REVIEW ARTICLE: PATHOPSIOLOGY OF DENGUE HEMORRAGHIC FEVER

Magister Farmasi Klinis Universitas Surabaya

Email : melanikhadijah@gmail.com

Abstract: Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are
4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection
results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever
(DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made
unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by
multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review
summarizes the current progress of studies on DHF pathogenesis, which may provide important information
for achieving effective control of dengue in the future.
Keywords: DENV; dengue hemorrhagic fever (DHF); NS1; genome; antibody-dependent enhancement
(ADE); T cell

INTRODUCTION 8-10 days. clinical manifestations ranging

Dengue hemorrhagic fever (DHF) is a
common disease in most tropical and
subtropical regions, particularly south-east
asia, middle America, USA and the
Caribbean. DBD natural hosts are humans,
agentnya is dengue virus belonging to the
family Flaviridae and genus flavivirus,
composed of four serotypes, namely Den-1,
Den-2, Den Den3 and -4, is transmitted to
humans through the bite of infected
mosquitoes, particularly mosquitoes Aedes
aegypti and Ae. albopictus are found in
almost all corners Indonesia(1). Dengue
virus incubation period in humans (intrinsic
incubation) ranges from 3 to 14 days before
symptoms appear, the average clinical
symptoms appear on the fourth day until the
seventh day, whereasextrinsic incubation
period (in the mosquito's body) lasts about
from asymptomatic infection fever, dengue
fever (DD) and dengue, characterized by
high fever continuously for 2-7 days;
bleeding diathesis as positive tourniquet
test, thrombocytopenia with platelet count ≤
100 x 109 / L and plasma leakage due to
increased permeability capillary. Three
stages of clinical presentations are classified
as fever, toxic and recovery. Toxic phase,
which lasts 24-48 hours, is the most critical
period, with rapid plasma leakage that leads
to circulatory blood disorders. There are 4
stages of severity of dengue, namely the
degree I with signs are fever accompanied
by non-specific symptoms and test
tourniquets + ( positive); stage II is grade I
plus spontaneous bleeding in the skin or
other bleeding,circulatory failure is
characterized by rapid and weak pulse and a

