Hindawi Publishing Corporation

ISRN Infectious Diseases

Volume 2013, Article ID 571646, 6 pages
http://dx.doi.org/10.5402/2013/571646
Review Article
Pathogenesis of Dengue Haemorrhagic Fever and Its Impact on
Case Management
Kolitha H. Sellahewa
Department of Medicine, Melaka Manipal Medical College, Jalan Batu Hampar, Bukit Baru, 75150 Melaka, Malaysia
Correspondence should be addressed to Kolitha H. Sellahewa; kolithah@gmail.com
Received 5 September 2012; Accepted 30 September 2012
Academic Editors: R. Bologna, R. Favory, and K. Sawanyawisuth
Copyright 2013 Kolitha H. Sellahewa. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Plasma leakage and intrinsic coagulopathy are the pathological hall marks in dengue haemorrhagic fever (DHF). Viral virulence,
infection enhancing antibodies, cytokines and chemical mediators in the setting of intense immune activation are the key players
implicated in the pathogenesis of DHF; the exact nature of which is yet to be fully understood. e pathophysiological changes the
attended clinical features of plasma leakage necessitate recognition of changing physiological parameters for the early recognition
of plasma leakage and appropriate uid therapy. On the other hand, the changes in the haematological indices resulting from
coagulopathy can tempt the clinician to initiate other modalities of therapy. A clearer understanding of the pathogenesis of
DHF and the appreciation that both of these fundamental pathological changes share common pathogenic mechanisms would
facilitate the appropriateness of management decisions and the early recognition of severe disease. us, thrombocytopaenia,
reduced brinogen, and prolonged partial thromboplastin time early in the disease course connoted severe disease and attended
plasma leakage rather than clinical bleeding. e detection of plasma cytokine prole by a multiple bead immunoassay could also
complement clinical parameters in predicting severe disease early in the disease course. us, MIP- indicates good prognosis
while IFN- portends severe disease.
1. Introduction
Infection by any one of the four serotypes of dengue virus
(DENV) remains asymptomatic in the vast majority. Clinical
spectrum among symptomatic infection ranges from undif-
ferentiated fever (viral syndrome), dengue fever (DF), and
dengue haemorrhagic fever (DHF) to the expanded dengue
syndrome with isolated organopathy (unusual manifesta-
tions). DF can be without haemorrhage or have unusual
haemorrhage, while DHFcanbe without shock or withshock,
that is, dengue shock syndrome [1].
e WHO criteria for the clinical diagnosis of DHF
requires the presence of acute and continuous fever of
2 to 7 days, haemorrhagic manifestations associated with
thrombocytopenia (100,000 cells/c.mm or less) and haemo-
concentration (haematocrit >20% from baseline of patient
or population of same age). Haemorrhagic manifestations
could be mucosal and or skin or even a positive tourniquet
test which is the commonest. Hepatomegaly occurs at some
stage of DHF and oen precedes plasma leakage and hence a
valuable early predictor of plasma leakage [1].
DHF is most commonly seen in children with secondary
dengue infection but has been documented in primary
infection with DENV-1 and DENV-3, as well as in infants.
ese infants had acquired maternal dengue antibody and
subsequently experienced a dengue infection [2]. Greater
baseline vascular permeability among children could also be
a contributor for more severe disease among children than
among adults [3]. Epidemiological and serological studies
done both in ailand and Cuba support the importance of
secondary dengue infections as a risk factor for DHF. Since
the rst observations by Halstead et al. in 170, DHF has
been present in situations where more than one serotype
circulates [4, 5]. e disease burden and a resurgence of
recurrent epidemics of DHF are attributable to social dynam-
ics and a variety of epidemiological factors such as a high
vector density, a high virus circulation, and a population at
risk of secondary infection by virtue of previous exposure
2 ISRN Infectious Diseases
[6]. Besides secondary infection, chronic diseases such as
bronchial asthma and diabetes have been suggested as risk
factors for DHF. Also, whites have higher risk of developing
DHF than blacks. DENV-2 virus is known to replicate to
higher concentration in the peripheral blood cells of whites
compared with those of blacks [6].
