1

INTRODUCTION
Dengue viral infections are one of the most important mosquito-borne diseases in the world.
Dengue infection is a infection that caused by dengue virus. The dengue virus has four serotype,
DEN-1, DEN-2, DEN-3, and DEN-4. Infection provides life-long immunity against the infecting
viral serotype, but not against the other serotypes. Dengue infections is characterized by a sudden
onset of high-grade fever with non-specific symptoms. The clinical presentations of dengue viral
infections range from asymptomatic to severe illness that may lead to death if not properly
managed. The symptomatic cases are categorized as undifferentiated febrile illness (UF), dengue
fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and unusual
dengue (UD) or expanded dengue syndrome (EDS). UF cannot be diagnosed clinically and the
diagnosis is based on serology or virology. DF is considered to be a mild disease because death is
rarely reported, but massive bleeding may be associated with DF. DHF clinical presentations
during the febrile phase are similar to those in DF. The pathophysiology of DHF is not clear, but
the main feature differentiating it from DF is an increase in vascular permeability, resulting in
leakage of fluid from the intravascular compartment to the extravascular space. The plasma
leakage is selective leakage into the pleural and peritoneal cavities that results in pleural effusion
and ascites. DSS presentations are the same as those in DHF but the plasma leakage is so severe
that the patient develops shock. UD is the most of the unusual cases are DHF cases with
prolonged shock or DHF together with other infections.1
EPIDEMIOLOGY
Ninety percent of DHF subjects are children less than 15 years of age. Based on annually case
reported from WHO, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are
among the leading causes of pediatric hospitalization in Asia, with up to 500,000 cases. In South
Asia, reported 300440 cases/100.000 population. In Indonesia showed that DEN-1 and DEN-2
were the prevalent serotypes until the late 1980s, the DEN-3 serotype has been the predominant
serotype in the recent outbreaks. In fact, DEN-3 has been associated with severe dengue
epidemics and it has been suggested that the DEN-3 virus may have certain characteristics that
make it more virulent.2

CHARACTERISTICS OF DENGUE VIRUS

Dengue virus is an enveloped positive-sense single- stranded RNA virus that belongs to the
flavivirus genus of the flaviviridae family. They are transmitted among humans by Aedes genus
mosquitoes such as Aedes aegypti, Aedes albopictus, and Aedes polynesiensis. The primary and
most important vector is A. aegypti, but A. albopictus and A. polynesiensis may act as vectors
depending on the geographic location. The mature virion consists of three structural (core,
membrane associated, and envelope) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a,
NS4b, and NS5) proteins. The NS proteins are assumed to be involved in the replication of viral
RNA. The proteins are synthesized as a large and single-polyprotein precursor of approximately
3400 amino acids.3
SIGN AND SYMPTOMS
Usually people who have infected by the dengue virus have asymptomatic symptoms or only
shown mild symptoms such as an uncomplicated fever or self-limiting febrile illness. Some
people may have more severe illness and in a small proportion it is a life-threatening condition
characterized by increased capillary permeability and shock.4 Dengue should be suspected when
a high fever (40C/ 104F) is accompanied by two of the following symptoms: severe headache,
pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands or rash. The
incubation period ranges from 314 days, but most often it is 47 days. Symptoms usually last
for 27 days, after an incubation period of 410 days after the bite from an infected mosquito.
Severe dengue is lead patient to death due to plasma leaking, fluid accumulation, respiratory
distress, severe bleeding, or organ impairment. Warning signs occur 37 days after the first
symptoms in conjunction with a decrease in temperature (below 38C/ 100F) and include:
severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums, fatigue, restlessness,
blood in vomit. The next 2448 hours of the critical stage can be lethal, proper medical care is
needed to avoid complications and risk of death.

