(W )−W (0) = θ1−υ L[μI (t) + μ A(t) − εW (t)].
s+υ(1−s)
Then we get
⎧
⎪
⎪ L(S) − Ss0 − s+υ(1−s) θ1−υ L[ − mS(t) − βp S(t)(I (t)
⎪
⎪
s
⎪
⎪ +κA(t)) − βw S(t)W (t)] = 0,
⎪
⎪
⎪
⎪ L(E) − Es0 − s+υ(1−s) θ1−υ L[βp S(t)(I (t) + κA(t))
⎪
⎪ s
⎪ +β
⎨ w S(t)W (t) − (1 − δ)ωE(t),
−δω E(t) − mE(t)] = 0, (25)
⎪
⎪
⎪ L(I ) − sA − s+υ(1−s) θ L[(1 − δ)ωE(t) − (γ + m)I (t)] = 0,
I0 s+υ(1−s) 1−υ
⎪
⎪
⎪
s
⎪
⎪ L(A) − 0
− θ1−υ L[δωp E(t) − (γ + m)A(t)] = 0,
⎪
⎪
s s
⎪
⎪ L(R) − s0 −
R
θ L[γI (t) + γ A(t) − mR(t)] = 0,
s+υ(1−s) 1−υ
⎪
⎩ s
L(W ) − s − W0
θ L[μI (t) + μ A(t) − εW (t)] = 0.
s+υ(1−s) 1−υ
s
Using the homotopy method, we define
N1 (φ1 (t; q), φ2 (t; q), φ3 (t; q), φ4 (t; q), φ5 (t; q), φ6 (t; q))
L = [ − mφ1 (t; q) − βp φ1 (t; q)φ3 (t; q) + κφ4 (t; q)) − βw φ1 (t; q)φ6 (t; q)],
= L[βp φ1 (t; q)(φ3 (t; q) + κφ4 (t; q))

+βw φ1 (t; q)φ6 (t; q) − (1 − δ)ωφ2 (t; q) − δω φ2 (t; q) − mφ2 (t; q)],
= L[(1 − δ)ωφ2 (t; q) − (γ + m)φ3 (t; q)],

= L[δωp φ2 (t; q) − (γ + m)φ4 (t; q)],

= L[γφ3 (t; q) + γ φ4 (t; q) − mφ5 (t; q)],

= L[μφ3 (t; q) + μ φ4 (t; q) − εφ6 (t; q)].
Then the deformation equations become
(1 − q)L[φ1 (t; q) − S0 (t)]

= qhH (t)N1 (φ1 (t; q), φ2 (t; q), φ3 (t; q), φ4 (t; q), φ5 (t; q), φ6 (t; q)),
(1 − q)L[φ2 (t; q) − E0 (t)]
(1 − q)L[φ3 (t; q) − I0 (t)]
(1 − q)L[φ4 (t; q) − A0 (t)]
(1 − q)L[φ5 (t; q) − R0 (t)]
(1 − q)L[φ6 (t; q) − W0 (t)]
where q ∈ [0, 1] denotes an embedding parameter;φi (t; q), i = 0, 1, are unknown

functions;S0 , E0 , I0 , A0 , R0 , W0 are initial guesses; L[.] is the Laplace operator;H (t) =
0 is an auxiliary function, and h = 0 is a nonzero auxiliary parameter. Clearly, for
q = 0 and q = 1 we have
⎧
⎪ φ1 (t; 0) = S0 (t)
⎪
⎪
, φ1 (t; 1) = S(t),
⎪
⎪ φ2 (t; 0) = E0 (t) , φ2 (t; 1) = E(t),
⎪
⎨
φ3 (t; 0) = I0 (t) , φ3 (t; 1) = I (t),
⎪ φ4 (t; 0) = A0 (t)
⎪ , φ4 (t; 1) = A(t),
⎪
⎪
⎪ φ5 (t; 0) = R0 (t)
⎪ , φ5 (t; 1) = R(t),
⎩
φ6 (t; 0) = W0 (t) , φ6 (t; 1) = W (t).
Thus, increasing q from zero to one varies the solution (φ1 (t; q), φ2 (t; q), φ3 (t; q),
φ4 (t; q), φ5 (t; q), φ6 (t; q)) from (S0 (t), E0 (t), I0 (t), A0 (t), R0 (t), W0 (t)) to (S(t),
E(t), I (t), A(t), R(t), W (t)). Now, we expand φi (t; q)(i = 1, 2, 3, 4, 5, 6) in the Tay-
lor series with regard to q. This procedure yields
∞
φ1 (t; q) = S0 + n=1 Sn (t)q ,
n
φ2 (t; q) = E0 + ∞ En (t)qn ,
∞ ∞n=1
φ3 (t; q) = I0 + n=1 In (t)qn , φ4 (t; q) = A0 + n=1 An (t)qn ,

φ5 (t; q) = R0 + ∞n=1 Rn (t)q ,
n
φ6 (t; q) = W0 + ∞ n=1 Wn (t)q ,
n
where
1 ∂ n φ1 (t;q) 1 ∂ n φ2 (t;q)
Sn (t) = n! ∂qn
|q=0 , En (t) =n! ∂qn
|q=0 ,
∂ n
φ (t;q) ∂ n
φ (t;q)
In (t) = n!1 ∂q3 n |q=0 , An (t) = n!1 ∂q4 n |q=0 , (26)
Rn (t) = n!1 ∂ φ∂q5 (t;q) Wn (t) = n!1 ∂ φ∂q6 (t;q)
n n
n |q=0 , n |q=0 .
If the auxiliary function H (t), the auxiliary parameter h, and the initial guesses are
properly chosen, then the series (26) converges at q = 1. Thus, we get

S(t) = S0 + ∞ n=1 Sn (t), + ∞
E(t) = E0 n=1 En (t),
I (t) = I0 + ∞
n=1 In (t), A(t) = A0 +
∞
∞
n=1 An (t),
R(t) = R0 + ∞ n=1 Rn (t), W (t) = W0 + n=1 Wn (t).
In addition, we can express the m-th order deformation equation by

⎧
⎪
⎪ L[Sn (t) − χn Sn−1 (t)] = hHT1,n (Sn−1 ),
⎪
⎪
⎪
⎪ L[E n (t) − χn En−1 (t)] = hHT2,n (En−1 ),
⎨
L[In (t) − χn In−1 (t)] = hHT3,n (In−1 ),
(27)
⎪ L[An (t) − χn An−1 (t)] = hHT4,n (An−1 ),
⎪
⎪
⎪
⎪
⎪ L[Rn (t) − χn Rn−1 (t)] = hHT5,n (Rn−1 ),
⎩
L[Wn (t) − χn Wn−1 (t)] = hHT6,n (Wn−1 ),
where
⎧
⎪ T1,n (Sn−1 (t) = L[Sn−1 (t)] − s (1 − χn ) − θ L[ − mSn−1 (t),
S0 s+υ(1−s) 1−υ
⎪
⎪
⎪
s
⎪
⎪ −β p Sn−1 (t)(I n−1 (t) + κAn−1 (t)) − βw Sn−1 (t)W n−1 (t)],
⎪
⎪
⎪
⎪ T2,n (En−1 (t)) = L[En−1 (t)] − Es0 (1 − χn )
⎪
⎪
⎪
⎪ − s+υ(1−s) θ1−υ L[βp Sn−1 (t)(In−1 (t) + κAn−1 (t)),
⎪
⎪
s
⎪
⎪ +βw Sn−1 (t)Wn−1 (t) − (1 − δ)ωEn−1 (t) − δω En−1 (t) − mEn−1 (t)],
⎪
⎪
⎪
⎨ T3,n (In−1 (t)) = L[In−1 (t)] − s (1 − χn )
I 0
− s+υ(1−s) θ1−υ L[(1 − δ)ωEn−1 (t) − (γ + m)In−1 (t)], (28)

⎪
⎪
s
⎪ T4,n (An−1 (t)) = L[An−1 (t)] − s (1 − χn )
⎪
A0
⎪
⎪
⎪ − s+υ(1−s)
⎪ θ1−υ L[δωp En−1 (t) − (γ + m)An−1 (t)],
⎪
⎪ s
⎪
⎪ T5,n (Rn−1 (t)) = L[Rn−1 (t)] − Rs0 (1 − χn )
⎪
⎪
⎪
⎪ − s+υ(1−s)

θ1−υ L[γIn−1 (t) + γ An−1 (t) − mRn−1 (t)],
⎪
⎪ s
⎪
⎪ T (W (t)) = L[Wn−1 (t)] − Ws0 (1 − χn ) − s+υ(1−s) θ1−υ L[μIn−1 (t)
⎪
⎩ 6,n n−1 s
+μ An−1 (t) − εWn−1 (t)],
and
0, n ≤ 1,
χn =
1, n > 1.
Applying the inverse Laplace transform to Eq. (27), we obtain
Sn (t) = χn Sn−1 (t) + hHL−1 [T1,n (Sn−1 )],
En (t) = χn En−1 (t) + hHL−1 [T2,n (En−1 )],
In (t) = χn In−1 (t) + hHL−1 [T3,n (In−1 )],
An (t) = χn An−1 (t) + hHL−1 [T4,n (An−1 )],
Rn (t) = χn Rn−1 (t) + hHL−1 [T5,n (Rn−1 )],

Wn (t) = χn Wn−1 (t) + hHL−1 [T6,n (Wn−1 )].
Solving these equations for different values of n = 1, 2, 3, ..., we derive

⎧
⎪ S1 (t) = −hH θ1−υ (1 + υ(t − 1))( − mS0 (t) − βp S0 (t)(I0 (t)
⎪
⎪
⎪
⎪ +κA0 (t)) − βw S0 (t)W0 (t)),
⎪
⎪
⎪
⎪ = −hHM1 θ1−υ (1 + υ(t − 1)),
⎪
⎪
⎪
⎪ E1 (t) = −hH θ1−υ (1 + υ(t − 1))(βp S0 (t)(I0 (t)
⎪
⎪
⎪
⎪ +κA0 (t)) + βw S0 (t)W0 (t) − (1 − δ)ωE0 (t),
⎪
⎪
⎪
⎪ −δω

E0 (t) − mE0 (t)) = −hHM2 θ1−υ (1 + υ(t − 1)),
⎪
⎨ I (t) = −hH θ1−υ (1 + υ(t − 1))((1 − δ)ωE (t)
1 0
⎪
⎪ −(γ + m)I 0 (t)) = −hHM 3 θ 1−υ
(1 + υ(t − 1)),
⎪
⎪ A1 (t) = −hH θ1−υ (1 + υ(t − 1))(δωp E0 (t)

⎪
⎪
⎪
⎪
⎪
⎪ −(γ + m)A0 (t)) = −hHM4 θ1−υ (1 + υ(t − 1)),
⎪
⎪
⎪
⎪ R1 (t) = −hH θ1−υ (1 + υ(t − 1))(γI0 (t)
⎪
⎪
⎪
⎪ +γ A0 (t) − mR0 (t)) = −hHM5 θ1−υ (1 + υ(t − 1)),
⎪
⎪
⎪
⎪ W (t) = −hH θ1−υ (1 + υ(t − 1))(μI0 (t) + μ A0 (t)
⎩ 1
−εW0 (t)) = −hHM6 θ1−υ (1 + υ(t − 1)),
where
⎧
⎪
⎪ M1 = − mS0 (t) − βp S0 (t)(I0 (t) + κA0 (t)) − βw S0 (t)W0 (t),
⎪
⎪
⎪
⎪ M2 = βp S0 (t)(I0 (t) + κA0 (t))
⎪ +β S (t)W (t) − (1 − δ)ωE (t) − δω E (t) − mE (t),
⎪
⎨ w 0 0 0 0 0
M3 = (1 − δ)ωE0 (t) − (γ + m)I0 (t),
⎪
⎪
⎪
⎪ M4 = δωp E0 (t) − (γ + m)A0 (t),
⎪
⎪
⎪
⎪ M = γI0 (t) + γ A0 (t) − mR0 (t),
⎩ 5
M6 = μI0 (t) + μ A0 (t) − εW0 (t).
Finally, the solutions of the system (30) are obtained as
S(t) = S0 (t) + S1 (t) + S2 (t) + ...,
E(t) = E0 (t) + E1 (t) + E2 (t) + ...,
I (t) = I0 (t) + I1 (t) + I2 (t) + ...,
A(t) = A0 (t) + A1 (t) + A2 (t) + ...,
R(t) = R0 (t) + R1 (t) + R2 (t) + ...,
W (t) = W0 (t) + W1 (t) + W2 (t) + ....

4.5 Numerical Results
In this section, we present a numerical simulation for the transmission model of

the COVID-19 (11) by using the homotopy analysis transform method(HATM). To
this end, we assume that the total population be N = 100 and since the birth rate
for China in 2020 is about 11.46 births per 1000 people, then = n × N = 1.146.
According to news released by the World Health Organization, the death rate is 3.4
% and the incubation period of COVID-19 is 14 days.
Because the information is changing and due to the lack of complete information
on many parameters related to the transmission of this virus, we had to consider
some of the coefficients hypothetically. In this simulation, according to the news we
have chosen the parameters as βp = 0.0025, βw = 0.001, κ = 0.05, δ = 0.25, ω =

0.071, ω = 0.1, γ = 0.047, γ = 0.1, μ = 0.003, μ = 0.001, ε = 0.033, and initial
values are S0 = 35, I0 = 25, R0 = 0, E0 = 25, A0 = 10, W0 = 5.
In Figs. 9, 10 and 11, we show the three te]rms solution of homotopy analysis
transform method (HATM) with the auxiliary parameter h = −1 and the auxiliary
function H = 1 corresponding to proposed model (11) for different values of υ and
modification parameter θ = 0.99.
Figures 9 and 10 show that the number of susceptible and exposed people increases
first with a birth rate of 1.146 and then with the COVID-19 infection, the population of
these two groups declines, and the population of the symptomatic and asymptomatic
infected people increases.
Figure 11 shows that the population of the out-group, ie the recovered and the
dead, also increases with time. The amount of virus in the reservoir also decreases
first and then increases as people enter the reservoir from the two infected groups. We
put Caputo fractional derivative in Model (11) instead of Caputo Fabrizio fractional
Fig. 9 Plots of approximate solutions of susceptible parameter S and exposed parameter E for
different values of υ = 1, 0.9, 0.8, 0.7, 0.6, 0.5
Fig. 10 Plots of approximate solutions of asymptomatic infected parameter A and symptomatic

infected parameter I for different values of υ = 1, 0.9, 0.8, 0.7, 0.6, 0.5
Fig. 11 Plots of approximate solutions of removed parameter R and COVID-19 reservoir parameter
W for different values of υ = 1, 0.9, 0.8, 0.7, 0.6, 0.5
derivative and solved the new model similarly and obtained the results of the two
derivatives for υ = 0.96. Then in Figs. 12, 13 and 14, we compared these results
for the system (11). We observe that the difference between the results of these two
derivative increases with time.
mS mI mR
ω
βSI γI
S I R
μI
Fig. 12 Plots of the results of Caputo derivative and Caputo Fabrizio derivative for S, E with
υ = 0.96
Fig. 13 Plots of the results of Caputo derivative and Caputo Fabrizio derivative for A, I with
υ = 0.96
Fig. 14 Plots of the results of Caputo derivative and Caputo Fabrizio derivative for R, W with
υ = 0.96
5 Fractional SIRD Model
In this section, we provide a SIRD model for the transmission of COVID-19 with
the fractional Caputo derivative. In sird models, the population is usually considered
constant, but in this model, we also consider the natural birth and death rates. We
divide the population N (t) into four groups: Susceptible people S(t), Infected people
I (t), Recovered people R(t), Died people with this disease D(t) so that N (t) =
S(t) + I (t) + R(t) + D(t). The diagram of the model is as follows
To describe the mechanism of the spread of the COVID-19, we consider the
compartmental mathematical model as follows:
⎧ dS
⎪ = − βS(t)I (t) − mS(t),
⎪ dt
⎪ dI
⎨ = βS(t)I (t) − (γ + μ + m)I (t),
dt
(29)
⎪
⎪ dt = γI (t) − mR(t),
dR
⎪
⎩ dD
dt
= μI (t)
where S(0) = S0 , I (0) = I0 , R(0) = R0 , D(0) = D0 are the initial conditions and all
of them are nonnegative.
The parameters of model are: the per capita birth rate , the transmission rate β,
the recovery rate γ, the virus-induced average fatality rate μ and the per capita natural
death rate m. The fractional-order system (FDEs) is related to systems with memory,
history, or nonlocal effects which exist in the many biological systems that shows
the realistic biphasic decline behavior of infection or diseases but at a slower rate.
In the integer-order system (29), since the internal memory effects of the biological
system of the COVID-19 infection are not include, so it is better that we extend
the proposed ordinary model to a fractional model. We replace the integer-order

derivative with the Caputo derivative of fractional order υ. In this alternative, the
equality of the dimensions of both sides of the equation is disturbed, and we use an
auxiliary parameter θ, with the dimension of sec., to solve this problem. Thus the
fractional-order model for the spread of COVID-19 is given as follows
⎧ υ−1 C υ
⎪
⎪ θ D S(t) = − βS(t)I (t) − mS(t),
⎨ υ−1 C tυ
θ Dt I (t) = βS(t)I (t) − (γ + μ + m)I (t),
υ−1 C υ (30)
⎪
⎪ θ D R(t) = γI (t) − mR(t),
⎩ υ−1 C tυ
θ Dt D(t) = μI (t),
Where t ≥ 0 and 0 < υ < 1.
5.1 Feasibility Region
Suppose athat B = {(S, I , R, D) ∈ R+

4 : D ≤ S + I + R ≤ m }. At the following, we
prove that the feasibility region of the system (30) is equal to B.
Lemma 5.1 With respect to the system (30), the set B is positively invariant.
Proof To show that solutions are non-negative, we have
θυ−1 CD0υ+ S|S=0 = ≥ 0, θυ−1 CD0υ+ I |I =0 = 0,
θυ−1 CD0υ+ R|R=0 = γI ≥ 0, θυ−1 CD0υ+ D|D=0 = μI ≥ 0,
since all of above values are nonnegative, then the solutions are nonnegative. In the
following, we first add the first three equations of the system (30). So
θυ−1 CDtυ (S + R + I ) = − m(S + R + I ) − μI
≤ − m(S + I + R).
Using the Laplace transform, we obtain
(S + I + R)(t) = (S + I + R)(0)Eυ (−mθ1−υ t υ )

t
+ θ1−υ η υ−1 Eυ,υ (−mθ1−υ η υ )d η,
0
where S(0), I (0), R(0) are the initial size of Susceptible, Infected and Recovered
population, respectively. With some calculations, we get
(S + I + R)(t) = (S + I + R)(0)Eυ (−mθ1−υ t υ )

t ∞
(−1)i mi θi(1−υ) η iυ
+ θ1−υ η υ−1 dη
i=0
(iυ + υ)
0
θ1−υ 1−υ υ θ1−υ
= + Eυ (−mθ t )((S + I + R)(0) − ),
mθ1−υ mθ1−υ

= + Eυ (−mθ1−υ t υ )((S + I + R)(0) − ).
m m
thus, if (S + I + R)(0) ≤ m
, then for t > 0, (S + I + R)(t) ≤ m
.
If D(0) ∈ B, since D(t) ≤ S(t) + I (t) + R(t) ≤ m
for all t ≥ 0, then D(t) ≤
m
. Con-
sequently, with respect to the system (30), the set B is positively invariant.
5.2 Reproduction Number and Equilibrium Points
The first equilibrium point that shows the non-diseased point is the point that it which
I = 0, which is obtained by simplifying the equations of point E 0 = ( m
, 0, 0, N −

m
). To find the other equilibrium point, Since D(t) does not appear in the first three
equations of the system, we remove the fourth equation and form the following
algebraic equations.
C υ
D S(t) =C Dυ I (t) =C Dυ R(t) = 0.
We solve the above equations and obtain the equilibrium point E ∗ = (S ∗ , I ∗ , R∗ )

such that
γ+μ+m
S∗ = ,
β
β − γm − m2 − mμ
I∗ = ,
β(γ + μ + m)
γ(β − γm − m2 − mμ)
R∗ = .
β(γ + μ + m)m
To find the basic reproduction number R0 , we use the next generation method. First,
we consider the first three equations of System (30) as a compact form as follows
C υ
D ϕ = F(ϕ) − V (ϕ),
where
⎡ ⎤
−βSI
F(ϕ) = θ1−υ ⎣ βSI ⎦
0
and ⎡ ⎤
mS −
V (ϕ) = θ1−υ ⎣(m + μ + γ)I ⎦
mR − γI
The value of the Jacobin matrix of F and V at the equilibrium point E 0 is as

⎡ ⎤ ⎡ ⎤
0 −β
m
0 m 0 0
JF (E0 ) = θ1−υ ⎣0 β
m
0⎦ , Jv (E0 ) = θ
1−υ ⎣
0 m + μ + γ 0⎦
0 0 0 0 −γ m
For the system (30), the next generation matrix is FV −1 so that R0 = ρ(FV −1 ). By
performing simple algebraic calculations, the value of R0 is obtained as follows
β
R0 = .
m(m + μ + γ)
The reproduction number is epidemiologically important and indicates the ability to

transmit the infection and the continuation of the disease.
5.3 Stability of Equilibrium Point
First, we calculate the Jacobian matrix for the fractional system (30),
⎡ ⎤
−βI − m −βS 0 0
⎢ βI
1−υ ⎢ βS − (m + μ + γ) 0 0⎥
J =θ ⎥
⎣ 0 γ −m 0⎦
0 μ 0 0
The value of the matrix J at the equilibrium point E0 is as follows

⎡ ⎤
−m −β m
0 0
⎢
1−υ ⎢ 0 β m − (m + μ + γ) 0 0⎥
J =θ ⎥
⎣ 0 γ −m 0⎦
0 μ 0 0
Theorem 5.1 If R0 < 1, the equilibrium point E 0 of system (30) is marginal stable.
Proof At the point E 0 , The characteristic equation of the Jacobian matrix is det(θI −
J (E 0 )) = 0. Then we obtain

θ1−υ θ(θ + m)(θ − [β − (m + μ + γ)]) = 0,
m
By simplify the above equations, the eigenvalues of characteristic equation are
obtained as θ1 = 0, θ2 = −m and θ3 = [β
m
− (m + μ + γ)]. If R0 < 1,
β β β
<1⇒ <m+μ+γ ⇒ − (m + μ + γ) < 0.
m(m + μ + γ) m m
So θ3 < 0. Since θ1 = 0, θ2 < 0, θ3 < 0 then the system (30) is marginal stable at
E0.
5.4 Sensitivity Analysis of R0
Since all of the parameters of model (30) are positive, to investigate the sensitivity
of R0 , we have
∂R0 β
= > 0,
∂ m(m + μ + γ)
∂R0
= > 0,
∂β m(m + μ + γ)
∂R0 −β(2m + μ + γ)
= < 0,
∂m m2 (m + μ + γ)2
∂R0 −βm
= 2 < 0,
∂μ m (m + μ + γ)2
∂R0 −βm
= 2 < 0,
∂γ m (m + μ + γ)2
As you can see, R0 is most sensitive to changes in model parameters. So that R0 is

increasing with , β and is decreasing with m, μ, γ.
To prove that System (30) has a unique solution, we first consider it as follows
⎧ υ−1 C υ
⎪ θυ−1 CDtυ S(t) = N1 (t, S(t)),
⎪
⎨
θ Dt I (t) = N2 (t, I (t)),
υ−1 C υ
⎪
⎪ θ D R(t) = N3 (t, R(t)),
⎩ υ−1 C tυ
θ Dt D(t) = N4 (t, D(t)).
On both sides of above equations, we By apply integral

⎧
⎪ t
⎪
⎪
⎪
⎪ S(t) − S(0) = (υ) N1 (ξ, S)(t − ξ)υ−1 d ξ,
θ1−υ
⎪
⎪
⎪
⎪
⎪
⎪
0
⎪
⎪ t
⎪
⎪
⎪ θ1−υ υ−1
⎪ I (t) − I (0) = (υ) N2 (ξ, I )(t − ξ) d ξ,
⎪
⎨
0
t (31)
⎪
⎪
⎪
⎪
⎪
⎪ R(t) − R(0) = (υ) N3 (ξ, R)(t − ξ)υ−1 d ξ,
θ1−υ
⎪
⎪
⎪
⎪
⎪
⎪
0
⎪
⎪ t
⎪
⎪
⎪ D(t) − D(0) = (υ) N4 (ξ, D)(t − ξ)υ−1 d ξ,
θ 1−υ
⎪
⎩
0
In the next theorem, we prove the Lipschitz and contraction conditions for kernels
N1 − N4 .
Theorem 5.2 The Lipschitz condition and contraction is established for N1 if the
following relation hold
0 ≤ βk2 + m < 1.
Proof According to the value of N1 in S and S1 can be written

N1 (t, S) − N1 (t, S1 )
=
− βI (S − S1 ) − m(S − S1 )
,
≤ (β
I
+ m)
S − S1
,
≤ (βk2 + m)
S − S1
.
By considering M1 = βk2 + m, where

I (t)
≤ k2 is bounded function, we obtain

N1 (t, S) − N1 (t, S1 )
≤ M1
S(t) − S1 (t)
. (32)
Thus, for N1 the Lipschitz condition is obtained and if 0 ≤ βk2 + m < 1 then N1 is
a contraction.
As the same way, we can prove that the Ni , i = 2, 3, 4 satisfied at the Lipschitz
condition as follows
⎧
⎨
N2 (t, I ) − N2 (t, I1 )
≤ M2
I (t) − I1 (t)
,

N3 (t, R) − N3 (t, R1 )
≤ M3
R(t) − R1 (t)
,
⎩

N4 (t, D) − N4 (t, D1 )
≤ M4
D(t) − D1 (t)
,
where
S(t)
≤ k1 , and M2 = βk1 − (m + μ + γ), M3 = m, M4 = 0 are bounded.
The kernels N2 , N3 , N4 are contraction if for i = 2, 3, 4 we have 0 ≤ Mi < 1.
Suppose the following recursive forms respect to the system (30),
t
θ1−υ
1n (t) = Sn (t) − S(n−1) (t) = (N1 (ξ, S(n−1) ) − N1 (ξ, S(n−2) ))(t − ξ)υ−1 d ξ,
(υ)
0
t
θ1−υ
2n (t) = In (t) − I(n−1) (t) = (N2 (ξ, I(n−1) ) − N2 (ξ, I(n−2) ))(t − ξ)υ−1 d ξ,
(υ)
0
t
θ1−υ
3n (t) = Rn (t) − R(n−1) (t) = (N3 (ξ, R(n−1) ) − N3 (ξ, R(n−2) ))(t − ξ)υ−1 d ξ,
(υ)
0
t
θ1−υ
4n (t) = Dn (t) − D(n−1) (t) = (N4 (ξ, D(n−1) ) − N4 (ξ, D(n−2) ))(t − ξ)υ−1 d ξ,
(υ)
0
with initial conditions S(0) = S0 , I (0) = I0 , R(0) = R0 and D(0) = D0 . We take the
norm of 1n ,

1n (t)
=
Sn (t) − S(n−1) (t)
t
θ1−υ
=
(N1 (ξ, S(n−1) ) − N1 (ξ, S(n−2) ))(t − ξ)υ−1 d ξ
(υ)
0
t
θ1−υ
≤
N1 (ξ, S(n−1) ) − N1 (ξ, S(n−2) ))(t − ξ)υ−1
d ξ.
(υ)
0
By Lipschitz condition (32), we get
t
θ1−υ

1n (t)
≤ M1
1(n−1) (ξ)
d ξ. (33)
(υ)
0
Similarly, we obtain
t
θ1−υ

2n (t)
≤ M2
2(n−1) (ξ)
d ξ,
(υ)
0
t
θ1−υ

3n (t)
≤ M3
3(n−1) (ξ)
d ξ,
(υ)
0
t
θ1−υ

4n (t)
≤ M4
4(n−1) (ξ)
d ξ. (34)
(υ)
0
Then, we can obtain

n
n
n
n
Sn (t) = 1i (t), In (t) = 2i (t), Rn (t) = 3i (t), Dn (t) = 4i (t).
i=1 i=1 i=1 i=1
In the next theorem, we prove the existence of the solution for the system (30).
Theorem 5.3 The fractional-order transmission model of COVID-19 (30) has a
solution, if there exist te such that
θ1−υ
te Mi < 1
(υ)
Proof By considering the recursive technique, and Eqs. (33) and (34) we have
θ1−υ

1n (t)
≤
Sn (0)
[ M1 t]n ,
(υ)
θ1−υ

2n (t)
≤
In (0)
[ M2 t]n ,
(υ)
θ1−υ

3n (t)
≤
Rn (0)
[ M3 t]n ,
(υ)
θ1−υ

4n (t)
≤
Dn (0)
[ M4 t]n ,
(υ)
This shows that the system has a continuous solution. We claim that a solution of
system (30) is constructed by the above functions, for this purpose consider
S(t) − S(0) = Sn (t) − B1n (t),
I (t) − I (0) = In (t) − B2n (t),

R(t) − R(0) = Rn (t) − B3n (t),
D(t) − D(0) = Dn (t) − B4n (t),
So
t
θ1−υ

B1n (t)
=
(N1 (ξ, S) − N1 (ξ, S(n−1) ))d ξ
(υ)
0
t
θ1−υ
≤
N1 (ξ, S) − N1 (ξ, S(n−1) )
d ξ
(υ)
0
θ1−υ
≤ M1
S − S(n−1)
t.
(υ)
We repeat the method, then
θ1−υ n+1 n+1

B1n (t)
≤ [ t] M1 h.
(υ)
At te , we get
θ1−υ n+1 n+1

B1n (t)
≤ [ te ] M1 h.
(υ)
Then limn→∞
B1n (t)
→ 0. Similarly, we can show that
Bjn (t)
→ 0, j = 2, 3, 4.
Thus, the proof complete.
To prove the uniqueness of solution for system (30), we suppose that there exists
another solutions for system such as S1 (t) , I1 (t), R1 (t) and D1 (t). We can write
t
θ1−υ
S(t) − S1 (t) = (N1 (ξ, S) − N1 (ξ, S1 ))d ξ.
(υ)
0
By taking the norm from the latest equation, we get
t
θ1−υ

S(t) − S1 (t)
=
N1 (ξ, S) − N1 (ξ, S1 )
d ξ.
(υ)
0
By the Lipschitz condition (32), we obtain
θ1−υ

S(t) − S1 (t)
≤ M1 t
S(t) − S1 (t)
.
(υ)
Then
θ1−υ

S(t) − S1 (t)
(1 − M1 t) ≤ 0. (35)
(υ)
Theorem 5.4 If the following inequality hold then the solution of spread model of
COVID-19 is unique,
θ1−υ
1− M1 t > 0.
(υ)
Proof From the above condition, we obtain
θ1−υ

S(t) − S1 (t)
(1 − M1 t) > 0.
(υ)
With this inequality and (35), we conclude that . So, we obtain S(t) = S1 (t). Similarly
can be proved I (t) = I1 (t), R(t) = R1 (t), D(t) = D1 (t).
5.6 Optimal Control
There is currently no vaccine to control COVID-19 disease, so the spread of the

disease should be controlled by following health instructions and creating social
distance. Meanwhile, creating social distance plays an important role in controlling
the spread of COVID-19 disease. We denote the social distance by 1 − u where
u represents the social gathering so that if it is a social distance then it is u = 0
and if it is not a social distance it will be u = 1. Our goal is to reduce the number
of people infected with COVID-19 by creating social distance while reducing the
costs of implementing this control strategy. For this end, we consider the following
fractional control system
⎧C υ
⎪
⎪ D S(t) = θ1−υ [ − βu(t)S(t)I (t) − mS(t)],
⎪ C tυ
⎪
⎨ Dt I (t) = θ1−υ [βu(t)S(t)I (t) − (γ + μ + m)I (t)],
C υ
Dt R(t) = θ1−υ [γI (t) − mR(t)], (36)
⎪
⎪ C υ
⎪
⎪ D D(t) = θ 1−υ
[μI (t)],
⎩ t
S(0), I (0), R(0), D(0) ≥ 0.
If we remove the social distance, then it becomes u = 1 and the control system (36)
is reduced to the SIRD model (30). In the fractional-order system the optimal control
theory is based on Pontryagin maximum principle [13]. Our main aim is to reduce
the number of Infected people with social distance and also to reduce the costs of
doing so. We consider the cost functional for the dynamic constraints (36) as follows
tf
b2 n
J (u) = [b1 I (t) + u (t)] dt, n ∈ N − 1, (37)
n
0
where 0 < b1 , b2 < ∞ are weighting coefficients corresponding to the number of

infected people and the cost of implementing the strategy of control respectively and
0 ≤ u(t) ≤ 1 being the control space in [0, tf ]. We minimize the cost function J (u)
by finding optimal control u∗ where J (u∗ ) = min J (u(t)).
Theorem 5.5 Let the control function u(t) ∈ [0, 1] be measurable in [0, tf ]. Then
an optimal control
(λ1 − λ2 )βS(t)I (t)θ1−υ 1

u∗ = max{min{| | n−1 , 1}, 0},
b2
minimizing the function J (u) subject to system (36).
Proof We consider the Hamiltonian function as follows
b2 n
H = [b1 I (t) + u (t)]
n
+ λ1 (t)θ1−υ { − βu(t)S(t)I (t) − mS(t)},
+ λ2 (t)θ1−υ {βu(t)S(t)I (t) − (γ + μ + m)I (t)},
+ λ3 (t)θ1−υ {γI (t) − mR(t)},
+ λ4 (t)θ1−υ {μI (t)},
where λi (t), i = 1, 2, 3, 4 are the co-state variables with λi (tf ) = 0, and they satisfy
⎧C υ ∂H
⎪ t Dtf λ1 (t) = − ∂S = θ λ1 (t)(βu(t)I (t) + m) + θ1−υ λ2 (t)βu(t)I (t),
1−υ
⎪
⎪
⎪ CDυ λ (t) = − ∂H = θ1−υ βλ (t)u(t)S(t) + θ1−υ λ (t)(γ + μ + m − βu(t)S(t))
⎪
⎨ t tf 2 ∂I 1 2
−λ3 (t)θ1−υ γ − λ4 θ1−υ μ − b1 ,
⎪
⎪ C υ ∂H
⎪ t Dtf λ3 (t) = − ∂R = mλ3 (t)θ ,
1−υ
⎪
⎪
⎩ CDυ λ (t) = − ∂H = 0.
t tf 4 ∂D
(38)
which is a fractional system of right Caputo derivatives CtDtυf . Thus to find u∗ , it
suffices to minimize the Hamiltonian function relative to the control. By Pontryagin
principle, we obtain the following optimal condition
∂H (λ1 (t) − λ2 (t))βθ1−υ S(t)I (t) 1

