A PROJECT WORK ON

Dengue fever review

Submitted in partial fulfilment of the requirement of Lakshmi narain college of

Pharmacy for
The award of the Degree of
Bachelors
Ankit Kumar

Under the Supervision of

Mrs. Amreen Qureshi
(Assistance proff. L.N.C.P INDORE)

LAKSHMI NARIAN COLLEGE OF PHARMACY INDORE

MADHYAPRADESH
(2022-2023)
 DECLARATION

This is to certify that the Thesis Report entitled “DENGUE FEVER REVIEW” in

partial fulfilment of the requirement for the award of the degree of Bachelors in

Pharmacy, submitted to LAKSHMI NARIAN COLLEGE OF PHARMACY INDORE

, is an authentic record of bonafide work carried out by me , under the supervisoion of

Mrs. Amreen Qureshi the matter embodied in this report has not been submitted for

the award of any other degree of diploma to any University/Institution.

DATE : NAME : Ankit Kumar

PLACE – INDORE ROLL.NO: 0825PY191010

 CERTIFICATE
This is to certified that the entitled Thesis Report entitled “DENGUE FEVER

REVIEW” in partial fulfilment of the requirement for the award of the degree of Bachelors

in Pharmacy, submitted to Lakshmi narian college Pharmacy, Indore, Madhyapradesh, India,

is an authentic record of bonafide research work carried out by MR. ANKIT KUMAR , Roll

No : 0825PY191030, under the supervision of Mrs. Amreen Qureshi (Assistance prof.

Lakshmi narian college of pharmacy indore (M.P)

PROF (Mrs. AMREEN QURESHI )

 ACKNOWLEDGEMENT

First of all, I am thankful to god, Who gave me the strength and the ability to complete my
thesis without his divine help, I would have never been able to complete it.

In fact, there are many people to whom I must express my gratitude for their contributions to
the successful completion of this dissertation

I would like to express my sincere appreciation and thanks to my main supervisor, Mrs.
Amreen Qureshi , who greatly supported me in completing my work.

I will be grateful for his assistance and guidance forever. My heartiest thanks are due to my
highly respected Mother and my dearest thanks go to my Father, without whose constant
support and encouragement, particularly in difficult time, the whole endeavour of writing my
thesis would not have been fruitful.
 INDEX
SR.NO NAME PAGE
1 OVERVIEW 5
2 GLOBAL BURDEN 6
3 DISTRIBUTIONS 7
4 TRANSMITIONS 8
5 VECTOR ECOLOGY 9
6 DISEASE CHAR. 10
7 DIAGNOSTICS 11
8 VACCINATION 12
9 PREVENTION 13
10 WHO RESPONSE 14
Overview

Dengue is a mosquito-borne viral disease that has rapidly spread to all regions of WHO in recent
years. Dengue virus is transmitted by female mosquitoes mainly of the species Aedes aegypti and,
to a lesser extent, Ae. albopictus. These mosquitoes are also vectors of chikungunya, yellow fever
and Zika viruses. Dengue is widespread throughout the tropics, with local variations in risk
influenced by climate parameters as well as social and environmental factors.

Dengue causes a wide spectrum of disease. This can range from subclinical disease (people may
not know they are even infected) to severe flu-like symptoms in those infected. Although less
common, some people develop severe dengue, which can be any number of complications
associated with severe bleeding, organ impairment and/or plasma leakage. Severe dengue has a
higher risk of death when not managed appropriately. Severe dengue was first recognized in the
1950s during dengue epidemics in the Philippines and Thailand. Today, severe dengue affects
most Asian and Latin American countries and has become a leading cause of hospitalization and
death among children and adults in these regions.

Dengue is caused by a virus of the Flaviviridae family and there are four distinct, but closely
related, serotypes of the virus that cause dengue (DENV-1, DENV-2, DENV-3 and DENV-4).
Recovery from infection is believed to provide lifelong immunity against that serotype. However,
cross-immunity to the other serotypes after recovery is only partial, and temporary. Subsequent
infections (secondary infection) by other serotypes increase the risk of developing severe dengue.

Dengue has distinct epidemiological patterns, associated with the four serotypes of the virus.
These can co-circulate within a region, and indeed many countries are hyper-endemic for all four
serotypes. Dengue has an alarming impact on both human health and the global and national
economies. DENV is frequently transported from one place to another by infected travellers; when
susceptible vectors are present in these new areas, there is the potential for local transmission to
be established.
Global burden

The incidence of dengue has grown dramatically around the world in recent decades. A vast
majority of cases are asymptomatic or mild and self-managed, and hence the actual numbers of
dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses [1].