MELANI NAURITA, S.SI.,APT 1

decrease in pulse pressure (<20 mmHg),
hypotension (systolic decreased to <80
mmHg), cyanosis around the mouth, akral
cool, moist skin and pasen seemed agitated;
and stage IV characterized by severe shock
(profound shock) that is not palpable pulse
and blood pressure are not terukur.
Although DD and DHF is caused by the
same virus, but different patofisiologisnya
mechanism and cause clinical differences.
The main difference is the presence of a
typical shock in DHF induced plasma
leakage allegedly due to immunological
processes, in this case of dengue fever was
not terjadi. DD clinical manifestations arise
from the body's reaction to the entry of
viruses that evolved in the bloodstream and
is captured by macrophages. During the two
days there will be viremia (before
symptoms) and ended after five days of
onset of symptoms of heat. Macrophages
will become antigen presenting cells (APC)
and activate T-helper cells and other
macrophages to fagocyt attract more
viruses. T-helper will activate T cells which
will lysis of macrophages -sitotoksik
already fagocyt virus. Also activate B cells
that will release antibodies. There are 3
types of antibodies that have been identified,
namely neutralizing antibodies, antibody
hemagglutination, complement fixation
antibody. The process will lead to the
release of mediators that stimulate systemic
symptoms such as fever, joint pain, muscle,
malaise and other symptoms. 7 in the first week to the third, and
Pathophysiology of primary dengue fever
and dengue syock syndrome (DSS) is an
acute increase in vascular permeability
leading to plasma leakage into the
extravascular space, causing
hemoconcentration and decreased blood
pressure. In severe cases, the plasma volume
MELANI NAURITA, S.SI.,APT 2
decreased by more than 20%, it is supported
by the discovery of post mortem include
pleural effusion, hemoconcentration and
hipoproteinemi. Upon entry of the human
body, the dengue virus breed in
reticuloendothelial cells which is followed
by viremia that lasts 5-7 day. As a result of
this infection, appear immune response both
humoral and cellular, among other anti
neutralization, anti-hemagglutinin and anti-
complement. The antibodies appear in
general is IgG and IgM, in primary dengue
infection antibodies begin to form, and on
secondary infection antibody levels that
have been there so arise. Antibodies against
dengue virus can be found in the blood
around the 5th day of fever, increased in the
first week to the third, and disappeared after
60-90 days. Kinetic contrast to the kinetic
IgG IgM antibody levels, therefore kinetic
IgG antibodies to be distinguished between
primary and secondary infection. On
primary infection IgG antibodies increased
approximately fever day 14 was on the
secondary infection IgG antibodies
increased on the second day. Therefore,
early diagnosis of primary infection can
only be confirmed by detection of IgM
antibodies after the fifth day of illness, the
diagnosis of secondary infection can be
established early with an increase in IgG and
IgM antibodies were fast. Antibodies
against dengue virus can be found in the
blood around the 5th day of fever, increased
disappeared after 60-90 days. Kinetic
contrast to the kinetic IgG IgM antibody
levels, therefore kinetic IgG antibodies to be
distinguished between primary and
secondary infection. On primary infection
IgG antibodies increased approximately
fever day 14 was on the secondary infection
IgG antibodies increased on the second day.
Therefore, early diagnosis of primary
infection can only be confirmed by
detection of IgM antibodies after the fifth
day of illness, the diagnosis of secondary
infection can be established early with an
increase in IgG and IgM antibodies were
fast. Antibodies against dengue virus can be
found in the blood around the 5th day of
fever, increased in the first week to the third,
and disappeared after 60-90 days. Kinetic
contrast to the kinetic IgG IgM antibody
levels, therefore kinetic IgG antibodies to be
distinguished between primary and
secondary infection. On primary infection
IgG antibodies increased approximately
fever day 14 was on the secondary infection
IgG antibodies increased on the second day.
Therefore, early diagnosis of primary
infection can only be confirmed by
detection of IgM antibodies after the fifth
day of illness, the diagnosis of secondary
infection can be established early with an
increase in IgG and IgM antibodies were
fast. therefore kinetic IgG antibodies to be
distinguished between primary and
secondary infection. On primary infection
IgG antibodies increased approximately
fever day 14 was on the secondary infection
IgG antibodies increased on the second day.
Therefore, early diagnosis of primary
infection can only be confirmed by
detection of IgM antibodies after the fifth
day of illness, the diagnosis of secondary
infection can be established early with an
increase in IgG and IgM antibodies were
fast. therefore kinetic IgG antibodies to be