=0 ⇒ u=| | n−1 .
∂u b2
Then, according to the sign of ∂H ∂u

, we consider the optimal control as follows
∂H ∗
If ∂u < 0 then u = 0,
If ∂H = 0 then u∗ = | (λ1 (t)−λ2 (t))βθ S(t)I (t) n−1
1−υ 1
∂u b2
| ,
If ∂H
∂u
> 0 then u∗ = 1,
therefore, by solving the boundary value problem (36) and (38), the optimal control
is calculated.
To obtain the approximate solutions for the COVID-19 transmission model (30), we
use the fractional Euler method for Caputo derivative [12]. We consider the system
(30) in the compact form as follows
θυ−1 CDtυ y(t) = p(t, y(t)), y(0) = y0 , 0 ≤ t ≤ T < ∞, (39)
where y = (S, I , R, D) ∈ R4+ ,y0 = (S0 , I0 , R0 , D0 ) is the initial vector and p(t) ∈ R
is a continuous vector function satisfying Lipschitz condition

p(y1 (t)) − p(y2 (t))
≤ b
y1 (t) − y2 (t)
, b > 0.
We apply the fractional integral operator corresponding Caputo derivative to equation

(39),
y(t) = θ1−υ [y0 + I υ p(y(t))], 0 ≤ t ≤ T < ∞.
Set q = TN−0 and tn = nq, where t ∈ [0, T ] and N is a natural number and n =
0, 1, 2, ..., N . Let yn be the approximation of y(t) at t = tn . By the fractional Euler
method [12], we obtain
qυ n
yn+1 = θ1−υ [y0 + zn+1,j p(tj , yj )], j = 0, 1, 2, ..., N − 1, (40)
(υ + 1) j=0
where
zn+1,j = (n + 1 − j)υ − (n − j)υ , j = 0, 1, 2, ..., n.
For the system (30), we obtain the solution as follows
qυ n
S(n+1) = θ1−υ [S0 + zn+1,j g1 (tj , yj )],
(υ + 1) j=0
qυ n
I(n+1) = θ1−υ [I0 + zn+1,j g2 (tj , yj )],
(υ + 1) j=0
qυ n
R(n+1) = θ1−υ [R0 + zn+1,j g3 (tj , yj )],
(υ + 1) j=0
qυ n
D(n+1) = θ1−υ [D0 + zn+1,j g4 (tj , yj )],
(υ + 1) j=0
where zn+1,j = (n + 1 − j)υ − (n − j)υ , g1 (t, y(t)) = − βS(t)I (t) − mS(t), g2 (t,
y(t)) = βS(t)I (t) − (m + μ + γ)I (t), g3 (t, y(t)) = γI (t) − mR(t), g4 (t, y(t)) =
μI (t).
5.8 Simulation
Case I: Iran
Iran is the first country to experience a second peak among the countries with the
COVID-19 epidemic. For simulate the first and second wave of COVID-19 disease
in Iran, we use the reported data for infected cases at the Worldometer website. The
model (30) describe an endemic model (with vital dynamics) so that births add at
rate into the class S and deaths reduce the classes at rate m. Life expectancy in Iran
is almost 73 years, so m−1 = 73 years and = mN (balance of births and natural
deaths). Also, the other parameter is the average infectious periods γ −1 = 8 days and
the mortality rate with this disease is μ = 0.014 with the initial conditions for the
first peak at 22th February are S(0) = 83000000, I (0) = 34, R(0) = 6, D(0) = 2.
According to the reported cases by WHO for Infected people at the first peak of
COVID-19 in Iran, we use the fmincon software package and technique of mini-
mization and obtain β = 2.1 × 10−9 .
In Fig. 15, we have plotted the results of the fractional model and the integer model
along with the reported data. As can be seen, the COVID-19 transmission model with
a fractional derivative of order υ = 0.98 follows the real data better than the model
with the integer derivative of order υ = 1. With the outbreak of COVID-19 in Iran,
the government enforced quarantine rules until April 18, and as shown in Fig. 15,
the number of infected people has declined rapidly, and with the continuation of this
practice, the disease could be controlled in 100 days, but unfortunately, on April 18
the quarantine rules were lifted, and with the reopening of jobs, the second-wave of
COVID-19 began two weeks later, on 2th May. In the second wave, which starts on
May 5, according to the published information, the mortality rate is about μ = 0.034,
and with the fitting technique, the amount of β = 9.8 × 10−9 is obtained. Figure 16
shows the results of Model (30) with the derivative of fractional-order υ = 0.98 and
4
4 x 10
Fractional order
3.5
Integer order
Infected people − First peak
3 Real data
2.5
1.5
0.5
0
0 20 40 60 80 100 120
t(days)
Fig. 15 Plots of results of fractional-order (υ = 0.98) and integer-order (υ = 1) model of COVID-

19 for Infected people (I (t)),with the Infected people in Iran for the first wave (22Feb–18Apr)
4
3.5 x 10
Fractional order
Infected people I(t) − Second peak
3 Integer order
Real data
2.5
1.5
0.5
0
0 20 40 60 80 100 120
t(days)

19 for infected people (I (t)),with the infected people in Iran for the second wave (5th May to the
end of the wave)
the derivative of integer-order υ = 1, along with the reported cases for the number
of Infected people with COVID-19 from the 5th May, and again the model with the
fractional-order derivative follows the real data well. Figures 17 and 18 show the
forecasting for the spread of COVID-19 in Iran according to the second wave of
the disease, and as can be seen, it takes about eight months to complete the second
wave, and unfortunately, about 70,000 people die from this disease. Also, to check the
derivation order effect on the results obtained from Model (30), the results are plotted
for orders υ = 0.98, 0.96, 0.94, 0.92, 0.9, and the plots show that the derivation order
7 4
9 x 10 3.5 x 10
υ=0.98 υ=0.98
8 υ=0.96 υ=0.96
3
υ=0.94 υ=0.94
7 υ=0.92 υ=0.92
Susceptible people − S(t)
Infected people − I(t)

υ=0.9 2.5 υ=0.9
6
5 2
4 1.5
3
1
2
0.5
1
0 0
0 50 100 150 200 250 300 350 400 450 500 0 50 100 150 200 250 300 350 400 450 500
t(days from 5 May) t(days from 5 May)
Fig. 17 Prediction of susceptible group and infected group in Iran for υ=

0.98, 0.96, 0.94, 0.92, 0.9
5 4
3.6 x 10 8 x 10
7.5
3.4
7
Recovered people − R(t)
Died people − D(t)
6.5
3.2
6
3 5.5
5
2.8
υ=0.98 4.5 υ=0.98
υ=0.96 υ=0.96
4
2.6 υ=0.94 υ=0.94
υ=0.92 3.5 υ=0.92
υ=0.9 υ=0.9
2.4 3
0 50 100 150 200 250 300 350 400 450 500 0 50 100 150 200 250 300 350 400 450 500
t(days from 5 May) t(days from 5 May)
Fig. 18 Prediction of recovered people and died people in Iran for υ = 0.98, 0.96, 0.94, 0.92, 0.9
has no effect on the behavior of functions but the resulting values are different And
over time, that difference will increase.
Case II: Japan
We consider COVID-19 transmission second wave in Japan from June 30, and accord-
ing to the available data, the mortality rate of COVID-19 transmission second wave
in Japan is very low and is about μ = 0.007. Life expectancy in Japan is almost
85 years, so m−1 = 85 years. Also, the other parameter is the average infectious
periods γ −1 = 8 days and with the initial conditions S(0) = 19, 211, 669, I (0) =
7287, R(0) = 20, 534, D(0) = 1799 and consider θ = 0.99. According to the
reported cases by WHO for Infected people in Japan at the second peak of COVID-
14000
Integer order ,υ=1
12000
Fractional order, υ=0.975
10000 Real data
8000
6000
4000
2000
0
0 20 40 60 80 100 120 140 160 180
t(days)
Fig. 19 Prediction of infected people I (t) in Japan at the second wave from 30th June by fractional
model (υ = 0.975) and integer model (υ = 1) of COVID-19
19, we use the fmincon software package and technique of minimization and obtain
β = 1.6 × 10−9 .
In Fig. 19, we have plotted the results of the model (30) for the fractional and
the integer derivative along with reported cases from 30th June to 20th July. Also
this figure shows the forecast of COVID-19 transmission second wave in Japan,
which will take about 5 months for this wave to subside. Figures 20 and 21 show the
results of Model (30) for Japan, and it seems that the treatment process in Japan is
progressing well, and eventually by the end of the second wave, the number of deaths
will reach about 1150 people. Also in Figs. 20 and 21, where the results are plotted
for different degrees of the fractional derivative, you can see that small changes in
the derivative order make a big difference in the resulting values, while the function
behavior is the same.
Case III: Romania
To examine the second wave of COVID-19 in Romania, we consider the cases
reported from July 7 to July 20. Life expectancy in Romania is almost 76 years,
so m−1 = 76 years. Also the mortality rate with COVID-19 in Romania is about
κ = 0.05. We consider the average infectious periods is λ−1 = 8 days and S(0) =
126458437, I (0) = 798, R(0) = 16263, D(0) = 963 are initial conditions. Simi-
larly using the previous method, we obtain μ = 7.2 × 10−9 .
Figure 22 shows the prediction of COVID-19 transmission second wave using
the SIRD model with fractional-order υ = 0.965 and integer-order υ = 1. As we
expected, the fractional-order model follows the real data well. The rate of COVID-
19 transmission in Romania is higher than in Japan, and as a result, the second wave
lasts longer than Japan and lasts about 6 months. More importantly, at the peak of
the second wave, we will have about 13,000 infected in Japan, while in Romania this
number will be around 34,000. The results of the fractional-order model (30) for the
7
x 10
14 14000
υ=0.98 υ=0.98
υ=0.96 υ=0.96
12 υ=0.94 12000 υ=0.94
υ=0.92 υ=0.92
10 υ=0.9 10000 υ=0.9

8 8000
6 6000
4 4000
2 2000
0 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
t(days) t(days)
Fig. 20 Plots of susceptible people and Infected people for the COVID-19 model in Japan for
υ = 0.98, 0.96, 0.94, 0.92, 0.9
4
14 x 10 1160
υ=0.98 υ=0.98
υ=0.96 1140 υ=0.96
12 υ=0.94 υ=0.94
υ=0.92 1120 υ=0.92
υ=0.9 υ=0.9
10 1100
1080
8
1060
6
1040
4 1020
1000
2
980
0 960
0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180
t(days) t(days)
Fig. 21 Plots of recovered people and died people for the COVID-19 model in Japan for υ =
0.98, 0.96, 0.94, 0.92, 0.9
transmission of COVID-19 in Romania are shown in Figs. 23 and 24, which due to
the high mortality rate in Romania at the end of this wave the number of deaths will
be about 7000 people. To show the effect of derivation order on results, the model
results are shown for different fractional orders in these figures.
Case III: Saudi Arabia
In Saudi Arabia, shortly after the first wave, COVID-19 transmission second wave
began, which in this simulation we take into account the cases reported from
4
3.5 x 10
Integer order, υ=1
3
Real data
2.5
1.5
0.5
0
0 20 40 60 80 100 120 140 160 180 200
t(days)
Fig. 22 Plots of results of fractional model (υ = 0.98) and integer-order (υ = 1) model of COVID-
19 for infected people I (t), with the infected people in Romania for second wave of COVID-19
(from 7 July)
2 x 10
7 x 104
3.5
υ=0.98 υ=0.98
υ=0.96 υ=0.96
1.8
υ=0.94 3 υ=0.94
υ=0.92 υ=0.92
1.6 υ=0.9 υ=0.9

2.5
1.4
1.2 2
1 1.5
0.8
1
0.6
0.5
0.4
0.2 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
t(days) t(days)
Fig. 23 Plots of S(t) and I(t) for the COVID-19 model in Romania for υ =
0.98, 0.96, 0.94, 0.92, 0.9
June 3 to July 20. Since the life expectancy in Saudi Arabia is almost 75 years,
then m−1 = 76 years. Also the mortality rate with COVID-19 in Romania is
about κ = 0.014. We consider the average infectious periods is λ−1 = 8 days and
S(0) = 34722689, I (0) = 22444, R(0) = 68159, D(0) = 579 are the initial con-
ditions. Similarly using the previous method, we obtain μ = 3.4 × 10−9 .
5
2.5 x 10 8000
υ=0.98 υ=0.98
υ=0.96 υ=0.96
υ=0.94 7000 υ=0.94
2 υ=0.92 υ=0.92
υ=0.9 υ=0.9
6000

1.5
5000
4000
1
3000
0.5
2000
0 1000
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
t(days) t(days)
Fig. 24 Plots of R(t) and D(t) for the COVID-19 model in Romania forυ =
0.98, 0.96, 0.94, 0.92, 0.9
4
7 x 10
6 Integer order, υ=1
Real data
5
0
0 20 40 60 80 100 120 140 160 180 200
t(days)

19 for infected people I (t), with the infected cases of COVID-19 transmission second wave in Saudi
Arabia (from 3 June)
The forecast of COVID-19 transmission second wave in Saudi Arabia using the
fractional and integer order model and the reported cases of infected people is shown
in Fig. 25. As you can see, the second wave of the disease will last about 5.5 months
and the number of active cases will almost triple and then the new wave will have
a downward trend. The second wave in Saudi Arabia rises and decrease faster than
Japan and Romania, while Japan and Romania experience a peak after two months.
In Saudi Arabia, they cross the peak of second-wave after two months. In Figs. 26 and
6 4
3.5 x 10 7 x 10
υ=0.98 υ=0.98
υ=0.96 υ=0.96
3 υ=0.94 6 υ=0.94
υ=0.92 υ=0.92
υ=0.9

2.5 5 υ=0.9
2 4
1.5 3
1 2
0.5 1
0 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
t(days) t(days)
Fig. 26 Plots of susceptible people and infected people for the COVID-19 model in Saudi Arabia
for υ = 0.98, 0.96, 0.94, 0.92, 0.9
5
4 x 10 3500
3.5
3000
3
2500
2.5
2000
2
1500
1.5 υ=0.98 υ=0.98
υ=0.96 υ=0.96
1 υ=0.94 1000 υ=0.94
υ=0.92 υ=0.92
υ=0.9 υ=0.9
0.5 500
0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180
t(days) t(days)
Fig. 27 Plots of recovered people and died people for the COVID-19 model in Saudi Arabia for
υ = 0.98, 0.96, 0.94, 0.92, 0.9
27, the results of Model (30) are plotted for different fractional orders, which, similar
to the previous cases, show the effect of the order of derivation on the resulting values.
Also, by the end of the wave, the number of deaths with COVID-19 is expected to
be between 3,000 and 3,500.
6 Conclusion
At first, the SEIR model for the transmission of COVID-19 using the Caputo frac-
tional derivative has been presented. The feasibility region of the system and equi-
librium points have been calculated, and the stability of the equilibrium points has
been investigated. Using the fractional Euler method, an approximate answer to the
model has been calculated. To predict the transmission of COVID-19 in the world
and in Iran, the numerical simulations based on real data have been provided. The
results show that the number of infected people and the number of recovered people is
increasing and they are approaching the equilibrium point of the system. Also in the
numerical simulation, we have examined the advantage of using the fractional-order
derivative instead of the integer-order, and in Table 1 and Fig. 3, we have compared
the results of the model with the fractional- and integer-order derivative and the
real data. The results show that the fractional-order model has a better result in this
modeling.
In the following, we investigate a SEIARW model of the COVID-19 transmission
in different groups of people using the Caputo-Fabrizio fractional derivative. Using
the fixed point theorem, we prove a unique solution for the system. The resulting
differential system is solved using the homotopy analysis transform method (HATM),
and we obtain approximate solutions in convergent series. With the numerical results,
we present a simulation for COVID-19, which shows the rapid transmission of the
virus to different groups of people.
A fractional SIRD model with Caputo fractional-order derivative is presented to
investigate the release of COVID-19. The basic reproduction number and feasibility
region of the system have determined. With the continued spread of COVID-19,
a second wave of the disease has occurred in some countries. The second wave
of COVID-19 transmission in Iran, Japan, Romania and Saudi Arabia has been
simulated using this model. Different results have been obtained due to the fact that
different countries have made different management decisions to control the outbreak
of COVID-19. In Iran, Romania and Saudi Arabia, the death rate from COVID-19
is much higher than in Japan. Also, the number of infected people compared to the
population of countries in Japan is much less than the other three countries, which
indicates the country’s greater ability to manage the disease.
Topics we do not usually consider in our mathematical research are disinfectants
and surfaces. Disinfectants and antiseptics are extensively applies to purify surfaces
and spaces. If the disinfectant completely kills and removes microbical infecting
agents, we can consider that an area or a device is sterilized and purified. The ability of
a disinfectant to deactivate micro-organisms like bacteria, fungi and viruses depends
on the mode of action of the chemical, the molecular structure of the pathogen’s sur-
face, and the intracellular vulnerability. Recently, colloidal Zn-Ag-O nanopartiles
be considered as the base of synthesized disinfectant. High surface/volume ratio of
nanomaterial acts effective on performance of disinfectant so that with small amount
material we get high ability. Surface engineering of nanomaterials is playing impor-
tant role to increase effectiveness of disinfectant. A composition containing zinc-
silver oxide colloid modified by ascorbic acid is shown to have the effectiveness of
99.999997 % on HSV1and H1N1 viruses and E. coli, Staphylococcus aureus, Pseu-
domonas aeruginosa, Enterococcus hirae, MRSA bacteria and Candida albicans,
Aspergillus niger fungi in 30 s. After the advent of the Corona virus, many countries
tried to produce drugs and vaccines for Corona. One of the effective methods was the
use of nanomaterials. For example, the Aspe company was able to produce the Navier
nanodrug, which was highly effective in the treatment of the COVID-19 disease.
References
1. Ucar, E., Ozdemir, N., Altun, E.: Fractional order model of immune cells influenced by cancer
cells. Math. Model. Nat. Phenom. 14(3), 308–320 (2019)
2. Koca, I.: Analysis of rubella disease model with non-local and non-singular fractional deriva-
tives. Int. J. Optim. Control Theor. Appl., 8(1), 17–25 (2018)
3. Rezapour, Sh, Mohammadi, H.: A study on the AH1N1/09 influenza transmission model with
the fractional Caputo-Fabrizio derivative. Adv. Differ. Eq. 2020, 488 (2020). https://doi.org/
10.1186/s13662-020-02945-x
4. Chen, T., Rui, J., Wang, Q., Zhao, Z., Cui, J.A., Yin, L.: A mathematical model for simulating
the transmission of Wuhan novel Coronavirus. Infect Dis Poverty 9, 24 (2020)
5. Coopera, I., Mondalb, A., Antonopoulos, C.G.: A SIR model assumption for the spread of
COVID-19 in different communiti. Chaos. Solitons Fractals 2020 (2020)
6. Tuan, N.H., Mohammadi, H., Rezapour, S.h.: A mathematical model for COVID-19 transmis-
sion by using the Caputo fractional derivative. Chaos. Solitons and Fractals 140 (2020). https://
doi.org/10.1016/j.chaos.2020.110107
7. Rezapour, S.h., Mohammadi, H., Samei, M.E.: SEIR epidemic model for COVID-19 transmis-
sion by Caputo derivative of fractional order. Adv. Differ. Eq. article no:490 (2020). https://
doi.org/10.1186/s13662-020-02952-y
8. Samko, S.G., Kilbas, A.A., Marichev, O.I.: Fractional Integrals and Derivatives: Theory and
Applications. CRC Press, Florida (1993)
9. Baleanu, D., Mohammadi, H., Rezapour, Sh: A fractional differential equation model for the
COVID-19 transmission by using the Caputo-Fabrizio derivative. Adv. Differ. Equ. 2020, 299
(2020). https://doi.org/10.1186/s13662-020-02762-2
10. Losada, J., Nieto, J.J.: Properties of the new fractional derivative without singular kernel. Progr.
Fract. Differe. Appl. 1(2), 87–92 (2015)
11. Diethelm, K.A.: The Analysis of Fractional Differential Equations. Springer, Berlin (2010)
12. Li, C., Zeng, F.: The finite difference methods for fractional ordinary differential equations.
Numer. Funct. Anal. Optim. 34(2), 149–179 (2013)
13. Kamocki, R.: Pontryagin maximum principle for fractional ordinary optimal control problems.
Math. Methods Appl. Sci. 37(11), 1668–1686 (2014)
Nowcasting of COVID-19 Confirmed
Cases: Foundations, Trends,
and Challenges
Tanujit Chakraborty, Indrajit Ghosh, Tirna Mahajan, and Tejasvi Arora
Abstract The coronavirus disease 2019 (COVID-19) has become a public health
emergency of international concern affecting more than 200 countries and territories
worldwide. As of September 30, 2020, it has caused a pandemic outbreak with more
than 33 million confirmed infections, and more than 1 million reported deaths world-
wide. Several statistical, machine learning, and hybrid models have previously been
applied to forecast COVID-19 confirmed cases for profoundly affected countries.
Future predictions of daily COVID-19 cases are useful for the effective allocation
of healthcare resources and will act as an early-warning system for government
policymakers. However, due to the presence of extreme uncertainty in these time
series datasets, forecasting of COVID-19 confirmed cases has become a very chal-
lenging job. For univariate time series forecasting, there are various statistical and
machine learning models available in the literature. Still, nowcasting and forecast-
ing of COVID-19 cases are difficult due to insufficient input data, flaw in modeling
assumptions, lack of epidemiological features, inadequate past evidence on effects
of available interventions, and lack of transparency. This chapter focuses on assess-
ing different short-term forecasting models that are popularly used to forecast the
daily COVID-19 cases for various countries. This chapter provides strong empiri-
cal evidence that there is no universal method available that can accurately forecast
pandemic data.
Keywords Coronavirus disease · Statistical models · Machine learning models ·

Hybrid models · Forecasting
1 Introduction
In December 2019, clusters of pneumonia cases caused by the novel Coronavirus

(COVID-19) were identified at the Wuhan, Hubei province in China [44, 54] after
almost a hundred years of the 1918 Spanish flu [114]. Soon after the emergence of
T. Chakraborty · I. Ghosh (B) · T. Mahajan · T. Arora

Indian Statistical Institute, 203, B.T. Road, Kolkata 700108, West Bengal, India
1024 T. Chakraborty et al.
the novel beta coronavirus, World Health Organization (WHO) characterized this
contagious disease as a “global pandemic” due to its rapid spread worldwide [95].
Many scientists have attempted to make forecasts about its impact. However, despite
involving many excellent modelers, best intentions, and highly sophisticated tools,
forecasting COVID-19 pandemics is harder [60], and this is primarily due to the
following major factors: (a) Very less amount of data is available; (b) Less under-
standing of the factors that contribute to it; (c) Model accuracy is constrained by our
knowledge of the virus, however. With an emerging disease such as COVID-19, many
transmission-related biologic features are hard to measure and remain unknown; (d)
The most obvious source of uncertainty affecting all models is that we don’t know
how many people are or have been infected; (e) Ongoing issues with virologic test-
ing mean that we are certainly missing a substantial number of cases, so models
fitted to confirmed cases are likely to be highly uncertain [51]; (f) The problem of
using confirmed cases to fit models is further complicated because the fraction of
confirmed cases is spatially heterogeneous and time-varying [119]; and (g) Finally,
many parameters associated with COVID-19 transmission are poorly understood.
Amid enormous uncertainty about the future of the COVID-19 pandemic, sta-
tistical, machine learning, and epidemiological models are critical forecasting tools
for policymakers, clinicians, and public health practitioners [20, 31, 69, 72, 122,
126]. COVID-19 modeling studies generally follow one of two general approaches
that we will refer to as forecasting models and mechanistic models. Although there
are hybrid approaches, these two model types tend to address different questions on
different time scales, and they deal differently with uncertainty [38]. Compartmen-
tal epidemiological models have been developed over nearly a century and are well
tested on data from past epidemics. These models are based on modeling the actual
infection process and are useful for predicting long-term trajectories of the epidemic
curves [38]. Short-term Forecasting models are often statistical, fitting a line or curve
to data and extrapolating from there—like seeing a pattern in a sequence of numbers
and guessing the next number, without incorporating the process that produces the
pattern [20–22]. Well constructed statistical frameworks can be used for short-term
forecasts, using machine learning or regression. In statistical models, the uncertainty
of the prediction is generally presented as statistically computed prediction intervals
around an estimate [47, 61]. Given that what happens a month from now will depend
on what happens in the interim, the estimated uncertainty should increase as you look
further into the future. These models yield quantitative projections that policymakers
may need to allocate resources or plan interventions in the short-term.
Forecasting time series datasets have been a traditional research topic for decades,
and various models have been developed to improve forecasting accuracy [7, 23, 45].
There are numerous methods available to forecast time series, including traditional
statistical models and machine learning algorithms, providing many options for mod-
elers working on epidemiological forecasting [17, 19–21, 38, 76, 93]. Many research
efforts have focused on developing a universal forecasting model but failed, which
is also evident from the “No Free Lunch Theorem” [121]. This chapter focuses on
assessing popularly used short-term forecasting (nowcasting) models for COVID-19
from an empirical perspective. The findings of this chapter will fill the gap in the
Nowcasting of COVID-19 Confirmed Cases … 1025
literature of the nowcasting of COVID-19 by comparing various forecasting meth-

ods, understanding global characteristics of pandemic data, and discovering real
challenges for pandemic forecasters.
This chapter is organized as follows: in Sect. 2, we present a collection of recent
findings on COVID-19 forecasting. Some global characteristics of time series data are
outlined in Sect. 3. Several nowcasting models from statistical, machine learning and
hybrid algorithms are described in Sect. 4. Section 5 reports the experimental results
for the United States of America (USA), India, Brazil, Russia, and Peru data sets.
In Sect. 6, the experimental findings are briefly discussed. Finally, in Sect. 7, some
recommendations for policy-making decisions and limitations of these forecasting
tools have been presented.
2 Related Works
Researchers face unprecedented challenges during this global pandemic to fore-

cast future real-time cases with traditional mathematical, statistical, forecasting, and
machine learning tools [31, 69, 72, 122, 126]. Studies in March with simple yet
powerful forecasting methods like the exponential smoothing model predicted cases
ten days ahead that, despite the positive bias, had reasonable forecast error [87]. Early
linear and exponential model forecasts for better preparation regarding hospital beds,
ICU admission estimation, resource allocation, emergency funding, and proposing
strong containment measures were conducted [42] that projected about 869 ICU and
14542 ICU admissions in Italy for March 20, 2020. Health-care workers had to go
through immense mental stress left with a formidable choice of prioritizing young
and healthy adults over the elderly for allocation of life support, mostly unwanted
ignoring of those who are extremely unlikely to survive [30, 96]. Real estimates of
mortality with 14-days delay demonstrated underestimating of the COVID-19 out-
break and indicated a grave future with a global case fatality rate (CFR) of 5.7% in
March [10]. The contact tracing, quarantine, and isolation efforts have a differential
effect on the mortality due to COVID-19 among countries. Even though it seems
that the CFR of COVID-19 is less compared to other deadly epidemics, there are
concerns about it being eventually returning as the seasonal flu, causing a second
wave or future pandemic [85, 91].
Mechanistic models, like the Susceptible–Exposed–Infectious–Recovered (SEIR)
frameworks, try to mimic the way COVID-19 spreads and are used to forecast or
simulate future transmission scenarios under various assumptions about parameters
governing the transmission, disease, and immunity [5, 25, 48, 52, 73]. Mechanis-
tic modeling is one of the only ways to explore possible long-term epidemiologic
outcomes [4]. For example, the model from [35] that has been used to guide policy
responses in the United States and Britain examines how many COVID-19 deaths
may occur over the next two years under various social distancing measures. Kissler
et al. [66] ask whether we can expect seasonal, recurrent epidemics if immunity
against novel coronavirus functions similarly to immunity against the milder coron-
aviruses that we transmit seasonally. In a detailed mechanistic model of Boston-area

transmission, [1] simulate various lockdown “exit strategies”. These models are a
way to formalize what we know about viral transmission and explore possible futures
of a system that involves nonlinear interactions, which is almost impossible to do
using intuition alone [50, 81]. Although these epidemiological models are useful
for estimating the dynamics of transmission, targeting resources, and evaluating the
impact of intervention strategies, the models require parameters and depend on many
assumptions.
Several statistical and machine learning methods for real-time forecasting of the
new and cumulative confirmed cases of COVID-19 are developed to overcome limita-
tions of the epidemiological model approaches and assist public health planning and
policy-making [3, 20, 22, 38, 87]. Real-time forecasting with foretelling predictions
is required to reach a statistically validated conjecture in this current health crisis.
Some of the leading-edge research concerning real-time projections of COVID-19
confirmed cases, recovered cases, and mortality using statistical, machine learning,
and mathematical time series modeling are given in Table 1.
Table 1 Related works on nowcasting and forecasting of COVID-19 pandemic

Research topic Date Countries Model Results Main conclusion
Forecasting and January 30–31, Canada, France, ARIMA,Wavelet MAE and RMSE Hybrid
risk assessment 2020, to April 4, India, South ARIMA(WBF), least for Hybrid ARIMA-WBF
[20] 2020 Korea, UK Hybrid ARIMA-WBF performs better
ARIMA-WBF than traditional
methods and
important factors
that impact on
case fatality rates
are estimated
using regression
tree
Forecasting the Jan 22,2020 to World data TP-SMN-AR MAPE = 0.22 for Provided
confirmed and April 30, 2020 time series confirmed cases; reasonable
recovered cases (Autoregressive MAPE = 1.6 for forecasts in terms
[75] series based on Recovered cases of error and
two-piece scale model selection
mixture normal
distributions)
Short-term Inception—April Brazil ARIMA, Forecast errors SVR and
forecasting of 18–19, 2020 Random forest, lower than 6.9 stacking-
cumulative Ridge regression, percent ensemble
confirmed cases Support vector learning model
[93] regression, are suitable tools
Ensemble for forecasting
learning COVID-19
Modelling and January 11 to China Susceptible- Estimated Simulations
forecasting daily February 10, Infectious- average predicted a
cases [3] 2020 Recovered-Dead reproduction decline of the
(SIRD) model number outbreak at the
(R0 ) ∼ 2.6 and end of February
CFR ∼ 0.15%
(continued)
Table 1 (continued)
Research topic Date Countries Model Results Main conclusion
Forecasting January 22, 2020 Global data Exponential Ten-days-ahead Forecasts reflect
COVID-19 [87] to March 11, smoothing forecasts have the significant
2020 models actual cases increase in the
within 90% CI trend of global
cases with
growing
uncertainty
Real-time February 5to China Generalized Mean case All methods
forecasting [95] February 24, logistic growth estimates and perform similarly
2020 model (GLM) 95% prediction and and increase
and intervals in data inclusion
Sub-epidemic emulsifies the decreases the
wave model global picture width of
15-days ahead prediction
intervals
Predictions and Live forecast India Extended Live forecasts Lockdown has a
role of state-space SIR with broad high chance of
interventions [92] epidemiological confidence reducing the
models intervals number of
COVID-19 cases
Forecasting and Dec 31, 2019, to China Susceptible- R0 = 2.68 (95% COVID-19 is no
nowcasting Jan 28, 2020 exposed- CI 2.47, 2.86) ; longer contained
COVID-19 [122] infectious- epidemic within China, and
recovered (SEIR) doubling time = human-human
model 6.4 days (95% CI transmission
5.8, 7.1) became evident
Forecast [31] Jan, 22–March China, Italy and Susceptible, The recovery rate There is a certain
15, 2020 France infected, is the same for universality in the
recovered, dead Italy and China, time evolution of
(SIRD) model while infection COVID-19
and death rate
appear to be
different
AI-based Jan, 11 - February China Data driven Using the The accuracy of
forecasts [53] 27, 2020 AI-based multiple-step the AI-based
methods forecasting, methods for
forecasts are forecasting the
given till April trajectory of
19, 2020 for 34 COVID-19 was
provinces/cities high
Machine January 22, 2020, India Multi-layered Forecast of MLP method is
learning-based to April 10, 2020 perceptron confirmed, deaths giving good
forecasts [107] (MLP) model and recovered prediction results
cases for 69 days than other
methods
Long-term Starting—June Spain and Italy Integrated Basic ISA model shows
trajectories of 17, 2020 stochastic- reproduction significant
COVID-19 [38] deterministic number and improvement in
(ISA) approach estimated future the long-term
cases are forecasting of
computed COVID-19 cases
3 Global Characteristics of Pandemic Time Series
A univariate time series is the simplest form of temporal data and is a sequence of real
numbers collected regularly over time, where each number represents a value [16,
24]. There are broadly two major steps involved in univariate time series forecasting
[56]: (a) Studying the global characteristics of the time series data; and (b) Analysis
of data with the ‘best-fitted’ forecasting model.
Understanding the global characteristics of pandemic confirmed cases data can
help forecasters determine what kind of forecasting method will be appropriate for
the given situation [116]. As such, we aim to perform a meaningful data analysis,
including the study of time series characteristics, to provide a suitable and com-
prehensive knowledge foundation for the future step of selecting an apt forecasting
method. Thus, we take the path of using statistical measures to understand pandemic
time series characteristics to assist method selection and data analysis. These charac-
teristics will carry summarized information of the time series, capturing the ‘global
picture’ of the datasets. Based on the recommendation of [27, 70, 71, 118], we study
several classical and advanced time series characteristics of COVID-19 data. This
study considers eight global characteristics of the time series: periodicity, stationar-
ity, serial correlation, skewness, kurtosis, nonlinearity, long-term dependence, and
chaos. This collection of measures provides quantified descriptions and gives a rich
portrait of the pandemic time-series’ nature. A brief description of these statistical
and advanced time-series measures are given below.
3.1 Periodicity
A seasonal pattern exists when a time series is influenced by seasonal factors, such
as the month of the year or day of the week. The seasonality of a time series is
defined as a pattern that repeats itself over fixed intervals of time [16]. In general, the
seasonality can be found by identifying a large autocorrelation coefficient or a large
partial autocorrelation coefficient at the seasonal lag. Since the periodicity is very
important for determining the seasonality and examining the cyclic pattern of the
time series, the periodicity feature extraction becomes a necessity. Unfortunately,
many time series available from the dataset in different domains do not always
have known frequency or regular periodicity. Seasonal time series are sometimes
also called cyclic series, although there is a significant distinction between them.
Cyclic data have varying frequency lengths, but seasonality is of a fixed length over
each period. For time series with no seasonal pattern, the frequency is set to 1. The
seasonality is tested using the ‘stl’ function within the “stats” package in R statistical
software [56].
3.2 Stationarity
Stationarity is the foremost fundamental statistical property tested for in time series
analysis because most statistical models require that the underlying generating pro-
cesses be stationary [23]. Stationarity means that a time series (or rather the process
rendering it) do not change over time. In statistics, a unit root test tests whether a time
series variable is non-stationary and possesses a unit root [89]. The null hypothesis
is generally defined as the presence of a unit root, and the alternative hypothesis is
either stationarity, trend stationarity, or explosive root depending on the test used.
In econometrics, Kwiatkowski–Phillips–Schmidt–Shin (KPSS) tests are used for
testing a null hypothesis that an observable time series is stationary around a deter-
ministic trend (that is, trend-stationary) against the alternative of a unit root [104].
The KPSS test is done using the ‘kpss.test’ function within the “tseries” package in
R statistical software [113].
3.3 Serial Correlation
Serial correlation is the relationship between a variable and a lagged version of itself
over various time intervals. Serial correlation occurs in time-series studies when the
errors associated with a given time period carry over into future time periods [16]. We
have used Box-Pierce statistics [15] in our approach to estimate the serial correlation
measure and extract the measures from COVID-19 data. The Box-Pierce statistic
was designed by Box and Pierce in 1970 for testing residuals from a forecast model
[118]. It is a common portmanteau test for computing the measure. The mathematical
formula of the Box-Pierce statistic is as follows:

