LEARNING ACTIVITY NO.

COVID-19

A. CENSUS
Coronavirus disease 2019 has created a global health crisis that has had a deep
impact on the way we perceive our world and our everyday lives today. Not only the rate
of contagion and patterns of transmission threatens our sense of agency, but the safety
measures put in place to contain the spread of the virus also require social distancing by
refraining from doing what is inherently human, which is to find solace in the company
of others (Arriaga et. al, 2020).
As to the employment, the rapidly intensifying economic effects of COVID-19 on
the world of work are proving to be far worse than the 2008-9 financial crisis, with
cutbacks equivalent to nearly 200 million full-time workers expected (Clarke, 2020).
Workers in four sectors that have experienced the most “drastic” effects of the disease
and falling production are: food and accommodation (144 million workers), retail and
wholesale (482 million); business services and administration (157 million); and
manufacturing (463 million). Together, they add up to 37.5 per cent of global
employment and this is where the “sharp end” of the impact of the pandemic is being felt
now.
In terms of service disruptions, the main finding is that health services have been
partially or completely disrupted in many countries. More than half (53%) of the
countries surveyed have partially or completely disrupted services for hypertension
treatment; 49% for treatment for diabetes and diabetes-related complications; 42% for
cancer treatment, and 31% for cardiovascular emergencies. Rehabilitation services have
been disrupted in almost two-thirds (63%) of countries, even though rehabilitation is key
to a healthy recovery following severe illness from COVID-19 (Brunier & Harris, 2020).
As of November 6, 2020, the outbreak of the coronavirus disease (COVID-19)
had been confirmed in over 210 countries or territories. The virus had infected over 49.1
million people worldwide, and the number of deaths had totaled reached over 1.2 million.
The most severely affected countries include the U.S., Brazil, and Mexico (Elflein, 2020).
 Epidemiological Update. Since 31 December 2019 and as of 08 November 2020,
49 945 364 cases of COVID-19 (in accordance with the applied case definitions and
testing strategies in the affected countries) have been reported, including 1 250 275
deaths (Source: European Centre for Disease Prevention and Control). Cases have been
reported from:

 Africa: 1 871 007 cases; the five countries reporting most cases are South
Africa (735 906), Morocco (252 185), Egypt (108 962), Ethiopia (99 201)
and Tunisia (69 543).
 Asia: 14 157 654 cases; the five countries reporting most cases are India
(8 507 754), Iran (673 250), Iraq (496 019), Indonesia (433 836) and
Bangladesh (418 764).
 America: 21 737 147 cases; the five countries reporting most cases are
United States (9 860 958), Brazil (5 590 025), Argentina (1 236 838),
Colombia (1 136 447) and Mexico (961 938).
 Europe: 12 133 701 cases; the five countries reporting most cases are
Russia (1 753 836), France (1 748 705), Spain (1 328 832), United
Kingdom (1 171 441) and Italy (902 490).
 Oceania: 45 159 cases; the five countries reporting most cases are
Australia (27 652), French Polynesia (9 995), Guam (5 113), New Zealand
(1 626) and Papua New Guinea (597).
 Other: 696 cases have been reported from an international conveyance in
Japan.

Deaths have been reported from:

 Africa: 44 851 deaths; the five countries reporting most deaths are South
Africa (19 789), Egypt (6 355), Morocco (4 197), Algeria (2 036) and
Tunisia (1 794).
  Asia: 251 481 deaths; the five countries reporting most deaths are India
(126 121), Iran (37 832), Indonesia (14 540), Iraq (11 283) and Turkey (10
803).

 America: 659 135 deaths; the five countries reporting most deaths are
United States (237 113), Brazil (161 106), Mexico (94 808), Peru (34 840)
and Argentina (33 348).
 Europe: 293 730 deaths; the five countries reporting most deaths are
United Kingdom (48 888), Italy (41 063), France (40 169), Spain (38 833)
and Russia (30 251).
 Oceania: 1 071 deaths; the five countries reporting most deaths are
Australia (907), Guam (89), French Polynesia (39), New Zealand (25) and
Papua New Guinea (7).
 Other: 7 deaths have been reported from an international conveyance in
Japan.

B. PATHOPHYSIOLOGY
Coronavirus disease 2019 (COVID-19) is a major health concern and can be
devastating, especially for the elderly caused by the SARS-CoV-2 virus. Although much
is known about the mortality of the clinical disease, much less is known about its
pathophysiology. Although details of the cellular responses to this virus are not known, a
probable course of events can be postulated based on past studies with SARS-CoV. A
cellular biology perspective is useful for framing research questions and explaining the
clinical course by focusing on the areas of the respiratory tract that are involved. Based
on the cells that are likely infected, COVID-19 can be divided into three phases that
correspond to different clinical stages of the disease.