One modelling estimate indicates 390 million dengue virus infections per year (95% credible
interval 284–528 million), of which 96 million (67–136 million) manifest clinically (with any severity
of disease) [2]. Another study on the prevalence of dengue estimates that 3.9 billion people are at
risk of infection with dengue viruses. Despite a risk of infection existing in 129 countries [3], 70% of
the actual burden is in Asia [2].

The number of dengue cases reported to WHO increased over 8 fold over the last two decades,
from 505,430 cases in 2000, to over 2.4 million in 2010, and 5.2 million in 2019. Reported deaths
between the year 2000 and 2015 increased from 960 to 4032, affecting mostly younger age group.
The total number of cases seemingly decreased during years 2020 and 2021, as well as for
reported deaths. However, the data is not yet complete and COVID-19 pandemic might have also
hampered case reporting in several countries.

The overall alarming increase in case numbers over the last two decades is partly explained by a
change in national practices to record and report dengue to the Ministries of Health, and to the
WHO. But it also represents government recognition of the burden, and therefore the pertinence to
report dengue disease burden.
Distribution and outbreaks

Before 1970, only 9 countries had experienced severe dengue epidemics. The disease is now
endemic in more than 100 countries in the WHO regions of Africa, the Americas, the Eastern
Mediterranean, South-East Asia and the Western Pacific. The Americas, South-East Asia and
Western Pacific regions are the most seriously affected, with Asia representing ~70% of the global
burden of disease.

Not only is the number of cases increasing as the disease spreads to new areas including Europe,
but explosive outbreaks are occurring. In 2012, an outbreak of dengue on the Madeira islands of
Portugal resulted in over 2000 cases and imported cases were detected in mainland Portugal and
10 other countries in Europe. Autochthonous cases are now observed on an annual basis in few
European countries.

The largest number of dengue cases ever reported globally was in 2019. All regions were affected,
and dengue transmission was recorded in Afghanistan for the first time.

The American region alone reported 3.1 million cases, with more than 25,000 classified as severe.
Despite this alarming number of cases, deaths associated with dengue were fewer than in the
previous year.

High number of cases were reported in Bangladesh (101,000), Malaysia (131,000) Philippines
(420,000), Vietnam (320,000) in Asia.

In 2020, dengue affected several countries, with reports of increases in the numbers of cases in
Bangladesh, Brazil, Cook Islands, Ecuador, India, Indonesia, Maldives, Mauritania, Mayotte (Fr),
Nepal, Singapore, Sri Lanka, Sudan, Thailand, Timor-Leste and Yemen. Dengue continues to
affect Brazil, India, Vietnam, the Philippines, Cook Islands, Colombia, Fiji, Kenya, Paraguay, Peru
and, Reunion islands, in 2021.

The COVID-19 pandemic is placing immense pressure on health care and management systems
worldwide. WHO has emphasized the importance of sustaining efforts to prevent, detect and treat
vector-borne diseases during this pandemic such as dengue and other arboviral diseases, as case
numbers increase in several countries and place urban populations at highest risk for both
diseases.
Transmission
Transmission through mosquito bite
The virus is transmitted to humans through the bites of infected female mosquitoes, primarily the
Aedes aegypti mosquito. Other species within the Aedes genus can also act as vectors, but their
contribution is secondary to Aedes aegypti.

After feeding on an DENV-infected person, the virus replicates in the mosquito midgut, before it
disseminates to secondary tissues, including the salivary glands. The time it takes from ingesting
the virus to actual transmission to a new host is termed the extrinsic incubation period (EIP). The
EIP takes about 8-12 days when the ambient temperature is between 25-28°C [4-6]. Variations in
the extrinsic incubation period are not only influenced by ambient temperature; a number of factors
such as the magnitude of daily temperature fluctuations[7, 8], virus genotype [9], and initial viral
concentration [10] can also alter the time it takes for a mosquito to transmit virus. Once infectious,
the mosquito is capable of transmitting virus for the rest of its life.

Human-to-mosquito transmission
Mosquitoes can become infected from people who are viremic with DENV. This can be someone
who has a symptomatic dengue infection, someone who is yet to have a symptomatic infection
(they are pre-symptomatic), but also people who show no signs of illness as well (they are
asymptomatic) [11].

Human-to-mosquito transmission can occur up to 2 days before someone shows symptoms of the
illness [5, 11], up to 2 days after the fever has resolved [12].

Risk of mosquito infection is positively associated with high viremia and high fever in the patient;
conversely, high levels of DENV-specific antibodies are associated with a decreased risk of
mosquito infection (Nguyen et al. 2013 PNAS). Most people are viremic for about 4-5 days, but
viremia can last as long as 12 days [13].