h
Qh = n rk2 , (1)
k=1
where n is the length of the time series, h is the maximum lag being considered
(usually h is chosen as 20), and rk is the autocorrelation function. The portmanteau
test is done using the ‘Box.test’ function within the “stats” package in R statistical
software [58].
3.4 Nonlinearity
Nonlinear time series models have been used extensively to model complex dynamics
not adequately represented by linear models [63]. Nonlinearity is one important
time series characteristic to determine the selection of an appropriate forecasting
method [112]. There are many approaches to test the nonlinearity in time series
models, including a nonparametric kernel test and a Neural Network test [115]. In
the comparative studies between these two approaches, the Neural Network test has
been reported with better reliability [118]. In this research, we used Teräsvirta’s neural
network test [108] for measuring time series data nonlinearity. It has been widely
accepted and reported that it can correctly model the nonlinear structure of the data
[109]. It is a test for neglected nonlinearity, likely to have power against a range
of alternatives based on the NN model (augmented single-hidden-layer feedforward
neural network model). This takes large values when the series is nonlinear and
values near zero when the series is linear. The test is done using the ‘nonlinearityTest’
function within the “nonlinearTseries” package in R statistical software [37].
3.5 Skewness
Skewness is a measure of symmetry, or more precisely, the lack of symmetry. A

distribution, or dataset, is symmetric if it looks the same to the left and the right
of the center point [118]. A skewness measure is used to characterize the degree of
asymmetry of values around the mean value [79]. For univariate data Yt , the skewness
coefficient is
1 3
n
S= 3
Yt − Ȳ , (2)
nσ t=1
where Ȳ is the mean, σ is the standard deviation, and n is the number of data points.
The skewness for a normal distribution is zero, and any symmetric data should have
the skewness near zero. Negative values for the skewness indicate data that are skewed
left, and positive values for the skewness indicate data that are skewed right. In other
words, left skewness means that the left tail is heavier than the right tail. Similarly,
right skewness means the right tail is heavier than the left tail [65]. Skewness is
calculated using the ‘skewness’ function within the “e1071” package in R statistical
software [77].
3.6 Kurtosis (Heavy-Tails)
Kurtosis is a measure of whether the data are peaked or flat, relative to a normal
distribution [79]. A dataset with high kurtosis tends to have a distinct peak near the
mean, decline rather rapidly, and have heavy tails. Datasets with low kurtosis tend
to have a flat top near the mean rather than a sharp peak. For a univariate time series
4
Yt , the kurtosis coefficient is nσ1 4 nt=1 Yt − Ȳ . The kurtosis for a standard normal
distribution is 3. Therefore, the excess kurtosis is defined as
1 4
n
K= 4
Yt − Ȳ − 3. (3)
nσ t=1
So, the standard normal distribution has an excess kurtosis of zero. Positive kurtosis
indicates a ‘peaked’ distribution and negative kurtosis indicates a ‘flat’ distribution
[43]. Kurtosis is calculated using the ‘kurtosis’ function within the “Performance-
Analytics” package in R statistical software [86].
3.7 Long-Range Dependence
Processes with long-range dependence have attracted a good deal of attention from
a probabilistic perspective in time series analysis [94]. With such increasing impor-
tance of the ‘self-similarity’ or ‘long-range dependence’ as one of the time series
characteristics, we study this feature into the group of pandemic data characteristics.
The definition of self-similarity is most related to the self-similarity parameter, also
called Hurst exponent (H) [12]. The class of autoregressive fractionally integrated
moving average (ARFIMA) processes [40] is a good estimation method for comput-
ing H. In an ARIMA(p, d , q), p is the order of AR, d is the degree first differencing
involved, and q is the order of MA. If the time series is suspected of exhibiting
long-range dependency, parameter d may be replaced by certain non-integer values
in the ARFIMA model [18]. We fit an ARFIMA(0, d , 0) to the maximum likeli-
hood, which is approximated by using the fast and accurate method of Haslett and
Raftery [46]. We then estimate the Hurst parameter using the relation H = d + 0.5.
The self-similarity feature can only be detected in the RAW data of the time series.
The value of H can be obtained using the ‘hurstexp’ function within the “pracma”
package in R statistical software [13].
3.8 Chaos (Dynamic Systems)
Many systems in nature that were previously considered random processes are now
categorized as chaotic systems. For several years, Lyapunov Characteristic Expo-
nents are of interest in the study of dynamical systems to characterize quantitatively
their stochasticity properties, related essentially to the exponential divergence of
nearby orbits [34]. Nonlinear dynamical systems often exhibit chaos, characterized
by sensitive dependence on initial values, or more precisely by a positive Lyapunov
Exponent (LE) [33]. Recognizing and quantifying chaos in time series are essen-
tial steps toward understanding the nature of random behavior and revealing the
extent to which short-term forecasts may be improved [49]. LE, as a measure of
the divergence of nearby trajectories, has been used to qualifying chaos by giving a
quantitative value [11]. The algorithm of computing LE from time-series is applied
to continuous dynamical systems in an n-dimensional phase space [97]. LE is cal-

culated using the ‘Lyapunov exponent’ function within the “tseriesChaos” package
in R statistical software [6].
4 Popular Forecasting Methods for Pandemic Nowcasting
Time series forecasting models work by taking a series of historical observations

and extrapolating future patterns. These are great when the data are accurate; the
future is similar to the past. Forecasting tools are designed to predict possible future
alternatives and help current planing and decision making [7]. There are essentially
three general approaches to forecasting a time series [78]: (1) Generating forecasts
from an individual model; (2) Combining forecasts from many models (forecast
model averaging); and (3) Hybrid experts for time series forecasting.
Single (individual) forecasting models are either traditional statistical methods
or modern machine learning tools. We study ten popularly used single forecasting
models from classical time series, advanced statistics, and machine learning liter-
ature. There has been a vast literature on the forecast combinations motivated by
the seminal work of Bates and Granger [9] and followed by a plethora of empirical
applications showing that combination forecasts are often superior to their counter-
parts (see [14, 110], for example). Combining forecasts using a weighted average is
considered a successful way of hedging against the risk of selecting a misspecified
model [26]. A significant challenge is in choosing an appropriate set of weights,
and many attempts to do this have been worse than simply using equal weights –
something that has become known as the “forecast combination puzzle” (see [105]).
To overcome this, hybrid models became popular with the seminal work of [124]
and further extended for epidemic forecasting in [20–22]. The forecasting methods
can be briefly reviewed and organized in the architecture shown in Fig. 1.
4.1 Autoregressive Integrated Moving Average (ARIMA)

Model
The autoregressive integrated moving average (ARIMA) is one of the well-known

linear models in time-series forecasting, developed in the early 1970s [16]. It is
widely used to track linear tendencies in stationary time-series data. It is denoted
by ARIMA(p, d , q), where the three components have significant meanings. The
parameters p and q represent the order of AR and MA models, respectively, and d
denotes the level of differencing to convert nonstationary data into stationary time
series [74]. ARIMA model can be mathematically expressed as follows:
Time series
forecasting
methods
Classical Smoothing Advanced ML Hybrid Ensemble
ARIMA- ARIMA-
ARIMA ETS WARIMA ANN
ANN ETS-Theta
ARIMA- ARIMA-
SETAR TBATS BSTS ARNN
ARNN ETS-ARNN
ARIMA-
ARIMA-
ARFIMA Theta Theta-
WARIMA
ARNN
WARIMA- ETS-Theta-
ANN ARNN
ANN-
WARIMA-
ARNN-
ARNN
WARIMA
Fig. 1 A systemic view of the various forecasting methods to be used in this study

p

q
yt = α0 + βi yt−i + t − αj t−j , (4)
i=1 j=1
where yt denotes the actual value of the variable at time t, t denotes the random
error at time t, βi and αj are the coefficients of the model. Some necessary steps to be
followed for any given time-series dataset to build an ARIMA model are as follows:
• Identification of the model (achieving stationarity).
• Use autocorrelation function (ACF) and partial ACF plots to select the AR and
MA model parameters, respectively, and finally estimate model parameters for the
ARIMA model.
• The ‘best-fitted’ forecasting model can be found using the Akaike Information
Criteria (AIC) or the Bayesian Information Criteria (BIC). Finally, one checks the
model diagnostics to measure its performance.
An implementation in R statistical software is available using the ‘auto.arima’ func-
tion under the “forecast” package, which returns the ‘best’ ARIMA model according
to either AIC or BIC values [59].
4.2 Wavelet-Based ARIMA (WARIMA) Model
Wavelet analysis is a mathematical tool that can reveal information within the signals
in both the time and scale (frequency) domains. This property overcomes the pri-
mary drawback of Fourier analysis, and wavelet transforms the original signal data
(especially in the time domain) into a different domain for data analysis and process-
ing. Wavelet-based models are most suitable for nonstationary data, unlike standard
ARIMA. Most epidemic time-series datasets are nonstationary; therefore, wavelet
transforms are used as a forecasting model for these datasets [20]. When conducting
wavelet analysis in the context of time series analysis [2], the selection of the optimal
number of decomposition levels is vital to determine the performance of the model in
the wavelet domain. The following formula for the number of decomposition levels,
W L = int[log(n)], is used to select the number of decomposition levels, where n is
the time-series length.
The wavelet-based ARIMA (WARIMA) model transforms the time series data
by using a hybrid maximal overlap discrete wavelet transform (MODWT) algorithm
with a ‘haar’ filter [84]. Daubechies wavelets can produce identical events across
the observed time series in so many fashions that most other time series prediction
models cannot recognize. The necessary steps of a wavelet-based forecasting model,
defined by Aminghafari and Poggi [2], are as follows. Firstly, the Daubechies wavelet
transformation and a decomposition level are applied to the nonstationary time series
data. Secondly, the series is reconstructed by removing the high-frequency compo-
nent, using the wavelet denoising method. Lastly, an appropriate ARIMA model is
applied to the reconstructed series to generate out-of-sample forecasts of the given
time series data. Wavelets were first considered as a family of functions by Morlet
[117], constructed from the translations and dilation of a single function, which is
called “Mother Wavelet”. These wavelets are defined as follows:

1 t−n
φm,n (t) = √ φ ; m, n ∈ R, (5)
|m| m
where the parameter m (= 0) is denoted as the scaling parameter or scale, and it
measures the degree of compression. The parameter n is used to determine the time
location of the wavelet, and it is called the translation parameter. If the value |m| < 1,
then the wavelet in m is a compressed version (smaller support is the time domain)
of the mother wavelet and primarily corresponds to higher frequencies, and when
|m| > 1, then φ( m, n)(t) has larger time width than φ(t) and corresponds to lower
frequencies. Hence wavelets have time width adopted to their frequencies, which is
the main reason behind the success of the Morlet wavelets in signal processing and
time-frequency signal analysis [82]. An implementation of the WARIMA model is
available using the ‘WaveletFittingarma’ function under the “WaveletArima” pack-
age in R statistical software [83].
4.3 Autoregressive Fractionally Integrated Moving Average

(ARFIMA) Model
Fractionally autoregressive integrated moving average or autoregressive fractionally

integrated moving average models are the generalized version ARIMA model in time
series forecasting, which allow non-integer values of the differencing parameter [40].
It may sometimes happen that our time-series data is not stationary, but when we
try differencing with parameter d taking the value to be an integer, it may over
difference it. To overcome this problem, it is necessary to difference the time series
data using a fractional value. These models are useful in modeling time series, which
has deviations from the long-run mean decay more slowly than an exponential decay;
these models can deal with time-series data having long memory [90]. ARFIMA
models can be mathematically expressed as follows:

p

q
1− i B i
(1 − B) Xt = 1 +
d
θi B i
t , (6)
i=1 i=1
where B is is the backshift operator, p, q are ARIMA parameters, and d is the differ-
encing term (allowed to take non-integer values). An R implementation of ARFIMA
model can be done with ‘arfima’ function under the “forecast” package [59]. An
ARFIMA(p, d , q) model is selected and estimated automatically using the algo-
rithm by Hyndman et al. [55] which can select p and q and the algorithm by Haslett
and Raftery [46] can estimate the parameter d .
4.4 Exponential Smoothing State Space (ETS) Model
Exponential smoothing state space methods are very effective methods in case of time
series forecasting. Exponential smoothing was proposed in the late 1950s [120] and
has motivated some of the most successful forecasting methods. Forecasts produced
using exponential smoothing methods are weighted averages of past observations,
with the weights decaying exponentially as the observations get older. The ETS mod-
els belong to the family of state-space models, consisting of three-level components
such as an error component (E), a trend component (T), and a seasonal component
(S). This method is used to forecast univariate time series data. Each model consists
of a measurement equation that describes the observed data, and some state equations
that describe how the unobserved components or states (level, trend, seasonal) change
over time [56]. Hence, these are referred to as state-space models. The flexibility of
the ETS model lies in its ability to trend and seasonal components of different traits.
Errors can be of two types: Additive and Multiplicative. Trend Component can be
any of the following: None, Additive, Additive Damped, Multiplicative and Multi-
plicative Damped. Seasonal Component can be of three types: None, Additive, and
Multiplicative. Thus, there are 15 models with additive errors and 15 models with
multiplicative errors. To determine the best model of 30 ETS models, several cri-
teria such as Akaike’s Information Criterion (AIC), Akaike’s Information Criterion
correction (AICc), and Bayesian Information Criterion (BIC) can be used [55]. An
R implementation of the model is available in the ‘ets’ function under “forecast”
package [59].
4.5 Self-exciting Threshold Autoregressive (SETAR) Model
As an extension of autoregressive model, Self-exciting threshold autoregressive

(SETAR) model is used to model time series data, in order to allow for higher degree
of flexibility in model parameters through a regime switching behaviour [111]. Given
a time-series data yt , the SETAR model is used to predict future values, assuming
that the behavior of the time series changes once the series enters a different regime.
This switch from one to another regime depends on the past values of the series.
The model consists of k autoregressive (AR) parts, each for a different regime. The
model is usually denoted as SETAR (k, p) where k is the number of threshold, there
are k + 1 number of regime in the model and p is the order of the autoregressive part.
For example, suppose an AR(1) model is assumed in both regimes, then a 2-regime
SETAR model is given by Franses et al. [36]:
yt = φ0,1 + φ1,1 yt−1 + t if yt−1 ≤ c,

(7)
= φ0,2 + φ1,2 yt−1 + t if yt−1 > c,
where for the moment the t are assumed to be an i.i.d. white noise sequence con-
ditional upon the history of the time series and c is the threshold value. The SETAR
model assumes that the border between the two regimes is given by a specific value
of the threshold variable yt−1 . The model can be implemented using ‘setar’ function
under the “tsDyn” package in R [29].
4.6 Bayesian Structural Time Series (BSTS) Model
Bayesian Statistics has many applications in the field of statistical techniques such as
regression, classification, clustering, and time series analysis. Scott and Varian [100]
used structural time series models to show how Google search data can be used to
improve short-term forecasts of economic time series. In the structural time series
model, the observation in time t, yt is defined as follows:
yt = XtT βt + t (8)
where βt is the vector of latent variables, Xt is the vector of model parameters, and
t are assumed follow Normal distributions with zero mean and Ht as the variance.
In addition, βt is represented as follows:
βt+1 = St βt + Rt δt , (9)
where δt are assumed to follow Normal distributions with zero mean and Qt as the
variance. Gaussian distribution is selected as the prior of the BSTS model since we
use the occurred frequency values ranging from 0 to ∞ [62]. An R implementation
is available under the “bsts” package [101], where one can add local linear trend and
seasonal components as required. The state specification is passed as an argument to
‘bsts’ function, along with the data and the desired number of Markov chain Monte
Carlo (MCMC) iterations, and the model is fit using an MCMC algorithm [99].
4.7 Theta Model
The ‘Theta method’ or ‘Theta model’ is a univariate time series forecasting tech-
nique that performed particularly well in M3 forecasting competition and of interest
to forecasters [8]. The method decomposes the original data into two or more lines,
called theta lines, and extrapolates them using forecasting models. Finally, the pre-
dictions are combined to obtain the final forecasts. The theta lines can be estimated
by simply modifying the ‘curvatures’ of the original time series [106]. This change
is obtained from a coefficient, called θ coefficient, which is directly applied to the
second differences of the time series:
"
Ynew (θ ) = θ Ydata
"
, (10)
"
where Ydata = Yt − 2Yt−1 + Yt−2 at time t for t = 3, 4, . . . , n and {Y1 , Y2 , . . . , Yn }
denote the observed univariate time series. In practice, coefficient θ can be considered
as a transformation parameter which creates a series of the same mean and slope with
that of the original data but having different variances. Now, Eqn. (10) is a second-
order difference equation and has solution of the following form [57]:
Ynew (θ ) = aθ + bθ (t − 1) + θ Yt , (11)
where aθ and bθ are constants and t = 1, 2, · · · , n. Thus, Ynew (θ ) is equivalent to a

linear function of Yt with a linear trend added. The values of aθ and bθ are computed
by minimizing the sum of squared differences:

t
t
[Yt − Ynew (θ )]2 = [(1 − θ )Yt − aθ − bθ (t − 1)]2 . (12)
i=1 i=1
Forecasts from the Theta model are obtained by a weighted average of forecasts
of Ynew (θ ) for different values of θ . Also, the prediction intervals and likelihood-
based estimation of the parameters can be obtained based on a state-space model,
demonstrated in [57]. An R implementation of the Theta model is possible with
‘thetaf’ function in “forecast” package [59].
4.8 TBATS Model
The main objective of TBATS model is to deal with complex seasonal patterns using
exponential smoothing [28]. The name is acronyms for key features of the models:
Trigonometric seasonality (T), Box-Cox Transformation (B), ARMA errors (A),
Trend (T) and Seasonal (S) components. TBATS makes it easy for users to handle
data with multiple seasonal patterns. This model is preferable when the seasonality
changes over time [56]. TBATS models can be described as follows:
(μ)

T
(i)
yt = lt−1 + φbt−1 + st−m i
+ dt (13)
i=1
lt = lt−1 + φbt−1 + αdt
bt = φbt−1 + βdt

p

q
dt = ψi dt−i + θj et−j + et ;
i=1 j=1
(μ)
where yt is the time series at time point t (Box-Cox Transformed), st(i) is the
i-th seasonal component, lt is the local level, bt is the trend with damping, dt is
the ARMA(p, q) process for residuals and et as the Gaussian white noise. TBATS
model can be implemented using ‘tbats’ function under the “forecast” package in R
statistical software [59].
4.9 Artificial Neural Networks (ANN) Model
Forecasting with artificial neural networks (ANN) has received increasing interest
in various research and applied domains in the late 1990s. It has been given special
attention in epidemiological forecasting [88]. Multi-layered feed-forward neural net-
works with back-propagation learning rules are the most widely used models with
applications in classification and prediction problems [123]. There is a single hidden
layer between the input and output layers in a simple feed-forward neural net, and
where weights connect the layers. Denoting by ωji the weights between the input
layer and hidden layer and νkj denotes the weights between the hidden and out-
put layers. Based on the given inputs xi , the neuron’s net input is calculated as the
weighted sum of its inputs. The output layer of the neuron, yj , is based on a sigmoidal
function indicating the magnitude of this net-input [39]. For the jth hidden neuron,
the calculation for the net input and output are:

n
netjh = ωji xi (14)
i=1
yj = f (netjh ). (15)
For the kth output neuron:
J +1

netko = νkj yj (16)
j=1
ok = f (netko ), (17)
where f (net) = 1+e1−λnet with λ ∈ (0, 1) is a parameter used to control the gradient of
the function and J is the number of neurons in the hidden layer. The back-propagation
[98] learning algorithm is the most commonly used technique in ANN. In the error
back-propagation step, the weights in ANN are updated by minimizing
1
P K
E= (dpk − Opk )2 , (18)
2P p=1
k=1
where, dpk is the desired output of neuron k and for input pattern√p. The common
formula for number of neurons in the hidden layer is h = (i+j)2
+ d , for selecting
the number of hidden neurons, where i is the number of output yj and d denotes the
number of i training patterns in the input xi [125]. The application of ANN for time
series data is possible with ‘mlp’ function under “nnfor” package in R [68].
4.10 Autoregressive Neural Network (ARNN) Model
Autoregressive neural network (ARNN) received attention in time series literature

in late 1990s [32]. The architecture of a simple feedforward neural network can
be described as a network of neurons arranged in input layer, hidden layer, and
output layer in a prescribed order. Each layer passes the information to the next layer
using weights that are obtained using a learning algorithm [125]. ARNN model is a
modification to the simple ANN model especially designed for prediction problems
of time series datasets [32]. ARNN model uses a pre-specified number of lagged
values of the time series as inputs and number of hidden neurons in its architecture
is also fixed [56]. ARNN(p, k) model uses p lagged inputs of the time series data in
a one hidden layered feedforward neural network with k hidden units in the hidden
layer. Let x denotes a p-lagged inputs and f is a neural network of the following
architecture:
k

f (x) = c0 + wj φ aj + bj x ; (19)
j=1
where c0 , aj , wj are connecting weights, bj are p-dimensional weight vector and φ is

a bounded nonlinear sigmoidal function (e.g., logistic squasher function or tangent
hyperbolic activation function). These Weights are trained using a gradient descent
backpropagation [98]. Standard ANN faces the dilemma to choose the number of
hidden neurons in the hidden layer and optimal choice is unknown. But for ARNN
model, we adopt the formula k = [(p + 1)/2] for non-seasonal time series data where
p is the number of lagged inputs in an autoregressive model [56]. ARNN model can
be applied using the ‘nnetar’ function available in the R statistical package “forecast”
[59].
4.11 Ensemble Forecasting Models
The idea of ensemble time series forecasts was given by Bates and Granger (1969)
in their seminal work [9]. Forecasts generated from ARIMA, ETS, Theta, ARNN,
WARIMA can be combined with equal weights, weights based on in-sample errors, or
cross-validated weights. In the ensemble framework, cross-validation for time series
data with user-supplied models and forecasting functions is also possible to evaluate
model accuracy [102]. Combining several candidate models can hedge against an
incorrect model specification. Bates and Granger [9] suggested such an approach and
observed, somewhat surprisingly, that the combined forecast can even outperform
the single best component forecast. While combination weights selected equally or
proportionally to past model errors are possible approaches, many more sophisticated
combination schemes, have been suggested. For example, rather than normalizing
weights to sum to unity, unconstrained and even negative weights could be possible
[41]. The simple equal-weights combination might appear woefully obsolete and
probably non-competitive compared to the multitude of sophisticated combination
approaches or advanced machine learning and neural network forecasting models,
especially in the age of big data. However, such simple combinations can still be
competitive, particularly for pandemic time series [102]. A flow diagram of the
ensemble method is presented in Fig. 2.
The ensemble method by [9] produces forecasts out to a horizon h by applying a
weight wm to each m of the n model forecasts in the ensemble. The ensemble forecast
f (i) for time horizon 1 ≤ i ≤ h and with individual component model forecasts fm (i)
is then

n
f (i) = wm fm (i). (20)
m=1
The weights can be determined in several ways (for example, supplied by the user,
set equally, determined by in-sample errors, or determined by cross-validation). The
“forecastHybrid” package in R includes these component models in order to enhance
the “forecast” package base models with easy ensembling (e.g., ‘hybridModel’ func-
tion in R statistical software) [103].
Fig. 2 Flow diagram of the ensemble model where M1, M2, and M3 are three different univariate
time series models
4.12 Hybrid Forecasting Models
The idea of hybridizing time series models and combining different forecasts was
first introduced by [124] and further extended by [20–22, 64]. The hybrid forecasting
models are based on an error re-modeling approach, and there are broadly two types
of error calculations popular in the literature, which are given below [80]:
Definition 1 In the additive error model, the forecaster treats the expert’s estimate
as a variable, Ŷt , and thinks of it as the sum of two terms:
Ŷt = Yt + et , (21)
where Yt is the true value and et be the additive error term.

Definition 2 In the multiplicative error model, the forecaster treats the expert’s esti-
mate Ŷt as the product of two terms:
Ŷt = Yt × et , (22)
where Yt is the true value and et be the multiplicative error term.

Now, even if the relationship is of product type, in the log-log scale it becomes
additive. Hence, without loss of generality, we may assume the relationship to be
additive and expect errors (additive) of a forecasting model to be random shocks [22].
These hybrid models are useful for complex correlation structures where less amount
of knowledge is available about the data generating process. A simple example is the
daily confirmed cases of the COVID-19 cases for various countries where very little
is known about the structural properties of the current pandemic. The mathematical
formulation of the proposed hybrid model (Zt ) is as follows:
Zt = Lt + Nt , (23)
where Lt is the linear part and Nt is the nonlinear part of the hybrid model. We can
estimate both Lt and Nt from the available time series data. Let L̂t be the forecast
value of the linear model (e.g., ARIMA) at time t and t represent the error residuals
at time t, obtained from the linear model. Then, we write
t = Zt − L̂t . (24)
These left-out residuals are further modeled by a nonlinear model (e.g., ANN or
ARNN) and can be represented as follows:
t = f (t−1 , t−2 , ..., t−p ) + εt , (25)
where f is a nonlinear function, and the modeling is done by the nonlinear ANN or
ARNN model as defined in Eq. (19) and εt is supposed to be the random shocks.
Therefore, the combined forecast can be obtained as follows:
Ẑt = L̂t + N̂t , (26)
where N̂t is the forecasted value of the nonlinear time series model. An overall flow
diagram of the proposed hybrid model is given in Fig. 3. In the hybrid model, a
nonlinear model is applied in the second stage to re-model the left-over autocorre-
lations in the residuals, which the linear model could not model. Thus, this can be
considered as an error re-modeling approach. This is important because due to model
misspecification and disturbances in the pandemic rate time series, the linear models
may fail to generate white noise behavior for the forecast residuals. Thus, hybrid
approaches eventually can improve the predictions for the epidemiological forecast-
ing problems, as shown in [20–22]. These hybrid models only assume that the linear
and nonlinear components of the epidemic time series can be separated individually.
The implementation of the hybrid models used in this study are available in https://
github.com/indrajitg-r/COVID.
5 Experimental Analysis
Five time series COVID-19 datasets for the USA, India, Russia, Brazil, and Peru UK
are considered for assessing twenty forecasting models (individual, ensemble, and
hybrid). The datasets are mostly nonlinear, nonstationary, and non-gaussian in nature.
We have used root mean square error (RMSE), mean absolute error (MAE), mean
absolute percentage error (MAPE), and symmetric MAPE (SMAPE) to evaluate the
predictive performance of the models used in this study. Since the number of data
points in both the datasets is limited, advanced deep learning techniques will over-fit
the datasets [47].
Fig. 3 Flow diagram of the hybrid forecasting model
5.1 Datasets
We use publicly available datasets to compare various forecasting frameworks.

COVID-19 cases of five countries with the highest number of cases were collected
from https://www.worldometers.info/ and https://ourworldindata.org/. The datasets
and their description is presented in Table 2.
5.2 Global Characteristics
Characteristics of these five time series were examined using Hurst exponent, KPSS
test and Terasvirta test and other measures as described in 3. Hurst exponent (denoted
Table 2 Description of COVID-19 datasets

Countries Start date End date Length
USA 20/01/2020 15/09/2020 240
India 29/01/2020 15/09/2020 231
Brazil 25/02/2020 15/09/2020 204
Russia 31/01/2020 15/09/2020 229
Peru 06/03/2020 15/09/2020 194
by H), which ranges between zero to one, is calculated to measure the long-range
dependency in a time series and provides a measure of long-term nonlinearity. For
values of H near zero, the time series under consideration is mean-reverting. An
increase in the value will be followed by a decrease in the series and vice versa.
When H is close to 0.5, the series has no autocorrelation with past values. These
types of series are often called Brownian motion. When H is near one, an increase
or decrease in the value is most likely to be followed by a similar movement in
the future. All the five COVID-19 datasets in this study possess the Hurst exponent
value near one, which indicates that these time series datasets have a strong trend of
increase followed by an increase or decrease followed by another decline.
KPSS tests are performed to examine the stationarity of a given time series. The
null hypothesis for the KPSS test is that the time series is stationary. Thus, the
series is nonstationary when the p-value less than a threshold. From Table 3, all the
five datasets can be characterized as non-stationary as the p-value < 0.01 in each
instances. Terasvirta test examines the linearity of a time series against the alternative
that a nonlinear process has generated the series. It is observed that the USA, India,
Russia, and Brazil COVID-19 datasets are likely to follow a nonlinear trend. On the
other hand, Peru data shows some linear trend.
Further, we examine serial correlation, skewness, kurtosis, and maximum Lya-
punov exponent for the five COVID-19 datasets. The results are reported in Table 4.
The serial correlation of the datasets is computed using the Box-Pierce test statistic
for the null hypothesis of independence in a given time series. The p-values related
to each of the datasets were found to be below the significant level (see Table 4).
This indicates that these COVID-19 datasets have no serial correlation when lag
equals one. Skewness for Russia COVID-19 dataset is found to be negative, whereas
the other four datasets are positively skewed. This means for the Russia dataset;
the left tail is heavier than the right tail. For the other four datasets, the right tail is
heavier than the left tail. The Kurtosis values for the India dataset are found positive
while the other four datasets have negative kurtosis values. Therefore, the COVID-19
dataset of India tends to have a peaked distribution, and the other four datasets may
have a flat distribution. We observe that each of the five datasets is non-chaotic in
nature, i.e., the maximum Lyapunov exponents are less than unity. A summary of
the implementation tools is presented in Table 5.
Table 3 Test results on COVID-19 datasets

Countries Hurst exponent KPSS test Terasvirta test
USA 0.9996 p-value < 0.01 p-value = 0.01
India 0.9997 p-value < 0.01 p-value < 0.01
Brazil 0.9974 p-value < 0.01 p-value < 0.01
Russia 0.9992 p-value < 0.01 p-value = 0.05
Peru 0.9983 p-value < 0.01 p-value = 0.84
Table 4 Characteristics of COVID-19 datasets

Countries Box test Skewness Kurtosis Chaotic/non-
chaotic
USA p-value < 0.01 0.4971 −0.7465 Non-chaotic
India p-value < 0.01 1.4981 0.9422 Non-chaotic
Brazil p-value < 0.01 0.6897 −0.7124 Non-chaotic
Russia p-value < 0.01 −0.0544 −1.4439 Non-chaotic
Peru p-value < 0.01 0.4421 −0.2142 Non-chaotic
Table 5 R functions and packages for implementation

Model R function R package References
ARIMA auto.arima Forecast [58]
ETS ets Forecast [58]
SETAR setar tsDyn [29]
TBATS tbats Forecast [58]
Theta thetaf Forecast [58]
ANN mlp nnfor [67]
ARNN nnetar Forecast [58]
WARIMA WaveletFittingarma WaveletArima [83]
BSTS bsts bsts [101]
ARFIMA arfima Forecast [58]
Ensemble models hybridModel forecastHybrid [103]
Hybrid models – – https://github.com/
indrajitg-r/COVID
5.3 Accuracy Metrics
We used four popular accuracy metrics to evaluate the performance of different time
series forecasting models. The expressions of these metrics are given below.

n
1 1
n
RMSE = (yi − ŷi )2 ; MAE = |yi − ŷi |;
n i=1 n i=1
1 ŷi − yi 1 |ŷi − yi |
n n
MAPE = | | × 100; SMAPE = × 100; (27)
n i=1 yi n i=1 (|ŷi | + |yi |)/2
where yi are actual series values, ŷi are the predictions by different models and n
represent the number of data points of the time series. The models with least accuracy
metrics is the best forecasting model.
5.4 Analysis of Results
This subsection is devoted to the experimental analysis of confirmed COVID-19

cases using different time series forecasting models. The test period is chosen to
be 15 days and 30 days, whereas the rest of the data is used as training data (see
Table 2). In first columns of Tables 6 and 7, we present training data and test data for
USA, India, Brazil, Russia and Peru. The autocorrelation function (ACF) and partial
autocorrelation function (PACF) plots are also depicted for the training period of
each of the five countries in Tables 6 and 7. ACF and PACF plots are generated
after applying the required number of differencing of each training data using the r
function ‘diff’. The required order of differencing is obtained by using the R function
Table 6 Pandemic datasets and corresponding ACF, PACF plots with 15-days test data
Country Data ACF plot PACF plot
COVID−19 cases in USA ACF plot PACF plot
80000 1.0
60000 0.2
0.5
USA
Cases
series
PACF
ACF
40000
test
0.0
20000
0.0
−0.2
0 50 100 150 200 250 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in India ACF plot PACF plot

100000 1.00
0.2
0.75
75000
0.0
India
0.50
Cases
series
PACF
ACF
50000
test
0.25
−0.2
25000
0.00
−0.4
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Brazil ACF plot PACF plot

