CLINICAL SCIENCE OF DENGUE

A. Definition
Dengue fever is a mosquito-borne tropical disease caused by the dengue virus.

B. Epidemiology
In Indonesia, where more than 35% of the country’s population lives in urban areas, 150 000 cases
were reported in 2007 (the highest on record) with over 25 000 cases reported from both Jakarta
and West Java. The case-fatality rate was approximately 1%.

C. RF and Etiology
Risk Factor :

Etiology : Dengue virus

Vector : Aedes aegepty and Aedes albopictus

D. Type

i. Undifferentiated fever
Infants, children and adults who have been infected with dengue virus, especially for the first time
(i.e. primary dengue infection), may develop a simple fever indistinguishable from other viral
infections. Maculopapular rashes may accompany the fever or may appear during defervescence.
Upper respiratory and gastrointestinal symptoms are common.
ii. Dengue fever
Dengue fever (DF) is most common in older children, adolescents and adults. It is generally an acute
febrile illness, and sometimes biphasic fever with severe headache, myalgias, arthralgias, rashes,
leucopenia and thrombocytopenia may also be observed. Occasionally unusual haemorrhage such
as gastrointestinal bleeding, hypermenorrhea and massive epistaxis occur.
iii. Dengue haemorrhagic fever
 Dengue haemorrhagic fever (DHF) is more common in children less than 15 years of age in
hyperendemic areas, in association with repeated dengue infections. DHF is characterized by the
acute onset of high fever and is associated with signs and symptoms similar to DF in the early febrile
phase. There are common haemorrhagic diatheses such as positive tourniquet test (TT), petechiae,
easy bruising and/or GI haemorrhage in severe cases.
By the end of the febrile phase, there is a tendency to develop hypovolemic shock (dengue shock
syndrome) due to plasma leakage. The presence of preceding warning signs such as persistent
vomiting, abdominal pain, lethargy or restlessness, or irritability and oliguria are important for
intervention to prevent shock. Abnormal haemostasis and plasma leakage are the main
pathophysiological hallmarks of DHF.
iv. Expanded dengue syndrome
Unusual manifestations of patients with severe organ involvement such as liver, kidneys, brain or
heart associated with dengue infection have been increasingly reported in DHF and also in dengue
patients who do not have evidence of plasma leakage. These unusual manifestations may be
associated with coinfections, comorbidities or complications of prolonged shock. Exhaustive
investigations should be done in these cases.

E. Clinical Features
i. Dengue Fever
Physical Exam :
After an average intrinsic incubation period of 4–6 days (range 3–14 days), various non-specific,
constitutional symptoms and headache, backache and general malaise may develop.
 Fever: The body temperature is usually between 39 °C and 40 °C, and the fever may be
biphasic, lasting 5–7 days in the majority of cases. Sudden sharp rise.
 Rash: Diffuse flushing or fleeting eruptions may be observed on the face, neck and chest
during the first two to three days, and a conspicuous rash that may be maculopapular or
rubelliform appears on approximately the third or fourth day. Towards the end of the
febrile period or immediately after defervescence, the generalized rash fades and localized
clusters of petechiae may appear over the dorsum of the feet, on the legs, and on the
hands and arms. This convalescent rash is characterized by confluent petechiae
surrounding scattered pale, round areas of normal skin.
 Haemorrhagic manifestations: Skin haemorrhage may be present as a positive tourniquet
test and/or petechiae. Other bleeding such as massive epistaxis, hypermenorrhea and
gastrointestinal bleeding rarely occur in DF, complicated with thrombocytopenia.
 Retro-orbital pain on eye movement or eye pressure, photophobia
 Backache, and pain in the muscles and joints/bones.

Lab Exam
 Total WBC is usually normal at the onset of fever; then leucopenia develops with decreasing
neutrophils and lasts throughout the febrile period.
 Platelet counts are usually normal, as are other components of the blood clotting
mechanism. Mild thrombocytopenia (100 000 to 150 000 cells/mm3) is common
 Mild haematocrit rise (≈10%) may be found as a consequence of dehydration associated
with high fever, vomiting, anorexia and poor oral intake.
 Serum biochemistry is usually normal but liver enzymes and aspartate amino transferase
(AST) levels may be elevated.
F. DD

ii. Dengue Haemorrhagic Fever

Physical Exam:
The major pathophysiological changes that determine the severity of DHF and differentiate it from
DF and other viral haemorrhagic fevers are abnormal haemostasis and leakage of plasma selectively
in pleural and abdominal cavities.
 Fever: acute onset, high and continuous, lasting two to seven days in most cases.
  Any of the following haemorrhagic manifestations including a positive tourniquet testg
(the most common), petechiae, purpura (at venepuncture sites), ecchymosis, epistaxis, gum
bleeding, and haematemesis and/or melena.
 Enlargement of the liver (hepatomegaly) is observed at some stage of the illness in 90%–
98% of children. The frequency varies with time and/or the observer.
Lab Exam
 Thrombocytopenia (100 000 cells per mm3 or less)h.
 Haemoconcentration; haematocrit increase of ≥20%i from the baseline of patient or
population of the same age.
 Serum biochemistry is usually normal but liver enzymes and aspartate amino transferase
(AST) levels may be elevated

The first two clinical criteria, plus thrombocytopenia and haemoconcentration or a rising
haematocrit, are sufficient to establish a clinical diagnosis of DHF. The presence of liver
enlargement in addition to the first two clinical criteria is suggestive of DHF before the onset of
plasma leakage.

