1

ACKNOWLEDGMENTS

We thank the Almighty One for giving us opportunity to finish this case
report, Dengue Haemorrhagic Fever and Expanded dengue Syndrome. This
case report is a requirement to complete the clinical assistance program in
Department of Child Health in Haji Adam Malik General Hospital, Medical
Faculty of North Sumatera University.
We also would like to thank to our supervisor and adviser, dr. Supriatmo,
M.Ked(Ped), Sp.A(K) for the time given to gave us guidance, comments, and
suggestions. We are grateful because without him, this case report wouldnt have
taken its present shape.
This case report has gone through series of developments and corrections.
There were critical but constructive and relevants suggestions from the reviewers.
Hopefully the content will be useful for everyone the future.

Medan, February 2017

Writers
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CONTENTS

ACKNOWLEDGMENTS.......................................................................... i
CONTENTS................................................................................................ ii
CHAPTER 1 INTRODUCTION................................................................ 1
CHAPTER 2 LITERATURE REVIEW...................................................... 4
CHAPTER 3 CASE REPORT.................................................................... 18
CHAPTER 4 DISCUSSION....................................................................... 29
CHAPTER 5 SUMMARY.......................................................................... 32
REFERENCES .......................................................................................... 33
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CHAPTER I
INTRODUCTION

1.1 Background
Dengue is a mosquito-borne viral disease that has rapidly spread in all
regions around the world in recent years. Dengue virus is transmitted by
female mosquitoes mainly of the species Aedes aegypti and, to a lesser
extent, Aedes albopictus. This mosquito also transmits chikungunya, yellow
fever and Zika infection. Dengue is widespread throughout the tropics, with
local variations in risk influenced by rainfall, temperature and unplanned rapid
urbanization.2
Severe dengue (also known as Dengue Haemorrhagic Fever) was first
recognized in the 1950s during dengue epidemics in the Philippines and
Thailand. Today, severe dengue affects most Asian and Latin American
countries and has become a leading cause of hospitalization and death among
children and adults in these regions.2
There are 4 distinct, but closely related, serotypes of the virus that cause
dengue (DEN-1, DEN-2, DEN-3 and DEN-4). Recovery from infection by one
provides lifelong immunity against that particular serotype. However, cross-
immunity to the other serotypes after recovery is only partial and temporary.
Subsequent infections by other serotypes increase the risk of developing severe
dengue.3
Morbidity and mortality from viral infection are also influenced by
other factors such as host immunity, density of vector mosquitoes, dengue
virus virulency and local geographical conditions. Pattern outbreak of dengue
virus infection is also influenced by climate and humidity, where the hot
temperatures (28 32 degree Celcius) and high humidity is an intermediate
vector of dengue virus in order to stay alive.3
The incidence of dengue has grown dramatically around the world in
recent decades. The actual numbers of dengue cases are underreported and
many cases are misclassified. One recent estimate indicates 390 million dengue
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infections per year (95% credible interval 284528 million), of which 96

million (67136 million) manifest clinically (with any severity of
disease). Another study, of the prevalence of dengue, estimates that 3.9 billion
people, in 128 countries, are at risk of infection with dengue viruses.2

Cases across the Americas, South-East Asia and Western Pacific

exceeded 1.2 million in 2008 and over 3.2 million in 2015(based on official
data submitted by Member States). Recently the number of reported cases has
continued to increase. In 2015, 2.35 million cases of dengue were reported in
the Americas alone, of which 10 200 cases were diagnosed as severe dengue
causing 1181 deaths.5

Cases have occurred in Florida (United States of America) and Yunnan

province of China. Dengue also continues to affect several South American
countries, notably Costa Rica, Honduras and Mexico. In Asia, Singapore has
reported an increase in cases after a lapse of several years and outbreaks have
also been reported in Laos. In 2014, trends indicate increases in the number of
cases in the People's Republic of China, the Cook Islands, Fiji, Malaysia and
Vanuatu, with Dengue Type 3 (DEN 3) affecting the Pacific Island countries
after a lapse of over 10 years.2,5
The year 2015 was characterized by large dengue outbreaks worldwide,
with the Philippines reporting more than 169 000 cases and Malaysia
exceeding 111 000 suspected cases of dengue, representing a 59.5% and 16%
increase in case numbers to the previous year, respectively.2