distinguished between primary and
secondary infection(2). On primary
infection IgG antibodies increased
approximately fever day 14 was on the
secondary infection IgG antibodies
MELANI NAURITA, S.SI.,APT 3
increased on the second day. Therefore,
early diagnosis of primary infection can
only be confirmed by detection of IgM
antibodies after the fifth day of illness, the
diagnosis of secondary infection can be
established early with an increase in IgG and
IgM antibodies were fast.
DHF is a consequence of DENV
infection that is most threatening. Previous
studies have suggested that these two factors
the virus and the host may contribute to the
pathogenesis of these diseases, including the
virus antigen nonstructural protein 1 (NS1)
and antibodies, variation and virulence of
the virus, the RNA subgenomik, increased
dependence antibody (ADE), and the
presence of memory T cells cross-reactive.
Further studies of the pathogenesis of DHF
may provide new targets for the prevention
and control of dengue infection disease(3).
ROLE OF DENV NONSTRUCTURAL
PROTEIN-1(NS-1) AND ITS
ANTIBODIES IN DHF
NS1, nonstructural protein encoded by
DENV, expressed in various forms
oligomers and present in a variety of cellular
locations, including on the cellular
membrane, the cell surface and in the
extracellular as lipopartikel soluble,
secreted. During infection DENV acute,
protein NS1 secreted given in the serum of
patients at a high level, which may correlate
with the severity of the disease and
contributes to the pathogenesis of DHF in
the host. Indeed, DENV NS1 may directly
bind to the surface of the host cell to cause
tissue damage. A recent study showed that
DENV NS1 led to the production of
inflammatory cytokines by activating
macrophage cells and human peripheral
blood mononuclear (PBMC) via receptors
like oll-like 4 (TLR4), thus causing a
disruption integrity of the monolayer of
endothelial cells in the vessels direction.
Additionally, DENV NS1 ga ju can trigger
complement activation, resulting in leakage
of plasma(4). During these roses, DENV
NS1 dissolved is released from infected
cells and independently activate the
complement factor present in the liquid
phase. A strong correlation has been found
between the concentration of DENV NS1
and complex formation C5b-C9. 5b-C9
complex can stimulate a strong expression
of Tokin-inflammatory cytokines associated
with the development of DHF. Recently, it
has been reported that DENV NS1 can
induce autophagy in human endothelial cell
line HMEC-1 and also in mice, and that this
utophagy mediated by the secretion of
macrophage migration inhibiting factor
associated with S1 (MIF). In addition NS1
protein itself, NS1 antibodies may also
contribute to the pathogenesis of dengue. for
example, anti-NS1 antibody binding to the
NS1 protein that GPI anchored to the cell
membrane to enable the flow of cellular
signal transduction, leading to protein
tyrosine phosphorylation, which can
increase the eplikasi DENV-infected cells.
In addition, protein phosphorylation and F-
κB activation has been observed after
stimulating the cells of MEC-1 human anti-
DENV NS1 antibody. Further, the
expression of several cytokines and
chemokines, such as IL-6, IL-8 and MCP-1,
endothelial cells increased after treatment
with anti-DENV antibodies S1, which
indicates that the DENV NS1 antibodies
may stimulate the release - ria inflammatory
MELANI NAURITA, S.SI.,APT 4
factors that depend on NF-κB. Irregular
cytokine release considered as the main
factor underlying the pathogenesis of
dengue. Therefore, the activation of the
immune response mediated NS1 antibodies
can play an important role in the
development of dengue-mediated
thrombocytopenia and vascular leakage
during the critical phase of DHF / DSS.
More recently, the induction of autoimmune
disorder by an anti-NS1 antibodies have
also been described as factors contributing
to the pathogenesis of dengue. Because no
sequence homology between DENV NS1
and some self antigens, such as plasminogen
and integrin, a protein on human endothelial
cells and platelets, auto antibodies induced
by NS1 may cross-react with self-antigen.
These reactions stimulate the expression of
nitric oxide (NO) and cell apoptosis in
endothelial cells and causes cell lysis and
inhibition of platelet aggregation. Damage
to endothelial cells and platelets can
contribute to thrombocytopenia,
coagulopathies and vascular leakage in DHF
DENV GENOM ROLE IN DHF
PATHOGENESIS
Different between genotype DENV-related
genetic with differential viral virulence to
contribute on the development of severe
disease, DHF and DSS. Some genotypes of
DENV has virulensi and greater epidemic
potential than others. This viewpoint is
especially introduced based
epidemiological observations. In America
Dengue outbreaks which occurred in 1981,
the Asian genotype DENV-2 enggara
appear more virulent than the original
American genotype. Indeed, evidence has
shown that Irus genotype DENV-2 replicate