Abnormal haemostasis and plasma leakage are the main
pathophysiological hall marks in DHF. Even though more
than half a century has elapsed since plasma leakage was rst
identied its precise mechanism remains elusive. e main
factor implicated in the development of DHF rather than
the relatively innocuous DF in dengue infection is secondary
dengue infection but other factors like viral virulence and
host characteristics are also important. Severe disease is
the result of a complex interaction between the virus and
the immune response evoked by the host with secondary
infection [7].
2. Plasma Leakage in DHF
2.1. Pathophysiology. Plasma leakage is specic to the pleural
and peritoneal surfaces. In DHF there is no vasculitis and
hence no injury to the vessel walls, and plasma leakage results
from cytokine mediated increase in vascular permeability.
e ensuing movement of albumin and the resultant reduc-
tion of intravascular oncotic pressure facilitate further loss of
uid from the intravascular compartment. e basic Starling
principle still holds true in explaining microvascular ultral-
tration based on the balance of the oncotic and hydrostatic
pressures. However the glycocalyx, which is a gelatinous
layer lining the vascular endothelium is also implicated in
controlling uid movement by the adherence of albumin
molecules in to its matrix, damage of which, leads to loss of
albumin into the extravascular compartment [811].
2.2. Immunopathogenesis. e immune system is implicated
inthe pathogenesis of DHF owing to the increased propensity
to develop DHF with secondary dengue infection. e innate
immune mechanisms comprising the complement pathway
and NK cells as well as humoral and cell-mediated immune
mechanisms launched in response to antigenic stimulation
are involved in the clinical manifestations. Complement
activation as well as vascular permeability may be inuenced
by viral products like NS1. Dierent immune mechanisms in
the form of antibody enhanced viral replication leading to an
exaggerated cytokine response impacts vascular permeability
[1214].
Infection with one dengue serotype elicits immunity to
that serotype but does not provide long-termcross-protective
immunity to the remaining serotypes. Subsequent infection
with a dierent serotype results in the binding of the new
virus to cross reactive nonneutralising antibody from the
previous infection facilitating the uptake by mononuclear
phagocytes enabling amplied viral replication. e resulting
increase in viral load then drives an immunopathogenic
cascade andthe resultant exaggeratedcytokine response leads
to a transient increase in microvascularpermeability. e
precise way in which microvascular permeability is altered
is not clear but is more likely to be a functional change
rather than structural damage, as dengue shock is rapidly
recoverable, and no inammation is evident in the leaking
surfaces [1519]. Adding to the complexity of the under-
lying immunopathogenic mechanisms resulting in changes
in vascular permeability is the proposal of an alternative
mechanismwhereby the rapid mobilisation of serotype cross-
reactive memory Tcells trigger the release of biological medi-
ators. Some of the other factors implicated in this orchestra-
tion include viral virulence, molecular mimicry, and immune
complex and/or complement mediated dysregulation, and
genetic predisposition, all of which have beenshownto corre-
late with disease severity. However, as yet no mechanism has
been identied that links any of these established immuno-
logical derangements with a denitive eect on microvascu-
lar structure or function consistent with the observed alter-
ation in permeability. In addition, most of the immunological
abnormalities so far identied do not dier substantially from
those seen in other infections without an apparent eect on
permeability.
Neutralising antibodies are key factors in the aetiopatho-
genesis of the disease. However, the cellular immune
response is also important. It has been demonstrated that
memory dengue T lymphocyte response aer a primary
infection includes both serotype-specic and serotype-cross-
reactive T lymphocytes [20]. NS3 protein seems to be the
major target for CD4+ and CD8+ T cells.
Cytokines that may induce plasma leakage such as inter-
feron g, interleukin (IL) 2, and tumour necrosis factor (TNF)
are increased in DHF cases [20, 21]. Also, interferon
enhances uptake of dengue particles by target cells through
increasing Fc cell receptors [22]. Other cytokines suchas IL-6,
IL-8, and IL-10 are also increased. Aprotein of 2225 kDa has
been associated with the pathogenesis of DHF. is cytotoxic
factor able to induce increased capillary permeability in mice
is capable of reproducing in mice all the pathological lesions
that are seen in human beings, and has been detected in sera
of DHF patients [23].