Figure 1. Clinical course of dengue fever

Therefore, travelers returning from endemic areas are unlikely to have dengue if fever or other
symptoms start more than 14 days after arriving home. Children often experience symptoms
similar to those of the common cold and gastroenteritis (vomiting and diarrhea) and have a
greater risk of severe complications, though initial symptoms are generally mild but include high
fever. Warning signs for severe disease is important include abdominal pain, evidence of fluid
accumulation, hepatomegaly and increases in haematocrit accompanied by a fall in the platelet
count.4

Figure 2. Dengue fever flow chart

The clinical presentations of dengue viral infections range from asymptomatic to severe illness
that may lead to death if not properly managed. The symptomatic cases are devided into some
category such as undifferentiated febrile illness (UF), dengue fever (DF), dengue hemorrhagic
fever (DHF), dengue shock syndrome (DSS) and unusual dengue (UD) or expanded dengue
syndrome (EDS).5
Undifferentiated febrile illness (UF) have no spesific clinical symptom so it cannot be
diagnosed as UF only by physical examination and the diagnosis is based on serology or
virology. The symptoms mostly like headache, malaise, nausea/vomiting, abdominal pain and
sometimes rash. A maculo-papular rash occurs mostly in young children. Upper respiratory
features, especially pharyngitis, are common.6
Dengue fever (DF) patients mostly have some symptoms like retro-orbital pain, myalgia and
arthralgia, is considered to be a mild disease because death is rarely reported, but massive
bleeding may be associated with DF. In DF there are three phase febrile phase, critical phase
and recovery phase. The fever may be happen in 3 until 7 days and have the other symptoms like
severe headache, retro-orbital pain, fatigue, nausea, vomiting, generalised aches, arthralgia and
myalgia explaining the historical name of break-bone fever. The skin may appear flushed that
appearing during the critical phase and a maculo-papular rash appearing in early convalescence.
Haemorrhagic manifestations range from mild to severe; cutaneous petechiae and purpura, gum
bleeding, epistaxis, gastrointestinal haemorrhage all can occur.6 Recovery may be prolonged with
weakness

and depression.

Laboratory

findings

thrombocytopaenia and elevated liver enzymes.

include

neutropaenia,

lymphocytosis,

Figure 3. Schematic depiction of the symptoms of dengue fever

Dengue hemorrhagic fever (DHF) clinical presentations during the febrile phase are similar
to those in DF.

But in DHF the vascular permeability (plasma leakage) is increase that

differentiates DHF from DF. The plasma leakage is selective leakage into the pleural and
peritoneal cavities that results in pleural effusion and ascites. 5 Patients either recover or progress
to the plasma leakage stage remaining ill despite normalisation of temperature. Plasma leakage is
characterized by tachycardia and hypotension with sweating, restlessness and cold extremities.
Most patients recover, but in severe cases patients may develop circulatory shock. It usually
follows a secondary dengue infection and is characterized by high fever, haemorrhages,
circulatory failure and hepatomegaly.6 DHF is divided into three phases: febrile phase (27
days), critical or leakage phase (2448 hours), and convalescence or recovery phase (27 days).
The laboratory findings are leucopaenia and thrombocytopaenia (less than 100,000/mm 3) usually
found between days 3 and 8, the elevated of liver enzymes are common.
Dengue shock syndrome (DSS) presentations are the same as those in DHF but the plasma
leakage is so severe that the patient develops shock. DSS is associated with almost 50%

mortality cases, cause of the death of the patients come from multi organ failure and
disseminated intravascular coagulation. Warning signs include sustained abdominal pain,
vomiting, irritability or somnolence, a fall in body temperature and decrease in platelet count. 6
DSS may be accompanied by encephalopathy caused by haemostatic disturbances that come
from the vascular changes, thrombocytopaenia and coagulation disorders arising from a
decreased fibrinogen level and increased level of fibrinogen degradation products. Other
complications that reported include liver failure, myocarditis and acute renal failure.
Unusual dengue (UD) most of the unusual cases are DHF cases with prolonged shock or
DHF inpatients with co-morbidities or DHF together with other infections. The majority of the
cases are UF and DF.5 DHF/DSS accounts for about 10% of the symptomatic cases.
According to the WHO 2011 case definition, dengue infection is suspected in a patient with high
fever and two of the following signs or symptoms:5
-

Headache
Retro-orbital pain
Myalgia
Arthralgia/ bone pain
Rash
Bleeding manifestations: petechiae, epistaxis, gum bleeding, hematemesis, melena, or
positive tourniquet test.