0.9
0.6
60000
0.4 0.6
Brazil
40000
0.2
Cases
series
PACF
ACF
test 0.3
0.0
20000
0.0
−0.2
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Russia ACF plot PACF plot

12000 0.25
1.00
9000 0.75
0.00
Russia
0.50
Cases
series
PACF
ACF
6000
test −0.25
0.25
3000
−0.50
0.00
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Peru ACF plot PACF plot

0.4
10000 0.9
7500 0.6
0.2
Peru
Cases
series
PACF
ACF
5000
test 0.3
0.0
2500
0.0
−0.2
0
−0.3
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20
Days Lag Lag
Table 7 Pandemic datasets and corresponding ACF, PACF plots with 30-days test data
Country Data ACF plot PACF plot
COVID−19 cases in USA ACF plot PACF plot
80000 1.0
0.3
0.2
60000
0.1
0.5
USA
Cases
series
PACF
ACF
40000
test 0.0
−0.1
20000
0.0
−0.2
0
−0.3
0 50 100 150 200 250 0 5 10 15 20 0 5 10 15 20
Days Lag Lag
COVID−19 cases in India ACF plot PACF plot

100000 1.00
0.2
0.75
75000
0.50
0.0
India
Cases
series
PACF
ACF
50000
test
0.25
−0.2
25000
0.00
−0.4
0
−0.25
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Brazil ACF plot PACF plot
0.6
60000
0.4
0.5
Brazil
40000
0.2
Cases
series
PACF
ACF
test
0.0
20000
0.0
−0.2
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Russia ACF plot PACF plot

12000 0.25
1.00
0.75
9000
0.00
Russia
0.50
Cases
series
PACF
ACF
6000
test −0.25
0.25
3000
−0.50
0.00
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
COVID−19 cases in Peru ACF plot PACF plot
10000
0.2
0.75
7500
0.1
0.50
Peru
Cases
series
PACF
ACF
5000 0.0
test
0.25
−0.1
2500
0.00
−0.2
0 50 100 150 200 0 5 10 15 20 0 5 10 15 20

Days Lag Lag
‘ndiffs’ which estimate the number of differences required to make a given time series
stationary. The integer-valued order of differencing is then used as the value of ’d ’
in the ARIMA(p, d , q) model. Other two parameters ‘p’ and ‘q’ of the model are
obtained from ACF and PACF plots respectively (see Tables 6 and 7). However, we
choose the ‘best’ fitted ARIMA model using AIC value for each training dataset.
Table 6 presents the training data (black colored) and test data (red-colored) and
corresponding ACF and PACF plots for the five time-series datasets.
Further, we checked twenty different forecasting models as competitors for the
short-term forecasting of COVID-19 confirmed cases in five countries. 15-days and
30-days ahead forecasts were generated for each model, and accuracy metrics were
computed to determine the best predictive models. From the ten popular single
models, we choose the best one based on the accuracy metrics. On the other hand,
one hybrid/ensemble model is selected from the rest of the ten models. The best-
fitted ARIMA parameters, ETS, ARNN, and ARFIMA models for each country are
reported in the respective tables. Table 7 presents the training data (black colored) and
test data (red-colored) and corresponding plots for the five datasets. Twenty forecast-
ing models are implemented on these pandemic time-series datasets. Table 5 gives
the essential details about the functions and packages required for implementation.
5.4.1 Results for USA COVID-19 Data
Among the single models, ARIMA(2,1,4) performs best in terms of accuracy metrics
for 15-days ahead forecasts. TBATS and ARNN(16,8) also have competitive accu-
racy metrics. Hybrid ARIMA-ARNN model improves the earlier ARIMA forecasts
and has the best accuracy among all hybrid/ensemble models (see Table 8). Hybrid
ARIMA-WARIMA also does a good job and improves ARIMA model forecasts.
In-sample and out-of-sample forecasts obtained from ARIMA and hybrid ARIMA-
ARNN models are depicted in Fig. 4a. Out-of-sample forecasts are generated using
the whole dataset as training data.
Table 8 Performance metrics with 15 days-ahead test set for USA

Model 15-days ahead forecast
RMSE MAE MAPE SMAPE
ARIMA(2,1,4) 7187.02 6094.95 16.89 16.07
ETS(A,N,N) 8318.73 6759.65 17.82 17.86
SETAR 8203.21 6725.96 18.19 17.77
TBATS 7351.04 6367.46 17.86 16.73
Theta 8112.22 6791.52 18.51 17.95
ANN 9677.105 8386.223 25.15 21.69
ARNN(16,8) 7633.92 6647.18 19.75 17.42
WARIMA 9631.98 8182.84 21.09 22.21
BSTS 10,666.15 8527.72 20.91 23.26
ARFIMA(1,0.14,1) 8413.33 6696.09 17.48 17.68
Hybrid ARIMA-ANN 7113.72 6058.29 16.90 15.99
Hybrid ARIMA-ARNN 5978.04 4650.89 13.22 12.45
Hybrid ARIMA-WARIMA 6582.93 5217.023 14.33 13.80
Hybrid WARIMA-ANN 10,633.97 8729.11 21.85 24.22
Hybrid WARIMA-ARNN 9558.34 8138.71 21.05 22.05
Ensemble ARIMA-ETS-Theta 7602.06 6388.96 17.32 16.89
Ensemble ARIMA-ETS-ARNN 7012.95 6184.23 18.09 16.45
Ensemble ARIMA-Theta-ARNN 6933.88 6054.97 17.42 16.07
Ensemble ETS-Theta-ARNN 7044.20 5950.40 16.97 15.82
Ensemble ANN-ARNN-WARIMA 7437.21 6465.18 18.66 17.11
Fig. 4 Plots of a 15-days ahead forecast results for USA COVID-19 data obtained using ARIMA
and hybrid ARIMA-ARNN models. b 30-days ahead forecast results from ARFIMA and hybrid
ARIMA-WARIMA models
ARFIMA(2,0,0) is found to have the best accuracy metrics for 30-days ahead fore-
casts among single forecasting models. BSTS and SETAR also have good agreement
with the test data in terms of accuracy metrics. Hybrid ARIMA-WARIMA model and
has the best accuracy among all hybrid/ensemble models (see Table 9). In-sample
Table 9 Performance metrics with 30 days-ahead test set for USA

RMSE MAE MAPE SMAPE
ARIMA(2,1,4) with drift 12,370.18 10,499.44 29.87 24.26
ETS(A,Ad,N) 11,929.897 9951.090 28.95 23.49
SETAR 8593.527 6904.605 20.18 17.25
TBATS 10,314.23 8587.83 24.95 20.73
Theta 12,234.16 9858.115 29.03 23.24
ANN 15,241.65 12,973.2 37.11 28.86
ARNN(16,8) 19,000.09 17,311.86 46.95 36.01
WARIMA 12,455.31 9501.018 22.55 27.45
BSTS 8459.763 6444.994 15.94 16.87
ARFIMA(2,0,0) 6847.32 5651.33 14.83 14.40
Hybrid ARIMA-ANN 12,269.99 10,339.18 29.46 23.92
Hybrid ARIMA-ARNN 12,584.03 10,566.16 30.14 24.32
Hybrid WARIMA-ANN 14,983.09 11,918.16 28.55 36.52
Hybrid WARIMA-ARNN 12,294.48 9330.15 22.14 26.88
Ensemble ARIMA-ETS-Theta 12,014.39 9978.22 29.04 23.49
Ensemble ARIMA-ETS-ARNN 11,484.49 10,035.78 28.35 23.49
Ensemble ARIMA-Theta-ARNN 13,596.9 12,000.69 33.86 27.21
Ensemble ETS-Theta-ARNN 13,074.13 11,429.5 32.52 26.26
Ensemble ANN-ARNN-WARIMA 11,652.2 9947.16 30.60 24.23
and out-of-sample forecasts obtained from ARFIMA and hybrid ARIMA-WARIMA

models are depicted in Fig. 4b.
5.4.2 Results for India COVID-19 Data
Among the single models, ANN performs best in terms of accuracy metrics for 15-
days ahead forecasts. ARIMA(1,2,5) also has competitive accuracy metrics in the test
period. Hybrid ARIMA-ARNN model improves the ARIMA(1,2,5) forecasts and has
the best accuracy among all hybrid/ensemble models (see Table 10). Hybrid ARIMA-
ANN and hybrid ARIMA-WARIMA also do a good job and improves ARIMA
model forecasts. In-sample and out-of-sample forecasts obtained from ANN and
hybrid ARIMA-ARNN models are depicted in Fig. 5a. Out-of-sample forecasts are
generated using the whole dataset as training data (see Fig. 5).
ANN is found to have the best accuracy metrics for 30-days ahead forecasts
among single forecasting models for India COVID-19 data. Ensemble ANN-ARNN-
WARIMA model and has the best accuracy among all hybrid/ensemble models (see
Table 11). In-sample and out-of-sample forecasts obtained from ANN and ensemble
ANN-ARNN-WARIMA models are depicted in Fig. 5b.
Table 10 Performance metrics with 15 days-ahead test set for India

RMSE MAE MAPE SMAPE
ARIMA(1,2,5) 8141.76 7479.43 8.36 8.72
ETS(A,A,N) 15,431 14,415.73 15.92 17.18
SETAR 22,835.95 21,851.45 24.24 27.84
TBATS 11,764.61 10,837.68 12.00 12.89
Theta 18,405.29 17,403.03 19.24 21.50
ANN 6663.10 5891.94 6.54 6.81
ARNN(2,2) 25,617.9 24,539.67 27.23 31.86
WARIMA 12,201.48 11,103.41 12.25 13.18
BSTS 13,535.1 12,402.34 13.65 14.84
ARFIMA(0,0.49,4) 34,848.86 33,323.88 37.03 46.25
Hybrid ARIMA-ANN 8080.862 7399.7 8.28 8.64
Hybrid WARIMA-ARNN 11,623.15 10,339.16 11.33 12.17
Ensemble ARIMA-ETS-Theta 13,734.28 12,641.35 13.93 15.14
Ensemble ANN-ARNN-WARIMA 14,512.1 13,496.63 14.88 16.25
Fig. 5 Plots of a 15-days ahead forecast results for India COVID-19 data obtained using ANN and
hybrid ARIMA-ARNN models and b 30-days ahead forecast results from ANN and ANN-ARNN-
WARIMA (AAW) models
Table 11 Performance metrics with 30 days-ahead test set for India

RMSE MAE MAPE SMAPE
ARIMA(1,2,5) 177,55.52 15,657.27 18.67 21.01
ETS(A,A,N) 14,873.78 13,051.98 15.57 17.18
SETAR 21,527.58 18,609.71 21.98 25.49
TBATS 24,849.07 21,843.15 25.96 30.82
Theta 21,713.03 19,191.21 22.84 26.47
ANN 6379.91 4800.13 6.48 6.13
ARNN(8,4) 13,225.43 10,287.29 11.90 13.06
WARIMA 14,720.81 12,738.66 15.15 16.72
BSTS 14,332.3 12,493.74 14.88 16.34
ARFIMA(0,0.5,4) 40,115.62 36,452.33 43.87 58.73
Hybrid ARIMA-ANN 17,640.51 15,535.58 18.53 20.83
Hybrid ARIMA-WARIMA 17,869.14 15,771.05 18.78 21.19
Hybrid WARIMA-ANN 14,616.89 12,613.57 15 16.53
5.4.3 Results for Brazil COVID-19 Data
Among the single models, SETAR performs best in terms of accuracy metrics for
15-days ahead forecasts. Ensemble ETS-Theta-ARNN (EFN) model has the best
accuracy among all hybrid/ensemble models (see Table 12). In-sample and out-of-
sample forecasts obtained from SETAR and ensemble EFN models are depicted in
Fig. 6a.
WARIMA is found to have the best accuracy metrics for 30-days ahead forecasts
among single forecasting models for Brazil COVID-19 data. Hybrid WARIMA-ANN
model has the best accuracy among all hybrid/ensemble models (see Table 13). In-
sample and out-of-sample forecasts obtained from WARIMA and hybrid WARIMA-
ANN models are depicted in Fig. 6b.
5.4.4 Results for Russia COVID-19 Data
BSTS performs best in terms of accuracy metrics for a 15-days ahead forecast in the
case of Russia COVID-19 data among single models. Theta and ARNN(3,2) also
show competitive accuracy measures. Ensemble ETS-Theta-ARNN (EFN) model
Table 12 Performance metrics with 15 days-ahead test set for Brazil

RMSE MAE MAPE SMAPE
ARIMA(3,1,2) 16,553.75 12,530.04 76.62 41.66
ETS(A,A,N) 13,793.618 11,038.765 63.41 38.99
SETAR 11,645.6 10,148.91 49.77 37.35
TBATS 15,842.01 11,803.72 72.67 40.05
Theta 16,263.93 12,614.74 65.71 42.21
ANN 19,622.3 16,536.91 83.45 53.78
ARNN((19,10)) 13,733.19 11,951.27 57.59 40.36
WARIMA 17,167.66 13,487.76 80.45 43.85
BSTS 21,154.89 16,702.38 98.97 49.62
ARFIMA(2,0.5,1) 14,023.22 11,109.03 63.94 39.03
Hybrid ARIMA-ANN 17,541.86 13,436.8 81.47 42.93
Ensemble ETS-Theta-ARNN 13,431.11 11324.4 62.67 39.83
Fig. 6 Plots of a 15-days ahead forecast results for Brazil COVID-19 data obtained using SETAR
and ETS-Theta-ARNN (EFN) models and b 30-days ahead forecast results from WARIMA and
hybrid WARIMA-ANN models
Table 13 Performance metrics with 30 days-ahead test set for Brazil

RMSE MAE MAPE SMAPE
ARIMA(5,1,1) with drift 17,647.13 14924.74 69.57 41.85
ETS(A,A,N) 20,270.82 15,186.14 81.30 42.45
SETAR 16,136.69 15,085.91 52.75 49.03
TBATS 14,166.74 10,629.13 56.19 33.78
Theta 17,662.39 12,880.03 70.55 38.38
ANN 22,403 18,241.79 90.86 47.29
ARNN(9,5) 13,458.51 10,884.02 40.10 30.92
WARIMA 10,628.51 9075.32 38.24 30.41
BSTS 16,876.78 15,314.18 45.58 50.17
ARFIMA(2,0.5,1) 12,647.79 11,616.15 47.49 37.56
Hybrid ARIMA-ANN 17,559.43 14,810.82 69.11 41.58
Hybrid WARIMA-ANN 10,841.65 8886.71 35.56 29.76
Hybrid WARIMA-ARNN 10,649.35 9104.54 38.39 30.48
Ensemble ARIMA-ETS-ARNN 16,186 13,705.63 64.26 39.84
Table 14 Performance metrics with 15 days-ahead test set for Russia

RMSE MAE MAPE SMAPE
ARIMA(0,2,3) 307.34 260.18 4.87 5.02
ETS(A,Ad,N) 215.43 178.64 3.36 3.42
SETAR 436.81 383.72 7.19 7.52
TBATS 215.61 178.79 3.36 3.42
Theta 186.06 157.30 2.97 3.01
ANN 367.19 313.66 5.87 6.09
ARNN(3,2) 208.58 184.74 3.61 3.52
WARIMA 568.44 499.58 9.35 9.92
BSTS 160.18 132.28 2.51 2.53
ARFIMA(1,0.1,0) 351.12 297.92 5.57 5.77
Hybrid ARIMA-ANN 308.49 261.17 4.89 5.03
Hybrid WARIMA-ANN 489.38 425.98 7.98 8.38
has the best accuracy among all hybrid/ensemble models (see Table 14). Ensemble
ARIMA-ETS-ARNN and ensemble ARIMA-Theta-ARNN also performs well in the
test period. In-sample and out-of-sample forecasts obtained from BSTS and ensemble
EFN models are depicted in Fig. 7a.
SETAR is found to have the best accuracy metrics for 30-days ahead forecasts
among single forecasting models for Russia COVID-19 data. Ensemble ARIMA-
Theta-ARNN (AFN) model has the best accuracy among all hybrid/ensemble models
(see Table 15). All five ensemble models show promising results for this dataset.
In-sample and out-of-sample forecasts obtained from SETAR and ensemble AFN
models are depicted in Fig. 7b.
Fig. 7 Plots of a 15-days ahead forecast results for Russia COVID-19 data obtained using BSTS and
ETS-Theta-ARNN (EFN) models and b 30-days ahead forecast results from SETAR and ARIMA-
Theta-ARNN (AFN) models
Table 15 Performance metrics with 30 days-ahead test set for Russia

RMSE MAE MAPE SMAPE
ARIMA(1,2,1) 732.12 546.87 10.40 11.44
ETS(A,Ad,N) 337.44 264.40 5.08 5.25
SETAR 285.41 217.23 4.25 4.24
TBATS 337.78 264.62 5.08 5.25
Theta 327.46 297.91 6.04 5.82
ANN 460 340.96 6.48 6.86
ARNN(3,2) 727.63 693.61 13.98 12.97
WARIMA 961.24 727.34 13.86 15.73
BSTS 686.06 509.87 9.79 10.59
ARFIMA(1,0.01,0) 303.35 239.76 4.63 4.74
Hybrid ARIMA-ANN 734.05 548.49 10.43 11.48
Ensemble ETS-Theta-ARNN 337.63 293.23 6 5.77
5.4.5 Results for Peru COVID-19 Data
WARIMA and ARFIMA(2,0.09,1) perform better than other single models for
15-days ahead forecasts in Peru. Hybrid WARIMA-ARNN model improves the
WARIMA forecasts and has the best accuracy among all hybrid/ensemble models
(see Table 16). In-sample and out-of-sample forecasts obtained from WARIMA and
hybrid WARIMA-ARNN models are depicted in Fig. 8a. ARFIMA(2,0,0) and ANN
depict competitive accuracy metrics for 30-days ahead forecasts among single fore-
casting models for Peru COVID-19 data. Ensemble ANN-ARNN-WARIMA (AAW)
model has the best accuracy among all hybrid/ensemble models (see Table 17). In-
sample and out-of-sample forecasts obtained from ARFIMA(2,0,0) and ensemble
AAW models are depicted in Fig. 8b.
Results from all the five datasets reveal that none of the forecasting models per-
forms uniformly, and therefore, one should be carefully select the appropriate fore-
casting model while dealing with COVID-19 datasets.
Table 16 Performance metrics with 15 days-ahead test set for Peru

RMSE MAE MAPE SMAPE
ARIMA(1,1,1) with drift 2275.49 1686.84 49.97 28.99
ETS(M,A,N) 1689.96 1189.05 31.89 23.15
SETAR 1935.78 1286.56 41.57 23.71
TBATS 1944.26 1301.07 41.72 24.06
Theta 1831.88 1146.27 38.37 21.92
ANN 1771.59 1211.24 38.89 22.75
ARNN(15,8) 2564.65 2244.78 57.13 35.78
WARIMA 1659.24 1060.67 35.22 20.85
BSTS 1740.18 1082.16 36.48 21.07
ARFIMA(2,0.09,1) 1712.47 1022.55 35.65 20.13
Hybrid ARIMA-ANN 2189.18 1596.80 47.93 27.96
Fig. 8 Plots of a 15-days ahead forecast results for Peru COVID-19 data obtained using WARIMA
and hybrid WARIMA-ARNN models and b 30-days ahead forecast results from ARFIMA and
ensemble ANN-ARNN-WARIMA (AAW) models
Table 17 Performance metrics with 30 days-ahead test set for Peru

RMSE MAE MAPE SMAPE
ARIMA(1,1,1) with drift 3889.85 3288.04 70.17 41.92
ETS(M,A,N) 7881.14 6892.41 81.37 66.91
SETAR 4598.98 4077.59 83.67 48.90
TBATS 2924.92 2366.84 52.90 33.13
Theta 3862.84 3374.84 70.68 42.93
ANN 2183.98 1818.07 30.57 32.12
ARNN(15,8) 2833.39 2339.49 49.10 32.92
WARIMA 5579.69 4840.75 89.04 54.14
BSTS 5422.13 4851.34 87.98 54.82
ARFIMA(2,0,0) 2052.01 1513.62 35.37 23.27
Hybrid ARIMA-ANN 3756.5 3131.88 67.50 40.46
6 Discussions
In this study, we assessed several individuals and combined statistical learning mod-
els on the confirmed cases of COVID-19 data sets for the five countries, namely
the USA, India, Brazil, Russia, and Peru. These COVID-19 daily cases datasets
mostly exhibit nonlinear and nonstationary behavior. Twenty forecasting models
were applied to five datasets, and an empirical comparison is presented here. All
five different countries, except Brazil and Peru, will face a diminishing trend in the
number of new confirmed cases of the COVID-19 pandemic. Based on the short-term
out of sample forecasts reported in this study, the lockdown and shutdown periods
can be adjusted accordingly to handle the uncertain and vulnerable situations of
the COVID-19 pandemic. Authorities and health care can modify their planning in
stockpiles and hospital-beds, depending on these COVID-19 pandemic forecasts.
The empirical findings suggest no universal method exists that can outperform
every other model for all the datasets in COVID-19 nowcasting. Still, the future
forecasts obtained from models with the best accuracy will be useful in decision
and policy makings for government officials and policymakers to allocate adequate
health care resources for the coming days in responding to the crisis. However, we
recommend updating the datasets regularly and comparing the accuracy metrics to
obtain the best model. As this is evident from this empirical study that no model
can perform consistently as the best forecasting model, one must update the datasets
regularly to generate useful forecasts. Time series of epidemics can oscillate heavily
due to various epidemiological factors, and these fluctuations are challenging to be
captured adequately for precise forecasting.
7 Conclusion and Future Challenges
In this research, we have focused on analyzing the nature of the COVID-19 time series
data and understanding the data characteristics of the time series. This empirical work
studied a wide range of statistical forecasting methods and machine learning algo-
rithms. We have also presented more systematic representations of single, ensemble,
and hybrid approaches available for epidemic forecasting. This quantitative study
could be used to assess the COVID-19 confirmed case forecasts and will benefit
epidemiologists and modelers working on COVID-19 forecasting and modeling.
Considering the scope of this study, we present a set of challenges of pandemic
forecasting (short-term) with the available forecasting tools presented in this chapter.
To obtain better out-of-sample forecasts of daily COVID-19 cases, it is necessary to
(a) collect more data on the factors that contribute to daily confirmed cases of COVID-
19; (b) model the entire predictive distribution, with particular focus on accurately
quantifying uncertainty [51]; and (c) continuously monitor the performance of any
model against real data and either re-adjust or discard models based on accruing
evidence. It is confirmed from the experimental study that there is no universal
model that can generate ‘best’ short-term forecasts of COVID-19 confirmed cases.
Epidemiological estimates and compartmental models can be useful for long-term
pandemic trajectory prediction, but they often assume some unrealistic assumptions
[60]. Thus, future research is needed to collect, clean, and curate data and develop
a coherent approach to evaluate the suitability of models with regard to COVID-19
predictions and forecast uncertainties.
Data and Codes
For the sake of repeatability and reproducibility of this study, all codes and data sets
are made available at https://github.com/indrajitg-r/Forecasting-COVID-19-cases.
References
1. Aleta, A., Martin-Corral, D., Piontti, A.P., Ajelli, M., Litvinova, M., Chinazzi, M., Dean, N.E.,
Halloran, M.E., Longini Jr, I.M., Merler, S., et al.: Modeling the impact of social distancing,
testing, contact tracing and household quarantine on second-wave scenarios of the Covid-19
epidemic. medRxiv (2020)
2. Aminghafari, M., Poggi, J.M.: Forecasting time series using wavelets. Int. J. Wavelets Mul-
tiresolut. Inf. Process. 5(05), 709–724 (2007)
3. Anastassopoulou, C., Russo, L., Tsakris, A., Siettos, C.: Data-based analysis, modelling and
forecasting of the Covid-19 outbreak. PLoS ONE 15(3) (2020)
4. Anderson, R.M., Anderson, B., May, R.M.: Infectious Diseases of Humans: Dynamics and
Control. Oxford University Press, Oxford (1992)
5. Annas, S., Pratama, M.I., Rifandi, M., Sanusi, W., Side, S.: Stability analysis and numerical
simulation of Seir model for pandemic Covid-19 spread in Indonesia. Chaos, Solitons Fractals
139 (2020)
6. Antonio, F.D.N., Hegger, H.K., Schreiber, T., Di Narzo, M.A.F.: Package ‘tserieschaos’.
dimension 1 (2013)
7. Armstrong, J.S.: Principles of Forecasting: A Handbook for Researchers and Practitioners,
vol 30. Springer Science & Business Media (2001)
8. Assimakopoulos, V., Nikolopoulos, K.: The theta model: a decomposition approach to fore-
casting. Int. J. Forecast. 16(4), 521–530 (2000)
9. Bates, J.M., Granger, C.W.: The combination of forecasts. J. Oper. Res. Soc. 20(4), 451–468
(1969)
10. Baud, D., Qi, X., Nielsen-Saines, K., Musso, D., Pomar, L., Favre, G.: Real estimates of
mortality following Covid-19 infection. Lancet Infect, Dis (2020)
11. Benettin, G., Galgani, L., Giorgilli, A., Strelcyn, J.M.: Lyapunov characteristic exponents for
smooth dynamical systems and for Hamiltonian systems; a method for computing all of them,
part 1: Theory. Meccanica 15(1), 9–20 (1980)
12. Black, R., Hurst, H., Simaika, Y.: Long-term storage: an experimental study. Constable (1965)
13. Borchers, H.W., Borchers, M.H.W.: Package ‘pracma’ (2019)
14. Bordley, R.F.: The combination of forecasts: a Bayesian approach. J. Oper. Res. Soc. 33(2),
171–174 (1982)
15. Box, G.E., Pierce, D.A.: Distribution of residual autocorrelations in autoregressive-integrated
moving average time series models. J. Am. Stat. Assoc. 65(332), 1509–1526 (1970)
16. Box, G.E., Jenkins, G.M., Reinsel, G.C., Ljung, G.M.: Time Series Analysis: Forecasting and
Control. Wiley, New York (2015)
17. Brady, O.J., Gething, P.W., Bhatt, S., Messina, J.P., Brownstein, J.S., Hoen, A.G., Moyes,
C.L., Farlow, A.W., Scott, T.W., Hay, S.I.: Refining the global spatial limits of dengue virus
transmission by evidence-based consensus. PLoS Negl. Trop. Dis. 6(8) (2012)
18. Brockwell, P.J., Davis, R.A,. Fienberg, S.E.: Time Series: Theory and Methods: Theory and
Methods. Springer Science & Business Media (1991)
19. Buczak, A.L., Baugher, B., Moniz, L.J., Bagley, T., Babin, S.M., Guven, E.: Ensemble method
for dengue prediction. PLoS ONE 13(1) (2018)
20. Chakraborty, T., Ghosh, I.: Real-time forecasts and risk assessment of novel coronavirus
(Covid-19) cases: A data-driven analysis, p. 135. Chaos, Solitons and Fractals (2020)
21. Chakraborty, T., Chattopadhyay, S., Ghosh, I.: Forecasting Dengue Epidemics Using a Hybrid
Methodology. Physica A: Statistical Mechanics and its Applications, p. 121266 (2019)
22. Chakraborty, T., Bhattacharyya, A., Pattnaik, M.: Theta autoregressive neural network model
for Covid-19 outbreak predictions. medRxiv (2020)
23. Chatfield, C.: Time-Series Forecasting. CRC Press, Boca Raton (2000)
24. Chatfield, C.: The Analysis of Time Series: An Introduction. Chapman and Hall/CRC (2016)
25. Chen, Y.C., Lu, P.E., Chang, C.S., Liu, T.H.: A time-dependent sir model for Covid-19 with
undetectable infected persons. IEEE Trans. Netw. Sci, Eng (2020)
26. Clemen, R.T.: Combining forecasts: a review and annotated bibliography. Int. J. Forecast.
5(4), 559–583 (1989)
27. De Gooijer, J.G., Hyndman, R.J.: 25 years of time series forecasting. Int. J. Forecast. 22(3),
443–473 (2006)
28. De Livera, A.M., Hyndman, R.J., Snyder, R.D.: Forecasting time series with complex seasonal
patterns using exponential smoothing. J. Am. Stat. Assoc. 106(496), 1513–1527 (2011)
29. Di Narzo, A.F., Aznarte, J.L., Stigler, M.: Package ’tsdyn’ (2020)
30. Emanuel, E.J., Persad, G., Upshur, R., Thome, B., Parker, M., Glickman, A., Zhang, C.,
Boyle, C., Smith, M., Phillips, J.P.: Fair allocation of scarce medical resources in the time of
Covid-19 (2020)
31. Fanelli, D., Piazza, F.: Analysis and forecast of Covid-19 spreading in China, Italy and France.
Chaos, Solitons Fractals 134 (2020)
32. Faraway, J., Chatfield, C.: Time series forecasting with neural networks: a comparative study
using the air line data. J. Roy. Stat. Soc.: Ser. C (Appl. Stat.) 47(2), 231–250 (1998)
33. Farmer, J.D.: Chaotic attractors of an infinite-dimensional dynamical system. Phys. D 4(3),
366–393 (1982)
34. Farmer, J.D., Sidorowich, J.J.: Predicting chaotic time series. Phys. Rev. Lett. 59(8), 845
(1987)
35. Ferguson, N., Laydon, D., Nedjati Gilani, G., Imai, N., Ainslie, K., Baguelin, M., Bhatia,
S., Boonyasiri, A., Cucunuba Perez, Z., Cuomo-Dannenburg, G., et al.: Report 9: Impact of
non-pharmaceutical interventions (npis) to reduce Covid19 mortality and healthcare demand
(2020)
36. Franses, P.H., Van Dijk, D., et al.: Non-linear Time Series Models in Empirical Finance.
Cambridge University Press, Cambridge (2000)
37. Garcia, C., Sawitzki, G.: Nonlinear tseries: nonlinear time series analysis (2015)
38. Ghosh, I., Chakraborty, T.: An integrated deterministic-stochastic approach for forecasting the
long-term trajectories of Covid-19 (2020). medRxiv preprint https://doi.org/101101/202005
39. Goodfellow, I., Bengio, Y., Courville, A., Bengio, Y.: Deep Learning, vol. 1. MIT Press
Cambridge, Cambridge (2016)
40. Granger, C.W., Joyeux, R.: An introduction to long-memory time series models and fractional
differencing. J. Time Ser. Anal. 1(1), 15–29 (1980)
41. Granger, C.W., Ramanathan, R.: Improved methods of combining forecasts. J. Forecast. 3(2),
197–204 (1984)
42. Grasselli, G., Pesenti, A., Cecconi, M.: Critical care utilization for the Covid-19 outbreak in
Lombardy, Italy: early experience and forecast during an emergency response. JAMA 323(16),
1545–1546 (2020)
43. Groeneveld, R.A., Meeden, G.: Measuring skewness and kurtosis. J. R. Stat. Soc. Ser. D (The
Statistician) 33(4), 391–399 (1984)
44. Guan, W.J., Zy, N.I., Hu, Y., Liang, W.h., Ou, C.Q., He, J.X., Liu, L., Shan, H., Lei, C.L., Hui,
D.S., et al.: Clinical characteristics of Coronavirus disease 2019 in China. N. Engl. J. Med.
382(18), 1708–1720 (2020)
45. Hanke, J.E., Reitsch, A.G., Wichern, D.W.: Business Forecasting, Vol. 9. Prentice Hall New
Jersey (2001)
46. Haslett, J., Raftery, A.E.: Space-time modelling with long-memory dependence: assessing
Ireland’s wind power resource. J. Roy. Stat. Soc.: Ser. C (Appl. Stat.) 38(1), 1–21 (1989)
47. Hastie, T., Tibshirani, R., Friedman, J.: The Elements of Statistical Learning: Data Mining,
Inference, and Prediction. Springer Science & Business Media (2009)
48. He, S., Peng, Y., Sun, K.: Seir modeling of the Covid-19 and its dynamics. Nonlinear Dyn.
1–14 (2020)
49. Hegger, R., Kantz, H., Schreiber, T.: Practical implementation of nonlinear time series meth-
ods: the Tisean package. Chaos: Interdisc. J. Nonlinear Sci. 9(2), 413–435 (1999)
Kucharski, A.J., Edmunds, W.J., Sun, F., et al.: Feasibility of controlling Covid-19 outbreaks
by isolation of cases and contacts. Lancet Global Health (2020)
51. Holmdahl, I., Buckee, C.: Wrong but useful-what Covid-19 epidemiologic models can and
cannot tell us. New Engl. J, Med (2020)
52. Hou, C., Chen, J., Zhou, Y., Hua, L., Yuan, J., He, S., Guo, Y., Zhang, S., Jia, Q., Zhao, C.,
et al.: The effectiveness of quarantine of Wuhan city against the corona virus disease 2019
(Covid-19): a well-mixed seir model analysis. J. Med, Virol (2020)
53. Hu, Z., Ge, Q., Jin, L., Xiong, M.: Artificial intelligence forecasting of Covid-19 in China
(2020). arXiv preprint arXiv:200207112
54. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al.:
Clinical features of patients infected with 2019 novel coronavirus in wuhan, china. Lancet
395(10223), 497–506 (2020)
55. Hyndman, R., Koehler, A.B., Ord, J.K., Snyder, R.D.: Forecasting with Exponential Smooth-
ing: The State Space Approach. Springer Science & Business Media (2008)
56. Hyndman, R.J., Athanasopoulos, G.: Forecasting: principles and practice. OTexts (2018)
57. Hyndman, R.J., Billah, B.: Unmasking the theta method. Int. J. Forecast. 19(2), 287–290
(2003)
58. Hyndman, R.J., Khandakar, Y., et al.: Automatic Time Series for Forecasting: The Forecast
Package for R. 6/07, Monash University, Department of Econometrics and Business Statistics
(2007)
59. Hyndman, R.J., Athanasopoulos, G., Bergmeir, C., Caceres, G., Chhay, L., O’Hara-Wild,
M., Petropoulos, F., Razbash, S., Wang, E.: Package ‘forecast’ (2020). Https://cran.r-
project.org/web/packages/forecast/forecast
60. Ioannidis, J.P., Cripps, S., Tanner, M.A.: Forecasting for Covid-19 has failed. Int. J. Forecast.
(2020)
61. James, G., Witten, D., Hastie, T., Tibshirani, R.: An introduction to Statistical Learning, Vol.
112. Springer (2013)
62. Jammalamadaka, S.R., Qiu, J., Ning, N.: Multivariate bayesian structural time series model.
J. Mach. Learn. Res. 19(1), 2744–2776 (2018)
63. Kantz, H., Schreiber, T.: Nonlinear time series analysis, vol. 7. Cambridge University Press,
Cambridge (2004)
64. Khashei, M., Bijari, M.: An artificial neural network (p, d, q) model for timeseries forecasting.
Expert Syst. Appl. 37(1), 479–489 (2010)
65. Kim, H.Y.: Statistical notes for clinical researchers: assessing normal distribution (2) using
skewness and kurtosis. Restorative Dentist. Endodontics 38(1), 52–54 (2013)
66. Kissler, S.M., Tedijanto, C., Goldstein, E., Grad, Y.H., Lipsitch, M.: Projecting the transmis-
sion dynamics of sars-cov-2 through the postpandemic period. Science 368(6493), 860–868
(2020)
67. Kourentzes, N.: Nnfor: Time series forecasting with neural networks (2017a)
68. Kourentzes, N.: nnfor: Time series forecasting with neural networks. r package version 0.9.
6 (2017b)
F., Jit, M., Munday, J.D., et al.: Early dynamics of transmission and control of covid-19: a
mathematical modelling study. Lancet Infect, Dis (2020)
70. Lemke, C., Gabrys, B.: Meta-learning for time series forecasting and forecast combination.
Neurocomputing 73(10–12), 2006–2016 (2010)
71. Lemke, C., Budka, M., Gabrys, B.: Metalearning: a survey of trends and technologies. Artif.
Intell. Rev. 44(1), 117–130 (2015)
72. Li, Q., Feng, W., Quan, Y.H.: Trend and forecasting of the Covid-19 outbreak in China. J.
Infect. 80(4), 469–496 (2020)
73. López, L., Rodó, X.: The end of social confinement and covid-19 re-emergence risk. Nat.
Hum. Behav. 4(7), 746–755 (2020)
74. Makridakis, S., Hibon, M.: Arma models and the box-jenkins methodology. J. Forecast. 16(3),
147–163 (1997)
75. Maleki, M., Mahmoudi, M.R., Wraith, D., Pho, K.H.: Time series modelling to forecast the
confirmed and recovered cases of Covid-19. Travel Med. Infect. Dis. 101742 (2020)
76. Messina, J.P., Brady, O.J., Scott, T.W., Zou, C., Pigott, D.M., Duda, K.A., Bhatt, S., Katzelnick,
L., Howes, R.E., Battle, K.E., et al.: Global spread of dengue virus types: mapping the 70
year history. Trends Microbiol. 22(3), 138–146 (2014)
77. Meyer, D., Dimitriadou, E., Hornik, K., Weingessel, A., Leisch, F., Chang, C.C., Lin, C.C.,
Meyer, M.D.: Package ‘e1071’. R J. (2019)
78. Montero-Manso, P., Athanasopoulos, G., Hyndman, R.J., Talagala, T.S.: Fforma: Feature-
based forecast model averaging. Int. J. Forecast. 36(1), 86–92 (2020)
79. Mood, A.M.: Introduction to the Theory of Statistics. McGraw-Hill (1950)
80. Mosleh, A., Apostolakis, G.: The assessment of probability distributions from expert opinions
with an application to seismic fragility curves. Risk Anal. 6(4), 447–461 (1986)
81. Mossong, J., Hens, N., Jit, M., Beutels, P., Auranen, K., Mikolajczyk, R., Massari, M.,
Salmaso, S., Tomba, G.S., Wallinga, J., et al.: Social contacts and mixing patterns relevant to
the spread of infectious diseases. PLoS Med. 5(3), (2008)
82. Nury, A.H., Hasan, K., Alam, M.J.B.: Comparative study of wavelet-arima and wavelet-ann
models for temperature time series data in northeastern bangladesh. J. King Saud Univ.-Sci.
29(1), 47–61 (2017)
83. Paul, R.K., Samanta, S., Paul, M.R.K., LazyData, T.: Package ‘waveletarima’. Seed 500, 1–5
(2017)
84. Percival, D.B., Walden, A.T.: Wavelet Methods for Time Series Analysis, Vol. 4. Cambridge
University Press (2000)
85. Petersen, E., Koopmans, M., Go, U., Hamer, D.H., Petrosillo, N., Castelli, F., Storgaard, M.,
Al Khalili, S., Simonsen, L.: Comparing sars-cov-2 with sars-cov and influenza pandemics.
Lancet Infect, Dis (2020)
86. Peterson, B.G., Carl, P., Boudt, K., Bennett, R., Ulrich, J., Zivot, E., Cornilly, D., Hung,
E., Lestel, M., Balkissoon, K., et al.: Package ‘performanceanalytics’. R Team Cooperation
(2018)
87. Petropoulos, F., Makridakis, S.: Forecasting the novel coronavirus Covid-19. PLoS ONE
15(3) (2020)
88. Philemon, M.D., Ismail, Z., Dare, J.: A review of epidemic forecasting using artificial neural
networks. Int. J. Epidemiol. Res. 6(3), 132–143 (2019)
89. Phillips, P.C., Perron, P.: Testing for a unit root in time series regression. Biometrika 75(2),
335–346 (1988)
90. Pumi, G., Valk, M., Bisognin, C., Bayer, F.M., Prass, T.S.: Beta autoregressive fractionally
integrated moving average models. J. Stat. Plann. Inference 200, 196–212 (2019)
91. Rajgor, D.D., Lee, M.H., Archuleta, S., Bagdasarian, N., Quek, S.C.: The many estimates of
the covid-19 case fatality rate. Lancet. Infect. Dis 20(7), 776–777 (2020)
92. Ray, D., Salvatore, M., Bhattacharyya, R., Wang, L., Du, J., Mohammed, S., Purkayastha,
S., Halder, A., Rix, A., Barker, D., et al.: Predictions, role of interventions and effects of a
historic national lockdown in india’s response to the covid-19 pandemic: data science call to
arms. Harvard Data Sci. Rev. 2020(Suppl 1), (2020)
93. Ribeiro, M.H.D.M., da Silva, R.G., Mariani, V.C., dos Santos Coelho, L.: Short-term forecast-
ing covid-19 cumulative confirmed cases: perspectives for brazil. Chaos, Solitons Fractals,
109853 (2020)
94. Robinson, P.M.: Log-periodogram regression of time series with long range dependence. Ann.
Stat. 1048–1072 (1995)
95. Roosa, K., Lee, Y., Luo, R., Kirpich, A., Rothenberg, R., Hyman, J., Yan, P., Chowell, G.:
Real-time forecasts of the covid-19 epidemic in China from february 5th to february 24th,
2020. Infect. Dis. Modell. 5, 256–263 (2020)
96. Rosenbaum, L.: Facing Covid-19 in Italy-ethics, logistics, and therapeutics on the epidemic’s
front line. N. Engl. J. Med. 382(20), 1873–1875 (2020)
97. Rosenstein, M.T., Collins, J.J., De Luca, C.J.: A practical method for calculating largest
lyapunov exponents from small data sets. Phys. D 65(1–2), 117–134 (1993)
98. Rumelhart, D.E., Hinton, G.E., Williams, R.J.: Learning internal representations by error
propagation. California Univ San Diego La Jolla Inst for Cognitive Science, Tech. rep (1985)
99. Scott, S.L., Varian, H.R.: Bayesian variable selection for nowcasting economic time series.
Tech. rep, National Bureau of Economic Research (2013)
100. Scott, S.L., Varian, H.R.: Predicting the present with bayesian structural time series. Int. J.
Math. Modell. Numer. Optim. 5(1–2), 4–23 (2014)
101. Scott, S.L., Scott, M.S.L., Scott, M.S., BoomSpikeSlab, D., Boom, L.: Package ‘bsts’ (2020)
102. Shaub, D.: Fast and accurate yearly time series forecasting with forecast combinations. Int.
J. Forecast. 36(1), 116–120 (2020)
103. Shaub, D., Ellis, P.: forecasthybrid: Convenient functions for ensemble time series forecasts.
R package: https://CRANR-projectorg/package=forecastHybrid 4(17), 238 (2019)
104. Shin, Y., Schmidt, P.: The kpss stationarity test as a unit root test. Econ. Lett. 38(4), 387–392
(1992)
105. Smith, J., Wallis, K.F.: A simple explanation of the forecast combination puzzle. Oxford Bull.
Econ. Stat. 71(3), 331–355 (2009)
106. Spiliotis, E., Assimakopoulos, V., Makridakis, S.: Generalizing the theta method for automatic
forecasting. Eur. J. Oper. Res. 284(2), 550–558 (2020)
107. Sujath, R., Chatterjee, J.M., Hassanien, A.E.: A machine learning forecasting model for covid-
19 pandemic in India. Stochastic Environmental Research and Risk Assessment p. 1 (2020)
108. Teräsvirta, T., Lin, C.F., Granger, C.W.: Power of the neural network linearity test. J. Time
Ser. Anal. 14(2), 209–220 (1993)
109. Teräsvirta, T., Van Dijk, D., Medeiros, M.C.: Linear models, smooth transition autoregres-
sions, and neural networks for forecasting macroeconomic time series: a re-examination. Int.
J. Forecast. 21(4), 755–774 (2005)
110. Timmermann, A.: Forecast combinations. handbook of economic forecasting (2006)
111. Tong, H.: Non-linear Time Series: A Dynamical System Approach. Oxford University Press
(1990)
112. Tong, H.: Nonlinear time series analysis since 1990: Some personal reflections. Acta Math.
Appl. Sin. 18(2), 177 (2002)
113. Trapletti, A., Hornik, K., LeBaron, B.: tseries: Time series analysis and computational finance.
R package version 010–11 (2007)
114. Trilla, A., Trilla, G., Daer, C.: The 1918 “spanish flu” in spain. Clin. Infect. Dis. 47(5),
668–673 (2008)
115. Tsay, R.S.: Nonlinearity tests for time series. Biometrika 73(2), 461–466 (1986)
116. Tsay, R.S.: Time series and forecasting: Brief history and future research. J. Am. Stat. Assoc.
95(450), 638–643 (2000)
117. Wang, W.S.: Multiple time scales analysis of hydrological time series with wavelet transform.
J. Sichuan Univ. Eng. Sci. Edn. 34(6), 14–17 (2002)
118. Wang, X., Smith-Miles, K., Hyndman, R.: Rule induction for forecasting method selection:
meta-learning the characteristics of univariate time series. Neurocomputing 72(10–12), 2581–
2594 (2009)
119. Weinberger, D.M., Cohen, T., Crawford, F.W., Mostashari, F., Olson, D., Pitzer, V.E., Reich,
N.G., Russi, M., Simonsen, L., Watkins, A., et al.: Estimating the early death toll of covid-19
in the United States. bioRxiv (2020)
120. Winters, P.R.: Forecasting sales by exponentially weighted moving averages. Manage. Sci.
6(3), 324–342 (1960)
121. Wolpert, D.H., Macready, W.G.: No free lunch theorems for optimization. IEEE Trans. Evol.
Comput. 1(1), 67–82 (1997)
international spread of the 2019-ncov outbreak originating in wuhan, china: a modelling study.
Lancet 395(10225), 689–697 (2020)
123. Zhang, G., Patuwo, B.E., Hu, M.Y.: Forecasting with artificial neural networks: the state of
the art. Int. J. Forecast. 14(1), 35–62 (1998)
124. Zhang, G.P.: Time series forecasting using a hybrid arima and neural network model. Neuro-
computing 50, 159–175 (2003)
125. Zhang, G.P., Qi, M.: Neural network forecasting for seasonal and trend time series. Eur. J.
Oper. Res. 160(2), 501–514 (2005)
126. Zhuang, Z., Cao, P., Zhao, S., Lou, Y., Wang, W., Yang, S., Yang, L., He, D.: Estimation of
local novel coronavirus (covid-19) cases in wuhan, china from off-site reported cases and
population flow data from different sources. medRxiv (2020)
Covid-19 Pandemic and Coronaviruses
from Discovery to Treatment: A Tale
of Two Decades of 21st Century
Muhammad Akhlaq , Zaheer-Ud-Din Babar, Mahvish Ajaz,