Maternal transmission
The primary mode of transmission of DENV between humans involves mosquito vectors. There is
evidence however, of the possibility of maternal transmission (from a pregnant mother to her
baby). While vertical transmission rates appear low, with the risk of vertical transmission
seemingly linked to the timing of the dengue infection during the pregnancy [14-17]. When a mother
does have a DENV infection when she is pregnant, babies may suffer from pre-term birth, low
birthweight, and fetal distress [18].

Other transmission modes

Rare cases of transmission via blood products, organ donation and transfusions have been
recorded. Similarly, transovarial transmission of the virus within mosquitoes have also been
recorded.
VECTOR ECOLOGY
The Aedes aegypti mosquito is considered the primary vector of DENV. It could breed in natural
containers such as tree holes and bromeliads, but nowadays it has well adapted to urban habitats
and breeds mostly in man-made containers including buckets, mud pots, discarded containers and
used tyres, storm water drains etc., thus making dengue an insidious disease in densely populated
urban centers. Ae. aegypti is a day-time feeder; its peak biting periods are early in the morning
and in the evening before sunset [19] Female Ae. aegypti frequently feed multiple times between
each egg-laying period leading to clusters of infected individuals [20]. Once a female has laid her
eggs, these eggs can remain viable for several months in dry condition, and will hatch when they
are in contact with water.

Aedes albopictus, a secondary dengue vector and, has spread to more than 32 states in the USA,
and more than 25 countries in the European Region, largely due to the international trade in used
tyres (a breeding habitat) and other goods (e.g. lucky bamboo). It favors breeding sites close to
dense vegetation including plantations which is linked to increased risk of exposure for rural
workers such as those in rubber and palm oil plantation, but it is also found to be established
abundantly in urban areas. Ae. albopictus is highly adaptive. Its geographical spread is largely due
to its tolerance of colder conditions, as an egg and adult [21, 22]. Similar to Ae. aegypti, Ae.
albopictus is also a day biter and it has been implicated as the primary vector of DENV in a limited
number of outbreak, where Aedes aegypti is either not present, or present in low numbers [23, 24]
Disease characteristics (signs and symptoms)
While majority of dengue cases are asymptomatic or show mild symptoms, it can manifest as a
severe, flu-like illness that affects infants, young children and adults, but seldom causes death.
Symptoms usually last for 2–7 days, after an incubation period of 4–10 days after the bite from an
infected mosquito [25]. The World Health Organization classifies dengue into 2 major categories:
dengue (with / without warning signs) and severe dengue. The sub-classification of dengue with or
without warning signs is designed to help health practitioners triage patients for hospital
admission, ensuring close observation, and to minimize the risk of developing the more severe
dengue[25] .

Dengue
Dengue should be suspected when a high fever (40°C/104°F) is accompanied by 2 of the following
symptoms during the febrile phase (2-7 days):
• severe headache
• pain behind the eyes
• muscle and joint pains
• nausea
• vomiting
• swollen glands
• rash.

Severe dengue
A patient enters what is called the critical phase normally about 3-7 days after illness onset. During
the 24-48 hours of critical phase, a small portion of patients may manifest sudden deterioration of
symptoms. It is at this time, when the fever is dropping (below 38°C/100°F) in the patient, that
warning signs associated with severe dengue can manifest. Severe dengue is a potentially fatal
complication, due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding, or
organ impairment.

Warning signs that doctors should look for include:

• severe abdominal pain
• persistent vomiting
• rapid breathing
• bleeding gums or nose
• fatigue
• restlessness
• liver enlargement
• blood in vomit or stool.

If patients manifest these symptoms during the critical phase, close observation for the next 24–48
hours is essential so that proper medical care can be provided, to avoid complications and risk of
death. Close monitoring should also continue during the convalescent phase.
Diagnostics
Several methods can be used for diagnosis of DENV infection. Depending on the time of patient
presentation, the application of different diagnostic methods may be more or less appropriate.
Patient samples collected during the first week of illness should be tested by both methods
mentioned below:

Virus isolation methods

The virus may be isolated from the blood during the first few days of infection. Various reverse
transcriptase–polymerase chain reaction (RT–PCR) methods are available and are considered the
gold standard. However, they require specialised equipment and training for staff to perform these
tests.

The virus may also be detected by testing for a virus-produced protein, called NS1. There are
commercially-produced rapid diagnostic tests available for this, and it takes only ~20 mins to
determine the result, and the test does not require specialized laboratory techniques or equipment.

