CASE REPORT Dengue Haemorrhagic Fever Presenter: Thaneswaran .M Sumita .M Day/Date: Tuesday/30 th November 2010 Supervisor : dr.Hj.Tiangsa br.Sembiring,SpA(K) INTRODUCTION Dengue fever (DF) or Dengue haemorrhagic fever (DHF) is a growing public health problem in the subtropics. In South-East Asia, with a total population of 1.5 billion, approximately 1.3 billion people live at risk of acquiring DF or DHF. Currently, DHF is the leading cause of hospital admissions and death among children in this region. 1 Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with 1 of the 4 serotypes of dengue virus, family Flaviviridae, genus Flavivirus ,single-stranded nonsegmented RNA viruses. Dengue is transmitted by mosquitoes of the genus Aedes, which are widely distributed in subtropical 1 | Page
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CASE REPORT
Dengue Haemorrhagic Fever
Presenter: Thaneswaran .M
Sumita .M
Day/Date: Tuesday/30th November 2010
Supervisor : dr.Hj.Tiangsa br.Sembiring,SpA(K)
INTRODUCTION
Dengue fever (DF) or Dengue haemorrhagic fever (DHF) is a growing public
health problem in the subtropics. In South-East Asia, with a total population of 1.5
billion, approximately 1.3 billion people live at risk of acquiring DF or DHF.
Currently, DHF is the leading cause of hospital admissions and death among
children in this region.1
Dengue, the most common arboviral illness transmitted worldwide, is caused
by infection with 1 of the 4 serotypes of dengue virus, family Flaviviridae, genus
Flavivirus ,single-stranded nonsegmented RNA viruses. Dengue is transmitted by
mosquitoes of the genus Aedes, which are widely distributed in subtropical and
tropical areas of the world, and is classified as a major global health threat by the
World Health Organization (WHO).9 Most patients with dengue infection have
only mild disease or classic dengue fever, with influenza-like symptoms, severe
headache, and aching joints and muscles. However, in a small percentage of
patients maybe half a million people every year potentially lethal forms of
dengue called dengue hemorrhagic fever and dengue shock syndrome develop.2
Dengue virus transmission follows two general patterns which is epidemic dengue
and hyperendemic dengue. Epidemic dengue transmission occurs when dengue
virus is introduced into a region as an isolated event that involves a single viral
strain. If the number of vectors and susceptible pediatric and adult hosts is
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sufficient, explosive transmission can occur, with an infection incidence of 25%-
50%. Mosquito-control efforts, changes in weather, and herd immunity contribute
to the control of these epidemics. Transmission appears to begin in urban centers
and then spreads to the rest of a country. This is the current pattern of transmission
in parts of Africa and South America, areas of Asia where the virus has
reemerged, and small island nations. Travelers to these areas are at increased risk
of acquiring dengue during these periods of epidemic transmission.2
At present, the only method of controlling or preventing dengue and DHF
is to combat the vector mosquitoes. Aedes aegypti breeds primarily in man-made
containers like earthenware jars, metal drums and concrete cisterns used for
domestic water storage, as well as discarded plastic food containers, used
automobile tyres and other items that collect rainwater. It can also breed
extensively in natural habitats such as tree holes and leaf axils. In recent years,
Aedes albopictus, a secondary dengue vector in Asia, has become established in
the United States, several Latin American and Caribbean countries, in parts of
Europe and in one African country. The rapid geographic spread of this species
has been largely attributed to the international trade in used tyres. Dengue
continues to be a global challenge because the pathogenesis of DHF is not fully
understood, there is no immediate prospect of a vaccine and the mosquito control
measures are inadequate. The wide spread DHF epidemics during 2003 reinforces
the belief that DHF has come to stay in this country and will continue to spread to
newer areas unless vector control measures are taken up on war footing.3
EPIDEMIOLOGY
Dengue haemorrhagic fever is now endemic in more than 100 countries in
Africa, the Americas, the Eastern Mediterranean, Southeast Asia and the Western
Pacific, Southeast Asia and the Western Pacific are most seriously affected. Some
2500 million people two fifths of the world.’s population are now at risk from
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dengue. WHO currently estimated 50 million cases of dengue infection worldwide
every year and during epidemics of dengue, attack rates among susceptibles are 40
to 90%. An estimated 500,000 cases of DHF require hospitalization each year, of
whom a very large proportion are children.3
Figure 1: Dengue, countries or areas at risk, 2008
Indonesia is the largest country in the region with a population of 245
million. Almost sixty per cent of the people live on the island of Java, which is
most severely afflicted by periodic outbreaks of dengue disease. However, the
disease is endemic in many large cities and small towns throughout the country
and has also spread to certain smaller villages, where population movement and
density are high.Epidemic DF has been reported in all 27 Indonesian provinces,
whereas in 1968 only two provinces had reported dengue cases.1
Figure 2: The incidence rate and case-fatality rate of DHF in Indonesia in
2005.