Laboratory finding:
-

Leukopenia (WBC 5,000 cells/mm3)

Platelet count 150,000 cell/mm3
Hematocrit (Hct) rising 510%.
IgM antibodies are the first to appear and are detectable in 50% of patients by days 3 5
after onset of illness, increasing to 80% by day 5.6
IgG antibody is detectable at low titres at the end of first week, increasing thereafter and still
detectable after several months. During secondary dengue infection antibody titres rise
rapidly and react broadly against many flaviviruses.6

DENGUE HEMORRHAGIC FEVER

Dengue hemorrhagic fever (DHF) is a severe form of dengue fever (DF) with fever, hemorrhagic
manifestation, increase in hematocrit, thrombocytopenia, a prolonged bleeding time, and an
increased prothrombin time and plasma leakage. DHF clinical course is divided into three
phases: febrile phase (27 days), critical or leakage phase (2448 hours), and recovery phase (2
7 days). Illness starts with fever, malaise, vomiting, headache, anorexia, and cough. In crisis
phase or when capillary leakage occurs, the temperature returns to normal, patient may get shock
syndrome, dysfunction of organ, increase of Hct and thrombocytopenia. If the patient treated
well and properly, the recovery phase may occurs.1
Based on the modified criteria of WHO/SEARO 2011, there are major and minor criteria for case
definition of DHF. Major criteria of DHF are high fever and plasma leakage where there is
elevation of Hct 20%, detection of ascites, pleural effusion by physical examination, chest film
(right lateral decubitus position) or ultrasound. Minor criteria are based on bleeding evidence or
positive tourniquet test and platelet counts 100,000 cells/mm3.1
The World Health Organization (WHO) categorizes DHF into four grades based on the severity,
from less severe (grade 1) to severe (grade 4). Grade 1 are characterized by fever and without
spontaneous bleeding but positive result of tourniquet test while in grade 2, there is spontaneous
bleeding such as petechiae, ecchymoses or purpura, hematemesis or melaena. In grades 3, there
is circulatory failure manifested by a rapid and weak pulse with narrowing pulse pressure ( 20
mmHg) or hypotension. And in grade 4, profound shock in which pulse and blood pressure are
not detectable. It is note worthy that patients who are in threatened shock or shock stage, also
known as dengue shock syndrome (DSS).1,7
Pathogenesis of Dengue Hemorrhagic Fever
The pathogenesis of DHF has been explained by two theories. One theory is based on the
virulence of infecting dengue viruses while the other is based on immunopathogenesis.
Based on epidemiologic data, most of DHF cases is mediated by immune response which
involving role of non-neutralizing antibodies usually called as antibody-dependent enhancement
(ADE) theory. Human that infected by dengue virus (primary infection) will make antibody
serum which can neutralize the virus that belongs to the same serotype in their body. If there is

new infection from different serotype (secondary infection), new dengue virus and previous
antibodies that lack of neutralizing activity will form virusantibody complexes. Virusantibody
complexes bind to Fc receptors on the target cells. As a immune response to the dengue virus
infected, cells infected will produced many cytokines. Monocyte and endothelial cells will
produced TNF-. It has also been reported that a mast cell/basophile line infected with dengue
viruses can produce IL-1 and IL-6. Some of the cytokines, IFN-, IL-2, and TNF-, were also
produced because of virus-specific T lymphocytes activation and those all cause increasing of
vascular permeability and lead to plasma leakage that induces hemorrhagic manifestation.7
MANAGEMENT DENGUE FEVER
There are no specific treatments for dengue fever.1 Treatment depends on the symptoms,
Oral rehydration therapy at home with close follow-up, to hospital admission with administration
of intravenous fluids and/or blood transfusion. A decision for hospital admission is typically
based on the presence of the "warning signs" listed in the table above, especially in those with
preexisting health condition.
Intravenous hydration is usually only needed for one or two days. The rate of fluid
administration is titrated to a urinary output of 0.51 mL/kg/hr, stable vital signs and
normalization of hematocrit.
Invasive medical procedures such as nasogastric intubation, intramuscular injections and arterial
punctures are avoided, in view of the bleeding risk.5 Paracetamol (acetaminophen) is used for
fever and discomfort while NSAIDs such as ibuprofen and aspirin are avoided as they might
aggravate the risk of bleeding.
Blood transfusion is initiated early in patients presenting with unstable vital signs in the face of
a decreasing hematocrit, rather than waiting for the hemoglobin concentration to decrease to
some predetermined "transfusion trigger" level. Packed red blood cells or whole blood are
recommended, while platelets and fresh frozen plasma are usually not.
During the recovery phase intravenous fluids are discontinued to prevent a state of fluid
overload. If fluid overload occurs and vital signs are stable, stopping further fluid may be all that
is needed. If a person is outside of the critical phase, a loop diuretic such as furosemide may be
used to eliminate excess fluid from the circulation.3
MANAGEMENT OF SEVERE DENGUE (DHF)