Stage 1: Asymptomatic state (initial 1–2 days of infection). The inhaled virus SARS-
CoV-2 likely binds to epithelial cells in the nasal cavity and starts replicating. ACE2 is
the main receptor for both SARS-CoV2 and SARS-CoV. In vitro data with SARS-CoV
indicate that the ciliated cells are primary cells infected in the conducting airways.
However, this concept might need some revision, since single-cell RNA indicates low
level of ACE2 expression in conducting airway cells and no obvious cell type preference.
There is local propagation of the virus but a limited innate immune response. At this
stage the virus can be detected by nasal swabs. Although the viral burden may be low,
these individuals are infectious. The RT-PCR value for the viral RNA might be useful to
predict the viral load and the subsequent infectivity and clinical course. Perhaps super
spreaders could be detected by these studies. For the RT-PCR cycle number to be useful,
the sample collection procedure would have to be standardized. Nasal swabs might be
more sensitive than throat swabs.

Stage 2: Upper airway and conducting airway response (next few days). The virus
propagates and migrates down the respiratory tract along the conducting airways, and a
more robust innate immune response is triggered. Nasal swabs or sputum should yield the
virus (SARS-CoV-2) as well as early markers of the innate immune response. At this
time, the disease COVID-19 is clinically manifest. The level of CXCL10 (or some other
innate response cytokine) may be predictive of the subsequent clinical course. Viral
infected epithelial cells are a major source of beta and lambda interferons . CXCL10 is an
interferon responsive gene that has an excellent signal to noise ratio in the alveolar type II
cell response to both SARS-CoV and influenza. CXCL10 has also been reported to be
useful as disease marker in SARS. Determining the host innate immune response might
improve predictions on the subsequent course of the disease and need for more
aggressive monitoring. For about 80% of the infected patients, the disease will be mild
and mostly restricted to the upper and conducting airways. These individuals may be
monitored at home with conservative symptomatic therapy.

Stage 3: Hypoxia, ground glass infiltrates, and progression to ARDS. Unfortunately,

about 20% of the infected patients will progress to stage 3 disease and will develop
pulmonary infiltrates and some of these will develop very severe disease. Initial estimates
of the fatality rate are around 2%, but this varies markedly with age. The fatality and
morbidity rates may be revised once the prevalence of mild and asymptomatic cases is
better defined. The virus now reaches the gas exchange units of the lung and infects
alveolar type II cells. Both SARS-CoV and influenza preferentially infect type II cells
compared to type I cells. The infected alveolar units tend to be peripheral and subpleural.
SARS-CoV propagates within type II cells, large number of viral particles are released,
and the cells undergo apoptosis and die. The end result is likely a self-replicating
pulmonary toxin as the released viral particles infect type II cells in adjacent units. I
suspect areas of the lung will likely lose most of their type II cells, and secondary
pathway for epithelial regeneration will be triggered. Normally, type II cells are the
precursor cells for type I cells. This postulated sequence of events has been shown in the
murine model of influenza pneumonia. The pathological result of SARS and COVID-19
is diffuse alveolar damage with fibrin rich hyaline membranes and a few multinucleated
giant cells. The aberrant wound healing may lead to more severe scarring and fibrosis
than other forms of ARDS. Recovery will require a vigorous innate and acquired immune
response and epithelial regeneration. From my perspective, similar to influenza,
administrating epithelial growth factors such as KGF might be detrimental and might
increase the viral load by producing more ACE2 expressing cells. Elderly individuals are
particularly at risk because of their diminished immune response and reduced ability to
repair the damaged epithelium. The elderly also have reduced mucociliary clearance, and
this may allow the virus to spread to the gas exchange units of the lung more readily.
In conclusion, COVID-19 confined to the conducting airways should be mild and
treated symptomatically at home. However, COVID-19 that has progressed to the gas
exchange units of the lung must be monitored carefully and supported to the best of our
ability, as we await the development and testing of specific antiviral drugs.
C. UPDATES ON MANAGEMENT
No specific antiviral therapeutic agents or vaccine for SARS-CoV-2 are currently
available to save the infected patients, protect health care workers and others at high risk
of infection. Therefore, to control the rapidly growing SARS-CoV-2 outbreak, the WHO,
announced on March 18, 2020, the launch of SOLIDARITY, which is an unprecedented
multinational coordinated effort to collect rapidly robust clinical and scientific data
during the SARS-CoV-2 pandemic, giving hope and planning to eradicate the SARS-
CoV-2 virus. Various antiviral therapies with much broader landscapes are being selected
by WHO, including the experimental antiviral drug Remdesivir; the Malaria medication
Chloroquine/Hydroxychloroquine; a combination of Human Immunodeficiency Viruses
(HIV) drugs such as Lopinavir and Ritonavir; and finally, a combination of HIV drugs
added to Interferon-beta (Kumar & Al Khodor, 2020).
Remdesivir was originally developed by Gilead Sciences to combat Ebola and
other related viruses by inhibiting viral replication. Remdesivir is an adenosine analogue
with broad-spectrum antiviral activities. A nucleoside analogue competes with natural
nucleosides during replication for the RdRp active site, thus inhibiting the viral
replication. This drug is currently being extensively evaluated against SARS-CoV-2 in
the United States and Europe, and according to the latest information, the efficacy of
Remdesivir is found ambiguous against severely infected patients. Despite its
controversial results, the US Food and Drug Administration (FDA) approved the
emergency use of the experimental Remdesivir to treat hospitalized SARS-CoV-2
patients
Chloroquine and hydroxy-chloroquine have received intense attention worldwide
because of the positive results generated from the preliminary studies of their use to treat
SARS-CoV-2 patients. Chloroquine and hydroxychloroquine possibly decrease acidity in
endosomes compartments of infected cells and can inactivate the virus. In addition,
chloroquine and hydroxy-chloroquine can also impair the terminal glycosylation of the
ACE2 receptor, thus inhibiting the viral penetration into the cells. However, ex-vivo
studies performed in the cell culture model have suggested that chloroquine and hydroxy-
chloroquine can cripple the SARS-CoV-2 virus, but the effective dose required is usually
high, which can cause severe toxicity. After reviewing the safety concerns of antimalarial
drugs, the WHO temporarily suspended the hydroxy-chloroquine arm of its Solidarity
trial.