Indonesia is a country in Southeast Asia included in dengue endemic

areas. In 2006, Indonesia had the highest incidence of DHF in Southeast Asia.4
Since first discovered in 1968 in Surabaya, DHF cases in Indonesia have been
increasing. Nowadays, all provinces in Indonesia have reported dengue cases.
Based on the reports of the Indonesian Ministry of Health in 2009, it was noted
that West Java Province was region with the highest number of dengue cases.5
Basic Health Research Survey in West Java province in 2007 showed the
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prevalence of dengue in Bandung, which is the capital of West Java province,

was above the average prevalence of all provinces.6

Medan is one of the areas considered endemic in the province of North

Sumatra. Medan City Health Department report data in the year 2013 there were
as many as 1270 cases of dengue fever dengue cases with the death of as many
as 9 cases. In 2014 the prevalence of dengue cases with 15 cases of death from
total of 1698 cases in the city of Medan. District of Medan Helvetia, Sunggal
Medan, Medan Baru, Medan Denai and Medan Selayang is one of five districts
of the most high case according to Medan City Health Office. Medan is one of
the cities with dense populations and high population mobility, and is one
endemic region that has great potential for the occurrence of dengue
haemorrhagic fever.6
Dengue hemorrhagic fever is a disease that is always exist throughout
the year in Indonesia. This disease shows an increase in the number of people
who develop every 4-5 years. The group often affected are children aged 4-10
years, although it can also be about infants under 1 year of age. Lately many of
the young adults aged 18-25 years. Men and women alike may be exposed
without exception.11
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CHAPTER II
LITERATURE REVIEW

2.1. Dengue Haemorrhagic Fever

2.1.1. Definition2
Clinical criteria that define DHF include a 2-7 day illness with high
fever headache, retro-orbital pain, myalgia, arthralgia/ bone pain, rash and
haemorrhagic manifestations eg; positive tourniquet test, or petechial, with
evidence of plasma leakage. The following criteria are necessary for the case
definition of DHF :
1. High fever or recent history of acute fever
2. Haemorrhagic manifestations.
3. Thrombocytopenia of 100,000 cell/mm
4. Objective evidence of leaky capillaries.

2.1.2. Epidemiology3
The Dengue virus ( DEN-1, DEN-2, DEN-3 and DEN-4) originated in
monkeys and independently jumped to humans in Africa or Southeast Asia
between 100 and 800 years ago. Dengue remained a relatively minor,
geographically restricted disease until the middle of the 20 th century. Dengue was
first documented only in 1950s during epidemics in the Philippines and Thailand.
Today about 2.5 Billion people, 40 % of the worlds population, lives in areas
where there is a risk of dengue transmission. Dengue is endemic in at least 100
countries in Asia, The Pacific, America and The Caribbean. According to WHO
estimation around 50 to 100 Million infection occur yearly. Including 500.000
DHF cases and 22.000 deaths among children.3

2.1.3. Etiology and Pathogenesis6, 8

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The most common etiology in DHF is the dengue virus which is

transmitted by agent which belong to the family Flaviridae and genus flavivirus,
composed of 4 serotype is Den-1, Den-2 and Den-3 Den-4 and is transmitted to
natural hosts, humans through the bite infected mosquitoes, especially mosquitoes
Aedes aegypti and Aedes albopictus. The vector of DHF also known as the Tiger
mosquito, due to the characteristic striped body appearance. It is a highly
domesticated mosquito and lays eggs and produces larvae preferentially in
artificial containers. Two peaks of biting activity are known for the mosquito 2-3
hours after the daybreak and in the evening a couple of hours before sundown. It
often feeds on several persons during a single blood meal in a short period of
time.6

After the component structure assembled, the virus is released from the
sel. These infections cause a reaction immunity protective against the virus
serotypes but there is no cross-protective again. In vitro, antibodies against the
virus Dengue has four biological function that is virus neutralization, complement
cytolysis, antibody dependent cell-mediated cytotoxity (ADCC) and ADE. Based
on role, consist of antibody neutralization or neutralizing antibodies that have the
specific serotype that can prevent infection virus and antibody non netralising
serotype having a cross reactive role.6

The immune response is known to play a role in the pathogenesis of DHF :8

a) humoral response in the form of antibodies that play a role in the process of
virus neutralization, complement-mediated cytolysis and antibody-mediated
cytotoxicity. Antibodies against dengue virus plays a role in accelerating viral
replication in monocytes or macrophages. This hypothesis is called antibody
dependent enhancement (ADE).

b) T lymphocytes both T-helper (CD4) and T cytotoxic (CD8) play role in the
cellular immune response to dengue virus. TH1 differentiation of T helper that
will produce interferon gamma, IL-2 and lymphokine, while Th2 produces IL-4,
IL-5, IL-6 and IL-10;
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c) Monocytes and macrophages play a role in phagocytosis by opsonization virus

antibodies. But the process of phagocytosis leads to increased viral replication and
secretion of cytokines by macrophages;

d) In addition, The activation of complement by immune complexes led to the

formation of C3a and C5a.