Muzammil Ahmad Khan, Erkan Kilinc, Muhammad Adeel,
Muhammad Badar, Asif Nawaz, and Aamir Jalil
Abstract A new world map was led to progression after Pandemic Covid-19. The
said arrangement narrowed the circle of life. A huge number of literatures could be
seen on the electronic screens especially in 2020. But, truly observing one may find
the word “Corona” early in the twenty-first century starting from China with a minor
pandemic approach. Later in 2012 and now in 2019 and 2020 with an enormous
spread around the globe. The current compilation comprehends the published litera-
ture on Pandemic Covid-19, summarizing the outbreak, diagnosis, management and
the treatments including natural and synthetic molecules, during the last two decades.
Keywords Pandemic approaches · Corona life · Sars viruses · Corona impact
1 Introduction
Pandemic Covid-19 categorically led to the development of a new world map; before
and after the outbreak of coronavirus early in 2020. The whispered virus made the
life hard in low-to-middle income countries. The corona and hunger viruses hunted
M. Akhlaq (B) · M. A. Khan · M. Adeel · M. Badar · A. Nawaz

Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan
e-mail: dr.akhlaq@gu.edu.pk
Z.-U.-D. Babar
School of Applied Sciences, University of Huddersfield, Huddersfield, UK
M. Ajaz
Department of Eastern Medicines and Surgery, University of Poonch, Rawalkot, Azad Kashmir,
Pakistan
E. Kilinc
Medical Faculty, Department of Physiology, Bolu Abant Izzet Baysal University, Bolu, Turkey
A. Jalil
Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of
Pharmacy, University of Innsbruck, Innsbruck, Austria
1066 M. Akhlaq et al.
the humans altogether in joint venture. China stood pioneer in designing the corona-
atlas. Europe and United State proved to be more efficient and effectual in gaining
the adversities. The globe soon after the outbreak filled with the dead bodies within
a short span of seven months only.
Diagnostic as well as the treatment tools were then made alive to support and
shoulder the survivors. Both natural and synthetics resources have continuously been
browbeaten by the scientists to extract the antidot of the outburst. A list of treat-
ment submissions could be seen on the electronic devices to defeat the coronavirus.
Antiviral drugs were thrown in the market as a suitable source for the treatment
against coronavirus. Adjuvants as non-antiviral drugs were also thought to be the
best treatment modes. The number of recoveries proved that the anticipations are
still there. Hopes then thrived throughout the brains of the thinkers, scholars and
scientists all over the world unanimously to save and secure the humanity. Each day
brought new approaches of endurance put forward by the medical, pharmaceutical
and chemical scientists, leading to anticipations of a glorious victory ahead against
COVID-19.
2 Pandemic Disaster and Control Methodologies
2.1 The Outburst of Covid-19
Outbreak of coronavirus (Covid-19) was first received by W.H.O. from Chinese

Officials highlighting pneumonia caused by unknown virus dated December 2019
in Wuhan city [1]. In order to control the spread Chinese officials placed de-facto
quarantine encircle uptight 50.0 million people in Hubei province from Wuhan and
nearby cities [2]. The situation was alarming around the globe, but no containment
strategies were being planned by the rest of the world to save the spread of virus.
Hence, the outbreak started traveling straight from china initially to Italy, Iran and
Europe. Significantly the virus spread in the European countries and hited much
harder in comparison to china. The first set out for the corona virus was detected in
Italy the most travel destination in the world along with 93 countries across all five
continents. The W.H.O. officially declared the Pandemic outbreak of Covid-19 on
11, March 2020. However, on 31, January 2020 WHO formerly deputed Covid-19
a “Public Health Emergency of International Concern” but was reluctant to name
it pandemic at that time, which was a big mistake [3]. So, no serious international
concerns were publicized and no health warnings were issued up till that time. The
inter air-links were not closed that contributed in fast spread of the disease. The travel
from China transmit infection to utmost countries counting Germany, Russia, India,
USA, Italy, Korea [4].
Covid-19 Pandemic and Coronaviruses from Discovery to Treatment … 1067
3 Corona Atlas on Globe
No doubt, the outbreak began in Wuhan, China is one of the most populous cities in
the world. The Chinese government took preventive measures on time to control the
infectious disease by separating affected regions. But in no time, this virus travels
from china to other parts of the world including Europe specially Italy, showing
its worst effects in short time. The world was socially, economically and politically
resketched due to emerging Covid-19 threat. It stretches its drastic effects from Africa
to Latin America [5]. According to the current statistics the Pandemic Covid-19
worldwide confirmed, recovered and deaths cases are shown in Figs. 1 and 2.
Initially, over 82,870 cases and 3339 deaths have been accepted by Chinese
health authorities and endured the blemishes of Covid-19. However, by doing control
measures the 5000 cases per day were declined to 39 new cases in Mid-February
which was an exceptional achievement. Hence in the world new cases were imported
from other countries, but for now China has its outbreak under control. However,
the outbreak started to revive in the rest of the world, things were downturn in
china [6]. At Least 214 countries and territories are now confirmed with Covid-
19. Highest number of Covid-19 has been recorded in the US, India, Brazil and
Russia. The highest number of deaths were also recorded in USA Europe having
219,343 including 61 new deaths, in India 108,523 including 152 new deaths, in
Brazil 150,338 including 102 new deaths [7].
Spain had the second highest number of cases numbering 148,220 confirmed
infections and 14,792 deaths. All the schools, non-essential supermarkets, bars and
restaurants were sealed by the government and the citizens were in complete lock-
down. The citizens were only allowed to leave their home to go to work and to buy
food [8]. State of Bavaria Germany enforced a complete lockdown as the confirmed
cases of infection raises to 113,296 and death toll up to 2,349, however, it was much
lower in comparison to other European places [9]. However, number of people recov-
ering from infection, but spreading at the fastest rate due its contagious nature. Yet
there is a progressive increase in number of coronavirus cases. Globally 34.9 million
Covid-19 cases were reported and 1 million deaths since China reported its first cases
[10]. It is also expected that in winter the pandemic will again hit badly in winters
as the temperature drops drown below the freezing point in some parts of the world.
3.1 Journey of Coronaviruses and Emergence of Covid-19
Coronaviruses (coronaviridae) considered to be responsible for gastrointestinal,

respiratory, hepatic and neurological diseases in animals and humans. RNA viruses
are famous for their highest rate of mutation and offenly become inert causing no
infections. The first coronavirus was isolated in 1937 from chicken embryos. Initially,
cases of Severe Acute Respiratory Syndrome (SARS) emerged as communicable
disease reported in southern China with challenging indisposition and mortality with
Fig. 1 The schematic diagram portraying the latest world map in the context of pandemic Covid-19
with confirmed cases round the globe in a single screenshot, showing United states, Spain, Italy,
Germany, France, China, United Kingdome and Iran in pandemic region with deep-rooted cases
and higher death toll, the data was retrieved on October 4, 2020 [10]
a high rate of transmission between humans [11]. SARS-COV was introduced in

humans from the civet cats and bats were considered as the basic reservoir hosts [12].
Early in 2003, there was a serious outbreak of SARS in Hong Kong and within a
couple of days, the disease was blown out to the states of Singapore, Canada, Taiwan,
Germany and America. Within a period of two month 7296 cases were reported in
almost 30 countries, with a death clatter of 526 humans [13]. Another, coronavirus
Fig. 2 Diagrammatic representation of total number of confirmed, death and recovered cases of
pandemic Covid-19 worldwide. The data was retrieved on October 4, 2020 [7]
outbreak was reported by WHO in September 2012 as a Novel Middle East Respira-
tory Syndrome Coronavirus (MERSCov) causing severe pneumonia in humans. But
fortunately, It was only transmitted from person to person only in healthcare settings.
Shortly thereafter the Human Coronavirus England 1 was recovered. The inception
of disease was drawn back to even a previous spell of 2012 when a number of cases
were reported in health workers in Jordan at hospital [14]. The genome arrangements
were investigated for the three virus collected from Saudi Arabia (JX869059.2),
Jordan (KC776174.1), and United Kingdom (KC164505.2). It was discovered that
> 99% sequence similarity was found (∼100 nucleotide variations in a 30.1-kb
genome), signifying that the three viruses are breed from a common antecedent.
Recently, in December 2019 patients reported with symptoms of pneumonia having
unknow prophylaxis in Wuhan, China. It was identified as a viral infection and later
on discovered as a novel coronavirus (SARS-CoV 2, KCDC03) and the disease was
named as Covid-19 by WHO [15].
Coronaviruses have the ability to infect both human as well as animals and may
spread via direct contact with a contaminated surface or via droplets produced during
sneezing, coughing or louder talking both by symptomatic as well as asymptomatic
cases [15].
Epidemic studies have shown that SARS-CoV-2 is a third reported spillover of
zoonotic coronaviruses to humans in only two decades that became pandemic from
epidemic. Owing to the zoonotic nature of infection, it’s not unlikely that other novel
coronaviruses might emerge as epidemics and cause global emergencies in near
future [16]. Chu et al. explained that six zoonotic corona viruses have been reported
in humans so far, and it is the 7th in a row (SARS-CoV-2). Family of corona virus
consists of four genera i.e. α, β, γ, and δ, in which SARS-CoV-2 belongs to the beta
subgroup and are the largest among the RNA viruses [17]. The genome of SAR-CoV-
2 comprises 30,000 bp, contains 15 genes, which encodes four different structural
proteins named Envelope (E), Membrane (M), Nucleocapsid (N) and Spike (S) and
Non- Structural Proteins [18]. The Spike (S) proteins help the virus to anchor the
host cells and make their entry. Spike proteins are considered important in terms of
adaptation to various hosts, as their receptor binding domain is the most variable
region because of random mutations. The non-structural proteins on the other hand
are reported to be conserved instead [19, 20].
4 Identification and Diagnostic Approaches of Covid-19
In COVID-19 pandemic situation, diagnosis and isolation of suspects is currently

the best strategy to prevents its spread, until the researcher launches safe and vali-
dated treatment approach. Several research articles have been published during this
very short time span regarding the perfect diagnosis of SARS-CoV-2 virus infec-
tion. Of these researches, Dong et al. [21] has established RT-qPCR technique as the
only gold standard method for diagnosis and detection of SARS-CoV-2 in suspected
persons. Moreover, they also focused on Digital Droplet PCR (ddPCR) technique
which is more precise and sensitive method of detection with improved diagnostic
capability in comparison to normal TaqMan assay. In current ongoing situation, FDA
has enlisted several companies that have developed RT-PCR based molecular diag-
nostic assays. Some of these have obtained FDA emergency approval and some are
under consideration (visit FDA website for details). In addition, immunodiagnostic
based point of care tests have also been developed, however, it has low reliability.
Parallel to this, selection of correct specimen also has a significant impact on diag-
nostic efficiency [21]. Wang et al. [6] also performed test to detect SARS-CoV-2 via
RT-PCR in range of different specimens (during disease onset) that include Feces,
Sputum, Blood, Urine, Nasal sample, Bronchoalveolar Lavage, Fibrobroncho-scope
brush Biopsy. Their investigation revealed that Bronchoalveolar lavage fluid had the
highest probability of identifying the virus in comparison to Blood, Nasal Swabs,
Sputum, Feces, Fibrobroncho-scope Brush Biopsy however, it was not detected in
urine specimens. Hence, it shows that the virus may be transmitted via these routes,
beside the respiratory droplets of infected person [22].
4.1 COVID-19 Testing Techniques
Two kinds of tests are available for COVID-19; theses are virus detection testing
and antibodies tests. A viral test can exactly tell you about current infection status.
Whereas an antibodies based testing reveals that whether infection is still present or
an immune response has been generated. However, later one is not specific about the
disease type and can give a false positive detection of the infection. Other techniques
include; checking for elevated body temperature, or low blood oxygen level.
4.1.1 Detection of Virus via PCR and CRISPR
Virus is detected by known technique of Reverse transcription polymerase chain

reaction. In polymerase chain reaction (PCR) a small amount of well-defined segment
of DNA was amplified many hundreds of thousands of times, creating enough of it
for analysis. Test samples are treated with certain reagents that allow DNA to be
extracted. Reverse transcription converts RNA into DNA.
Reverse transcription polymerase chain reaction (RT-PCR) first uses reverse tran-
scription to obtain DNA, followed by PCR to amplify that DNA, creating enough to
be analyzed. RT-PCR can thereby detect SARS-CoV-2, which contains only RNA.
The RT-PCR process generally requires a few hours.
Another technique for detection of virus is known as isothermal amplification
assays. They are faster than PCR because they don’t involve repeated heating and
cooling cycles. These tests typically detect DNA using fluorescent tags, which are
read out with specialized machines. CRISPR gene editing technology was modified
to perform the detection: if the CRISPR enzyme attaches to the sequence, it colors
a paper strip. The researchers expect the resulting test to be cheap and easy to use
in point-of-care settings. The test amplifies RNA directly, without the RNA-to-DNA
conversion step of RT-PCR.
4.1.2 Antibody Testing
The body responds to a viral infection by producing antibodies that help neutralize
the virus. Blood tests (serology tests) can detect the presence of such antibodies. Anti-
body tests can be used to assess what fraction of a population has once been infected,
which can then be used to calculate the disease’s mortality rate.
Considerations for who should get tested.
• People having symptoms of COVID-19
• People having close contact (within 6 feet of an infected person for at least 15 min)
with confirmed COVID-19 patient.
• People having been referred by their healthcare provider, or state health depart-
ment.
There are two school of thoughts about whom shall get tested, everyone or selected
ones. If test results get positive, then one should self-quarantine/isolate at home and
take hygienic measure.
5 Pathogenesis and Diseases Cycle
5.1 Pathophysiology of Disease of SARS-CoV-2
Corresponding to previously reported Coronavirus including MERS-CoV and

SARS-CoV-2, the lung epithelial cells of the human respiratory system emerge to
be the primary attack of SARS-CoV-2. The comorbidities such as hypertension,
diabetes, cardiovascular problems and respiratory disorders, may, however, aggravate
the situation and results in organs failure [23, 24].
Angiotensin converting enzyme (ACE-2), which is a transmembrane metallo
carboxypeptidase, expressed in kidneys, intestine lungs and blood cells, plays the
major role in facilitating entry of both SARS-CoV2 and SAR-CoV, into the epithe-
lial cells of lungs [25]. The receptor basic function, though, is the maturation of
angiotensin, which controls blood pressure and vasoconstriction. In the first step,
virus attached to the host cell’s via binding its spike protein to the ACE-2 receptor
on the outer membrane of the host cells. Most of the amino acid residues of spike (S)
proteins of SARS-CoV-2 and SARS-CoV are similar [25]. Hence, they show affinity
for the same receptors. The spike (S) protein consists of two distinct domains namely,
S1 and S2. S1 is the domain for N-terminal and S2 is the domain for C-terminal.
The S2 domain is elaborated for membrane fusion and S1 is plays its role in receptor
binding. The ACE-2 receptor binds with the viral spike(s) protein via S1subunit.The
spike (S) Protein is the splits into cellular protease at S1/S2 site, which dissociates
S1 from S2, while S2 remains bound to the viral membrane. This is followed by
agglutination of host and viral cell membranes facilitated via protein domain S2 that
binds to a merging peptide on the host cell [26].
The use of ACE inhibitors in patients suffering from diabetes and hypertension can
lead to overexpression of ACE-2 in these patients and hence further facilitate attach-
ment of SARS-CoV-2 into the cells [2]. This could probably justify the increased
risk for COVID-19 associated complications and mortality in these patients.
Human coronaviruses, on the other hand, can also enter the host cells via endo-
cytosis where cathepsins activates the spike proteins and release the viral genome
into the cytoplasm of the host cells. However, most of the coronaviruses fused with
membrane to enter host cells, as this is less likely to trigger immune response [27].
After the viral RNA is detached into the host cytoplasm, the translation proteins-
initiated coding and decoding. The viral genome encodes two types of proteins;
structural and nonstructural protein. The nonstructural protein helps in viral RNA
synthesis while the structural proteins participate in virion assembly. The two
polyproteins named polyprotein 1a (pp1a) and polyprotein 1ab (pp1ab) are first
translated by free ribosomes and then split by two enclose viral enzymes named
Papain-like protease (PLpro ) and chymotrypsin-like protease (3CLpro ) to produce
functional non-structural proteins. From the replication-transcription complex these
nonstructural proteins which help in replication of structural protein RNA [28]. The
structural protein RNA is then translated by the Endoplasmic Reticulum (ER) asso-
ciated ribosomes to produce Proteins like Membrane (M), Envelope (E) and Spike
(S) which are later translocated to the endoplasmic reticulum (ER) membrane in
preparation for virion assembly. The nucleocapsid (N) proteins, however, stay in the
cytoplasm after translation and associate themselves with the genomic RNA. The
vesicles studded with the viral structural proteins are then moved from endoplasmic
reticulum (ER) to golgi apparatus (GR) where they are packaged into virions by
incorporating the viral genomic RNA. The mature virions then escape the host cell
via exocytosis [29].
5.2 Potential Relation Between Mast Cell Activation

and Respiratory Symptoms
As it is well known, deaths from SARS CoV-2 (Covid-19) outbreak, which is a

current issue and became a pandemic, are increasing day by day [30]. However, there
is no vaccine or approved management therapy for SARS CoV-2 yet. For this reason,
prevention and treatment of pulmonary complications developing during SARS CoV-
2 infection is of great importance for the survival of patients. In the present discussion,
it was attempted to explore the potential relationship between pulmonary compli-
cation and lung mast cells Covid-19 infection and the possible use of mast cell
stabilizers that may contribute to the reduction and improvement of the pulmonary
complications in the context of current literature. We are of the opinion that this
present chapter of review may contribute to clinicians and researchers interested in
the COVID-19 treatment.
SARS-CoV-2 is settled in respiratory tracts and the lungs after it is transmitted
by mainly droplets and respiratory secretions. It causes SARS, shortness of breath,
fever and cough. The deaths from SARS-CoV-2 infection stem from a combination
of SARS and pneumonia, especially in elderly individuals and debilitated subjects.
Therefore, supportive therapies have great importance to combat against death-
causing symptoms of SARS-CoV-2 infection. Mast cells are multifunctional immune
cells that are widely dispersed round the body [31, 32]. MCs are present in respi-
ratory tracts and the lungs for playing their defensive role. MCs are involved in a
wide range of pathophysiological processes including innate and adaptive immunity,
inflammation, allergies, migraine and pulmonary hypertension [33]. MCs contain a
great variety of inflammatory mediators including proteases, cytokines, chemokines,
substance-P, serotonin, prostaglandins, bradykinin and histamine [34]. When MCs
are activated, they release these mediators to their resident environment to include
an inflammatory response through the process of degranulation. While normal acti-
vation of MCs is needed to sustain immune homeostasis of the body, their abnormal
activation leads to immunological complications like allergic asthma and allergies.
There are wide range of immunologic and nonimmunologic substances that are able
to activate MCs like IgE, antigens, anaphylatoxins, viruses, bacteria, toxins, deter-
gents, neuropeptides, and pollutants [35]. Activation of MCs can be triggered by
IgE-dependent and IgE-independent pathways.
While IgE-dependent activation of MCs are mediated by FcRI receptors on the

cell membrane and non-IgE mediated activation of MCs is mediated by toll like
receptors (TLR) and G-protein coupled receptors pathways that can be triggered
by viruses, chemokines, cytokines, pathogen-associated molecular patterns, certain
hormones and neuropeptides [36].
In particular, TLRs are capable of recognizing viruses and bacteria. Therefore,
SARS-CoV-2 may activate MCs to stimulate release of inflammatory mediators
through TLRs and cross-linking induction of IgE-FcεRI.
From the mast cells SARS-CoV-2 induces the release of the mediators like IL-8,
TNF-α, Interleukin (IL)-1, Histamine, prostaglandin (PG)D2, Leukotriene (LT) C4
and chymase can lead to worsening of existing inflammation, bronchoconstriction
and mucosal edema in the respiratory system, and pulmonary fibrosis [37].
It is well known that viruses, regardless of type, can induce release of such proin-
flammatory cytokines such as IL-1, IL6 and TNF-α and IL-8 that are pioneer medi-
ators of inflammatory responses. These pro-inflammatory cytokines may cause lung
and tissue inflammation, fever and pulmonary fibrosis, ii) further aggravate existing
inflammation condition in the respiratory system during SARS-CoV-2 infection [38].
It was previously reported the elevated plasma amount of IL-1beta, TNF-α and
IL-6 in pediatric patients with SARS-associated coronavirus infection. In addition,
it was reported that expressions of TNF-α, Interleukin1β and Interleukin-6, were
accumulated in the SARS-CoV-infected lung and bronchial autopsy tissues from
subjects of SARS. Additionally, a study shows that SARS-CoV infection lead to an
increase in expression of TLR4 and 9 which are closely related to activation of MCs
[39]. Moreover, it is reported that there is a correlation between elevated IL-6 levels
and severity of pulmonary symptoms in the SARS CoV-2 -infected patients [40].
On the other hand, histamine, PGD2 and LTC4 are powerful constrictors of smooth
muscles in the respiratory system. The virus-induced release of these mediators
from MCs can trigger bronchoconstriction, mucus secretion and mucosal edema in
respiratory tracts in infected patients of SARS CoV-2. Such a situation can facilitate
the process leading to death in elderly and debilitated patients during the infection
of SARS CoV-2.
Moreover, it is proposed that pulmonary fibrosis may be one of the substan-
tial complications in SARS-CoV-2-infected subjects. Mechanisms underlying
pulmonary fibrosis induced by SARS CoV-2 are not clear but previous studies demon-
strated that increased number of MCs and mediators from activated MCs such as,
IL-1 and chymase in the lungs contribute to pulmonary fibrosis [41].
Our hypothesis suggests a potent relationship between mast cell activation and
pulmonary complications in infection of SAR CoV-2 linked in previous reports.
We can speculate that SARS-CoV-2- induced Severe Acute Respiratory
Syndrome, severe pneumonia, pulmonary fibrosis and bronchoconstriction are asso-
ciated with increased release of pro-inflammatory cytokines such as interleukin-1β,
interleukin-6, interleukin-8 and tumor necrotizing factor-α, and potent bronchocon-
strictor mediators such as PGD2, LTC4 and histamine from activated MCs in the
respiratory system.
Therefore, endogenous or chemical MCS stabilizers as a sympathetic therapy may

be useful to reduce deadly inflammatory exacerbation and respiratory Obstructions
in SARS-CoV-2 infection.
There are a wide range of mast cell stabilizers including endogenous ones such
as anandamide, progesterone, testosterone and chondroitin sulphate, and chemical
such as ketotifen, cromolyn, quercetin, luteolin, thymoquinone. Moreover, cromolyn
of those mast cell stabilizers is clinically administered to treat some disorders
like asthma, allergic rhinitis and mastocytosis which are associated with mast cell
activation [42].
Taken together, we suggest that suppression of overactivation of lung mast cells by
endogenous or chemical mast cell stabilizers may contribute to ameliorate inflam-
matory response and respiratory interference in order to lower the expirations in
SARS-CoV-2 infection. Moreover, such a promising treatment approach can also
improve life quality of survivors by reducing or preventing lung damage such as
pulmonary fibrosis.
6 Treatment and Management of COVID-19
The infection from SARSCoV-2 can be broadly categorized into three stages i.e. stage
I, II and III. The individuals at stage I are asymptomatic, with or without detectable
virus. the individuals at this stage are silent carriers and may spread disease without
knowing it. This type of asymptomatic transmission was reported in Germany. At
stage II, the individuals are symptomatic but non-severe with a detectable virus load in
the body. At stage III, the viral load is even higher and severe respiratory symptoms
or organ failure due to cytokine rush are evident. Response of the individual to
viral infection is heterogenous owing to physiologic development, immunity profile,
comorbidity, treatments given.
Following an incubation of the virus i.e. non-symptomatic (stage I) and non-
severe symptomatic (stage II) an adaptive immune response is initiated by the body to
overcome the foreign invasion and resist the progression of the disease to sever stage.
The individual having appropriate genetic background or appropriate endogenous
immunity can combat the viral infestation and elicit a specific immune response to
the virus.
In cases where the protective immune response is impaired, the invading virus
will continue to replicate in the body resulting in a massive destruction of the tissues
having higher ACE2 expression such as kidney, intestine, heart. The damaged cells
consequent chemotaxis and Cytokin storm which results in inflammatory lungs that
causes severe stage life-threatening respiratory disorders (Fig. 3).
To date, there is no specific vaccine or medication for COVID-19. The world is
desperate to find effective medication for this pandemic disease. Several drugs and
vaccines are under clinical trials. The drugs being tested range from regenerate flu
treatments to malfunction ebola drugs, to malaria treatments that were first developed
Fig. 3 Immune boosters as a leading protector against COVID-19
decades ago. Here, researchers and doctors have several treatment methods to help
fight Covid-19.
6.1 Allopathic Strategies and Drugs
6.1.1 Chloroquine/Hydroxychloroquine and Azithromycin
In 1955, antimalarial treatment was first approved by the United states and HCQ
is the derivative of Chloroquine. U.S. Food and Drug Administration (US-F&DA)
approved the Chloroquine and Hydroxychloroquine for the treatment of Rheumatoid
Arthritis, Malaria and lupus syndrome. Recently few studies shows that the drug
is effective against COVID-19. Previously it has been reported that chloroquine
is effective against SARS-CoV when applied to infected human cells in culture.
SARS-CoV is closely related to the novel coronavirus.
HCQs have the ability to regulate the inflammatory reaction is one reason why
it’s been proposed for the treatment of Covid 19. The inflammatory response can be
prevalent that it causes severe damage to the lungs, that is the reason that patients
with severe cases often need ventilators.
According to Gao et al. [43] Chloroquine phosphate is shown to have apparent

efficacy and acceptable safety against COVID-19 associated pneumonia in multi-
center clinical trials conducted in China [43]. Similarly another study conducted by
Author links open overlay panel Gautret et al., 2020 found that there is a remark-
able disappearance of Covid-19 patients by using Hydroxychloroquine [44] and its
effect is propped up by azithromycin. Doctors are giving drugs to some patients
with Covid-19 in China, North Korea, US and France with promising, admitting,
unreliable results so far.
However, randomized study did not calculate the clinical benefits related with
treatment. The doctors should be cautious when recommending chloroquine and
hydroxychloroquine to patients with chronic disease, such as kidney failure,
and patients receiving medication that may cause arrhythmias [45]. In literature
confirming fatal outcome of this therapy has been reported due to toxicity.
Moreover, chloroquine and its derivative are very much helpful in transporting
zinc across the cell membrane. Zinc binds with viral RNA and terminate replication
inside the host cell by terminating RNA polymerase. Zinc as a metal ion cannot
cross the lipid bilayer membrane and it always need an ionophore for intracellular
transportation. So, these chloroquine derivatives acts as an ionophore and transport
the zinc across the cell membrane eventually increasing its intracellular concentration
resulting in termination of viral RNA replication.
6.2 Antiviral Drugs
6.2.1 Remdesivir
Remdesivir is Drug having broad antiviral activity tested against Ebola virus and
has been used as an investigational intravenous drug. Remdesivir is re-purposed for
the treatment of COVID-19. Wang et al. [6] found that it can prevent the human
cell from being infected from SARS-CoV-2 in petri dish, Remdesivir is currently
approved by FDA to use for the treatment of Covid-19. Remdesivir cripples RNA
polymerase enzymes that specifically target SARS-CoV-2 replication in the host cell.
Unfortunately, it works good only in animal and in-vitro studies and not as much
effective in humans [46]. Different clinical trials on remdsevir has been analyzed
whether it may increase or decrease the disease course on covid-19 patients in China
and U.S. Many doctors and researchers are excited about the drug’s potential against
COVID-19.
6.2.2 Favipiravir
Favipiravir is an antiviral drug, developed by Fujifilm Toyama Chemical in Japan.