A recent study has demonstrated the plasma cytokine
prole in dengue fever from a Brailian population which
was detected by a multiplex bead immunoassay. MIP-
was indicated as a good prognostic marker which is in
contrast to IFN- that was associated with severe disease.
Both cytokines serve to discriminate mild from severe cases.
It has also been shown that during the course of dengue
dierent cytokine proles may be present and vary according
to determined clinical manifestations. e cytokine proles
identied by bead array multiplex systemmay favour an early
identication of patients with the worst prognosis and may
contribute to the establishment of more directed therapeutic
procedures than the present ones [24].
Complement activation as a result of immune com-
plexes (virus-antibody) or immune activation and cytokine
production could also be involved in the mechanism of
plasma leakage. Certain complement fragments such as C3a
and C5a are known to enhance permeability. NS1 antigen
in dengue virus has been shown to regulate complement
activation and hence could play a role in the pathogenesis
of DHF [12, 13, 2527]. Clearly immunopathogenic mech-
anisms are involved in plasma leakage and coagulopathy.
ISRN Infectious Diseases 3
However alternate immune pathways are also implicated in a
protective role adding to the complexity and intricacy of the
pathogenesis of DHF. Activated NKcells release granzyme A,
which has cytolytic functions. MIP-1 produced by human
monocytes and dendritic cells as well as activated NK cells
and lymphocytes is chemoattractant for NK cells, recruiting
them to inammatory sites. ese mechanisms could play a
protective role in the immunopathology of DHF by the early
and ecient clearance of DENV by direct or indirect NK
functions thereby limiting viral replication and its attended
cascading cytokine mediated plasma leakage. NK cells have
been associated with mild dengue [28, 29].
Insummary monocytes, macrophages, anddendritic cells
are the major targets for DENV.
During secondary infection with a dierent DENV
serotype cross-reactive nonneutralising antibodies bind to
DENV and facilitate uptake via Fc receptors resulting in
enhanced viral replication. e resultant higher viral antigen
load leads to an exaggerated activation of cross-reactive
dengue specic T cells. iological mediators released by
the activated T cells as well as virus infected cells along
with complement activation by viral proteins, and immune
complexes are implicated in increasing vascular permeability
and coagulopathy.
ese biological mediators inuence clinical outcomes
to a variable extent. us IL-1, IFN-, IL-4, IL-6, IL-
13, IL-7, and GM-CSF are associated with severe clinical
manifestations while MIP-1 is elevated in patients with mild
dengue. Marked thrombocytopaenia is evident in patients
with elevated IL-1, IL-8, TNF-, and MIP-1, while increased
levels of MIP-1 and GM-CSF correlated with hypotension
[24].
2.3. Haemorrhagic Manifestations in DHF. e pathogenesis
of bleeding in DHF is unclear even though well-recognised
coagulation disturbances do exist. e clinical haemorrhagic
manifestations range from a mere positive tourniquet test,
skinpetechiae andecchymoses toepistaxis, andgumbleeding
to severe gastrointestinal haemorrhages. rombocytopaenia
is a consistent nding, while prolonged partial thrombo-
plastin time and reduced brinogen concentration are the
other abnormal haemostatic indices evident fromearly in the
disease course. ese haematological abnormalities seem to
correlate better withthe timing andseverity of plasma leakage
rather than the clinical haemorrhagic manifestations [30].
ese recent ndings raise the possibility for common
pathogenic mechanisms responsible for both plasma leakage
and abnormalities in the haemostatic indices. e true nature
of the intrinsic coagulopathy evident early in the disease
course and in mild forms of dengue can be confounded by
the advent of hypovolemic shock and hypoxia in DHF with
severe plasma leakage with less than optimal correction.
rombocytopaenia is initially due to bone marrow
suppression during the febrile viraemic phase of the illness.
Progressive thrombocytopaenia with defervescence result
from immune mediated platelet destruction. Virus-antibody
complexes have been detected on the platelet surface of DHF
patients suggesting a role for immune-mediated destruction
of platelets [31, 32]. Augmented platelet adhesiveness to
vascular endothelial cells resulting from the release of high
levels of platelet-activating factor by monocytes with het-
erologous secondary infection also contributes to the throm-
bocytopaenia [33]. rombocytopaenia however correlates
poorly with bleeding manifestations. Spontaneous bleeding
been uncommon evenwith counts below100,000 cells/c.mm.
