1

Immune responses that are prioritized to play a role in the pathogenesis of DHF are:

a). humoral response in the form of antibody formation which plays a role in the
neutralization process of the virus, complement mediated cytolysis and antibody mediated
cytotoxicity. Antibodies to dengue virus play a role in accelerating viral replication in monocytes
ormmacrophages. This hypothesis is called dependent enhancement antibody (ADE);
b). T lymphocytes both T-helper (CD4) and T-cytotoxic (CD8) play a role in the cellular
immune response to the dengue virus. Differentiation of TH1 T helper will produce interferon
gamma, lL-2 and lymphokine, whereas TH2 produces lL-4, lL-5, lL-6 and lL-10;
c). monocytes and macrophages play a role in viral phagocytosis with opsonization of
antibodies. However, this phagocytic process causes an increase in viral replication and
cytokine secretion by macrophages;
d). besides complement activation by the immune complex causes C3a and C5a to form.
Halstead in 1973 proposed a secondory heterologous infection hypothesis which states that
DHF occurs when someone is re-infected with a different type of dengue virus. Reinfection
causes the antibody's amnestic reaction resulting in a high concentration of immune complexes.
Kurane and Ennis in 1994 summarized Halstead's and other researchers' opinions; states that
dengue virus infection causes activation of macrophages which phagocytosis of non-neutralized
viral-antibody complexes so that the virus replicates in macrophages.

The occurrence of macrophage infection by dengue virus causes T-heLper and T-cytotoxic
activation to produce lymphokines and interferon gamma. Inferonone gamma activates
monocytes so that secretion of inflammatory mediators such as TNF-a, lL-1, PAF (plotelet
octivoting foctor), lL-6 and histamine is secreted which results in endothelial cell dysfunction and
plasma leakage. Increases in C3a and C5a occur through activation by a virus-antibody
complex which also results in plasma leakage.

Thrombocytopenia in dengue infection occurs through the mechanism: 1). Bone marrow
suppression, 2). destruction and shortening of platelet life.
The bone marrow picture in the initial phase of infection (<5 days) shows a hypocellular
state and megakaryocyte suppression. After a nadir is reached there will be an increase in the
hematopoiesis process including megakariopoiesis. Levels of thrombopoietin in the blood at the
time of thrombocytopenia actually showed an increase, this indicates the occurrence of
thrombopoiesis stimulation as a mechanism of compensation for the state of thrombocytopenia.
Platelet destruction occurs through binding of C3g fragments, presence of dengue virus
antibodies, platelet consumption during coagulopathy and peripheral sequestration. Disorders of
platelet function occur through the mechanism of ADP release disorder, elevated levels of b-
thromboglobulin and PF4 which are markers of platelet degranulation.
Coagulopathy occurs as a result of viral and endothelial interactions that cause
endothelial dysfunction. Various studies have shown the occurrence of consumptive
coagulopathy in dengue hemorrhagic fever III and IV. Coagulation activation in dengue
hemorrhagic fever occurs through activation of the extrinsic pathway (fissue foctor pathwoy).
Intrinsic pathways also play a role through activation of factor Xla but not through contact
activation (colicreine C1-inhlbitor complex).
There was no significant difference for the duration of fever between
children and adults.The state of fever is regulated by a system of regulating
body temperature as the body maintains temperature. The thermostat will
be reset in response to the presence of endogenous pyrogens namely
cytokines: interleukin (IL) 1β and IL6, TNFα, and interferon β and γ.15

In children, the immune system is still developing and not as perfect

as adults until puberty where sex hormones are thought to be
responsible for the full maturation of the child's immune system. In
infants there is a decrease in IFN production by lymphocytes and a
decrease in the response of macrophages to IFN activation In addition,
there is also a decrease in the production of cytokine Th1 by mononuclear
phagocytes. So that the body's ability
to respond to the presence of a virus with the occurrence of fever is not
optimal. This can be
factors that cause long-term fever in children are relatively shorter than
adults
where the younger the age, the longer the fever tends to be shorter.

There is a difference with the study of Ole Wichmann et al., Which states
that peteki and gum bleeding are more common in adults, whereas
epistaxis is more in children. in children greater than adults.20 This is
thought to be a factor that explains why bleeding especially peteki,
ecchymosis, and purpura is more common in children than adults.

Vascular permeability in children is greater than adults.20 This is thought

to be a factor that explains why bleeding especially peteki, ecchymosis,
and purpura are more common in children than adults.

The percentage of the age group with the highest liver enlargement is the
age of 5-10 years. Hepatocytes are directly involved as a place of infection,
namely replication of the dengue virus.21 This causes injury to the liver
and stimulates apoptosis.22 The child's immune system is not perfect
so it has not been able to eliminate viruses in the body as optimally
as adults. Thus, the more viruses that replicate in liver cells, the more
hepatocytes are damaged. This can help explain why liver
enlargement tends to occur more in children than adults.
the most frequent age group experiencing shock is 0-5 years This study is
similar to Samantha's study that shock often occurs in infants) and children
. This shows that the more age increases, the incidence of shock
decreases. There are two factors that influence the incidence of shock
in patients, namely vascular permeability and hemoestasis factors.
Higher vascular permeability in children causes plasma leakage and
permeation of coagulation factors out of the blood vessels higher.
This explains why the incidence of shock is higher in children than
adults.

In this study, plasma leakage in children (88.0%) was more frequent than
adults (39.5%). This difference was statistically significant (p <0.001). In
accordance with Samantha's study, the incidence of plasma leakage in
adults (15%) is less than for infants (40%) and children (30%).

Blood vessel permeability will decrease with age. So that the incidence
of plasma leakage in adults is less common than in children.8
Microvascular permeability during childhood is thought to be the result of
the density and surface of the microvascular which grows larger than
adults. This helps explain why children are more likely to develop into DSS
than adults. Vascular permeability in children is higher than that of adults.
This causes children more at risk of developing severe dengue infection
than adults.20 From various clinical profiles available, it was found that the
duration of fever tends to be shorter due to an imperfect immune system,
spontaneous bleeding is more common in children, liver enlargement,
plasma leakage, and the incidence of shock is more in children