Picture 1. Pathogenesis Of DHF

2.1.4 Classification13, 14
DHF classified into 4 grops according to severity, where garde III and IV
are considered to be Dengue Shock Syndrome (DSS). The presence of
thrombocytopenia with concurrent haemoconcentration differentiates gardes I and
II DHF from Dengue Fever (DF).13
Grade I : Fever accompanied by constitutional non-specific symptoms; the
only haemorrhagic manifestation is a positive tourniquet test and/ or easy
bruising.
Grade II : Spontaneous bleeding in addition to the manifestations of Grade
I patients, usually in the forms of skin or other haemorrhages.
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Garde III : Circulatory failure manifested by a rapid, weak pulse and pulse
pressure or hypotension, with the presence of cold, clammy skin and
restlessness.
Grade IV : Profound shock with undetectable blood pressure or pulse.14
2.1.5. Pathophysiology2,5
The most important pathophysiology of DHF is the plasma leakage which
because it causes the haemorrhagic manifestation to human.
Plasma leakage is specific 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. The ensuing
movement of albumin and the resultant reduction of intravascular oncotic pressure
facilitate further loss of fuid from the intravascular compartment. The basic
Starling principle still holds true in explaining microvascular ultrafiltration 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 fuid movement by the adherence of albumin molecules in to its matrix,
damage of which, leads to loss of albumin into the extravascular compartment.2
More severe infection occurs when a person is infected for a second time
with a different serotype in2-4%of individuals. How a second dengue infection
causes a severe disease and why only some patients get severe disease remains
unclear. It is suggested that residual antibodies produced during the first infection
are unable to neutralize a second infection with another serotype, and the second
infection, under the influence of enhancing antibodies, results in severe infection
and disease. This phenomenon is referred to as antibody-dependent enhancement.
The pre-existing non neutralizing antibodies generated from previous primary
infection cross-react with viral serotypes involved in secondary infections and
bind to the virions, but do not neutralize them. Such antibody-coated virions are
taken up more rapidly than uncoated virus particles by tissues, dendritic cells,
monocytes and macrophages. This leads to a higher viral load and enhanced
antigen presentation by the infected dendritic cells to the T cells, resulting in
extensive T-cell activation and proliferation of memory T-cells. This extensive T-
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cell activation supposedly causes the T-cells to become stunned, whereby their
IFN- expression remains low. Common gross pathologic findings in dengue
infection include petechial hemorrhages and ecchymoses, serous pleural and
peritoneal effusions, and pulmonary edema. Vasculitis of small vessels in visceral
and soft tissues is found on microscopy, and so are focal midzonal hepatic
necrosis, subendocardial left ventricle hemorrhage, and gastric mucosal
hemorrhage.5

2.1.6 Clinical Manifestations4,5,9,10

Dengue virus infections may be asymptomatic or may have three main
clinical manifestations. DHF have a significantly higher viral load and a slower
rate of clearance of viral load and virus-containing immune complexes than
patients with dengue fever. DHF splits into DHF without shock and Dengue shock
syndrome (DSS).
DHF usually begins with a sudden rise in temperature and other symptoms
identical to those of dengue fever. The temperature remains high for 2 to 7 days.
Hepatomegaly and splenomegaly are occasionally seen, especially in infants.
Hemorrhagic tendency may manifest in many ways: positive tourniquet test;
petechiae, ecchymoses or purpura; mucosal bleeding; and, hematemesis or
melena. The most common hemorrhagic features are petechiae, easy bruising, and
bleeding at venipuncture sites. Epistaxis and gingival bleeding are uncommon,
and gastrointestinal bleeding may be observed in severe cases. Occasionally, the
bleeding may be occult; intracranial bleeding is rare. In DHF, bleeding may not
correlate with the platelet counts and usually occurs once the fever has settled.4,5
According to WHO, a case of DHF should meet all of the following
clinical criteria: acute onset fever, any hemorrhagic manifestation,
thrombocytopenia ( 100,000 platelets per L), and objective evidence of
increased capillary permeability and plasma leakage manifested by an increase in
hematocrit levels equal to or greater than 20%, a drop in hematocrit levels greater
than 20% following fluid therapy, signs of plasma leakage (pleural effusion,
ascites, hypoalbuminemia or hypoproteinemia).9
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Hematological changes that are consistently found in DHF include bone