DHF clinical course is divided into three phases: febrile phase (27 days), critical or leakage
phase (2448 hours), and convalescence phase (27 days). In the febrile phase, only supportive
and symptomatic treatment is conducted. At the end of the febrile phase, plasma leakage begins.
More severe cases, i.e. those with moderate to severe plasma leakage and without adequate oral
intake, need hospital admission and proper intravenous replacement. Milder cases with minimal
plasma leakage and adequate oral intake may recover without treatment. It should be noted that
after the critical period, ascites and pleural effusion will be reabsorbed back into the circulation
1224 hours after leakage stops, i.e. 3648 hours after shock or 6072 hours after plasma
leakage.
Management of patients
The management of patients with dengue infections depends on the phase of illness, as follows:

1.

Febrile phase:

Early diagnosis of dengue infection:

High fever with positive Tourniquet test + leukopenia (WBC 5,000 cells/mm3) positive
predictive value 7083%. 1
a. Reduction of high fever: paracetamol only, tepid sponge
b. Promote oral feeding: soft diet, milk, fruit juice, oral rehydration solution (ORS). Avoid
IV fluid if there is no vomiting and moderate/ severe dehydration
c. Follow up CBC everyday
d. Advise to come back to the hospital ASAP when there is no clinical improvement despite
a lack of fever, severe abdominal pain/ vomiting, bleeding, restless/ irritable, drowsy,
refusal to eat or drink (some patients may be thirsty), urine not passed for 46 hours
2. Critical/ Leakage phase:
Proper IV fluid management during the critical period:

Isotonic salt solution in the critical period, e.g. 5% dextrose in normal saline solution
(NSS), 5% Ringer Acetate, 5% Ringer-Lactate. The 5% dextrose in NSS is preferable
because the severe cases needing admission are those with poor appetite, nausea/

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vomiting and abdominal pain.

The total amount of fluid needed during the critical period of 2448 hours is estimated to
be maintenance + 5% deficit (M+5%D), including oral and IV fluids. In DSS patients the

duration of IV fluid may be 2436 hours and in non-shock DHF 4860 hours.
The rate of IV fluid should be adjusted according to clinical vital signs (BP, pulse,

respiratory rate, temperature), hematocrit (Hct) and urine output (0.5 ml/kg/hr)
The IV fluid resuscitation for DHF grade III is less than that recommended for other
kinds of shock, i.e. only 10 ml/kg/hr, not 20 ml/kg/hr or over. A larger amount of IV fluid
is needed for DHF grade IV, but the rate should be reduced to 10 ml/kg/hr as soon as the

blood pressure is restored.