The presence of pleural effusion (chest X-ray or ultrasound) is the most objective evidence of
plasma leakage while hypoalbuminaemia provides supporting evidence. This is particularly useful
for diagnosis of DHF in the following patients:
 anaemia.
 severe haemorrhage.
 where there is no baseline haematocrit.
 rise in haematocrit to <20% because of early intravenous therapy.

Convalescence in DHF
Diuresis and the return of appetite are signs of recovery and are indications to stop volume
replacement. Common findings in convalescence include sinus bradycardia or arrhythmia and the
characteristic dengue confluent petechial rash as described for dengue fever. Convalescence in
patients with or without shock is usually short and uneventful. Even in cases with profound shock,
once the shock is overcome with proper treatment the surviving patients recover within 2 – 3 days.
 However, those who have prolonged shock and multiorgan failure will require specific treatment and
experience a longer convalescence. It should be noted that the mortality in this group would be high
even with specific treatment.

iii. Dengue Shock Syndrome

Shock is reversible and of short duration if timely and adequate treatment with volume-replacement
is given. Without treatment, the patient may die within 12 to 24 hours. Patients with prolonged or
uncorrected shock may give rise to a more complicated course with metabolic acidosis and
electrolyte imbalance, multiorgan failure and severe bleeding from various organs.

Physical Exam:
 Rapid and weak pulse with narrowing of the pulse pressure ≤20 mmHg with an increased
diastolic pressure, e.g. 100/90 mmHg, or hypotension.
 Reduced tissue perfusion are: delayed capillary refill (>3 seconds), cold clammy skin and
restlessness. It is noteworthy that most patients remain conscious almost to the terminal
stage.
Hepatic and renal failure are commonly observed in prolonged shock. Encephalopathy may occur in
association with multiorgan failure, metabolic and electrolyte disturbances. Intracranial
haemorrhage is rare and may be a late event. Patients with prolonged or uncorrected shock have a
poor prognosis and high mortality.
Lab Exam
 High haematocrit (rise more than equal 20%) and marked thrombocytopenia (>100,000
cell/mm3)
 A low ESR (<10 mm/first hour)
G. Grading Severity

H. Complications
i. DF complications
DF with haemorrhage can occur in association with underlying disease such as peptic ulcers, severe
thrombocytopenia and trauma. DHF is not a continuum of DF.
ii. DHF complications
These occur usually in association with profound/prolonged shock leading to metabolic acidosis and
severe bleeding as a result of DIC and multiorgan failure such as hepatic and renal dysfunction.

J. Complication
- metabolic acidosis and severe bleeding as a result of DIC and multiorgan failure such as hepatic and
renal dysfunction.
- excessive fluid replacement during the plasma leakage period leads to massive effusions causing
respiratory compromise, acute pulmonary congestion and/or heart failure.

K. Serology

5 basic test for Dengue serology test :

 hemagglutination-inhibition (HI),
  complement fixation (CF),
 Neutralization test (NT),
 IgM capture ELISA (MACELISA),
 indirect IgG ELISA.

Antibody response to infection comprises the appearance of different types of immunoglobulins; and
IgM and IgG immunoglobulin isotypes are of diagnostic value in dengue. IgM antibodies are detectable
by days 3–5 after the onset of illness, rise quickly by about two weeks and decline to undetectable levels
after 2–3 months. IgG antibodies are detectable at low level by the end of the first week, increase
subsequently and remain for a longer period (for many years). Because of the late appearance of IgM
antibody, i.e. after five days of onset of fever, serological tests based on this antibody done during the
first five days of clinical illness are usually negative.

During the secondary dengue infection (when the host has previously been infected by denguevirus),
antibody titres rise rapidly. IgG antibodies are detectable at high levels, even in the initial phase, and
persist from several months to a lifelong period. IgM antibody levels are significantly lower in secondary
infection cases. Hence, a ratio of IgM/IgG is commonly used to differentiate between primary and
secondary dengue infections.

Infeksi primer, jika IgM/IgG rasio

>1/2.

Infeksi sekunder jika <1/2.

Thrombocytopenia is usually
observed between the third and
eighth day of illness followed by
other haematocrit changes.