Serological methods
Serological methods, such as enzyme-linked immunosorbent assays (ELISA), may confirm the
presence of a recent or past infection, with the detection of anti-dengue antibodies. IgM antibodies
are detectable ~1 week after infection and remain detectable for about 3 months. The presence of
IgM is indicative of a recent DENV infection. IgG antibody levels take longer to develop and
remains in the body for years. The presence of IgG is indicative of a past infection.
Vaccination against dengue
The first dengue vaccine, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur was licensed in
December 2015 and has now been approved by regulatory authorities in ~20 countries. In
November 2017, the results of an additional analysis to retrospectively determine serostatus at the
time of vaccination were released. The analysis showed that the subset of trial participants who
were inferred to be seronegative at time of first vaccination had a higher risk of more severe
dengue and hospitalizations from dengue compared to unvaccinated participants. As such, use of
the CYD-TDV vaccine is targeted for persons living in endemic areas, 9-45 years of age, who
have had at least 1 episode of dengue virus infection in the past. Several additional dengue
vaccine candidates are under evaluation.

WHO position on the CYD-TDV vaccine[26]

As described in the WHO position paper on the Dengvaxia vaccine (September 2018) [26] the live
attenuated dengue vaccine CYD-TDV has been shown in clinical trials to be efficacious and safe
in persons who have had a previous dengue virus infection (seropositive individuals). For
countries considering vaccination as part of their dengue control programme, pre-vaccination
screening is the recommended strategy. With this strategy, only persons with evidence of a past
dengue infection would be vaccinated (based on an antibody test, or on a documented laboratory
confirmed dengue infection in the past). Decisions about implementing a pre-vaccination
screening strategy will require careful assessment at the country level, including consideration of
the sensitivity and specificity of available tests and of local priorities, dengue epidemiology,
country-specific dengue hospitalization rates, and affordability of both CYD-TDV and screening
tests.

Vaccination should be considered as part of an integrated dengue prevention and control strategy.
There is an ongoing need to adhere to other disease preventive measures such as well-executed
and sustained vector control. Individuals, whether vaccinated or not, should seek prompt medical
care if dengue-like symptoms occur.
Prevention and control
If you know you have dengue, avoid getting further mosquito bites during the first week of illness.
Virus may be circulating in the blood during this time, and therefore you may transmit the virus to
new uninfected mosquitoes, who may in turn infect other people.

The proximity of mosquito vector breeding sites to human habitation is a significant risk factor for
dengue. At present, the main method to control or prevent the transmission of dengue virus is to
combat the mosquito vectors. This is achieved through:
• Prevention of mosquito breeding:
o Preventing mosquitoes from accessing egg-laying habitats by environmental
management and modification;
o Disposing of solid waste properly and removing artificial man-made habitats that can
hold water;
o Covering, emptying and cleaning of domestic water storage containers on a weekly
basis;
o Applying appropriate insecticides to water storage outdoor containers;
• Personal protection from mosquito bites:
o Using of personal household protection measures, such as window screens,
repellents, coils and vaporizers. These measures must be observed during the day
both inside and outside of the home (e.g.: at work/school) because the primary
mosquito vectors bites throughout the day;
o Wearing clothing that minimises skin exposure to mosquitoes is advised;
• Community engagement:
o Educating the community on the risks of mosquito-borne diseases;
o Engaging with the community to improve participation and mobilization for sustained
vector control;
• Active mosquito and virus surveillance:
o Active monitoring and surveillance of vector abundance and species composition
should be carried out to determine effectiveness of control interventions;
o Prospectively monitor prevalence of virus in the mosquito population, with active
screening of sentinel mosquito collections;
o Vector surveillance can be combined with clinical and environment surveillance.

In addition, there is ongoing research amongst many groups of international collaborators in

search of novel tools and innovative strategies that will contribute in global efforts to interrupt
transmission of dengue. The integration of vector management approaches is encouraged by
WHO to achieve sustainable, effective locally adapted vector control interventions.
WHO response
WHO responds to dengue in the following ways:
• supports countries in the confirmation of outbreaks through its collaborating network of
laboratories;
• provides technical support and guidance to countries for the effective management of
dengue outbreaks;
• supports countries to improve their reporting systems and capture the true burden of the
disease;
• provides training on clinical management, diagnosis and vector control at the country and
regional level with some of its collaborating centres;
• formulates evidence-based strategies and policies;
• support countries in the development of dengue prevention and control strategies and
adopting the Global Vector Control Response (2017-2030)
• reviews the development of new tools, including insecticide products and application
technologies;
• gathers official records of dengue and severe dengue from over 100 Member States; and
• publishes guidelines and handbooks for surveillance, case management, diagnosis, dengue
prevention and control for Member States.