The administration of IV fluid should begin at a slower rate if leakage is in the earlier
stage, i.e. platelet count is between 50,000 and 100,000 cells/mm3. The rate of IV should
be more rapid when the leakage has continued for some time, i.e. platelet count < 50,000

cells/mm3.
If the clinical response is not good (re-shock, unstable vital signs, inability to reduce the
rate of IV fluid) investigate and correct the following laboratory data:
A Acidosis blood gas (capillary or venous), if present, check liver and renal
functions. Correct acidosis when blood pH is < 7.35 and HCO3 < 15 mEq/L.
B Bleeding Hct: if high, dextran is indicated, if low or not rising, consider blood
transfusion and consider giving vitamin K1 intravenously.
C iCa and other electrolytes: Na, K. Give cagluconate 1 ml/kg/dose diluted twice
with IV fluid and IV push slowly. Maximum dose is 10 ml/dose.
S Blood sugar

Colloidal solution: only plasma expander that has an osmolarity higher than that of
plasma is recommended, e.g. 10% Dextran-40 in NSS. Bolus dose of 10 ml/kg/hr in
children or 500 ml/hr in adults is recommended, and this will usually bring the Hct down
to 10 points in cases with signs of fluid overload or persistently high Hct.
In cases with significant bleeding, i.e. > 68 ml/kg ideal body weight in children or 300
ml in adult, blood transfusion is recommended as soon as possible. The amount to
transfuse is equal to the estimated amount. If it is impossible to estimate (concealed
internal bleeding), transfuse 10 ml/kg of fresh whole blood (FWB) or 5 ml/kg of packed
red cells (PRC) in children to raise Hct by 5 points. In adults, transfuse 1 unit of FWB or
PRC.
Platelets are indicated in cases with significant bleeding. If the patient already has signs

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of fluid overload, however, do not give platelets because this will cause fluid overload
(possibly acute pulmonary edema). Platelet transfusion is only adjunct therapy, not
specific treatment. There is no platelet prophylaxis in children, no matter how low the
platelet count. Clinicians may consider prophylactic platelet transfusion in adults with
underlying hypertension or heart disease and a platelet count < 10,000 cells/mm3.
Plasma has almost no role in the management of acute DHF in the critical phase.
Steroid has no role in the management of DSS.
DHF/DSS patients were treated with NSS (100%), Dextran-40 (2025%), blood
transfusion (1015%) and platelet transfusion (0.4%).
3. Convalescence phase:
Stop IV fluid when there are signs of recovery: convalescence rash, itching, increase in
appetite or > 30 hours after shock and > 60 hours after plasma leakage.
Sinus bradycardia may be observed in some patients.
Patients who have massive ascites and pleural effusion may need diuretic during this
period of reabsorption of extravasated plasma into the circulation.
Some patients may not regain their appetite in this period. This may be due to diuresis
and loss of potassium in the urine. Potassium supplement may be necessary in this phase.
Fruit (bananas, oranges) and fruit juice are rich in potassium and are preferred by most
patients

SUMMARY
Dengue viral infections are one of the most important mosquito-borne diseases in the world.
Dengue infection is a infection that caused by dengue virus. Usually people who have infected
by the dengue virus have asymptomatic symptoms or only shown mild symptoms such as an
uncomplicated fever or self-limiting febrile illness. Some people may have more severe illness
and in a small proportion it is a life-threatening condition characterized by increased capillary
permeability and shock.4 There are no specific treatments for dengue fever. Treatment depends
on the symptoms. The management of patients with dengue infections depends on the phase of

12

illness

References :
1. Kalayanarooj, Siripen. Clinical Manifestations and Management of Dengue/DHF/DSS.
Tropical Medicine and Health. 2011. 39(4):83-87.
2. Malavige GN, Fernando S, Fernando DJ, Seneviratne, SL. Dengue Viral Infections.
Postgrad Med J. 2004. 80:588601.
3. Chuansumrit A, Tangnararatchakit K. Pathophysiology and Management of Dengue
Hemorrhage Fever. TATM. 2006. 8:3-11
4. Whitehorn J, Farrar J (2010). "Dengue".
doi:10.1093/bmb/ldq019
5. Kalayanarooj S (2011).

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Dengue/DHF/DSS. Tropical Medicine and Health. 39: 83-87. doi:10.2149/tmh.2011S10

6. Tavodova M (2012). Dengue Fever. South Sudan Medical Journal. 5: 13-16.
7. Kurane, I. Dengue Hemorrhagic Fever with Special Emphasis on Immunopathogenesis.
CIMID. 2007. 30:329-340.