DENGUE HEMORRHAGIC FEVER

INTRODUCTION

Dengue is a mosquito-borne infection that in recent decades has become a major

international public health concern. Dengue is found in tropical and sub-tropical regions
around the world, predominantly in urban and semi-urban areas.

Dengue hemorrhagic fever (DHF), a potentially lethal complication, was first recognized
in the 1950s during dengue epidemics in the Philippines and Thailand. Today DHF
affects most Asian countries and has become a leading cause of hospitalization and death
among children in the region.

Is an acute viral infection caused by a bite of an infected mosquito;

Common during rainy season and commonly affects young population;
Causative Agents: Dengue virus 1, 2, 3, 4
Incubation Period: 3 - 7 days;

Transmission

Dengue viruses are transmitted to humans through the bites of

infective female Aedes Aegypti mosquitoes.

-low-flying (3 ft)
-day-biting( 2 hours after the WHO/TDR/Stammers
sunrise and 2 hours before the
sunset)
-usually found in urban areas;
-with white stripes on legs;
-resides on stagnant water

Mosquitoes generally acquire the virus while feeding on the blood of an infected person.
After virus incubation for eight to 10 days, an infected mosquito is capable, during
probing and blood feeding, of transmitting the virus for the rest of its life. Infected female
mosquitoes may also transmit the virus to their offspring by transovarial (via the eggs)
transmission, but the role of this in sustaining transmission of the virus to humans has not
yet been defined.

Infected humans are the main carriers and multipliers of the virus, serving as a source of
the virus for uninfected mosquitoes. The virus circulates in the blood of infected humans
for two to seven days, at approximately the same time that they have a fever; Aedes
mosquitoes may acquire the virus when they feed on an individual during this period.
Clinical Manifestations:
– Grade I
Fever, 3-7 days duration, low-to-moderate grade;
Anorexia
Abdominal pain
Bone and joint pains (“breakbone fever”)
Pain behind the eyes
Vomiting
Petechiae
***Herman’s rash – generalized flushing of the skin with center isle in the
skin
(+) Tourniquet test – to determine vascular resistance and platelet
function.
– > 20 petecchiae per in2 (ANTECUBITAL FOSSA)

– Grade II

grade I + any sign of spontaneous bleeding;

epistaxis

gum bleeding

melena

hematochezia

vomiting of coffee-ground material

– Grade III

grade II + any sign of circulatory collapse or impending shock;

hypotension

tachycardia

tachypnea

weak and rapid peripheral pulses

cold, clammy skin

restlessness or change in LOC

– Grade IV (or Dengue Shock Syndrome)

signs of hypovolemic shock;

 absence of BP and peripheral pulses

tachycardia/ bradycardia

altered LOC or coma

PATHOPHYSIOLOGY

Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes:

dengue virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue
virus 4 (DENV-4). Genetic studies of sylvatic strains suggest that the 4 viruses evolved from a
common ancestor in primate populations approximately 1000 years ago and that all 4 viruses
separately emerged into a human urban transmission cycle 500 years ago in either Asia or Africa.
Albert Sabin speciated these viruses in 1944. Each serotype is known to have several different
genotypes.

Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period
of partial heterotypic immunity, but each individual can eventually be infected by all 4 serotypes.
Several serotypes can be in circulation during an epidemic.

Dengue viruses are transmitted by the bite of an infected Aedes (subgenus Stegomyia) mosquito.
Globally, A aegypti is the predominant highly efficient mosquito vector for dengue infection, but
A albopictus and other Aedes species can also transmit dengue with varying degrees of
efficiency.

Aedes mosquito species have adapted well to human habitation, often breeding around dwellings
in small amounts of stagnant water found in old tires or other small containers discarded by
humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are
easily disturbed during a blood meal, causing them to move on to finish a meal on another
individual, making them efficient vectors. Entire families who develop infection within a 24- to
36-hour period, presumably from the bites of a single infected vector, are not unusual.

Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in
Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes
acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it
immediately bites another host. In addition, transmission occurs after 8-12 days of viral
replication in the mosquito's salivary glands (extrinsic incubation period). The mosquito remains
infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in
mosquitoes has been documented.9 The eggs of Aedes mosquitoes withstand long periods of
desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C.

Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d)
while viral replication takes place in target dendritic cells. Infection of target cells, primarily
those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells,
result in the production of immune mediators that serve to shape the quantity, type, and duration
of cellular and humoral immune response to both the initial and subsequent virus infections.
Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by
7-10 days.

Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to
seventh day of illness, approximately at the time of defervescence. The major pathophysiological
abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include the rapid
onset of plasma leakage, altered hemostasis, and damage to the liver, resulting in severe fluid
losses and bleeding. Plasma leakage is caused by increased capillary permeability and may
manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by
capillary fragility and thrombocytopenia and may manifest in various forms, ranging from
petechial skin hemorrhages to life-threatening gastrointestinal bleeding. Liver damage manifests
as increases in levels of alanine aminotransferase and aspartate aminotransferase, low albumin
levels, and deranged coagulationparameters(PT,PTT).

In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of
hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–
alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola
infections.

Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior
infection with one or more dengue serotypes. In individuals with low levels of neutralizing
antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and
monocyte Fc receptors, have been proposed to result in increased viral entry and replication and
increased cytokine production and complement activation. This phenomenon is called antibody-
dependent enhancement.

Some researchers suggest T-cell immunopathology may play a role, with increased T-cell
activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days
following fever onset during symptomatic secondary dengue infections. The activation of
cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has
been correlated with disease severity. Cuban studies have shown that stored serum sample
analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as
the interval since DENV-1 infection increased. In addition, certain dengue strains, particularly
those of DENV-2, have been proposed to be more virulent, in part because more epidemics of
dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.

 DIAGNOSTIC EXAMINATION
 Hemoconcentration – more than 20% increase from the baseline Hct;
 Thrombocytopenia – less than 100,000/mm3;
 Chest X-ray – presence of pleural and pericardial effusion;
 Bleeding parameters (BT, CT, PT, or aPTT)
Laboratory Studies

 Complete blood cell count findings include the following:

o Leukopenia, often with lymphopenia, is observed near the end of the febrile phase
of illness. Lymphocytosis, with atypical lymphocytes, commonly develops before
defervescence or shock. A recent systematic review found that patients with
dengue had significantly lower total WBC, neutrophil, and platelet counts than
patients with other febrile illnesses in dengue-endemic populations.
o
o A hematocrit level rise of greater than 20% is a sign of hemoconcentration and
precedes shock. The hematocrit level should be monitored at least every 24 hours
to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in
severe cases of dengue hemorrhagic fever or dengue shock syndrome.
o
o Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases.
Platelet counts of less than 100,000 cells/μL are seen in dengue hemorrhagic fever
or dengue shock syndrome and occur before defervescence and the onset of
shock. The platelet count should be monitored at least every 24 hours to facilitate
early recognition of dengue hemorrhagic fever.
 Basic metabolic panel findings include the following:
o Hyponatremia is the most common electrolyte abnormality in patients with
dengue hemorrhagic fever or dengue shock syndrome.
o Metabolic acidosis is observed in those with shock and must be corrected rapidly.
o Elevated BUN levels are observed in those with shock. Acute kidney injury is
uncommon.
 Liver injury panel findings include the following:
o Transaminase levels may be mildly elevated into the several thousands in patients
with dengue hemorrhagic fever who have acute hepatitis.
o Low albumin levels are a sign of hemoconcentration.
 Coagulation studies may help to guide therapy in patients with severe hemorrhagic
manifestations. Findings are as follows:
o Prothrombin time is prolonged.
o Activated partial thromboplastin time is prolonged.
o Low fibrinogen and elevated fibrin degradation product levels are signs of
disseminated intravascular coagulation.
 Typing and crossmatching of blood should be performed in cases of severe dengue
hemorrhagic fever or dengue shock syndrome because blood products may be required.
 Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral
isolation. Because the signs and symptoms of dengue fever are nonspecific, attempting
laboratory confirmation of dengue infection is important.
o Serodiagnosis is made based on a rise in antibody titer in paired IgG or IgM
specimens. Results vary depending on whether the infection is primary or
secondary.
o The IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) has
become the most widely used assay, although other tests, including complement
 fixation (CF), neutralization test (NT), hemagglutination inhibition (HI), and IgG
ELISA are also used.
o A recent European study found that, if only a single serum sample is available, a
single positive result on ELISA (PanBio IgM or IgG) was found to have a high
rate of false positivity and should be confirmed using a second more specific
diagnostic technique.
o In order to provide a more rapid reliable diagnosis, clinically available PCR
studies are being developed.
 Cultures of blood, urine, CSF, and other body fluids should be performed as necessary to
exclude or confirm other potential causes of the patient's condition.