Favipiravir has been used in Japan to treat influenza. Recently, drug have shown a
promising outcome in treating at least mild to moderate cases of COVID-19. Favipi-

ravir was now approved as an experimental treatment for COVID-19 infections.
Favipiravir has been tested in several individuals and it has been suggested that the
drug has a high degree of safety and is clearly effective in treatment of COVID-
19 patients. Favipiravir significantly improved the latency to relief for pyrexia and
cough.
6.2.3 Other Antiviral Drugs
The combination of ritonavir and lopinavir created an excitement towards the treat-
ment. However, according to Cao et al. [47], reported that the combination does not
discovered to be beneficial for the patients [47]. This study was conducted on 199
patients, with no standard care treatment for 14 days who were receiving twice a day
Lopinavir-Ritonavir (400 mg and 100 mg respectively). No benefit was observed
with lopinavir–ritonavir treatment beyond standard care.
While fewer people taking the drug died. In another study conducted by Steb-
bing et al. [48], three different antiviral drugs (Baricitinib, Ruxolitinib and Fedra-
tinib) were tested in combination with anti-inflammatory drugs [48]. These drugs
had a potential therapeutic activity against SARS coronavirus 2 (SARS-CoV-2; the
causative organism in COVID-19) by inhibiting clathrin-mediated endocytosis and
thereby inhibiting viral infection of cells.
However, there is an inert possibility and studies are going that will bring some
combination profits. If this drug will be given as an earlier antiviral course it will
likely to work better. V Antiviral EIDD-2801.
An antiviral drug named “EIDD-2801” has been tested and showed promise
evidence of its effectiveness against SARS-CoV-2 in test-tube experiments. Scien-
tists reported online April 6 in the journal Science Translation Medicine about the
possible effectiveness of this drug. The drug might even be more efficient than its
predecessors at mingling with the viral proteins to stop the novel coronavirus, SARS-
CoV-2, than remdesivir. In contrast to remdesivir, this drug despite of stopping viral
replication entirely introduces genetic mutations into the virus’s RNA. So many
damaging mutations cumulate and virus is no longer able to pathogenic. The drug
has also potential against several RNA viruses, and it is predicted by the researchers
that it could be a multipurpose antiviral drug in the future.
In addition to this property, this antiviral drug can be given oral unlike remdesivir
which can only be administered intravenously. Timothy Sheahan et al. stated that
EIDD-2801 is considered to be an oral drug that could be administered at home by
patients early after diagnosis. This report is generated by the Department of Epidemi-
ology at the University of North Carolina at Chapel Hill. He further elaborated that
this drug has the potential to treat Covid 19 in the future on further investigation
regarding its safety and effective.
6.2.4 Viavigan
Fujifilm Toyama Chemical in Japan has developed an antiviral drug named AVIGAN.
Testing of this drug against SARS-CoV-2 showed optimistic results in treating at least
mild to moderate cases of COVID-19, Live Science previously reported.
The antiviral drug Avigan, has been approved in Japan to treat COVID-19, which
is previously used to treat influenza infections.
6.3 Immunosuppressants
6.3.1 Tocilizumab
Tocilizumab is an immunosuppressant drug. This drug blocks the cell receptor and
binds with the interleukin6 (IL-6) is a cytokine protein that fights against different
dangerous inflammatory cascades and is approved by FDA to treat rheumatoid
arthritis. Tocilizumab introduces a new method for the treatment of fetal infectious
disease and in severe Covid-19 patients [49]. The effect of tocilizumab was investi-
gated on the severe or critical COVID-19 patient in China. It was found that within a
few days, symptoms resolved significantly and temperature of the patients returned
to normal [58].
6.3.2 Hyaluronase
During acute respiratory distress the cytokine storm is coupled with a profuse secre-
tion of fluid into the alveoli resulting in compromised oxygen exchange at the level
of alveoli. Lung epithelial cells in this vicinity secrete HA synthase (HAS) prompts
formation of HA having capability to absorb fluid and form gel based glassy bead
in the lungs. Physicians are prescribing Hyaluronidase through intranasal route
to resolve this gel and clear the airway. Similarly, other inhibitors such as HAS
Hymecromone obtained from the bile secretion has also been found effective for the
disintegration of the jelly.
6.4 Antibodies and Vaccine of Covid-19
6.4.1 Convalescent Plasma (CP)
Patients recovered from COVID-19 are described with a high concentration of

neutralizing antibody in their plasma. Due to the fact, their plasma is considered
valuable source of CP, which can be used for the treatment COVID 19. This method-
ology has been applied to the prevention and treatment of many infectious diseases
for more than one century.
Over the past two decades, this approach was successfully employed for the treat-
ment of different viral pandemics such as SARS, MERS, and 2009 H1N1 pandemic
with significant efficacy and safety. Administration of one dose (200 mL) of CP to
severely ill 10 patients of COVID 19 resulted in an increase or maintenance of the
neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d.
Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3
d. Radiological examination showed varying degrees of absorption of lung lesions
within 7 d. These results indicate that CP can serve as a promising rescue option for
severe COVID-19. Nevertheless, parameters for optimal dose and time will deter-
mine the clinical benefits of CP therapy. As it needs further investigation in larger
well-controlled trials.
6.4.2 COVID Vaccine
In view of the pandemic outbreak, many of the global organizations such as WHO,
welcomes trust, Bill and Malinda gate trust, CEPI for supporting research projects
relating to the development of the COVID vaccine. According to a report published
in Nature around 75 research organizations are aiming to develop vaccine. Of these
5 have initiated phase I clinical trials (Tables 1 and 2; Figs. 4 and 5).
6.5 Non-Antiviral Drugs as Adjuvant Therapy
Beside antiviral drugs, several other class of drugs can also be helpful in Covid-19
conditions; these drugs are carfilzomib, bortezomib, montelukast, polydatin, disul-
firam, carmofur, shikonin, ebselen, tideglusib and cinanserin. Carfilzomib is an anti-
cancer drug already approved by FDA, act as a proteasome inhibitor can become
potential inhibitor for Covid-19 protease [50]. Bortezomib [51] is another anticancer
agent, also act as proteasome inhibitor; its potential as Covid-19 drug is under trials
[52]. Montelukast is used in treatment of asthma may be proposed as adjuvant therapy
for Covid-19 patients [53]. Polydatin has numerous activities like antioxidant, anti-
inflammatory, platelet aggregation inhibition, antiviral and antibacterial. Due to these
properties polydatin can be a preventive measure for people professionally exposed
to the risk of contagion like Covid-19 and positive corona virus patients [54] (Fig. 6).
Table 1 Vaccine effective against COVID-19

Candidate Vaccine characteristics Lead developer Status
mRNA-1273 LNP-encapsulated Moderna Phase I
mRNA (NCT04283461)
Vaccine encoding S
protein
Ad5-nCoV Adenovirus type 5 CanSino Biologicals Phase I
vector that express S (NCT04313127)
protein
INO-4800 DNA plasmid encoding Inovio Pharmaceuticals Phase I
S protein delivered by NCT04336410)
electroporation
LV-SMENP-DC DCs modified with Shenzhen Geno-Immune Phase I
lentiviral vector Medical Institute (NCT04276896)
expressing synthetic
minigene based on
domains of selected
viral proteins;
administered with
antigen-specific CTLs
Pathogen-specific aAPCs modified with Shenzhen Geno-Immune Phase I
aAPC lentiviral vector Medical Institute (NCT04299724)
expressing synthetic
minigene based on
domains of selected
viral proteins
6.6 Herbal Treatment Approach
The novel coronavirus was tried to be treated with a number of drugs obtained from
natural origin. The said drugs, being natural, were thought to be effective, safe and
immune system booster. The historical background of the natural medicines has
proved that these sorts of sources have continuously been used by the physicians.
The effeteness and safety of herbal medicines may also be judged from the fact that
the number of these drugs are exponentially increasing in the pharmacy shelves in
the current decade [55].
6.6.1 Licorice
For centuries chines used Glycyrrhiza Glabra (Licorice) as medicine and as natural
practice. The most potent antiviral activity in Glycyrrhiza Glabra is due to the pres-
ence of substances, i.e. Glabridin liquiritigenin, glycyrrhizin. Licorice root extract
effective against RSV, Herpes Virus, HIV, and a serious type of pneumonia causing
virus (SARS-COV) severe acute respiratory syndrome virus, which is been demon-
strated by test tube studies [56]. Futhermore, Glycyrrhizin has been reported to
Table 2 Attributes refer to genaral attributres of platform, and assessments are not intended as infrences about a particular candidate. NIAID denotes National
1082
Institutre of Allergy and Infectious Diseases, and WRAIR Walter Reed Army Institute of Research
Vaccine platforms, their attribute, and the status of vaccine candidates
Technology Attributes Candidates in preclinical Candidates in phase 1
Single dose Licensed platform Speed Current scale development
DNA No No Fast Medium Inovio Pharmaceuticals
Takis/Applied DNA
Sciences/Evvivax Zydus
Cadila
Inactivated No Yes Medium Medium to high Sinovac
Live attended Yes Yes Slow High Codagenix/Serum Institute of
India
Nonreplicating vector Yes No Medium High Geovax/BravoVax Janssen CanSino Biologics
Pharmaceutical Companies, (ChiCTR20000 30,906)
University of Oxford,
Altimmune, Greffex, Vaxart,
ExpresS2ion
(continued)
M. Akhlaq et al.
Table 2 (continued)
Protein subunit No Yes Medium to fast High WRAIR/US. Army Medical
Research Institute of
Infectious Diseases Clover
Biopharmaceuticals Inc/GSK
Vaxil Bio
AJ Vaccines
Genrex/EpiVax/University of
Georgia, Sanofi Pasteur,
Noavax
Heat Biologics/University of
Miami, University of
Queensland/GSK/Baylor
College of Medcine
iBio/CC-Pharming
Replicating viral vector Yes Yes Medium High Zydun Cadila
Institute Pasture/Themis
Tonix Pharma/Southern
Research
RNA No No Fast Low to medium Fudan University/Shanghai Moderna/NIAID
Jiao Tong (NCT04283461)
University/RNACure
Covid-19 Pandemic and Coronaviruses from Discovery to Treatment …
Biopharma
Chine CDC/Tongji
University/Stermina
Arcturus/Duke-NUS
Imperial College London
Curevac
BioNTech/Pfizer
(continued)
1083
Table 2 (continued)
1084

Uncertain University of Pittsburgh
University og Saskatchewan
ImmunoPrecise
MIGAL Galilee Research
Institute, Doherty Institute,
Tulane University
M. Akhlaq et al.
Fig. 4 Antiviral drugs for Covid-19 treatment
decrease the endocytotic activity and reduced the virus uptake ultimately inhibited
the influenza A virus uptake into the cell, arbitrated by its interaction with the cell
membrane [55].
6.6.2 Sambucus
Sambucus is a family of Adoxaceae and a genus of flowering plants, also known as

Elder or Elderberry. Inhibition of immune system response and influenza A virus by
using Elderberry juice have been reported with Sambucus. However, in a review of
27
Fig. 5 Antiviral drugs for Covid-19 treatment
four studies in one hundred- and eighty-people direct use of elderberry supplements
reduced the viral infection regarding upper respiratory tract infection. In-vitro potent
antioxidant activity in elderberry anthocyanins has been demonstrated the sequen-
tially effectively protected against oxidative stress taken by endothelial cells. Studies
have shown to inhibit and decrease infectivity of influenza A and B virus by taken
standardized 38% of elder berries extract syrup sambucol® .
Fig. 6 Non-antiviral drugs for Covid-19 treatment
Studies have also shown that elderberry extract have immuno-modulating activity
against individual having viral infection and healthy individual as well. Activated
Phagocytes facilitates and move toward 16 inflamed tissue due to production of
certain cytokines.
6.6.3 Ginger
Ginger is an herbaceous flowering plant with rhizome products such as elixirs, root
tea, and lozenges are popular natural remedies having health benefits. Gingerols and
zingerone are the most efficient compound present in ginger has been shown by
various studies to have very effective antiviral activity. Ginger has potent antiviral
effect against Avian (Bird) Influenza, Fenile Calicivirus (FCV in cats), Respiratory
Syncytial Virus (RSV), which is comparable to human norovirus demonstrated by
test tube research. Additionally, research have been shown that effective compound
in ginger like gingerols and zingerone inhibit virus from entering into the host cell,
as well as suppress its replication [57]
6.6.4 Garlic
For decades Allium sativum, Garlic due to the presence of variety of biological
compound has been used as a traditional natural remedy to treat various health condi-
tion, including viral infections. Furthermore, a study was conducted on 23 person
with warts, originated by human papillimavirus (HPV) after 1–14 days of treatment
with the garlic extract applying two times a day abolish warts.1617. Older Test Tube
studies indicated that antiviral action may be induce by garlic against various common
cold causing viruses, i.e. Rhinovirus, HIV,HIS-1, viral pneumonia and influenza A
and B. However current research is deficient. Animal and Test tube studies demon-
strated, Garlic prevent against viral infection by stimulating and protection immune
cells ultimately enhances immune system. Numerious compounds have been detected
having the potential to effect immunity from the AGE-4 garlic (Allium sativum L.)
extract manufactured from the grown garlic cloves that are slice and soaked in a
hydro-ethonolic solution aged up to 20 mo, inclusive of Lectin tribe, which is known
to combine with pathogen recognition receptor on the surface of immune cell [58]
(Fig. 7).
6.6.5 Basil
Studies have been shown that Tulsi (Holy basil) help fight various viral infection
and boost the immunity. Several sweet and holy types of Basil have the tendency to
fight certain viral infections. Test tube study demonstrated that sweet basil extract
containing the potent compound i.e., ursolic acid, and apigenin reveals powerful
effect against enterovirus, hep B, and herpes virus.11.
A study was conducted on 24 adults by giving 300 mg holy basil extract supple-
ment for 28 days results in elevated level of immune cells, both natural killer cells
and T-cells which are very helpful in protecting and defending body against viral
infection [59].
Fig. 7 The natural resources rich of the remedial components effective against coronavirus.
a Sambucus b Licorice c Basil d Ginger e Garlic
6.6.6 Medicinal Mushroom
Medicinal mushroom has been used since ancient times to prevent and treat infection
and disease. Many types of medicinal mushrooms have been studied for their immune
boosting potential. Over 270 recognized species of medicinal mushroom are known to
have immune enhancing properties. Cordyceps, lion’s mane, maitake, shitake, turkey
tail, reshiare all type that have shown immune health. Some research demonstrates
that supplementing with specific type of medicinal mushrooms may enhance immune
health in several ways and reduce symptoms of certain conditions, including asthma
an lung infections For example a study in mice with tuberculosis, a serious bacterial
disease, found that treatment with Condyceps significantly reduced bacterial load in
the lungs, enhance immune response and reduce inflammation, compared with the
placebo group in a randomized 8 week study in 79 adults supplementing with 168gms
of cordyceps mycellum culture extract led to a significant 38% increase in the activity
of natural killer(NK) cells a type of white blood cells that protect against infection
[60]. Turkey tail is another medicinal mushroom that has powerful effects on immune
health research in humans indicates that turkey tail may enhance immune response
especially in people with certain types of cancer. Many other medicinal mushrooms
have been studied for their beneficial effects on immune health as well. Medicinal
mushroom products can be found in the form of tinctures, tears and supplements
[61].
7 In-Silico Studies at a Glance
On the basis of in-silico studies and enzyme activity test numerous agents found
to have potential against SARS Covid-19. These agents are remdesivir, indinavir,
saquinavir, lopinavir, carfilzomib, ritonavir, atazanavir, darunavir, tipranavir, fosam-
prenavir, enzaplatovir, presatovir, abacavir, bortezomib, elvitegravir, maribavir, ralte-
gravir, montelukast, polydatin, chalcone, disulfiram, carmofur, shikonin, ebselen,
tideglusib, PX12, TDZD-8, cyclosporin A, and cinanserin [60].
Redesvir has shown invitro activity against SARS Covid-19; in a clinical trial
a bit improvement was observed in patients that were administered with remdesvir
[61, 62]. A most recent study shows that Nelfinavir can inhibit replication of covid-
19 virus. On the basis of direct antiviral properties and its potency enhancements
during MERS and SARS outbreaks, Ribavarine can become a potential candidate
against Covid-19. Amantadine inhibits the release of Covid-19 virus nucleus into the
cell cytoplasm [6]. Lopinavir is a protease inhibitor; as protease is the key enzyme in
corona virus replication, thus it inhibits viral replication. Just like lopinavir; ritonavir
is also protease inhibitor and used in combination with lopinavir to enhance potency
against viral replication. Favipiravir has shown activity against RNA virus and has
potential against Covid-19. Indinavir and darunavir both are protease inhibitors and
in-silico studies has shown that both of these drugs has great binding affinity with
Covid-19. A study shows saquinavir as potent inhibitor of SARS-Cov2 and has
potential against Covid-19. Atazanavir has great bioavailability with respiratory tract
and its ability to impair viral replication are major reason for its selection as drug
against Covid-19. In an insilico study it was observed tripinavir and raltegravir have
shown best molecular interaction with protease of SARS-Cov2 and can become
excellent candidate for Covid-19. Fosamprenavir is HIV-protease inhibitor and can
become potential candidate as drug against Covid-19. Based on insilico studies and
their viral protease inhibition; enzaplatovir, presatovir, abacavir and maribavir have
potential to play as drugs against Covid-19 [62].
8 Preventive Measures and WHO Guideline
Preventive actions of COVID-19 involve both individual as well as society base

measures. According to world health organization (WHO), individuals should take
following safety measures in order to avoid the spread and onset of disease e.g.,
cleaning of hands with soap and water, use of alcohol-based hand sanitizer, observing
a safe distance from anyone who is coughing or sneezing, wearing mask in the
crowded place, avoid touching eyes, nose or mouth, covering of nose and mouth with
elbow or a tissue during coughing or sneezing. Also, avoid contact with animals as
well. Being part of a society, the individuals should also play their role by restricting
themselves to their home, avoid crowded gatherings, indoor activities. Pakistan has
been observing a new strategy of partial and smart lockdown. In case of partial
lockdown, a specific time frame was given to the general public only for the purpose
of grocery, while beyond the specific time complete curfew was imposed in the
city. And, in case of smart lockdown, upon the appearance of COVID-19 diagnosed
person, a specific local area within the city was locked down. Both of these strategies
were implemented in parallel and it was observed to be the best policy for controlling
COVID-19.
9 Results
In order to prevent the spread of pandemic new strategies have been employed.
The best example in this scenario is of Wuhan, China. Chinese officials were not
only successful to contain the viral spread within Wuhan but also take effective
measures along the country. There efforts bring a successful result although the
spread outside the China was unrollable. The viral infection spread throughout the
world and hit hard across Europe, United states and other parts of the world as
well. Governments implemented lockdown strategies and controlled the virus for
time being. Unfortunately, plans of social distancing is a limiting solution to the
present situation and clinicians and scientist all over the world are devising different
management therapied. The present treatments available for treating the COVID 19
are improving day by day. However, the single therapy plan has not been devised up
till now. Reengining from symptomatic management to control the different aspects
of immune response had been trialed. But the spread of pandemic is still greater than
the efforts made to control it clinically. Clinicians and physicians from different part
of the world devised new therapy plan including the herbal treatment, immune booster
and immune suppressants. But the clinical course of the COVID 19 is different along
the glob depending upon the socio-economic conditions, weather conditions and
cultural backgrounds. Moreover, genomic make up of people also played a wide role
in pathophysiology of the disease. It is now a unanimous agreement that an effective
vaccine will play a game changing role in the present scenario. Multiple techniques
have been employed for the development of COVID 19 vaccine. Among these, either
DNA or RNA based vaccines will be of greatest potential or followed by those for
developing recombinant-subunit vaccines. Use of next-generation sequencing and
reverse genetics may also cut development time of more conventional vaccines during
epidemics. Even with novel platforms, some questions relating to the development of
SARS-CoV-2 vaccine are still unanswered. First, although the virus’s spike protein
is a promising immunogen for protection, optimizing antigen design is critical to
ensure optimal immune response, for example, targeting the full-length protein or
only the receptor-binding domain. As with naturally acquired infection, the potential
duration of immunity is unknown; similarly, whether single-dose vaccines will confer
immunity or not, is still uncertain.
10 Conclusion
Pandemic of COVID 19 badly affected the socio-economic condition of the world. In

large, almost whole humanity suffered a lot from the outbreak. Fast-evolving outburst
situation, it was not easy to figure out a specific outcome that makes progress against
Covid-19 and break the pandemic condition. It seems generally all the efforts are
being made jointly by the scientists around the world are less in comparison to the
problem we are facing. More or less, every government are making their efforts to
defeat the virus and save their population from the pandemic and exerting a combined
effort altogether in one direction in order to save the humanity. History will remember
this chapter either in good or bad words portraying the apex of moral values in the
lap of civilization in the context of Covid-19. All the scientists and clinicians are
pushing hard themselves to bring new therapy regimen or introduce better way of
managing people health. The ultimate solution to this problem is the discovery of
effective vaccine. Only the last hope for humanity to come out of the situation is to
wait for vaccinate the whole world population which in itself is a big task. Logistic
support and a huge manufacturing effort will be needed to accomplish the goal and
come out of this pandemic situation. However, humanity always finds a way out to
survive on this planet earth.
11 Future Prospects
The pandemic situation of COVID-19 continues to cause chaos worldwide due to the
lack of understanding, risk assessment, rapid outburst, and tendency to hasty severe
disease in comorbid conditions. In an attempt to fulfill the demand for prophy-
lactic and treatment measures to intercept the ongoing outbreak, the drug develop-
ment process is facing several obstacles and renaissance in clinical trials, including
vaccines, antivirals, immunomodulators, plasma therapy, and traditional medicines.
However, the development in the medical field and understanding of the disease
pattern by the clinician has solved many mysteries up till now. But due to virus
mutation, infection is changing its course, and medical community is still facing
a challenge. The ultimate solution seems to this situation is vaccine. In our view,
even after the vaccine, pandemic will be hard to contained and economy of a region
will have a key role in such situation. There are many questions still in our path
from vaccine discovery to its affordability and logistics management as well. It is
speculated that even after the induction of vaccine, world will need 5 years to vacci-
nate all the people around the globe and around 7–10 years to completely eliminate
this virus from the world. Therefore, we should adopt the substitute treatments, use
precautionary measures or alternatively we should put it on fate to decide the future
of humanity.
References
1. Wan, Y., et al.: An analysis based on decade-long structural studies of SARS 3, JVI Accepted
Manuscript Posted Online 29 January 2020. J. Virol. (2020)
origin. Nature 579(7798), 270–273 (2020)
3. Cucinotta, D., Vanelli, M.: WHO declares COVID-19 a pandemic. Acta Bio Medica: Atenei
Parmensis 91(1), 157 (2020)
4. Al-Mandhari, A., et al.: Coronavirus disease 2019 outbreak: preparedness and readiness of
countries in the Eastern Mediterranean Region (2020). https://coronavirus1science.com/item/
6166e6044a2114454e136505bc74865c1c52e8da
5. Sifuentes-Rodríguez, E., Palacios-Reyes, D.: COVID-19: The outbreak caused by a new
coronavirus. Boletin Medico del Hospital Infantil de Mexico 77(2), 47–53 (2020)
6. Wang, C., et al.: Evolving epidemiology and impact of non-pharmaceutical interventions on
the outbreak of Coronavirus disease 2019 in Wuhan, China. MedRxiv (2020)
7. Cases, C. and D. by Country: Territory, or conveyance. Peim doctypy. https://www.worldo
meters.info/coronavirus
8. Rodríguez-Rey, R., Garrido-Hernansaiz, H., Collado, S.: Psychological impact and associated
factors during the initial stage of the coronavirus (COVID-19) pandemic among the general
population in Spain. Front. Psychol. 11, 1540 (2020)
9. Bol, D., et al.: The effect of COVID-19 lockdowns on political support: Some good news for
democracy? Eur. J. Polit. Res. (2020)
10. Chen, E., Lerman, K., Ferrara, E.: Tracking social media discourse about the COVID-19
pandemic: development of a public coronavirus Twitter data set. JMIR Public Health Surveill.
6(2), e19273 (2020)
11. Assiri, A., et al.: Hospital outbreak of Middle East respiratory syndrome coronavirus. N. Engl.
J. Med. 369(5), 407–416 (2013)
12. Van Der Hoek, L., et al.: Identification of a new human coronavirus. Nat. Med. 10(4), 368–373
(2004)
13. Korber, B., et al.: Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases
infectivity of the COVID-19 virus. Cell 182(4), 812–827. e19 (2020)
14. Zaki, A.M., et al.: Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.
N. Engl. J. Med. 367(19), 1814–1820 (2012)
15. Wang, W., et al.: Discovery, diversity and evolution of novel coronaviruses sampled from
rodents in China. Virology 474, 19–27 (2015)
16. Drosten, C., et al.: Identification of a novel coronavirus in patients with severe acute respiratory
syndrome. N. Engl. J. Med. 348(20), 1967–1976 (2003)
17. Shen, K., et al.: Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in
children: experts’ consensus statement. World J. Pediatrics, 1–9 (2020)
18. Ahmad, T., et al.: COVID-19: Zoonotic aspects. Travel Medicine and Infectious Disease (2020)
19. Fan, W., Holmes Edward, C., Yong-Zhen, Z.: A new coronavirus associated with human
respiratory disease in China. Nature 579(7798), 265–269 (2020)
origin. Nature [Internet]. 579(7798), 270–273 (2020)
Drug Discov. & Ther. 14(1), 58–60 (2020)
22. Wang, M., et al.: Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res. 30(3), 269–271 (2020)
23. Huang, C., et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan.
China. The Lancet 395(10223), 497–506 (2020)
24. Yang, J., et al.: Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19)
infection: a systematic review and meta-analysis. Int. J. Infect. Dis. (2020)
25. Hoffmann, M., et al.: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked
by a clinically proven protease inhibitor. Cell (2020)
26. Li, W., et al.: Angiotensin-converting enzyme 2 is a functional receptor for the SARS
coronavirus. Nature 426(6965), 450–454 (2003)
27. Shirato, K., Kawase, M., Matsuyama, S.: Wild-type human coronaviruses prefer cell-surface
TMPRSS2 to endosomal cathepsins for cell entry. Virol. 517, 9–15 (2018)
28. Ziebuhr, J., Snijder, E.J., Gorbalenya, A.E.: Virus-encoded proteinases and proteolytic
processing in the Nidovirales. J. Gen. Virol. 81(4), 853–879 (2000)
29. Song, Z., et al.: From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 11(1),
59 (2019)
30. Kilinç, E., Kilinç, Y.B.: Mast cell stabilizers as a supportive therapy can contribute to alleviate
fatal inflammatory responses and severity of pulmonary complications in COVID-19 infection.
Anadolu Kliniği Tıp Bilimleri Dergisi, 2020. 25(Special Issue on COVID 19), 111–118
31. Kilinc, E., et al.: Effects of Nigella sativa seeds and certain species of fungi extracts on number
and activation of dural mast cells in rats. Physio. Int. 104(1), 15–24 (2017)
32. Koyuncu Irmak, D., Kilinc, E., Tore, F.: Shared fate of meningeal mast cells and sensory
neurons in migraine. Front. Cell. Neurosci. 13, 136 (2013)
33. Theoharides, T.C., et al.: Mast cells and inflammation. Biochimica et Biophysica Acta (BBA)-
Molecular Basis of Disease 1822(1), 21–33 (2012)
34. Kilinc, E., et al.: Serotonergic mechanisms of trigeminal meningeal nociception: implications
for migraine pain. Neuropharmacology 116, 160–173 (2017)
35. Moon, T.C., Befus, A.D., Kulka, M.: Mast cell mediators: their differential release and the
secretory pathways involved. Front. Immunol. 5, 569 (2014)
36. Tore, F., Tuncel, N.: Mast cells: target and source of neuropeptides. Curr. Pharm. Des. 15(29),
3433–3445 (2009)
37. Kritas, S., et al.: Mast cells contribute to coronavirus-induced inflammation: new anti-
inflammatory strategy. J Biol. Regul. Homeost. Agents 34(1), 10.23812 (2020)
38. Conti, P., et al.: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation
by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul
Homeost Agents 34(2), 1 (2020)
39. Okabayashi, T., et al.: Cytokine regulation in SARS coronavirus infection compared to other
respiratory virus infections. J. Med. Virol. 78(4), 417–424 (2006)
40. Russell, B., et al.: Associations between immune-suppressive and stimulating drugs and novel
COVID-19—a systematic review of current evidence. Ecancermedicalscience, 14 (2020)
41. Andersson, C.K., et al.: Activated MC TC mast cells infiltrate diseased lung areas in cystic
fibrosis and idiopathic pulmonary fibrosis. Respir. Res. 12(1), 139 (2011)
42. Storms, W., Kaliner, M.A.: Cromolyn sodium: fitting an old friend into current asthma
treatment. J. Asthma 42(2), 79–89 (2005)
43. Gao, J., Tian, Z., Yang, X.: Breakthrough: Chloroquine phosphate has shown apparent efficacy
in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience Trends (2020)
44. Gautret, P., et al.: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results
of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents, 105949 (2020)
45. Cortegiani, A., et al.: A systematic review on the efficacy and safety of chloroquine for the
treatment of COVID-19. J. Crit.Al Care (2020)
46. Ko, W.-C., et al.: Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int.
J. Antimicrob. Agents (2020)
47. Cao, B., et al.: A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N.
Engl. J. Med. (2020)
48. Stebbing, J., et al.: COVID-19: combining antiviral and anti-inflammatory treatments. Lancet.
Infect. Dis 20(4), 400–402 (2020)
49. Xu, X., et al.: Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl.
Acad. Sci. 117(20), 10970–10975 (2020)
50. Ke, Y.-Y., et al.: Artificial intelligence approach fighting COVID-19 with repurposing drugs.
Biomedical J. (2020)
51. Wang, J.: Fast identification of possible drug treatment of coronavirus disease-19 (COVID-19)
through computational drug repurposing study? J. Chem. Inform. Modeling (2020)
52. Raaben, M., et al.: The proteasome inhibitor Velcade enhances rather than reduces disease in
mouse hepatitis coronavirus-infected mice. J. Virol. 84(15), 7880–7885 (2010)
53. Finelli, C., Parisi, S.: The clinical impact of COVID-19 epidemic in the hematologic setting.
Adv. Biol. Regul. 77, 100742 (2020)
54. Irani, M., Sarmadi, M., Bernard, F.: Leaves antimicrobial activity of Glycyrrhiza glabra L. IJPR
9(4), 425 (2010)
55. Wolkerstorfer, A., et al.: Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral
Res. 83(2), 171–178 (2009)
56. Messier, C., Grenier, D.: Effect of licorice compounds licochalcone A, glabridin and
glycyrrhizic acid on growth and virulence properties of Candida albicans. Mycoses 54(6),
e801–e806 (2011)
57. Aboubakr, H.A., et al.: In vitro antiviral activity of clove and ginger aqueous extracts against
feline calicivirus, a surrogate for human norovirus. J. Food Prot. 79(6), 1001–1012 (2016)
58. Ahmed, I., et al.: Anti-avian influenza virus H9N2 activity of aqueous extracts of Zingiber
officinalis (Ginger) and Allium sativum (Garlic) in chick embryos. Pak. J. Pharm. Sci 30(4),
1341–1344 (2017)
59. Mondal, S., et al.: Double-blinded randomized controlled trial for immunomodulatory effects
of Tulsi (Ocimum sanctum Linn.) leaf extract on healthy volunteers. J. Ethnopharmacol. 136(3),
452–456 (2011)
60. Johnson, E., et al.: Effect of an extract based on the medicinal mushroom Agaricus blazei murill
on release of cytokines, chemokines and leukocyte growth factors in human blood ex vivo and
in vivo. Scand. J. Immunol. 69(3), 242–250 (2009)
61. Chae, S.-W., et al.: Nutrigenomic study on immunomodulatory function of Cordyceps
mycelium extract (Paecilomyces hepiali) in Mitomycin C–treated mice. Food Nutr. Sci. 5(22),
2217 (2014)
62. Wire, M.B., Shelton, M.J., Studenberg, S.: Fosamprenavir. Clin. Pharmacokinet. 45(2), 137–
168 (2006)
Does Pandemics Effects Human Future?
Decisive Role of COVID-19 in Human
Evolution
Muhammad Akhlaq , Aamir Jalil, Abid Hussain, Aisha Siddiqua,
and Muhammad Imran
Abstract The depth and scale of the COVID-19 pandemic create the greatest global
crisis of this century. This catastrophe leads to one of the large-scale economic and
social disrupts in the history of mankind. Despite magnificent scientific progress and
technological advancement, nature upholds humans as a statue against the situation.
This crisis not only changed the economical and social courses but strongly shaken
the strings of cultural and religious believes and harmony. From a strong economy
to the highest moral values and unique religious believes did not help to fight the
situation. The post-pandemic era will be an opportunity to think about the existing
economical, social, and cultural faiths. It will also provoke an evaluation of the
difference between “how we did” and “how we should do” as well as to focus on
international cooperation to develop a combined strategy against such subsequent
challenges. Such brainstorming process will result in enormous change in policies
from the governments and re-shuffling of the beliefs including moral values in the
society. This review portrays the most challenging situations faced during a pandemic
and encompasses the discussion on lessons learned and predictive points about the
future human being and architecture of the economical and social structures. This
M. Akhlaq (B)
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, Dera Ismail Khan,
Pakistan
e-mail: dr.akhlaq@gu.edu.pk
A. Jalil (B)
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck,
Innrain 80-82, Innsbruck, Austria
A. Hussain
Department of Pharmacy, Faculty of Medical and Health Sciences, University of Poonch,
Rawalakot, Azad Jammu Kashmir, Pakistan
A. Siddiqua
Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan
M. Imran
Mohi Ud Din Islamic Institute of Pharmaceutical Sciences, Mohi Ud Din Islamic Univeristy,
Mirpur, Azad Jammu Kashmir, Pakistan
will provide a sketch of how present decisions will describe the world of future
human beings.
1 Introduction
The pandemic of COVID-19 will provide greatest intellectual explosion of futures