marrow suppression, leukopenia and thrombocytopenia. Bleeding mechanisms are
multiple such as vasculopathy, thrombocytopathy and disseminated intravascular
coagulation (DIC). Thrombocytopathy consisting of thrombocytopenia and
platelet dysfunction is caused by bone marrow suppression immune injury, and
infection of platelets by the dengue virus. DIC and prolonged bleeding are more
common in patients with shock, and cause death. Some patients with dengue
infection have varying degrees of mucosal and cutaneous bleeding with some
degree of thrombocytopenia. These patients may not demonstrate other criteria for
diagnosis of DHF/DSS, i.e., hemoconcentration or objective evidence of fluid
leak, e.g. ascites, pleural effusion. These patients are classified as having dengue
fever with unusual bleeding. Patients falling into this category may be seen in
significant numbers in epidemics. Since hypovolemia and hypotension do not
occur in this group of children, fluid requirement is lesser than in DHF. It is
therefore important to distinguish these children from those with classical DHF.
Convalescence in DHF is usually short and uneventful. The return of appetite is a
good indicator of recovery from shock. Bradycardia is also seen in this period. If
present, a confluent petechial rash with erythema and islands of pallor (usually
known as a recovery rash) are characteristic of dengue infections. During the
convalescent stage, many patients also complain of severe itching, especially on
the palms and soles.10
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Picture 2. Shows the progress of DHF

Most importanty in the case of DHF, evaluation of warning signs should to

be done to avoid patient fall in dengue shock syndrome. The Warning Signs are as
follow :
Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation
Mucosal bleed
Lethargy
Liver enlargement >2cm
Laboratory Findings : Increase in HCT concurrent with rapid decrease in platelet
count.10

2.1.7 Diagnostic Procedures1,9,10

a. History Findings
date of onset of fever/illness
quantity of oral fluid intake
diarrhoea; urine output (frequency, volume
and time of last voiding)
assessment of warning signs
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change in mental state/seizure/dizziness;

other important relevant history, such as
family or neighbourhood dengue, travel to
dengue-endemic areas
b. Physical Examintaion
assessment of mental state;
assessment of hydration status
assessment of haemodynamic status
checking for quiet tachypnoea/acidotic
breathing/pleural effusion;
checking for abdominal
tenderness/hepatomegaly/ascites;
examination for rash and bleeding
manifestations
Cappilary refill time (>2 seconds)
tourniquet test
c. Immunoserology
A diagnosis of dengue infection is confirmed by the detection of
the virus, the viral genome or NS1 Ag, or seroconversion of IgM or
IgG (from negative to positive IgM/IgG or four-fold increase in the
specific antibody titre) in paired sera (see Table 1).1

Table 1. shows the Immunoserology Tests

A positive IgM serology or a haemagglutinin inhibition test (HIA)

antibody titre of 1280 or higher (or comparable figures by ELISA
in a single specimen), are all diagnostic criteria of a probable
dengue infection.
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2.1.8 Differential Diagnosis7

During the febrile phase of the illness, there is usually an absence of
physical localizing signs and the differential diagnoses associated with DF are
diverse, including viral bacterial and protozoal infections.
Leptosirosis
Malaria
Chikungunya
Infectious Hepatitis
These diseases are eliminated from being working diagnose in the reason of the
presence of hemoconcentration along with thrombocytopenia,

2.1.9 Management9,10,11
According to some dengue care source patients are classified into three groups :
A. Patients that may be sent to home
Able to tolerate adequate volumes of oral fluids, pass urine at least
once every six hours and do not have any of the warning signs
Oral fluid intake to replace fluid loss from fever and vomiting.
Small amounts of oral fluids should be given frequently for those
with nausea and anorexia.
Give paracetamol for high fever if the patient is uncomfortable.
The recommended dose is 10 mg/kg/dose, not more than 34 times
in 24 hours in children and not more than 3 g/day in adults).
Sponge with tepid water if the patient still has a high fever. Do not
give acetylsalicylic acid (aspirin), ibuprofen or other non-steroidal
antiinflammatory agents (NSAIDs) or intramuscular injections, as
these aggravate gastritis or bleeding.
Instruct caregivers that the patient should be brought to hospital
immediately if any of the following occur: no clinical
improvement, deterioration around the time of defervescence,
severe abdominal pain, persistent vomiting, cold and clammy
extremities, lethargy or irritability/restlessness, bleeding
B. Referred for in hospital care
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patients who should be admitted for in-hospital management for