It is strongly associated with the severity of vascular leakage.
Counts below 100,000 cells/c.mm or a rapid drop in the
platelet count was associated with severe disease.
e role of the glycocalyx rather than the endothelial cells
per se in controlling ultraltration in the microvasculature
is increasingly recognised and in vivo animal studies have
shownthe permeationof brinogento the endothelial surface
similar to albumin [11].
e low plasma brinogen detected in DHF could thus
be a reection of loss into the interstitial spaces in the setting
of increased vascular permeability. Heparan sulphate forms
an integral part of the glycocalyx which when damaged by
the initial cytokine response in DHF gets liberated to the
circulationand acts like ananticoagulant which could explain
the prolonged APTT [34]. e disturbance in both these
important haemostatic indices are unlikely to cause sponta-
neous bleeding. Haemorrhages are triggeredby trauma inthis
setting of coagulopathy.
Development of antibodies potentially cross-reactive to
plasminogen could have a role in causing haemorrhage in
DHF [35]. However dierent studies have shown conicting
results as some have demonstrated an activation of brinol-
ysis while others have shown an inhibition of the brinolytic
pathway in DHF [30].
2.4. Endothelial Cells in DHF. Precise knowledge on the
extent to which DENV infects endothelial cells is lacking as
few studies have addressed the issue in the viraemic phase of
the illness. Even though DENV has infected endothelial cells
in vitro it is doubtful whether it reects the eect in human
infection as limited human autopsy studies have detected
only the dengue antigen but not the genome in various cell
types ranging from monocytes, liver sinusoidal cells, alveolar
macrophages, peripheral blood, and splenic lymphocytes.
How important these ndings are in the pathogenesis of
clinical features are uncertain as some studies have shown
swelling of endothelial cells but not cell death or vasculitis
[36], while others have detected apoptosis of endothelial cells
in lungs and intestinal mucosa in fatal DHF cases, but the
extent of apoptosis has not been documented [36]. DENV
alters the endothelial cell surface protein production, its
expression, and transcriptional activity.
Expression of ICAM-1 (intercellular adhesion molecule-
1) and beta-integrin on micro vascular endothelium by
DENV has been reported. DENV also aects the expression
of cytokine receptors. ese may contribute to the mecha-
nisms involved in plasma leakage in DHF.
e role of DENV infected endothelial cells in the
pathogenesis of coagulopathy in DHF is equally intriguing.
ere is upregulation of tissue plasminogen, thrombomod-
ulin, protease activated receptor-1, and tissue factor receptor,
4 ISRN Infectious Diseases
while there is downregulation of tissue factor inhibitor and
activated protein C.
3. Clinical Implications
DHF cases have increased in the recent past and will continue
to increase in numbers in time to come as DHF is commoner
in secondary dengue infection. e probability of secondary
dengue infection in a given population is expected to increase
owing to the presumed high prevalence of previous exposure
to clinical or asymptomatic dengue infection based on epi-
demiological data particularly in dengue endemic regions in
the world. Despite the complexity of the immunopathogenic
mechanism involved in severe disease, what is inexorable
is that all patients with DHF have plasma leakage, the
magnitude and progression of which will impact outcome.
Dengue infection must be diagnosed early and in all such
patients clinicians need to be alert and vigilant to identify
DHF patients early at the inception of plasma leakage before
shock sets in. Appropriate interventions with udicious uid
therapy at this stage could oset adverse outcomes and
ensure a favourable outcome. Immunopathogenic mecha-
nisms implicated in DHF could serve to meet the challenges
of identifying in the febrile phase patients who could behave
as DHF during the disease course. In this context assay of
specic biomarkers identied indengue could be useful. us
while MIP-1 indicates good prognosis, IFN- portends
severe disease. Clinicians should also appreciate that both
plasma leakage and disturbances of haemostatic indices share
common immunopathogenic mechanisms. Disturbances in
the haemostatic indices should thus be correlated to the
severity of plasma leakage rather than the tendency for
spontaneous clinical bleeding manifestations. Such consid-
erations would serve to complement the accuracy of the
prediction and identication of patients with severe disease.