Another underway ‘SOLIDARITY’ trial for SARS-CoV-2 treatment combines two

drugs, Lopinavir and Ritonavir. These drugs were originally developed to treat HIV
patients by inhibiting the protease enzyme that is needed by the virus to cleave long
polypeptides chains during the assembly of new viruses. Lopinavir and Ritonavir
effectively inhibit the 3C-like proteinase, which plays a key role in the processing of viral
polyproteins and posing a possible potent therapeutic option against SARS-CoV-2.
Although the preliminary data from the Chinese study is unclear , other clinical trials are
underway. In addition to the known antiviral drug combinations, some trials are currently
exploring these drugs in combination with the anti-interferon-beta, an anti-inflammatory
molecule.
Apart from the ‘SOLIDARITY’ trial, other therapeutic options are also being
explored against SARS-CoV-2 to improve the outcomes of critically ill patients. As of
Aug 12th, 2020, more than 1000 clinical trials are currently exploring different treatment
strategies against SARS-CoV-2, including drug repositioning, novel therapeutic options,
and vaccines. Potential treatment strategies that are currently in the testing phase against
SARS-CoV-2 or likely to be initiated as clinical trials are summarized in table-1. These
include drugs that can reduce inflammation (such as itolizumab that binds to CD6
receptor and blocks the activation of T lymphocytes and suppress the pro-inflammatory
cytokines or corticosteroids that decrease the cytokines storm), ACE-2 inhibitor, SARS-
CoV-2 specific siRNAs, and immunomodulators. In addition, a number of reposition
antiviral drugs such as Favipiravir (a nucleoside analogue inhibiting the RNA
polymerase), ribavirin (a guanosine analogue), are also being tested against moderate to
severe SARS-CoV-2 patients.
 In addition to the antiviral treatment options, systemic transfusion of convalescent
plasma collected from healthy donors who recovered from SARS CoV-2 is being tested
in different clinical trials on severely infected SARS-Cov-2 patients to reduce the
cytokines storm and to replenish the patient’s own antibodies during the acute phase of
the disease. Interestingly, the administration of convalescent plasma containing
neutralizing antibodies showed a significant decline in the viral load within few days
post-transfusion and a substantial improvement in the clinical conditions of the patients.
Several companies and universities, such as Takeda, Mount Sinai, and Hopkins are
evaluating the mass-production of monoclonal antibodies. Importantly, the success of the
convalescent sera transfusion has given clues on how the immune system combats SARS-
CoV-2, and how easily a vaccine can be made. In addition, virus-specific neutralizing
antibodies that can accelerate the virus clearance and/or prevent its entry into target cells
can serve as the primary mechanism for the restriction and clearance of the virus.