Southeast Asia there is a higher titer than
American genotype virus in humans and
mosquitoes. Other than that, the evolution of
intra-serotypes of DENV strains may be
another cause of epidemic viral rebound
viruses(5). Clinical manifestations and DHF
case fatality rate usually increases during
the next epidemic period, a phenomenon
observed in Cuban epidemic in 1981 and
1997, Townsville, Australia epidemic in
1992, and Oaxaca, Mexico. epidemic in
2005. DENV genome analysis showed that
circulating DENV may evolve greater
virulence through the patients during the
epidemic. Thus, variations in the genome of
DENV serves to determine the infectivity of
the virus in both the host and vector. In
addition to variations in the genome, RNA
virus flavigenik subgenomik (sfRNA) may
play a role in DENV replication in host
cells, thereby contributing to the
pathogenesis of dengue. During replication
of DENV, 11 kb genomic RNA can be
degraded incomplete from the 3
'untranslated (UTR) by the host
exoribonuclease to produce 0.3 to 0.5 kb
RNA called small sfRNA. sfRNA can
accumulate in the infected cells to suppress
the immune response of the host antiviral,
such as signaling between type I. sfRNA can
also facilitate replication of DENV through
changes in mRNA stability hosts, thus
acting as a player in immune evasion DENV
and pathogenesis of DHF. 11 kb genomic
RNA can be degraded incomplete from the
3 'untranslated (UTR) by the host exo
ribonuclease to produce 0.3 to 0.5 kb RNA
called small sfRNA. sfRNA can accumulate
in the infected cells to suppress the immune
response of the host antiviral, such as
signaling between type I. sfRNA can also
facilitate replication of DENV through
changes in mRNA stability hosts, thus
MELANI NAURITA, S.SI.,APT 5
acting as a player in immune evasion DENV
and pathogenesis of DHF. 11 kb genomic
RNA can be degraded incomplete from the
3 'untranslated (UTR) by the host
exoribonuclease to produce 0.3 to 0.5 kb
RNA called small sfRNA. sfRNA can
accumulate in the infected cells to suppress
the immune response of the host antiviral,
such as signaling between type I. sfRNA can
also facilitate replication of DENV through
changes in mRNA stability hosts, thus
acting as a player in immune evasion DENV
and pathogenesis of DHF. sfRNA can
accumulate in the infected cells to suppress
the immune response of the host antiviral,
such as signaling between type I. sfRNA can
also facilitate replication of DENV through
changes in mRNA stability hosts , thus
acting as a player in immune evasion DENV
and pathogenesis of DHF. sfRNA can
accumulate in the infected cells to suppress
the immune response of the host antiviral,
such as signaling between type I. sfRNA can
also facilitate replication of DENV through
changes in mRNA stability hosts (Moon et
al., 2012; Schnettler et al., 2012), thus acting
as a player in immune evasion DENV and
pathogenesis of DHF.
ENHANCING THE ROLE ANTIBODY-
DEPENDENT (ADE) IN
PATHOGENESIS DHF
Epidemiological evidence has shown that
the increased risk for DHF / DSS is
associated with a secondary infection from
a different DENV serotypes than that caused
the initial infection. Data collected from
Cuba, Hawaii and Thailand show that
individuals with DENV 1 circulating
antibodies are at increased risk for getting
dengue fever during DENV infection next 2
or DENV 3(3) . Furthermore, infants
infected with different serotypes of DENV
serotypes infected mothers have an
increased risk for DHF / DSS. Based on the
assessment of hospital patients, the
incidence of DHF / DSS during primary
dengue infection is 11 to 12 per 1000
compared with 118 to 208 per 1000 during
secondary dengue infection. The risk of
developing DHF during a secondary
infection of at least 10 times greater than the
risk of developing the condition during
primary infection. Increased levels of these
infections are caused by anti-body induced
from the first infection and has been called
the increase depends on the antibody.
Indeed, the ADE phenomenon has been
repeatedly shown in DENV infection in cell
culture and animals. When DENV
incubated with serum anti-DENV or
DENV-specific antibodies, virus replication
in human monocytes and some cell lines
significantly promoted. Passive
immunization with DENV antibody /
antisera prior to inoculation with the virus in
rhesus monkeys increases viral replication
more than 100-fold in the control animals.
However, not all cases of DHF / DSS
associated with ADE. Evidence from Phase
3 clinical trials of dengue vaccine (Sanofi
Pasteur) found no evidence of ADE
generation in the study population.
Although the ADE has been particularly
described in connection with DENV
infection, this phenomenon has also been
associated with several other virus species
by in vitro enhancement of infection.
Previous studies have shown that DE is
directed to the anti-E antibody and the
antibody anti-PRM. Although more
research has been designed to evaluate the
role of the protein E, PRM elah attract more