thinking in human history, and socio economic perspective of human society. History
tells us that “Pandemics change history by transforming populations, states, soci-
eties, economies, norms, and governing structures.” The biggest question in front of
humanity is to answer about How would the SARS-CoV-2 virus reshape our society
and our lives in the days, weeks, months, years, and even decades after this pandemic?
The present scenario is predicting that COVID-19 pandemic will obviously change
the social face of humanity, but it leaves some questions as well [1]. Such as, how it
will affect the healthcare systems especially in case of pregnancies, or will it affect
economic, political, and legal value systems, thus leading to the fall or rise of the
huge financial and economic hubs? If this results in major transformations will the
world be the same or changed, it only depends what we plan and how we prosecute
it effectively recover from the effects of this situation or not [2].
China adopts effective measures to find out from where the virus originated;
devised the methods to cope the crisis. Moreover, credit goes to the spirit of disci-
pline in Chinese people, their health infrastructure, plethora of research laboratories,
and also the great control on media as well [3]. The rest of the countries in the world
have wasted precious time after the first cases appeared, devising not a single effec-
tive strategy to control in dealing with the epidemic and information about it. The
pandemic will radically change the modern world, leading to unpredictable outcomes
[4].
Humankind since from the beginning passed through different stages of evolu-
tion. The most prominent stages of evolution always happened after every humani-
tarian crisis. These crises fueled new social perception of humankind that always led
towards better ethics and development in the society. The present crisis hopefully
will also provide us with an opportunity to make its mark on our social existence and
old behaviors. This will impact the current value system and will have political and
economic implications [5].
The post-epidemic era will result in a new human being who will different in his
daily manners and intellect that will be quite in comparison to pre COVID-19 time.
This will also changes the political, legal and economic parameters of the world. In
fact, humankind will face a generation who thinks differently from the pre-pandemic
generation [6]. The COVID-19 storm soon is passing but leave mankind having long
lasting marks due to loss of many lives and lively hood. Humankind will soon live in
a world that is very different from the one before the virus. However, the pandemic
will succeed where the other movements of the twentieth century have failed in their
struggle to establish democracy and human rights, and preserve a safe environment
for all.
Does Pandemics Effects Human Future? Decisive Role of COVID-19 … 1099
It is now very clear only those people survive who will establish strong bonds
with science. Because the current calamity is not of the pandemic alone as it will
have far consequences on human evolution. Such depiction should have to address
with the associated repercussions and should not be limited to taking ad-hoc costly
measures for the current situation only; instead, we should prompt innovative thinking
to take measures and actions that results in a good preparation for the future [7]. The
present discussion encompasses atlas of COVID-19, different diagnostic methodolo-
gies, compulsions on health system especially in pregnancies and socio economic
perspective that collectively will impact humankind reshaping humanity and humans
itself.
2 Scenario of Pandemic and Related Control Strategies
2.1 The Outburst of COVID-19
Outbreak of coronavirus (COVID-19) was first received by W.H.O. from Chinese

Officials highlighting pneumonia caused by unknown virus dated December 2019
in Wuhan city [8]. In order to control the spread Chinese officials placed de-facto
quarantine encircle uptight 50.0 million people in Hubei province from Wuhan and
nearby cities [9]. The situation was alarming around the globe, but no containment
strategies were being planned by the rest of the world to save the spread of virus.
Hence, the outbreak started traveling straight from china initially to Italy, Iran and
Europe. Significantly the virus spread in the European countries and hited much
harder in comparison to china. The first set out for the corona virus was detected in
Italy the most travel destination in the world along with 93 countries across all five
continents. The W.H.O. officially declared the Pandemic outbreak of COVID-19 on
11, March 2020. However, on 31, January 2020 WHO formerly deputed COVID-19
a “Public Health Emergency of International Concern” but was reluctant to name it
pandemic at that time, which was a big mistake [10]. So, no serious international
concerns were publicized and no health warnings were issued up till that time. The
inter air-links were not closed that contributed in fast spread of the disease. The travel
from China transmit infection to utmost countries counting Germany, Russia, India,
USA, Italy, Korea [11].
2.2 Corona Atlas on Globe
No doubt, the outbreak began in Wuhan, China is one of the most populous cities in
the world. The Chinese government took preventive measures on time to control the
infectious disease by separating affected regions. But in no time, this virus travels
from china to other parts of the world including Europe specially Italy, showing
its worst effects in short time. The world was socially, economically and politi-
cally resketched due to emerging COVID-19 threat. It stretches its drastic effects
from Africa to Latin America [12]. According to the current statistics the Pandemic
COVID-19 worldwide confirmed, recovered and deaths cases are shown in Figs. 1
and 2.
Initially, over 82,870 cases and 3339 deaths have been accepted by Chinese health
authorities and endured the blemishes of COVID-19. However, by doing control
measures the 5000 cases per day were declined to 39 new cases in Mid-February
which was an exceptional achievement. Hence in the world new cases were imported
from other countries, but for now China has its outbreak under control. However,
the outbreak started to revive in the rest of the world, things were downturn in
china [13]. At Least 214 countries and territories are now confirmed with COVID-
19. Highest number of COVID-19 has been recorded in the US, India, Brazil and
Russia. The highest number of deaths were also recorded in USA Europe having
219,343 including 61 new deaths, in India 108,523 including 152 new deaths, in
Brazil 150,338 including 102 new deaths [14].
Fig. 1 The schematic diagram portraying the latest world map in the context of pandemic COVID-
19 with confirmed cases round the globe in a single screenshot, showing United States, Spain, Italy,
Germany, France, China, United Kingdom and Iran in pandemic region with deep-rooted cases and
higher death toll, the data was retrieved on October 4, 2020 (10)
Fig. 2 Immune boosters as a leading protector against COVID-19
Spain had the second highest number of cases numbering 148,220 confirmed
infections and 14,792 deaths. All the schools, non-essential supermarkets, bars and
restaurants were sealed by the government and the citizens were in complete lock-
down. The citizens were only allowed to leave their home to go to work and to buy
food [15]. State of Bavaria Germany enforced a complete lockdown as the confirmed
cases of infection raises to 113,296 and death toll up to 2349, however, it was much
lower in comparison to other European places [16]. However, number of people
recovering from infection, but spreading at the fastest rate due its contagious nature.
Yet there is a progressive increase in number of coronavirus cases. Globally 34.9
million COVID-19 cases were reported and 1 million deaths since China reported its
first cases [17]. It is also expected that in winter the pandemic will again hit badly
in winters as the temperature drops drown below the freezing point in some parts of
the world.
3 Methodology
The literature search was performed using the following electronic databases:
EMBASE, PubMed and Google Scholar. Hand searching of the reference lists of the
retrieved studies was performed to identify further relevant publications. Terms and
keywords used to conduct the literature search included the following: “COVID-19,”
“Prevention,” “Pneumonia outbreak” and “Coronavirus.” Alternative search terms
were “2019-nCoV,” “novel coronaviruses” and “supportive care.” The filters were
set to search for studies related to humans and published in English. Attempts were
made to identify all literature related to COVID-19. Thus, no time limit was set for
the search. Screening of the titles and abstracts of the retrieved studies was conducted
to assess relevance. Studies included in the current literature review involved those
covering the following important aspects: aetiology, pathogenesis, mode of transmis-
sion, clinical diagnosis, special attention to sensitive populations, clinical manage-
ment and treatment; and early supportive therapy and monitoring. Studies that do not
cover any of the above-mentioned items were excluded. Data were extracted only
from the full-text articles, WHO interim guidelines and also from the Centres for
Disease Control and Prevention (CDC).
To elaborate the emergence of COVID-19 and its future Outcomes on humans,
a brief discussion on corona virus and their journey towards present pandemic is
studied chronologically. In addition, methods of their diagnosis and treatment plans
in relation to their relative impact on the situation is also included in this section.
3.1 Journey of Coronaviruses and Emergence of COVID-19
Coronaviruses (coronaviridae) considered to be responsible for gastrointestinal,

respiratory, hepatic and neurological diseases in animals and humans. RNA viruses
are famous for their highest rate of mutation and offenly become inert causing no
infections. The first coronavirus was isolated in 1937 from chicken embryos. Initially,
cases of Severe Acute Respiratory Syndrome (SARS) emerged as communicable
disease reported in southern China with challenging indisposition and mortality with
a high rate of transmission between humans [18]. SARS-CoV was introduced in
humans from the civet cats and bats were considered as the basic reservoir hosts [19].
Early in 2003, there was a serious outbreak of SARS in Hong Kong and within a
couple of days, the disease was blown out to the states of Singapore, Canada, Taiwan,
Germany and America. Within a period of two month 7296 cases were reported in
almost 30 countries, with a death clatter of 526 humans [20]. Another, coronavirus
outbreak was reported by WHO in September 2012 as a Novel Middle East Respira-
tory Syndrome Coronavirus (MERSCov) causing severe pneumonia in humans. But
fortunately, It was only transmitted from person to person only in healthcare settings.
Shortly thereafter the Human Coronavirus England 1 was recovered. The inception
of disease was drawn back to even a previous spell of 2012 when a number of cases
were reported in health workers in Jordan at hospital [21]. The genome arrangements
were investigated for the three virus collected from Saudi Arabia (JX869059.2),
Jordan (KC776174.1), and United Kingdom (KC164505.2). It was discovered that
> 99% sequence similarity was found (∼100 nucleotide variations in a 30.1-kb
genome), signifying that the three viruses are breed from a common antecedent.
Recently, in December 2019 patients reported with symptoms of pneumonia having
unknow prophylaxis in Wuhan, China. It was identified as a viral infection and later
on discovered as a novel coronavirus (SARS-CoV 2, KCDC03) and the disease was
named as COVID-19 by WHO [22].
Coronaviruses have the ability to infect both human as well as animals and may
spread via direct contact with a contaminated surface or via droplets produced during
sneezing, coughing or louder talking both by symptomatic as well as asymptomatic
cases [22].
Epidemic studies have shown that SARS-CoV-2 is a third reported spillover of
zoonotic coronaviruses to humans in only two decades that became pandemic from
epidemic. Owing to the zoonotic nature of infection, it’s not unlikely that other novel
coronaviruses might emerge as epidemics and cause global emergencies in near
future [23]. Chu et al. explained that six zoonotic corona viruses have been reported
in humans so far, and it is the 7th in a row (SARS-CoV-2). Family of corona virus
consists of four genera i.e. α, β, γ, and δ, in which SARS-CoV-2 belongs to the beta
subgroup and are the largest among the RNA viruses [24]. The genome of SAR-CoV-
2 comprises 30,000 bp, contains 15 genes, which encodes four different structural
proteins named Envelope (E), Membrane (M), Nucleocapsid (N) and Spike (S) and
Non- Structural Proteins [25]. The Spike (S) proteins help the virus to anchor the
host cells and make their entry. Spike proteins are considered important in terms of
adaptation to various hosts, as their receptor binding domain is the most variable
region because of random mutations. The non-structural proteins on the other hand
are reported to be conserved instead [26, 27].
3.2 Diagnosis Approaches
Reverse-transcription polymerase chain reaction (RT-PCR) is being used for

detecting the presence or absence of SARS-CoV-2. Sample for this diagnostic test
is usually collected from nasopharyngeal (NP) swabs. As per CDC recommenda-
tions, NP swab samples should be collected from asymptomatic individuals. In case
if a NP swab sample cannot be collected, an oropharyngeal (OP) swab can serve as
an alternative. Sample collection from bilateral anterior nares and mid-turbinate is
recommended for symptomatic individuals. Sputum sample should be obtained for
infected individuals suffering from productive cough (without deliberately inducing
sputum). Moreover, when the patient is clinically indicted (i.e. mechanically intu-
bated), sample collection from lower respiratory track using bronchioalveolar lavage
(BAL) is recommended [28].
Various reports suggest that sample-associated issues (e.g. improper handling or
shipment and sample collection in very initial or late stages of disease when there is
insufficient viral load) may result in falsely negative RT-PCR test for SARS-CoV-2.
Hence, there is a need to establish the diagnostic accuracy profile of RT-PCR test
[29]. Several patients whose computed tomography chest scans provided typical find-
ings (i.e. bilateral peripheral distribution along with multifocal lower lung involve-
ment), indicating SARS-CoV-2 infection, were tested negative on RT-PCR [30].
There are higher chances of getting a positive RT-PCR result from lower respiratory
tract samples than those collected from upper respiratory tract. In a study, positive
percentage was higher in case of BAL samples (~93%) than the NP samples (~72%)
[31]. Repeat testing, preferably using lower respiratory tract sample, is recommended
by WHO in situations where initial test result is negative but clinical symptoms are
there.
The antibody response in SARS-CoV-2 infected individuals is yet to be completely
understood. As of now, RT-PCR is serving as a reference standard diagnostic tool.
However, various studies are recommending serologic antibody testing along with
RT-PCR for more accurate and reliable diagnosis of SARS-CoV-2 infection. It can
prove to be helpful for diagnosing SARS-CoV-2 in asymptomatic or suspected
individuals with negative RT-PCR result.
In a study conducted in 173 patients, the median seroconversion time for anti-
SARS-CoV-2 immunoglobulin-M (IgM), and immunoglobulin-G (IgG) and total
antibodies was day-11, 12 and 14 respectively. Antibodies were detected in <40%
patients within 7 days of symptoms onset. On day 15, anti-SARS-CoV-2 IgM, IgG
and total antibodies were found in ~94.3%, ~79.8% and 100.0% patients. However,
RNA detectability declined over the time i.e. from 66.7% before day 7 to 45.5%
within 15–39 days [32].
In another study conducted in 285 COVID-19 patients, anti-SARS-CoV-2 IgG
antibodies were detected in 100% patients within 19 days of symptoms onset. Within
the same study, virus-specific IgG or IgM antibodies were found in 4 out of 52
individuals who were tested negative for RT-PCR test [33].
Rapid point-of-care testing, involves an IgG / IgM based test for detecting SARS-
CoV-2, is capable of providing results within ~20 min with good specificity i.e.
88.9%. However, low sensitivity i.e. ~36.4% makes it less efficient for screening
purposes [34]. Despite their aid in diagnosing COVID-19, several drawbacks are
associated with serological antibody tests such as variable sensitivity, specificity and
time duration required by the body to develop these antibodies.
Some studies have reported the presence of SARS-CoV-2 in blood and stool.
Hence, blood and stool examination may also aid in diagnosis [29].
3.3 Pathogenesis and Diseases Cycle
3.3.1 Pathophysiology of Disease of SARS-CoV-2
Corresponding to previously reported Coronavirus including MERS-CoV and

SARS-CoV-2, the lung epithelial cells of the human respiratory system emerge to
be the primary attack of SARS-CoV-2. The comorbidities such as hypertension,
diabetes, cardiovascular problems and respiratory disorders, may, however, aggravate
the situation and results in organs failure [35, 36].
Angiotensin converting enzyme (ACE-2), which is a transmembrane metallo
carboxypeptidase, expressed in kidneys, intestine lungs and blood cells, plays the
major role in facilitating entry of both SARS-CoV2 and SAR-CoV, into the epithe-
lial cells of lungs [37]. The receptor basic function, though, is the maturation of
angiotensin, which controls blood pressure and vasoconstriction. In the first step,
virus attached to the host cell’s via binding its spike protein to the ACE-2 receptor
on the outer membrane of the host cells. Most of the amino acid residues of spike (S)
proteins of SARS-CoV-2 and SARS-CoV are similar [37]. Hence, they show affinity
for the same receptors. The spike (S) protein consists of two distinct domains namely,
S1 and S2. S1 is the domain for N-terminal and S2 is the domain for C-terminal.
The S2 domain is elaborated for membrane fusion and S1 is plays its role in receptor
binding. The ACE-2 receptor binds with the viral spike(s) protein via S1subunit.The
spike (S) Protein is the splits into cellular protease at S1/S2 site, which dissociates
S1 from S2, while S2 remains bound to the viral membrane. This is followed by
agglutination of host and viral cell membranes facilitated via protein domain S2 that
binds to a merging peptide on the host cell [38].
The use of ACE inhibitors in patients suffering from diabetes and hypertension can
lead to overexpression of ACE-2 in these patients and hence further facilitate attach-
ment of SARS-CoV-2 into the cells [9]. This could probably justify the increased
risk for COVID-19 associated complications and mortality in these patients.
Human coronaviruses, on the other hand, can also enter the host cells via endo-
cytosis where cathepsins activates the spike proteins and release the viral genome
into the cytoplasm of the host cells. However, most of the coronaviruses fused with
membrane to enter host cells, as this is less likely to trigger immune response [39].
After the viral RNA is detached into the host cytoplasm, the translation proteins-
initiated coding and decoding. The viral genome encodes two types of proteins;
structural and nonstructural protein. The nonstructural protein helps in viral RNA
synthesis while the structural proteins participate in virion assembly. The two
polyproteins named polyprotein 1a (pp1a) and polyprotein 1ab (pp1ab) are first
translated by free ribosomes and then split by two enclose viral enzymes named
Papain-like protease (PLpro ) and chymotrypsin-like protease (3CLpro ) to produce
functional non-structural proteins. From the replication-transcription complex these
nonstructural proteins which help in replication of structural protein RNA [40]. The
structural protein RNA is then translated by the Endoplasmic Reticulum (ER) asso-
ciated ribosomes to produce Proteins like Membrane (M), Envelope (E) and Spike
(S) which are later translocated to the endoplasmic reticulum (ER) membrane in
preparation for virion assembly. The nucleocapsid (N) proteins, however, stay in the
cytoplasm after translation and associate themselves with the genomic RNA. The
vesicles studded with the viral structural proteins are then moved from endoplasmic
reticulum (ER) to golgi apparatus (GR) where they are packaged into virions by
incorporating the viral genomic RNA. The mature virions then escape the host cell
via exocytosis [41].
3.3.2 Potential Relation Between Mast Cell Activation and Respiratory

Symptoms
As it is well known, deaths from SARS CoV-2 (COVID-19) outbreak, which is a

current issue and became a pandemic, are increasing day by day [42]. However, there
is no vaccine or approved management therapy for SARS CoV-2 yet. For this reason,
prevention and treatment of pulmonary complications developing during SARS CoV-
2 infection is of great importance for the survival of patients. In the present discussion,
it was attempted to explore the potential relationship between pulmonary compli-
cation and lung mast cells COVID-19 infection and the possible use of mast cell
stabilizers that may contribute to the reduction and improvement of the pulmonary
complications in the context of current literature. We are of the opinion that this
present chapter of review may contribute to clinicians and researchers interested in
the COVID-19 treatment.
SARS-CoV-2 is settled in respiratory tracts and the lungs after it is transmitted
by mainly droplets and respiratory secretions. It causes SARS, shortness of breath,
fever and cough. The deaths from SARS-CoV-2 infection stem from a combination
of SARS and pneumonia, especially in elderly individuals and debilitated subjects.
Therefore, supportive therapies have great importance to combat against death-
causing symptoms of SARS-CoV-2 infection. Mast cells are multifunctional immune
cells that are widely dispersed round the body as depicted in Fig. 2. [43, 44].
MCs are present in respiratory tracts and the lungs for playing their defensive role.
MCs are involved in a wide range of pathophysiological processes including innate
and adaptive immunity, inflammation, allergies, migraine and pulmonary hyper-
tension [45]. MCs contain a great variety of inflammatory mediators including
proteases, cytokines, chemokines, substance-P, serotonin, prostaglandins, bradykinin
and histamine [46]. When MCs are activated, they release these mediators to their
resident environment to include an inflammatory response through the process of
degranulation. While normal activation of MCs is needed to sustain immune home-
ostasis of the body, their abnormal activation leads to immunological complica-
tions like allergic asthma and allergies. There are wide range of immunologic
and nonimmunologic substances that are able to activate MCs like IgE, antigens,
anaphylatoxins, viruses, bacteria, toxins, detergents, neuropeptides, and pollutants
[47]. Activation of MCs can be triggered by IgE-dependent and IgE-independent
pathways.
While IgE-dependent activation of MCs are mediated by FcRI receptors on the
cell membrane and non-IgE mediated activation of MCs is mediated by toll like
receptors (TLR) and G-protein coupled receptors pathways that can be triggered
by viruses, chemokines, cytokines, pathogen-associated molecular patterns, certain
hormones and neuropeptides [48].
In particular, TLRs are capable of recognizing viruses and bacteria. Therefore,
SARS-CoV-2 may activate MCs to stimulate release of inflammatory mediators
through TLRs and cross-linking induction of IgE-FcεRI.
From the mast cells SARS-CoV-2 induces the release of the mediators like IL-8,
TNF-α, Interleukin (IL)-1, Histamine, prostaglandin (PG)D2, Leukotriene (LT) C4
and chymase can lead to worsening of existing inflammation, bronchoconstriction

and mucosal edema in the respiratory system, and pulmonary fibrosis [49].
It is well known that viruses, regardless of type, can induce release of such proin-
flammatory cytokines such as IL-1, IL6 and TNF-α and IL-8 that are pioneer medi-
ators of inflammatory responses. These pro-inflammatory cytokines may cause lung
and tissue inflammation, fever and pulmonary fibrosis, ii) further aggravate existing
inflammation condition in the respiratory system during SARS-CoV-2 infection [50].
It was previously reported the elevated plasma amount of IL-1beta, TNF-α and
IL-6 in pediatric patients with SARS-associated coronavirus infection. In addition,
it was reported that expressions of TNF-α, Interleukin1β and Interleukin-6, were
accumulated in the SARS-CoV-infected lung and bronchial autopsy tissues from
subjects of SARS. Additionally, a study shows that SARS-CoV infection lead to an
increase in expression of TLR4 and 9 which are closely related to activation of MCs
[51]. Moreover, it is reported that there is a correlation between elevated IL-6 levels
and severity of pulmonary symptoms in the SARS CoV-2 -infected patients [52].
On the other hand, histamine, PGD2 and LTC4 are powerful constrictors of smooth
muscles in the respiratory system. The virus-induced release of these mediators
from MCs can trigger bronchoconstriction, mucus secretion and mucosal edema in
respiratory tracts in infected patients of SARS CoV-2. Such a situation can facilitate
the process leading to death in elderly and debilitated patients during the infection
of SARS CoV-2.
Moreover, it is proposed that pulmonary fibrosis may be one of the substan-
tial complications in SARS-CoV-2-infected subjects. Mechanisms underlying
pulmonary fibrosis induced by SARS CoV-2 are not clear but previous studies demon-
strated that increased number of MCs and mediators from activated MCs such as,
IL-1 and chymase in the lungs contribute to pulmonary fibrosis [53].
Our hypothesis suggests a potent relationship between mast cell activation and
pulmonary complications in infection of SAR CoV-2 linked in previous reports.
We can speculate that SARS-CoV-2—induced Severe Acute Respiratory
Syndrome, severe pneumonia, pulmonary fibrosis and bronchoconstriction are asso-
ciated with increased release of pro-inflammatory cytokines such as interleukin-1β,
interleukin-6, interleukin-8 and tumor necrotizing factor-α, and potent bronchocon-
strictor mediators such as PGD2, LTC4 and histamine from activated MCs in the
respiratory system.
Therefore, endogenous or chemical MCS stabilizers as a sympathetic therapy may
be useful to reduce deadly inflammatory exacerbation and respiratory Obstructions
in SARS-CoV-2 infection.
There are a wide range of mast cell stabilizers including endogenous ones such
as anandamide, progesterone, testosterone and chondroitin sulphate, and chemical
such as ketotifen, cromolyn, quercetin, luteolin, thymoquinone. Moreover, cromolyn
of those mast cell stabilizers is clinically administered to treat some disorders
like asthma, allergic rhinitis and mastocytosis which are associated with mast cell
activation [54].
Taken together, we suggest that suppression of overactivation of lung mast cells by

endogenous or chemical mast cell stabilizers may contribute to ameliorate inflam-
matory response and respiratory interference in order to lower the expirations in
SARS-CoV-2 infection. Moreover, such a promising treatment approach can also
improve life quality of survivors by reducing or preventing lung damage such as
pulmonary fibrosis.
3.4 Treatment and Management of COVID-19
The infection from SARSCoV-2 can be broadly categorized into three stages i.e. stage
I, II and III. The individuals at stage I are asymptomatic, with or without detectable
virus. the individuals at this stage are silent carriers and may spread disease without
knowing it. This type of asymptomatic transmission was reported in Germany. At
stage II, the individuals are symptomatic but non-severe with a detectable virus load in
the body. At stage III, the viral load is even higher and severe respiratory symptoms
or organ failure due to cytokine rush are evident. Response of the individual to
viral infection is heterogenous owing to physiologic development, immunity profile,
comorbidity, treatments given.
Following an incubation of the virus i.e. non-symptomatic (stage I) and non-
severe symptomatic (stage II) an adaptive immune response is initiated by the body to
overcome the foreign invasion and resist the progression of the disease to sever stage.
The individual having appropriate genetic background or appropriate endogenous
immunity can combat the viral infestation and elicit a specific immune response to
the virus.
In cases where the protective immune response is impaired, the invading virus
will continue to replicate in the body resulting in a massive destruction of the tissues
having higher ACE2 expression such as kidney, intestine, heart. The damaged cells
consequent chemotaxis and Cytokin storm which results in inflammatory lungs that
causes severe stage life-threatening respiratory disorders.
To date, there is no specific vaccine or medication for COVID-19. The world is
desperate to find effective medication for this pandemic disease. Several drugs and
vaccines are under clinical trials. The drugs being tested range from regenerate flu
treatments to malfunction ebola drugs, to malaria treatments that were first developed
decades ago. Here, researchers and doctors have several treatment methods to help
fight COVID-19.
3.4.1 COVID Vaccine
In view of the pandemic outbreak, many of the global organizations such as WHO,
welcomes trust, Bill and Malinda gate trust, CEPI for supporting research projects
relating to the development of the COVID vaccine. According to a report published
Table 1 Vaccine effective against COVID-19

Candidate Vaccine characteristics Lead developer Status
mRNA-1273 LNP-encapsulated mRNA Moderna Phase I
Vaccine encoding S (NCT04283461)
protein
Ad5-nCoV Adenovirus type 5 vector CanSino biologicals Phase I
that express S protein (NCT04313127)
INO-4800 DNA plasmid encoding S Inovio Phase I
protein delivered by Pharmaceuticals (NCT04336410)
electroporation
LV-SMENP-DC DCs modified with Shenzhen Phase I
lentiviral vector Geno-Immune (NCT04276896)
expressing synthetic Medical Institute
minigene based on
domains of selected viral
proteins; administered
with antigen-specific
CTLs
Pathogen-specific aAPCs modified with Shenzhen Phase I
aAPC lentiviral vector Geno-Immune (NCT04299724)
expressing synthetic Medical Institute
minigene based on
domains of selected viral
proteins
in Nature around 75 research organizations are aiming to develop vaccine (Tables 1

and 2). Of these 5 have initiated phase I clinical trials as discussed in Table 1.
4 Results
4.1 Pandemic Spread and Management
In order to prevent the spread of pandemic new strategies have been employed.
The best example in this scenario is of Wuhan, China. Chinese officials were not
only successful to contain the viral spread within Wuhan but also take effective
measures along the country. There efforts bring a successful result although the
spread outside the China was unrollable. The viral infection spread throughout the
world and hit hard across Europe, United states and other parts of the world as
well. Governments implemented lockdown strategies and controlled the virus for
time being. Unfortunately, plans of social distancing is a limiting solution to the
present situation and clinicians and scientist all over the world are devising different
management therapied. The present treatments available for treating the COVID-19
are improving day by day. However, the single therapy plan has not been devised up
Table 2 Attributes refer to genaral attributres of platform, and assessments are not intended as infrences about a particular candidate. NIAID denotes National
1110
Institutre of Allergy and Infectious Diseases, and WRAIR Walter Reed Army Institute of Research
Technology Attributes Candidates in Preclinical Candidates in phase 1
Single dose Licensed platform Speed Current Scale Development
DNA No No Fast Medium Inovio Pharmaceuticals
Takis/Applied DNA
Sciences/Evvivax Zydus
Cadila
Inactivated No Yes Medium Medium to Sinovac
high
Live attended Yes Yes Slow High Codagenix/Serum Institute of
India
Nonreplicating vector Yes No Medium High Geovax/BravoVax Janssen CanSino Biologics
Pharmaceutical Companies, (ChiCTR20000
University of Oxford, 30,906)
Altimmune, Greffex, Vaxart,
ExpresS2ion
(continued)
M. Akhlaq et al.
Table 2 (continued)
Protein subunit No Yes Medium to High WRAIR/US. Army Medical
fast Research Institute of
Infectious Diseases Clover
Biopharmaceuticals Inc/GSK
Vaxil Bio
AJ Vaccines
Genrex/EpiVax/University of
Georgia, Sanofi Pasteur,
Noavax
Heat Biologics/University of
Miami, University of
Queensland/GSK/Baylor
College of Medcine
iBio/CC-Pharming
Replicating viral vector Yes Yes Medium High Zydun Cadila
Institute Pasture/Themis
Tonix Pharma/Southern
Research
RNA No No Fast Low to Fudan University/Shanghai Moderna/NIAID
medium Jiao Tong (NCT04283461)
University/RNACure
Does Pandemics Effects Human Future? Decisive Role of COVID-19 …
Biopharma
Chine CDC/Tongji
University/Stermina
Arcturus/Duke-NUS
Imperial College London
Curevac
BioNTech/Pfizer
(continued)
1111
Table 2 (continued)
1112