close observation as they approach the critical phase and include
those patients with warning signs, with co-existing conditions such
as pregnancy, infancy or its management more complicated.
If the patient has dengue with warning signs or signs of
dehydration, judicious volume replacement by intravenous fluid
therapy : Give only isotonic solutions such as 0.9% saline, Ringer's
lactate or Hartmann's solution. Start with 57 ml/kg/hour for 12
hours, then reduce to 35 ml/kg/hour for 24 hours, and then
reduce to 23 ml/kg/hour or less according to the clinical response.
Assessment on the clinical status and repeat the haematocrit : If the
haematocrit remains the same or rises only minimally, continue at
the same rate (23 ml/kg/hour) for another 24 hours. If the vital
signs are worsening and the haematocrit is rising rapidly, increase
the rate to 510 ml/kg/hour for 12 hours.
minimum intravenous fluid volume required to maintain good
perfusion and an urine output of about 0.5 ml/kg/hour. Intravenous
fluids are usually needed for only 2448 hours. Reduce
intravenous fluids gradually when the rate of plasma leakage
decreases towards the end of the critical phase. This is indicated by
urine output and/or oral fluid intake improving, or the haematocrit
decreasing below the baseline value in a stable patient.
Warning signs should be monitored closely to reduce the risk
especially during the critical phase. A detailed fluid balance should
be maintained. Parameters that should be monitored include vital
signs and peripheral perfusion (14 hourly until the patient is out
of the critical phase), urine output (46 hourly), haematocrit
(before and after fluid replacement, then 612 hourly), blood
glucose and other organ functions (such as renal profile, liver
profile, coagulation profile, as indicated).
C. Require emergency treatment
These are patients with severe dengue who require emergency
treatment and urgent referral because they are in the critical phase
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of the disease and have severe plasma leakage leading to dengue

shock and/or fluid accumulation with respiratory distress; severe
haemorrhages, severe organ impairment (hepatic damage, renal
impairment, cardiomyopathy, encephalopathy or encephalitis).
All patients with severe dengue should be admitted to a hospital
with access to blood transfusion facilities.
Judicious intravenous fluid resuscitation is the essential and usually
sole intervention required. The crystalloid solution should be
isotonic and the volume just sufficient to maintain an effective
circulation during the period of plasma leakage. Plasma losses
should be replaced immediately and rapidly with isotonic
crystalloid solution: in the case of hypotensive shock.
Assessments on the haematocrit levels before and after fluid
resuscitation.
The goals of fluid resuscitation include:
improving central and peripheral circulation i.e. decreasing tachycardia,
improving BP and pulse volume, warm and pink extremities, a capillary refill time
< 2 seconds.
improving end-organ perfusion i.e. achieving a stable conscious level (more
alert or less restless), and urine output 0.5 ml/kg/hour or decreasing metabolic
acidosis.
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Picture 3. shows the chart of Intravenous fluid infusion in DHF.

Calculation of fluid quota for the critical period13

Fluid quota is only a guide for management of dengue patients during the critical
period of DHF.
Patients managed using fluid within this safe quota are less likely to
develop fluid overload.
When fluid requirement is calculated (both oral and IV), calculate it
for the Ideal Body Weight (IBW).
The total amount of fluid recommended during the Entire critical phase
(irrespective of its length)
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should be = M + 5% = Maintenance + 5% of body weight

Golden triad of Inward management of Critical phase of DHF13, 14

Early detection and prediction of the end of plasma leakage. Meticulous

monitoring, accurate and fine titration of fluids depending on the rate of leak
(Rate of infusion should match rate of leak)
Vigilance, early detection and treatment of concealed bleeding
and other complications
Calculation of total fluid quota for the critical period
M (Maintenance) = 100ml/kg for first 10 kg
+50 ml/kg for next 10 kg
+20 ml/kg for balance weight

5% of body weight = 50ml x body weight (kg)

2.1.10 Prognostic3
Prognosis dengue fever can vary, affected by the presence of antibodies
obtained passively or previous infection. In the case DHF, the death has occurred
in 40-50% of patients with shock, but with intensive treatment adequate death can
be reduced <1% of cases. Early and intensive management can lead to safety of
the patient. In rare cases, there are brain damage caused by prolonged shock or
intracranial hemorrhage.

2.2 Expanded Dengue Syndrome

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Expanded dengue is a terminology developed in the WHO guidelines of

year 2012.1 Unusual manifestations of patients with severe organ involvement
such as liver, kidneys, brain or heart associated with dengue infection have been
increasingly reported in dengue hemorrhagic fever (DHF) and also in dengue
patients who do not have evidence of plasma leakage. The unsusal manifestations
be associated with co-infections, co-morbidities or complications of prolonged
shock and can be clubbed under the expanded dengue syndrome. The unusual
manifestations may be underreported or unrecognized or not related to dengue.4

Picture 4. Shows The Algorithm of unsusal manifestations of Expanded

Dengue Syndrome.