attention since 2010, first proposed ethics
MELANI NAURITA, S.SI.,APT 6
that anti-PRM anti-bodies involved in the
phenomenon of ADE. Several groups have
demonstrated that anti-PRM MABS fat-
nature exhibit ADE in cell culture and in
models feksi DENV. ith Thus, antibody-
PRM tend to play an important role in the
pathogenesis of DHF there is human. ADE
mechanism only partially understand. Fcγ
receptor (FcγR) - taking virion-antibody
complex into permissive cells maybe one of
the explanation for the increase DENV
infection. FCR is a multi-subunit complex
ang distributed on the surface of many types
of cells mun, such as dendritic cells,
macrophages and mast cells, and recognize
the Fc region of the immunoglobulin.
During infection DENV antibodies with
infection enhancer activity is generated and
subsequently form complects virion-anti-
body. The complexes can rapidly
internalized into cells containing in through
interaction with FCR FCR, ang produce the
number of infected cells is much higher in
the presence versus absence of antibodies.
In addition, previous studies have shown
that infection with DENV is mediated FCR
may increase the suppression of viral
replication through intracellular antiviral
immune responses internally, including
interferon-mediated antiviral response, and
increased production of IL-10 in DENV-
infected cells. The suppression of the host
immune response may promote the
production of a large number of infectious
virions DENV. Clinical manifestations of
dengue include endothelial cell damage,
increased vascular permeability, the leakage
of plasma and liver injury. However, These
manifestations may not be a direct result of
cell death caused by DENV for viral
replication peaks during febrile phase and
rapidly decreases as dengue fever and
plasma leakage develops. In addition to
improving the entry of the virus, ADE
mediated directly FCR strong trigger
cytokine release from mast cells and other
immune cells, which can mediate vascular
endothelial cell dysfunction and improve
vascular permeability. Cytokine release
considered as the key factors that contribute
to the pathogenesis of DHF. ADE mediated
directly FCR strong trigger cytokine release
from mast cells and other immune cells,
which can mediate vascular endothelial cell
dysfunction and improve vascular
permeability. Cytokine release considered
as the key factors that contribute to the
pathogenesis of DHF. ADE mediated
directly FCR strong trigger cytokine release
from mast cells and other immune cells,
which can mediate vascular endothelial cell
dysfunction and improve vascular
permeability. Cytokine release considered
as the key factors that contribute to the
pathogenesis of DHF
ROLE OF T CELLS IN
PATHOGENESIS IN DHF
Increased production of cytokines and
activation of CD8 + T cells that have been
observed in patients with severe dengue
implies that cross-reactive T cells have a
role in mediating the pathogenesis of DHF.
Memory T-cells from the primary infection
iaktifkan by heterologous virus during a
second infection, showed an extremely high
cross reactivity that causes an affinity lower
natural inefficiency kill infected cells and
cleans new infective virus serotypes.
ebaliknya, cross-reactive T cells contributes
to be DHF with the substansial
imunopatologi. Dengue patients have been
reported to show eningkatan circulating
MELANI NAURITA, S.SI.,APT 7
cytokines and chemokines, IFN-γ, IL-2 an
TNF-α is produced by T cells cross-reactive
spesifik DENV activated, compared with
asien DF, showed a positive correlation
ntara cross-reactive T-cell activation and
related diseases dengue severity level(3).
Additionally, apoptosis T cells in patients
with DHF contribute related to dengue
disease severity. This previous studies
reported that IL-10 immunosuppressive
cytokines can cause cell apoptosis in
patients with acute dengue infection. The
concentration of IL-10 increased in serum of
patients ith severe dengue. Blockade of IL-
10 was significantly with a decrease in T cell
apoptosis in acute DENV Infection. In the
agreement, the number of T cells were
reduced in patients compared with patients
DHF.
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Guidelines of the treatment of
Malária. 2010;1–194.
2. Candra A. Demam Berdarah
Dengue : Epidemiologi , Patogenesis
, dan Faktor Risiko Penularan
Dengue Hemorrhagic Fever :
Epidemiology , Pathogenesis , and
Its Transmission Risk Factors.
2010;2(2):110–9.
3. Pang X, Zhang R, Cheng G.
Progress towards understanding the
pathogenesis of dengue hemorrhagic
fever. 2016;1–7.
4. Chen H, Lai Y, Yeh T. Dengue virus
non-structural protein 1 : a
pathogenic factor , therapeutic target
, and vaccine candidate. 2018;1–11.
5. Virol A, Guzman MG, Alvarez M,
Halstead SB. Secondary infection as
a risk factor for dengue hemorrhagic
fever / dengue shock syndrome : an
historical perspective and role of
antibody-dependent enhancement of
infection. 2013;

MELANI NAURITA, S.SI.,APT 8

Picture 1,

MELANI NAURITA, S.SI.,APT 9