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An increase in commercial air travel has subsequently aided the
transmission of the virus between populations so that dengue is now endemic in
over 100 countries throughout tropical and sub-tropical areas of the world. The
main vector Aedes aegypti is found worldwide between latitudes 35ºN and
35ºS .The principle areas affected include the Caribbean, South and Central
America, Mexico, Africa, the Pacific Islands, South East (SE) Asia, Indian sub-
continent, Hawaii, and Australia (see Figure 1). By 2002, more than 2.5 billion
people were at risk of infection (roughly 40% of the world’s population). An
estimated 50-100 million illnesses occur annually, 250,000-500,000 of which are
dengue haemorrhagic fever, many of these in children. The estimated global
mortality rate is 25,000 per annually.4
VIROLOGY
The genome of Dengue virus consists of a single stranded, non
segmented, positive sense ribonucleic acid (RNA) of about 11 kb in length . The
genome is translated into a single polypeptide which is co- and post-
translationally processed by host signalases as well as the virus encoded serine
protease into the three structural and seven non structural proteins (NS) in the
order C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5 that traverse the
Endoplasmic Reticulum (ER) membrane .Dengue and other flaviviruses are
thought to replicate in the cytoplasm, mature on intracellular membranes and
egress by exocytosis and in some cases by budding at the plasma membrane . The
host ER is the primary site of envelope glycoprotein biogenesis, genomic
replication, and particle assembly of flaviviruses. In the course of productive
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infection, flaviviruses induce proliferation and hypertrophy of the ER membranes
Moreover, a large amount of flaviviral proteins are synthesized in infected cells,
thus overwhelming the ER folding capacity. As a natural consequence, we
hypothesize that these events will lead to the activation of the ER stress response
which in turn will modulate various signaling pathways resulting in cell survival
or death decisions.5
TRANSMISSION
Transmission occurs following a bite from an infected Aedes mosquito. It
is most widely transmitted by Ae. aegypti and Ae. albopictus (Asia, Philippines
and Japan), other Aedes species also transmit disease in specific areas; Ae.
polynesiensis, Ae. scutellaris and Ae. pseudoscutallaris (Pacific Islands and New
Guinea), Ae. polynesiensis (Society Islands) and Ae. niveus (Philippines).4
The cycle of transmission typically involves humans and mosquitoes. The
virus is spread from an infected human to a mosquito and then to another human,
often in areas where there are dense human populations. The mosquito can
transmit dengue if it immediately bites another host. Humans are the main
reservoir for the dengue virus, although nonhuman primates in Asia and Africa
may also be infected.2,4
Figure 3: Mechanism of transmission
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Humans serve as the primary reservoir for dengue; however, certain non human
primates in Africa and Asia also serve as hosts but do not develop dengue
hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of
the virus. The mosquito can transmit dengue if it immediately bites another host.2
VECTORS
A. aegypti, found worldwide in the tropics and subtropics, is the principal
vector. The Aedes mosquito prefers to breed in water-filled receptacles, usually
close to human habitation. They often rest in dark rooms (e.g. in bathrooms and
under beds) and breed in clean, stagnant water in containers that collect rainwater,
such as tires, tin cans, pots, and buckets.4
Figure 4: Vector
Female Aedes are highly susceptible to dengue virus, feeds preferentially
on human blood, is a daytime feeder, has an almost imperceptible bite, and is
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capable of biting several people in a short period for one blood meal.6 They inflict
an innocuous bite and are easily disturbed during a blood meal, causing them to
move on to finish a meal on another individual, making them efficient vectors.3
In addition, transmission occurs after 8-12 days of viral replication in the
mosquito's salivary glands (extrinsic incubation period). The mosquito remains
infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of
dengue virus in mosquitoes has been documented. The eggs of Aedes mosquitoes
withstand long periods of desiccation, reportedly as long as 1 year, but are killed
by temperatures of less than 10°C.2
PATHOGENESIS
After an infected mosquito has bitten a person, the virus replicates in
regional lymph nodes and is disseminated through the lymphatic system and
blood to other tissues. Replication in the reticuloendothelial system and skin
results in viremia. The incubation period ranges from 3 to 14 days, but it is
usually 4 to 7 days. Infection with dengue virus of any of the four serotypes
causes a spectrum of illness, ranging from no symptoms or mild fever to severe
and fatal hemorrhage, depending largely on the patient’s age and immunologic
condition.6
Viral virulence and immune responses have been considered as two major
factors responsible for the pathogenesis of DHF. Virological studies areattempting
to define the molecular basis of viral virulence. The immunopathological
mechanisms appear to include a complex series of immune responses. A rapid
increase in the levels of cytokines and chemical mediators apparently plays a key
role in inducing plasma leakage, shock and haemorrhagic manifestations. It is