End of Solidarity Trial

WHO announced that the hydroxychloroquine (HCQ) arm of the Solidarity Trial to
find an effective COVID-19 treatment was being stopped. The trial's Executive Group
and principal investigators made the decision based on evidence from the Solidarity trial,
UK's Recovery trial and a Cochrane review of other evidence on hydroxychloroquine.
Data from Solidarity (including the French Discovery trial data) and the recently
announced results from the UK's Recovery trial both showed that hydroxychloroquine
does not result in the reduction of mortality of hospitalised COVID-19 patients, when
compared with standard of care. Investigators will not randomize further patients to
hydroxychloroquine in the Solidarity trial. Patients who have already started
hydroxychloroquine but who have not yet finished their course in the trial may complete
their course or stop at the discretion of the supervising physician. This decision applies
only to the conduct of the Solidarity trial and does not apply to the use or evaluation of
hydroxychloroquine in pre or post-exposure prophylaxis in patients exposed to COVID-
19.
D. UPDATES ON VACCINE
With the challenges known to be associated with generating a vaccine against
RNA viruses, experts feel that developing an efficacious vaccine for SARS-CoV-2 will
be very challenging. RNA viruses are known to be difficult when it comes to vaccine
development; however, more than 100 research groups, including biotech companies and
research institutes, are currently evaluating different approaches. While some of these
vaccines have initiated human trials, according to the latest data, some vaccine candidates
such as ChAdOxa nCoV-19 (containing spike protein to boost antibodies production
against spike protein), and Gam-COVID-Vac Lyo have shown an effective single-dose
immune response in clinical trials. However, most experts estimate that a successful
vaccine will not be available before 2021 (Kumar & Al Khodor, 2020).
According to Mckeever (2020) from the National Geographic, more than 150
coronavirus vaccines are in development across the world and hopes are high to bring one
to market in record time to ease the global crisis. Several efforts are underway to help
make that possible, including the U.S. government’s Operation Warp Speed initiative,
which has pledged $10 billion and aims to develop and deliver 300 million doses of a
safe, effective coronavirus vaccine by January 2021. The World Health Organization is
also coordinating global efforts to develop a vaccine, with an eye toward delivering two
billion doses by the end of 2021.
On September 24, Novavax announced the launch of its phase three trial in the
United Kingdom, which will evaluate the vaccine in up to 10,000 people, both with and
without underlying conditions. Up to 400 participants will also be vaccinated against the
seasonal flu as part of a sub-study that will help determine whether it is safe to give
patients both vaccines at the same time.
Johnson & Johnson announced the launch of a phase three ENSEMBLE trial to
evaluate the safety of the vaccine and how well it works among up to 60,000 adults from
a variety of countries. The trial will include “significant representation” from older
populations and those with underlying conditions that make them more susceptible to
COVID-19. On October 12, Johnson & Johnson announced that it has paused these trials
for an independent safety review due to an unexplained illness in a participant. The
company didn’t provide any details, in part to protect the patient’s privacy, but said that
illnesses and accidents are expected in large clinical studies. What’s more, study pauses
are routine for clinical trials and aren’t typically reported. On October 23, the company
announced it will resume trials.
Moderna announced it had started the third phase of its clinical trials, even as it
continues to monitor phase two results. Preliminary findings from phase one have shown
that healthy subjects—including elderly patients—produced coronavirus antibodies and a
reaction from T cells. Phase three will test the vaccine in 30,000 U.S. participants;
Moderna says it is on track to deliver at least 500 million doses per year beginning in
2021, thanks in part to the deal it has struck with Swiss manufacturer Lonza that will
allow it to manufacture up to one billion doses a year. In September, however, Moderna’s
chief executive Stéphane Bancel told the New York Times that it was unlikely the
vaccine would be widely available in the first half of 2021.
Pfizer and BioNTech launched a trial that combines phase two and three by
enrolling a diverse population in areas with significant SARS-CoV-2 transmission. It has
expanded the trial to include 44,000 people across multiple countries. The project is
aiming to seek regulatory review before the end of the year—and hopes to supply 1.3
billion doses by the end of 2021. Preliminary results of phase one/two data show the
vaccine produces antibodies and T-cell responses specific to the SARS-CoV-2 protein.
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Brunier, A. & Harris, M. (2020). COVID-19 Significantly Impacts Health Services for
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Clarke, G. (2020). COVID-19: impact could cause equivalent of 195 million job losses,
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Elflein, J. (2020). COVID-19 cases worldwide as of November 6, 2020, by country.

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Transl Med 18, 353 (2020). https://doi.org/10.1186/s12967-020-02520-8

World Health Organization (2020). Hydroxychloroquine arm of Solidarity Trial stops.

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