Intelligent application of such knowledge in relation to the
temporal relation of the disease course will also facilitate
interventional decision making and improve its accuracy and
appropriateness. us, low plasma brinogen and prolonged
APTT in the absence of shock early in the disease is to be
expected in DHF and interpreted as heralding plasma leakage
and not DIC, and its magnitude gives an idea of the severity
of leakage. On the contrary the same indices of coagulopathy
should have a dierent interpretation in the setting of shock
owing to the confounding eects of hypovolemia and hypoxia
and even the probability of associated DIC in such a setting.
Similarly thrombocytopaenia is best used as a marker
of severe disease particularly when it is <100,000 cells/c.mm
or when there is a rapid drop. Its usefulness is as an
indicator of prognosis during the disease course rather than
a parameter for therapeutic interventions. Recognising the
poor correlation of thrombocytopaenia with bleeding should
caution the clinician against the futility albeit danger of
prophylactic platelet transfusions.
Clinicians should also bear in mind that cytokines play
dierent roles in the pathogenesis of DHF. Some been
stimulatory while others tend to downregulate the immuno-
logical network.
Critical alterations in the cytokine balance with attended
adverse, rather than benecial outcomes could be expected if
corticosteroids are used for immunosuppression when such
management decisions are basedonthe supercial considera-
tion of immunological mechanisms as the underlying basis of
DHF pathogenesis. Even though cytokines are implicated in
the pathogenesis of increased vascular permeability absence
of inammation and the transient nature of altered perme-
ability with a tendency for spontaneous cessation of plasma
leakage also raises the irrationality of using steroids and other
anti-inammatory agents.
4. Concluding Remarks
Plasma leakage and coagulopathy are the fundamental
pathological changes responsible for clinical manifestations,
morbidity, and mortality in DHF. A complex interplay
between immunological mechanisms with viral and host
factors are implicated in the pathogenesis. Both humoral and
cell-mediated immune mechanisms eventually result in the
release of cytokines responsible for changes in the selective
microvascular permeability and the resultant plasma leakage.
Plasma leakage progresses either rapidly or slowly to cease
completely and predictably aer 24 to 48 hours of onset,
raising the possibility of existence of underlying functional
change rather than structural damage and inammation in
the vasculature. e inuence of DEN on endothelial cells
may be direct or indirect via release of mediators from
infected or activated immune cells. Changes in the expression
of adhesion molecules, enzymes, and cytokine receptors on
endothelial cells are implicated in increasing the vascular
permeability as well as activation of the coagulating system.
e two fundamental pathological attributes in DHF are
plasma leakage and intrinsic coagulopathy.
e balance of hydrostatic and oncotic pressures is
important in plasma leakage. However the glycocalyx also
plays a crucial role in uid uxes. e permeation of b-
rinogen apart from albumin into its matrix, as well as the
release of heparan sulphate from its brush surface impacts
both plasma leakage and intrinsic coagulopathy. e recog-
nition of the role of biological markers on these pathogenic
mechanisms can have far reaching diagnostic and therapeutic
implications.
Clinicians should strive to predict severe disease before
the advent of shock. Clinical predictors such as tender hep-
atomegaly and tachycardia aer defervescence are exceed-
ingly useful to suspect incipient plasma leakage. Technologi-
cal advances and the availability of multiplex cytokine prole
would facilitate these eorts. It could also open up new vistas
in developing interventions targeting specic cytokines to
reduce plasma leakage. However the importance of diligent
and accurate monitoring of heart rate, pulse pressure, urine
output, and haematocrit for the early detection of plasma
leakage and adustments to uid therapy should not be
overlooked and constitute an essential and integral part of
case management. Our understanding of the pathogenesis of
DHF and the availability of biological markers could serve
to complement the clinicians eorts. Prevention of immune
enhanced viral replication is another area to focus specic
ISRN Infectious Diseases 5
therapeutic interventions. Use of fresh frozen plasma for this
purpose is an exciting area of research [37].
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