Uncertain University of Pittsburgh
University og Saskatchewan
ImmunoPrecise
MIGAL Galilee Research
Institute, Doherty Institute,
Tulane University
M. Akhlaq et al.
till now. Reengaging from symptomatic management to control the different aspects
of immune response had been trialed. But the spread of pandemic is still greater than
the efforts made to control it clinically. Clinicians and physicians from different part
of the world devised new therapy plan including the herbal treatment, immune booster
and immune suppressants. But the clinical course of the COVID-19 is different along
the glob depending upon the socio-economic conditions, weather conditions and
cultural backgrounds. Moreover, genomic make up of people also played a wide role
in pathophysiology of the disease. It is now a unanimous agreement that an effective
vaccine will play a game changing role in the present scenario. Multiple techniques
have been employed for the development of COVID-19 vaccine. Among these, either
DNA or RNA based vaccines will be of greatest potential or followed by those for
developing recombinant-subunit vaccines. Use of next-generation sequencing and
reverse genetics may also cut development time of more conventional vaccines during
epidemics. Even with novel platforms, some questions relating to the development of
SARS-CoV-2 vaccine are still unanswered. First, although the virus’s spike protein
is a promising immunogen for protection, optimizing antigen design is critical to
ensure optimal immune response, for example, targeting the full-length protein or
only the receptor-binding domain. As with naturally acquired infection, the potential
duration of immunity is unknown; similarly, whether single-dose vaccines will confer
immunity or not, is still uncertain.
4.2 Diagnostic Findings
4.2.1 Laboratory Findings
SAR-CoV-2 infected hospitalized individuals exhibited varying white blood cell

counts. In a study, leukopenia (<4 × 109 per L), leukocytosis (>10 × 109 per L),
lymphopenia (< × 109 per L) and normal leukocyte counts (4–10 × 109 per L)
were observed in 25, 30, 63 and 45% patients. In another study, 33.7%and 36.2%
patients exhibited leukopenia and thrombocytopenia. A review and meta-analysis
involving 43 studies (~3600 infected individuals) suggested that C-reactive protein,
lymphopenia, and elevated lactate dehydrogenase (LDH) were the common labora-
tory abnormalities, observed in 68.6, 57.4 and 51.6% SARS-CoV-2 infected indi-
viduals respectively [55]. In another study, significantly high levels of interleukin 6
(IL-6), high sensitivity cardiac troponin I, serum ferritin and LDH were associated
with aggravated illness and mortality rates [56].
Elevated d-dimer levels were observed in hospitalized SARS-CoV-2 infected
patients. A retrospective analysis study conducted in China involving 1,099 COVID-
19 patients showed higher d-dimer levels in patients with serious illness than the
patients experiencing non-severe symptoms. In another study, conducted on 183
SARS-CoV-2 infected individuals, non-survivors (on admission) exhibited higher
d-dimer, fibrin degradation product (FDP) levels and lower fibrinogen, antithrombin
(AT) levels as well as prolonged prothrombin time (PT) than the survivors. In addition,
during hospitalization, a large number of non-survivors (71.4%) suffered from overt

disseminated intravascular coagulation (DIC) than the survivors (0.6%). These results
suggests that abnormal coagulation parameters in SARS-CoV-2 infected patients
were associated with poor prognosis [57]. Various studies have reported elevated
blood urea nitrogen and creatinine levels in patients with critical illness [58].
4.2.2 Radiological Findings
Common abnormalities observed in chest CT scans during early stages of SARS-

CoV-2 infection involve peripheral, focal or multifocal ground-glass opacities in
lungs in ~50–75% patients. Crazy paving and consolidation becomes prominent in
chest CT scans upon disease progression; peaking within 9–13 days. It then clears
slowly i.e. in ~1 month or more. Chest CT scan may appear normal in ~ 50% COVID-
19 patients in first 2 days after onset of symptoms [59]. Some studies have shown
abnormal chest CT scan findings in asymptomatic patients [60]. In a study, some
level of abnormality.
4.3 In-Silico Studies of Drugs
On the basis of in-silico studies and enzyme activity test numerous agents found
to have potential against SARS COVID-19. These agents are remdesivir, indinavir,
saquinavir, lopinavir, carfilzomib, ritonavir, atazanavir, darunavir, tipranavir, fosam-
prenavir, enzaplatovir, presatovir, abacavir, bortezomib, elvitegravir, maribavir, ralte-
gravir, montelukast, polydatin, chalcone, disulfiram, carmofur, shikonin, ebselen,
tideglusib, PX12, TDZD-8, cyclosporin A, and cinanserin.
Remdesvir has shown invitro activity against SARS COVID-19; in a clinical trial a
bit improvement was observed in patients that were administered with remdesvir. A
most recent study shows that Nelfinavir can inhibit replication of covid-19 virus.
On the basis of direct antiviral properties and its potency enhancements during
MERS and SARS outbreaks, Ribavarine can become a potential candidate against
COVID-19. Amantadine inhibits the release of COVID-19 virus nucleus into the
cell cytoplasm.6 Lopinavir is a protease inhibitor; as protease is the key enzyme in
corona virus replication, thus it inhibits viral replication. Just like lopinavir; ritonavir
is also protease inhibitor and used in combination with lopinavir to enhance potency
against viral replication. Favipiravir has shown activity against RNA virus and has
potential against COVID-19. Indinavir and darunavir both are protease inhibitors and
in-silico studies has shown that both of these drugs has great binding affinity with
COVID-19. A study shows saquinavir as potent inhibitor of SARS-Cov2 and has
potential against COVID-19. Atazanavir has great bioavailability with respiratory
tract and its ability to impair viral replication are major reason for its selection as
drug against COVID-19. In an insilico study it was observed tripinavir and raltegravir
have shown best molecular interaction with protease of SARS-Cov2 and can become
excellent candidate for COVID-19. Fosamprenavir is HIV-protease inhibitor and can

become potential candidate as drug against COVID-19. Based on insilico studies and
their viral protease inhibition; enzaplatovir, presatovir, abacavir and maribavir have
potential to play as drugs against COVID-19 [61].
5 Discussion
5.1 How the Pandemic Might Show Out in 2021 and After
(June 2021) SARS-CoV-2 virus is continuously spreading from past one and a half
year. Intermittent lockdowns are being imposed in order to stop or slow down the
rapid transmission of this virus. An approved vaccine against SARS-CoV-2 infec-
tion promises six months protection, however, its distribution has slowed down
due to international deal-making. SARS-CoV-2 has infected ~ 250 million people
worldwide with ~ 1.75 million deaths.
The epidemiologists are establishing short as well as long term projections in
order to mitigate the transmission and impact of COVID-19 causing SARS-CoV-2.
Currently, the modellers, in general, have agreed that SARS-CoV-2 will keep on
transmitting and the future relies upon various unknowns such as development of
long-lasting immunity in infected individuals, influence of weather on the spread of
this virus and the decisions made by authorities / governments as well as individuals.
According to Joseph Wu, a disease modeller, the future would greatly rely
upon the precautionary measures taken by the individuals and extent of social
mixing. Successful lockdown at various places have suggested that changes in social
behaviour and precautions can efficiently reduce the transmission of SARS-CoV-2.
5.2 What Will Happen When It Gets Cold?
It is evident now that summer season does not uniformly reduce the transmission of
SARS-CoV-2 infection. However, warm weather may contain its spread in temperate
regions. Experts think that SARS-CoV-2 infection will spread at a higher rate in the
winter season.
Various human respiratory viruses such as influenza, respiratory syncytial virus
(RSV) and coronaviruses spread rapidly and lead to outbreaks during winters. Hence,
it is being expected that novel SARS-CoV-2 would also follow this trend. Evidences
suggest that stability and spread of respiratory viruses ameliorate in the dry winter
air [62] and inhalation of such air may lead to impaired respiratory tract immune
response. Moreover, people prefer to stay indoors for most of the time during winters,
hence, there is an increased risk of virus transmission via droplets according to
Richard Neher, a computational biologist. Simulations from Neher’s group suggested
that seasonal changes would possibly influence transmission of SARS-CoV-2 virus

and its containment would be difficult in the Northern Hemisphere during cold
weather [63]. In future, there is a risk of SARS-CoV-2 outbreaks in waves every
winter. Individuals who are already infected with this virus are at lower risk, however,
it would rely upon the time duration for which the immunity to this virus lasts, adds
Neher. During winter and autumn season, it would be difficult to tackle a combina-
tion of RSV, influenza and SARS-CoV-2 infections, according to Velasco-Hernández,
who is constructing a model to predict the manner of interaction of such viruses. It
is yet to be estimated whether other CoVs infections can offer any immunity against
novel SARS-CoV-2. Antibodies from one virus bonded with other virus but were
unable to neutralize it in a cell-culture experiment involving SARS-CoV and the
novel SARS-CoV-2 [64].
There are two ways to end this pandemic i.e. elimination of virus worldwide
(which is currently impossible considering the spread of this virus at a large scale) or
development of immunity in 55 – 80% population via infection or vaccination [65].
5.3 What Happens in 2021 and Beyond?
The future of pandemic in the coming years would rely on the development of an
effective vaccine and the time duration for which the protection will be provided
by vaccination or recovery from COVID-19. Various vaccines govern immunity
for years (e.g. polio, measles) whereas others wear off with time (e.g. influenza,
whooping cough). Likewise, some viral infections induce a long-lasting immune
response, others a transient one. According to Grad, Harvard epidemiologist Marc
Lipsitch and co-workers “The incidence of COVID-19 by 2025 would rely on the
duration of immune response” [66].
Duration of immunity against SARS-CoV-2 infection is still not reliably known
as this is relatively a new virus. In a study [67], neutralizing antibodies persisted for
up to ~ 40 days in recovered individuals after the start of infection. In various other
studies, antibody levels diminished after few weeks or months. In case of SARS-CoV
infection, antibodies persisted for ~5 years at a high level and then slowly diminished
within 2–3 years. SARS-CoV-2 infection would probably follow the same trend [68].
Immunity, against future encounters with SARS-CoV-2, is also provided by memory
B and T cells as evident by various studies. However, their role in inducing immunity
against COVID-19 is not yet clearly known. Complete understanding on immunity
against SARS-CoV-2 infection would require examining a large number of recovered
individuals for a long period of time.
Currently, it is being speculated that in the absence of vaccine or long-lasting
immunity, SARS-CoV-2 would extensively keep on circulating in humans on regular
basis and remain a pandemic. In case preventable and treatable diseases, various
deaths are already being observed in several countries (e.g. malaria kills 0.4 million
people every year).
If SARS-CoV-2 would induce short-term immune response like other human

CoVs e.g. OC43 and HKU1 for which immunity persists for ~40 weeks, then,
reinfections could possibly result in annual outbreaks.
A CIDRAP report [69], after analyzing the pattern of eight influenza pandemics,
suggests that SARS-CoV-2 activity would remain significant for next ~ 1.5 – 2 years,
either in the form of declining peaks or valleys or as “slow burns” (would keep on
transmitting without a definite wave pattern). However, these are just speculations
because COVID-19 has so far not followed the influenza pandemic trend and there
are no precedents for this pandemic yet.
Another possibility includes permanent immune response against SARS-CoV-2.
In such scenario, after a world-sweeping outbreak, the virus may disappear itself even
without a vaccine by 2021. According to the Harvard team, if the immunity would
persist for moderate time (e.g. ~2 years), then, the virus would disappear temporarily
for a short duration of time and possibly return back by 2024. However, this forecast
did not include the development of a vaccine into consideration. There are high
chances that an effective vaccine would be available in the near future considering
the shear amount of effort being poured into the field. Currently, 26 COVID-19
vaccines are undergoing human trials according to World Health organization; 12
amongst them are in phase II and six in phase III trials. Even a vaccine capable
of inducing moderate immune response would prove to be helpful in reducing the
severity of infection and preventing hospitalization.
The countries with relatively more older population would possibly observe worst
scenario and high morbidity rates in the later stages of this pandemic as per a math-
ematical model published in June by Eggo and her team [70]. It was suggested that
susceptibility to infection in individuals < 20 years of age is almost half than the
older individuals.
Every country or community which is being infected by this virus has something
in common. However, complete information regarding this virus is still unknown.
Hence, there is going to be a lot of uncertainty until availability of sufficient and
reliable data.
5.4 Lessons Learned for Future Pandemics
Multitudinous lessons to be learned for future pandemics, as it is continues to develop

and taken the lives of populous. For promising global health emergencies it is very
exacting to establish clear tattler policies. This will allow for luminosity and help
encourage clinicians to bring important information to visible radiation promptly
they are detected. Precautionary measures such as, travel restriction and quarantine
should be implemented on the health threat high risk area identification. Furthermore,
development of substructure should be mount a threat status prior for pandemic [71].
Implementation of instant intervention on population should be difficult such as
social distancing, quarantine and isolation. However the gist for health care system
with global, regional and local forces work together for the better vigilance for the
further spreading of the disease in all conditions along with research and development
policies, hospital staff,supplies and beds and testing measures. Pandamic disaster paid
dearly so it is the nations responsibility to prevent the further spread and devote allot
funding [72].
5.5 The Advent of a Novel Human Being

in a Post-COVID-19 Era
Human being is passing through a new and unique experience of rapidly scattering
COVID-19 pandemic. Still, the scientists are striving to devise the most efficient
vaccine to cope with the present scenario. Almost, every scientific donor agency is
expending their resources to find a wise solution to this new world problem.
COVID-19, in every terms, has created social, economic, scientific and human-
itarian crises. Thus, it will leave a big question on the healthcare systems, polit-
ical regimes and legal systems, ultimately leading to the collapse of financial and
economic domains. So, apart from the healthcare system, one should also think about
the recovery of financial and economic system that is currently lying in the ICU.
According to the WHO, COVID-19 is not a solitary problem, but it is associated
with fear, panic and terror news spread by the social and electronic media, which
has been portraying the situation as if the world is going to an end. Thus, the current
crisis rather exert serious consequences on human behaviour. The discussion about
these consequences is to think about the innovative measures and actions that should
go beyond the pandemic. For instance, imposing quarantines, legislating new laws to
manage the pandemic, using modern and advance tools for e-learning and telework,
ensuring a minimum standard of living for all, granting loans, exemptions from
paying water and gas bills and taxes and assisting the unemployed.
The life of human being has been going through different humanitarian revo-
lutions, and ultimately has reached to an industrialized civilization. The most
predominance impact of this revolution is the modern means of communication.
The post-COVID-19 stage will see the emergence of a new human being, whose
everyday behaviour and thinking will be totally different from what it was before
the COVID-19 outburst. Our political, legal and economic systems should adapt to
this new human being. Despite the timely importance of the current safety measures
being put into action around the world, there is a great need for these to be integrated
into a comprehensive post-pandemic thinking.
6 Conclusion
Pandemic of COVID-19 badly affected the socio-economic condition of the world. In

large, almost whole humanity suffered a lot from the outbreak. Fast-evolving outburst
situation, it was not easy to figure out a specific outcome that makes progress against
COVID-19 and break the pandemic condition. It seems generally all the efforts are
being made jointly by the scientists around the world are less in comparison to the
problem we are facing. More or less, every government are making their efforts to
defeat the virus and save their population from the pandemic and exerting a combined
effort altogether in one direction in order to save the humanity. History will remember
this chapter either in good or bad words portraying the apex of moral values in the
lap of civilization in the context of COVID-19. All the scientists and clinicians are
pushing hard themselves to bring new therapy regimen or introduce better way of
managing people health. The ultimate solution to this problem is the discovery of
effective vaccine. Only the last hope for humanity to come out of the situation is to
wait for vaccinate the whole world population which in itself is a big task. Logistic
support and a huge manufacturing effort will be needed to accomplish the goal and
come out of this pandemic situation. However, humanity always finds a way out to
survive on this planet earth.
7 Future Prospects and Predictions
The faster we can create and deploy an effective and safe drug to treat and a vaccine
to prevent COVID-19 and future viruses, the faster it will be contained. Artificial
intelligence is an ideal partner in drug development because it can accelerate and
complement human endeavours. Our current reality will inform future efforts to
deploy AI in drug development.
Telemedicine will emerge as a new science in Post-COVID-19 era. This part of
medicine was, although, in consideration but COVId-19 will improve it to greater
extent. In this technique, rather rushing to the doctor or hospitals, the remote care will
enables the clinical services without an in-person visit. COVID-19 also improved
online shopping mode and increased our Reliance on Robots.
The pandemic situation of COVID-19 continues to cause chaos worldwide due
to the lack of understanding, risk assessment, rapid outburst, and tendency to hasty
severe disease in comorbid conditions. In an attempt to fulfill the demand for prophy-
lactic and treatment measures to intercept the ongoing outbreak, the drug develop-
ment process is facing several obstacles and renaissance in clinical trials, including
vaccines, antivirals, immunomodulators, plasma therapy, and traditional medicines.
However, the development in the medical field and understanding of the disease
pattern by the clinician has solved many mysteries up till now. But due to virus
mutation, infection is changing its course, and medical community is still facing
a challenge. The ultimate solution seems to this situation is vaccine. In our view,
even after the vaccine, pandemic will be hard to contained and economy of a region
will have a key role in such situation. There are many questions still in our path
from vaccine discovery to its affordability and logistics management as well. It is
speculated that even after the induction of vaccine, world will need 5 years to vacci-
nate all the people around the globe and around 7–10 years to completely eliminate
this virus from the world. Therefore, we should adopt the substitute treatments, use
precautionary measures or alternatively we should put it on fate to decide the future
of humanity.
References
1. Bashshur, R., et al.: Telemedicine and the COVID-19 pandemic, lessons for the future. Mary
Ann Liebert (2020)
2. Nicola, M., et al.: The socio-economic implications of the coronavirus pandemic (COVID-19):
A review. Int. J. Surg. 78, 185 (2020)
3. Chi, X., et al.: Prevalence and psychosocial correlates of mental health outcomes among chinese
college students during the coronavirus disease (covid-19) pandemic. Front. Psych. 11, 803
(2020)
4. Phan, D.H.B., Narayan, P.K.: Country responses and the reaction of the stock market to COVID-
19—A preliminary exposition. Emerg. Mark. Financ. Trade 56(10), 2138–2150 (2020)
5. Brüne, M., Wilson, D.R.: Evolutionary perspectives on human behavior during the Coronavirus
pandemic: insights from game theory. Evol., Med., Public Health 2020(1), 181–186 (2020)
6. Freedman, T.S., et al.: Lessons of COVID-19: A roadmap for post-pandemic science. J. Exp.
Med. 217(9) (2020)
7. Kołodko, G.W.: After the calamity: economics and politics in the post-pandemic world. Polish
Sociological Rev. 210(2), 137–156 (2020)
8. Wan, Y., et al.: An analysis based on decade-long structural studies of SARS 3, JVI Accepted
Manuscript Posted Online 29 January 2020. J. Virol. (2020)
origin. Nature 579(7798), 270–273 (2020)
10. Cucinotta, D., Vanelli, M.: WHO declares COVID-19 a pandemic. Acta Bio Med.: Atenei
Parm. 91(1), 157 (2020)
11. Al-Mandhari, A., et al.: Coronavirus disease 2019 outbreak: preparedness and readiness of
countries in the Eastern Mediterranean Region. https://coronavirus.1science.com/item/6166e6
044a2114454e136505bc74865c1c52e8da, 2020..
12. Sifuentes-Rodríguez, E., Palacios-Reyes, D.: COVID-19: The outbreak caused by a new
coronavirus. Bol. Med. Del Hosp. Infant. Mex. 77(2), 47–53 (2020)
13. Wang, C., et al.: Evolving epidemiology and impact of non-pharmaceutical interventions on
the outbreak of Coronavirus disease 2019 in Wuhan, China. MedRxiv (2020)
14. Cases, C., D. by Country: Territory, or conveyance. Peim doctypy: https://www.worldomet
ers.info/coronavirus.
15. Rodríguez-Rey, R., Garrido-Hernansaiz, H., Collado, S.: Psychological impact and associated
factors during the initial stage of the coronavirus (COVID-19) pandemic among the general
population in Spain. Front. Psychol. 11, 1540 (2020)
16. Bol, D., et al.: The effect of COVID-19 lockdowns on political support: Some good news for
democracy? Eur. J. Polit. Res. (2020)
17. Chen, E., Lerman, K., Ferrara, E.: Tracking social media discourse about the COVID-19
pandemic: development of a public coronavirus Twitter data set. JMIR Public Health Surveill.
6(2), e19273 (2020)
18. Assiri, A., et al.: Hospital outbreak of Middle East respiratory syndrome coronavirus. N. Engl.
J. Med. 369(5), 407–416 (2013)
19. Van Der Hoek, L., et al.: Identification of a new human coronavirus. Nat. Med. 10(4), 368–373
(2004)
20. Korber, B., et al.: Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases
infectivity of the COVID-19 virus. Cell 182(4), 812–827, e19 (2020)
21. Zaki, A.M., et al.: Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.
N. Engl. J. Med. 367(19), 1814–1820 (2012)
22. Wang, W., et al.: Discovery, diversity and evolution of novel coronaviruses sampled from
rodents in China. Virology 474, 19–27 (2015)
23. Drosten, C., et al.: Identification of a novel coronavirus in patients with severe acute respiratory
syndrome. N. Engl. J. Med. 348(20), 1967–1976 (2003)
24. Shen, K., et al.: Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in
children: experts’ consensus statement. World J. Pediatr., 1–9 (2020)
25. Ahmad, T., et al.: COVID-19: Zoonotic aspects. Travel Medicine and Infectious Disease (2020)
26. Fan, W., et al.: Holmes Edward C., Zhang Yong-Zhen. A new coronavirus associated with
human respiratory disease in China. Nature 579(7798), 265–269 (2020)
origin. Nature [Internet]. 579(7798), 270–273 (2020)
28. Control, C.FD. and Prevention: Centers for disease control and prevention coronavirus disease
2019 (COVID-19) 2020 (2020)
29. Organization, W.H.: Laboratory testing for coronavirus disease 2019 (COVID-19) in suspected
human cases: interim guidance, 2 March 2020. World Health Organization (2020)
30. Xie, X., et al.: Chest CT for typical 2019-nCoV pneumonia: relationship to negative RT-PCR
testing. Radiology, 200343 (2020)
31. Wang, W., et al.: Detection of SARS-CoV-2 in different types of clinical specimens. JAMA
323(18), 1843–1844 (2020)
32. Zhao, J., et al.: Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease
2019. Clinical Infectious Diseases (2020)
33. Long, Q.-X., et al.: Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature
medicine, 1–4 (2020)
34. Döhla, M., et al.: Rapid point-of-care testing for SARS-CoV-2 in a community screening setting
shows low sensitivity. Public health (2020)
35. Huang, C., et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan
China. . The Lancet 395(10223), 497–506 (2020)
36. Yang, J., et al.: Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19)
infection: a systematic review and meta-analysis. Int. J. Infect. Dis. (2020)
37. Hoffmann, M., et al.: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked
by a clinically proven protease inhibitor. Cell (2020)
38. Li, W., et al.: Angiotensin-converting enzyme 2 is a functional receptor for the SARS
coronavirus. Nature 426(6965), 450–454 (2003)
39. Shirato, K., Kawase, M., Matsuyama, S.: Wild-type human coronaviruses prefer cell-surface
TMPRSS2 to endosomal cathepsins for cell entry. Virology 517, 9–15 (2018)
40. Ziebuhr, J., Snijder, E.J., Gorbalenya, A.E.: Virus-encoded proteinases and proteolytic
processing in the Nidovirales. J. Gen. Virol. 81(4), 853–879 (2000)
41. Song, Z., et al.: From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 11(1),
59 (2019)
42. Kilinç, E., KILINÇ, Y.B.: Mast cell stabilizers as a supportive therapy can contribute to alleviate
fatal inflammatory responses and severity of pulmonary complications in COVID-19 infection.
Anadolu Klin. Tıp Bilim. Derg. 25(Special Issue on COVID-19), 111–118 (2020)
43. Kilinc, E., et al.: Effects of Nigella sativa seeds and certain species of fungi extracts on number
and activation of dural mast cells in rats. Physiology Int. 104(1), 15–24 (2017)
44. Koyuncu Irmak, D., Kilinc, E., Tore, F.: Shared fate of meningeal mast cells and sensory
neurons in migraine. Front. Cell. Neurosci. 13, 136 (2019)
45. Theoharides, T.C., et al.: Mast cells and inflammation. Biochimica et Biophysica Acta (BBA)-
Molecular Basis of Disease 1822(1), 21–33 (2012)
46. Kilinc, E., et al.: Serotonergic mechanisms of trigeminal meningeal nociception: implications
for migraine pain. Neuropharmacology 116, 160–173 (2017)
47. Moon, T.C., Befus, A.D., Kulka, M.: Mast cell mediators: their differential release and the
secretory pathways involved. Front. Immunol. 5, 569 (2014)
48. Tore, F., Tuncel, N.: Mast cells: target and source of neuropeptides. Curr. Pharm. Des. 15(29),
3433–3445 (2009)
49. Kritas, S., et al.: Mast cells contribute to coronavirus-induced inflammation: new anti-
inflammatory strategy. J Biol Regul Homeost Agents 34(1), 10.23812 (2020)
50. Conti, P., et al.: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation
by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul
Homeost Agents 34(2), 1 (2020)
51. Okabayashi, T., et al.: Cytokine regulation in SARS coronavirus infection compared to other
respiratory virus infections. J. Med. Virol. 78(4), 417–424 (2006)
52. Russell, B., et al.: Associations between immune-suppressive and stimulating drugs and novel
COVID-19—a systematic review of current evidence. ecancermedicalscience 14 (2020)
53. Andersson, C.K., et al.: Activated MC TC mast cells infiltrate diseased lung areas in cystic
fibrosis and idiopathic pulmonary fibrosis. Respir. Res. 12(1), 139 (2011)
54. Storms, W., Kaliner, M.A.: Cromolyn sodium: fitting an old friend into current asthma
treatment. J. Asthma 42(2), 79–89 (2005)
55. Fu, L., et al.: Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a
systematic review and meta-analysis. J. Infect. (2020)
56. Zhou, F., et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19
in Wuhan, China: a retrospective cohort study. The Lancet (2020)
57. Marietta, M., et al.: COVID-19 and haemostasis: a position paper from Italian Society on
Thrombosis and Haemostasis (SISET). Blood Transfus. 18(3), 167 (2020)
58. Wang, D., et al.: Clinical characteristics of 138 hospitalized patients with 2019 novel
coronavirus–infected pneumonia in Wuhan China. JAMA 323(11), 1061–1069 (2020)
59. Kanne, J.P., et al.: Essentials for radiologists on COVID-19: an update—radiology scientific
expert panel. Radiological Society of North America (2020)
60. Shi, H., et al.: Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan,
China: a descriptive study. The Lancet Infectious Diseases (2020)
61. Wire, M.B., Shelton, M.J., Studenberg, S.: Fosamprenavir. Clin. Pharmacokinet. 45(2), 137–
168 (2006)
62. Moriyama, M., Hugentobler, W.J., Iwasaki, A.: Seasonality of respiratory viral infections.
Annu. Rev. Virol. 7 (2020)
63. Nickerson, J.E., et al.: Difficult Delivery and Neonatal Resuscitation: A Novel Simulation for
Emergency Medicine Residents. West. J. Emerg. Med. 21(1), 102 (2020)
64. Juno, J.A., et al.: Humoral and circulating follicular helper T cell responses in recovered patients
with COVID-19. Nat. Med. 26(9), 1428–1434 (2020)
65. Kwok, K.O., et al.: Herd immunity–estimating the level required to halt the COVID-19
epidemics in affected countries. J. Infect. 80(6), e32–e33 (2020)
66. Kissler, S.M., et al.: Projecting the transmission dynamics of SARS-CoV-2 through the
postpandemic period. Science 368(6493), 860–868 (2020)
67. Linton, N.M., et al.: Incubation period and other epidemiological characteristics of 2019 novel
coronavirus infections with right truncation: a statistical analysis of publicly available case
data. J. Clin. Med. 9(2), 538 (2020)
68. Wu, L.-P., et al.: Duration of antibody responses after severe acute respiratory syndrome. Emerg.
Infect. Dis. 13(10), 1562 (2007)
69. Head, M.G., et al.: UK investments in global infectious disease research 1997–2010: a case
study. Lancet. Infect. Dis 13(1), 55–64 (2013)
70. Davies, N.G., et al.: Age-dependent effects in the transmission and control of COVID-19
epidemics. MedRxiv (2020)
71. Sohrabi, C., et al.: World Health Organization declares global emergency: A review of the 2019
novel coronavirus (COVID-19). Int. J. Surg. (2020)
72. Hick, J.L., Biddinger, P.D.: Novel coronavirus and old lessons—preparing the health system
for the pandemic. N. Engl. J. Med. 382(20), e55 (2020)

(Studies in Systems, Decision and Control, 366) Ahmad Taher Azar, Aboul Ella Hassanien - Modeling, Control and Drug Development For COVI

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

(Studies in Systems, Decision and Control, 366) Ahmad Taher Azar, Aboul Ella Hassanien - Modeling, Control and Drug Development For COVI

Uploaded by

Copyright:

Available Formats

Studies in Systems, Decision and Control 366

Ahmad Taher Azar

Modeling, Control and

More information about this series at http://www.springer.com/series/13304

Modeling, Control and Drug

ISSN 2198-4182 ISSN 2198-4190 (electronic)

Prof. Ahmad Taher Azar

Some Computational and Theoretical Results of COVID-19

COVID-19 Modeling Under Uncertainty: Statistical Data

Modeling SARS-CoV-2: Mitigation Interventions and Increased

The Multi-group Susceptible Infected Recovered Model

Eiman, Kamal Shah, Muhammad Sarwar, and Hussam Alrabaiah

Abstract In recent time a threatful outbreak known as Corona Virus-19 Infec-

Eiman · K. Shah (B) · M. Sarwar

Keywords Covid-19 mathematical model · Non singular derivative · Fixed point

ḣ(t) = a1 (t)h(t) − b1 (t)h(t)i(t),

i̇(t) = a2 (t)h(t)i(t) − b2 (t)i(t), (1)

where h0 ≥ 0, i0 ≥ 0. The coefficients are linear continues and bounded functions.

ḣ(t) = ah(t) − bh(t)i(t) + ei(t),

i̇(t) = bh(t)i(t) + ci(t) − di(t) − ei(t),

where the nonlinear functions f , g : J × R2 → R are continuous. Now as we know

where α ∈ (0, 1] and CF Dt denoted Caputo-Fabrizo derivative. The parameters

Table 1 Description of the parameters of the model (2)

M (α) is known as normalization function and statistics M (1) = M (0) = 1. More-

Definition 2 [38] Integral in Caputo-Fabrizo form of h is given as

Note: Corresponding to existence theory, let J = [0, τ ] and 0 ≤ t ≤ τ < ∞, we

Hence inview of the continuity of solutions it follows that h ≥ 0, i ≥ 0 for all t ≥ 0.

3 Existence and Uniqueness Results of Fractional Order

where the nonlinear functions f , g : J × R2 → R are continuous. Upon using inte-

Which further may be written as

h(t) h0 f (t, h(t), i(t))

Now to derive our results we define the following assumption as:

|F (t, W (t)) − F (t, W¯ (t))| ≤ LF [|W − W¯ |],

(A2) There exists constants CF , CF > 0 and MF > 0 such that

Using (5) and (6), the operators are defined as:

Proof Let B = {W ∈ Z : W  ≤ ρ, ρ > 0} be closed and convex subset of Z ,

From (8) one concludes that G is bounded. Also F is continuous so is G. In same

Proof Let define T:Z → Z by

Here we recall some definition of Ulam stability

we have at most one solution W¯ and constant CF such that

|W (t) − W¯ (t)| ≤ CF (ε), ∀ x ∈ J

Remark 2 Considered the perturbed problem

whose solution is provided by

Hence from (11) using Remark 1 as

From (12), we have after simplification as

Here we investigate the semi-analytical results. Applying Laplace transformation on

Using initial condition, (1) yields

and expressing nonlinear terms in terms of Adomian polynomials as

Here we compute few Adomian polynomials as

and so on. Using (17) and (18) in (19), we have

Comparing terms on both sides of (19), we have

Evaluating inverse Laplace transform and using D1 = ah0 − bh0 i0 + ei0 , D2 =

h(t) = h0 + h1 (t) + h2 (t) + · · · , i(t) = i0 + i1 (t) + i2 (t) + · · · . (23)

Theorem 6 If Z be the Banach spaces and T : Z → Z is nonlinear opera-

Further W0 = W0 ∈ Bρ (W ), with Bρ (W ) = {W¯ ∈ Z : W¯ − W  < ρ}. We have

Proof Here we prove first assertion of Theorem 6 by using mathematical induction

W − W0  = T(W ) − T(W0 ) (24)

Let the result is true for n = m − 1, then one has

Wm − W0  = TWm−1 − T(W )

From (26), we have Wn ∈ Bρ (W ). Further since

6 Results and Discussion

Fig. 1 Transmission of COVID-19 from 25 February 2020 to 10 June 2020

Fig. 2 Exponential growth of COVID-19 from 25 February 2020 to 10 June 2020

Proof Let B = {W ∈ Z : W ≤ ρ, ρ > 0} be closed and convex subset of Z ,

|W (t) − W¯ (t)| ≤ CF (ε), ∀ x ∈ J

Further W0 = W0 ∈ Bρ (W ), with Bρ (W ) = {W¯ ∈ Z : W¯ − W < ρ}. We have

W − W0 = T(W ) − T(W0 ) (24)

Wm − W0 = TWm−1 − T(W )

(1 − ν)φ y; μ, σ 2 ; ν = (ν, τ ) (1 − ν)I(u t =1) ;

( |x) = log g X t |X t−1 = x t−1 xt |ϕ x t−1 + μ, σ1 , σ2 , ν . (10)

for t = 1, . . . , n and i = 1, 2, where Tt = −∞, ϕ x t−1 + μ and N (·)IT (·)

In the TP-SMN-AR(p) with vector of parameters = (ϕ, μ, σ1 , σ2 , ν) , considering

where Tt = −∞, ϕ x t−1 + μ , t = 1, . . . , n. After ignoring constants and

where = (β, μ, σ1 , σ2 , ν) . Defining the quantities ẑ ti = E Z ti |, X and

calculation of Q–function, i.e., in the form of Q | = E θ ()| , X .

{Z t } ∼ T P−S M N (b, σ, ν, γ ), t = 0, ±1, ±2, . . . , (18)

Remark 1 Let {X t } ∼ T P−S M N −A R M A( p, q). The process {X t } has a one-

Considering sample X = (X 1 , . . . , X n ) and sub-samples in the form Xt−1 =

() = t () = log g X t − α Xt−1 − η z t−1 , (20)

for t = 1, . . . , n and i = 1, 2, where At = −∞, α Xt−1 + η z t−1 + μ and