likely that the entire process is initiated by infection with a socalled virulent
dengue virus, often with the help of enhancing antibodies in secondary infection,
and then triggered by rapidly elevated cytokines and chemical mediators produced
by intense immune activation.3
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The pathogenesis of DHF is poorly understood. DHF caused by primary or secondary
dengue infection is due to the occurrence of abnormal immune response involv ing
production of cytokines or chemokines, activation of T-lymphocytes and disturbance
of the hemostatic system. The elevated mediators include C3a, C5a, tumor necrosis
factor-α, interleukin (IL)-2, IL-6, IL-10, interferon-α and histamine.9–14 Halstead
described the antibody-dependent enhancement whereby, upon the second infection
with a heterotypic dengue virus,15 the subneutralizing concentration of the cross-
reacting antibody from the previous infection may opsonize the virus and enhance its
uptake and replication in the macrophage or mononuclear cells. Secondary infection
with a heterotypic dengue virus is associated with increased risk of developing DHF in
individuals who have recovered from a primary dengue virus with a first serotype. The
level of T-cell activation in a secondary dengue infection is also enhanced, occurring
as a phe- nomenon known as original antigenic sin,16,17 and is undergoing
programmed cell death. Many dengue- specific T-cells are of low affinity for the
infected virus and show higher affinity for other, probably previously encountered
serotypes. Profound T-cell activation and death during acute dengue infection may
suppress or delay viral elimination, leading to the higher viral loads and increased
immunopathology found in patients with DHF. 7
Most patients who develop dengue hemorrhagic fever or dengue shock
syndrome have had prior infection with one or more dengue serotypes. In
individuals with low levels of neutralizing antibodies, nonneutralizing antibodies
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to one dengue serotype, when bound by macrophage and monocyte Fc receptors,
have been proposed to result in increased viral entry and replication and increased
cytokine production and complement activation. This phenomenon is called
antibody-dependent enhancement.2
PATHOPHYSIOLOGY
Two main pathophysiological changes occur in DHF/DSS are increase in
vascular permeability that gives rise to loss of plasma from vascular compartment
and disorder in haemostasis.6
a. Evidence of plasma leakage
The plasma leakage is due to the increased vascular permeability induced
by several mediators such as C3a, C5a during the acute febrile stage and
prominent during the toxic stage. Capillary damage allows fluid, electrolytes,
small proteins, and, in some instances, red cells to leak into extravascular spaces.3
The evidence of plasma leakage includes hemoconcentration, hypoproteinemia/
hypoalbuminemia, pleural effusion, ascites, threatened shock and profound shock.
The rising hematocrit may not be evidenced because of either severe bleeding or
early intravenous fluid replacement.7
b. Bleeding tendency
The bleeding diathesis is caused by vasculopathy, thrombocytopenia,
platelet dysfunction and coagulopathy.2
Vasculopathy
A positive tourniquet test indicating the increased capillary fragility is
found in the early febrile stage. It may be a direct effect of dengue virus as it
appears in the first few days of illness during the viremic phase.7
Thrombocytopenia and platelet dysfunction
Patients with DHF usually have platelet counts less than 100 × 109/L.
Thrombocytopenia is most prominent during the toxic stage. The mechanisms of
thrombocytopenia include decreased platelet production and increased peripheral
destruction. 3
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Additionally, the increased peripheral destruction is markedly prominent
during 2 days before defervescence. The bone marrow then revealed
hypercellularity with an increase in the megakaryocyte, erythroblast and myeloid
precursors. Hemophagocytosis of young and mature erythroid and myeloid cells,
lymphocytes and platelets was observed.Survival of patients and transfused
platelets was markedly decreased because of immune-mediated injury of platelets.
Platelet dysfunction as evidenced by the absence of adenosine diphosphate (ADP)
release was initially demonstrated in patients with DHF during the convalescent
stage by Mitrakul et al. in 1977. The subsequent study during the febrile and early
convalescent stages by Srichaikul et al. in 1989 also demonstrated the impaired
platelet aggregation response to ADP that returned to a normal response 2–3
weeks later. An increase in plasma β-thromboglobulin and platelet factor 4,
indicating increased platelet secretory activity, was observed. The platelet
dysfunction might be the result of exhaustion from platelet activation triggered by
immune complexes containing dengue antigen.7
Coagulopathy
During the acute febrile stage, mild prolongation of the prothrombin time
and partial thromboplastin time, as well as reduced fibrinogen levels, have been
demonstrated in several studies. Variable reductions in the activities of several
coagulation factors, including prothrombin, factors V, VII, VIII, IX and X,
antithrombin and α-antiplasmin, have been demonstrated. Fibrin degradation
product or D-dimer is slightly elevated.9
Low levels of anticoagulant proteins C and S and antithrombin III were
found to be associated with increasing severity of shock, presumably due to
plasma leakage. Elevated levels of tissue factor, thrombomodulin and