Imaging Studies

 Chest radiography: Right-sided pleural effusion is typical. Bilateral pleural effusions are common
in patients with dengue shock syndrome.
 Serial ultrasonography
o Ultrasonography is a potentially timely, cost-effective, and easily used modality
in the evaluation of potential dengue hemorrhagic fever. Positive and reliable
ultrasonographic findings include fluid in the chest and abdominal cavities,
pericardial effusion, and a thickened gallbladder wall. Thickening of the
gallbladder wall may presage clinically significant vascular permeability. The
utility of previous studies was limited because of the use of single studies for
evaluation. However, a recent study involving 158 patients examined the role of
daily serial ultrasonographic examinations of the thorax and abdomen in the
evaluation of patients with suspected dengue hemorrhagic fever.. Plasma leakage
was detected in some patients within 3 days of fever onset. Pleural effusion was
the most common sign. Based on ultrasonographic findings, dengue hemorrhagic
fever was predicted in 12 patients before hemoconcentration criteria had been met

MEDICAL MANAGEMENT

Dengue fever is usually a self-limited illness, and only supportive care is required.
Acetaminophen may be used to treat patients with symptomatic fever. Aspirin,
nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids should be avoided.

Patients with known or suspected dengue fever should have their platelet count and
hematocrit measured daily from the third day of illness until 1-2 days after
defervescence.

Patients with a rising hematocrit level or falling platelet count should have intravascular
volume deficits replaced.

Patients who improve can continue to be monitored in an outpatient setting. Patients who
do not improve should be admitted to the hospital for continued hydration.

Patients who develop signs of dengue hemorrhagic fever warrant closer observation.
Patients who develop signs of dehydration, such as tachycardia, prolonged capillary refill
time, cool or mottled skin, diminished pulse amplitude, altered mental status, decreased
urine output, rise in hematocrit levels, narrowed pulse pressure, or hypotension, require
admission for intravenous fluid administration.

Successful management of severe dengue requires careful attention to fluid management

and proactive treatment of hemorrhage.

Intravascular volume deficits should be corrected with isotonic fluids such as Ringers
lactate solution. Boluses of 10-20 mL/kg should be given over 20 minutes and may be
repeated. If this fails to correct the deficit, the hematocrit value should be determined,
and, if it is rising, limited clinical information suggests that a plasma expander may be
administered. Starch, dextran 40, or albumin 5% at a dose of 10-20 mL/kg may be used.

One recent study has suggested that starch may be preferable because of hypersensitivity
reactions to dextran. If the patient does not improve after this, blood loss should be
considered. Patients with internal or gastrointestinal bleeding may require transfusion.
Patients with coagulopathy may require fresh frozen plasma.

After patients with dehydration are stabilized, they usually require intravenous fluids for
no more than 24-48 hours. Intravenous fluids should be stopped when the hematocrit
level falls below 40% and adequate intravascular volume is present. At this time, patients
reabsorb extravasated fluid and are at risk for volume overload if intravenous fluids are
continued. Do not interpret a falling hematocrit value in a clinically improving patient as
a sign of internal bleeding.

Platelet and fresh frozen plasma transfusions may be required to control severe bleeding.
A recent case report demonstrated good improvement following intravenous anti-D
globulin administration in two patients. The authors proposed that, similarly to
nondengue forms of immune thrombocytopenic purpura, intravenous anti-D produces Fcγ
receptor blockade to raise platelet counts.

Patients who are resuscitated from shock rapidly recover. Patients with dengue
hemorrhagic fever or dengue shock syndrome may be discharged from the hospital when
they meet the following criteria:

o Afebrile for 24 hours without antipyretics

o Good appetite, clinically improved condition
o Adequate urine output
o Stable hematocrit level
o At least 48 hours since recovery from shock
o Absence of respiratory distress
o Platelet count greater than 50,000 cells/Μl

-Supportive and symptomatic management.”

-IVF
 -Anti-ulcer drugs
-Antacids - AlMgOH
-H2-antagonists – Cimetidine, Ranitidine, Nizatidine, Famotidine
-Proton pump inhibitors – Omeprazole, Lansoprazole
-Mucosal protectors – Sucralfate
-Paracetamol
-Plasma expanders – Dextran

NURSING MANAGEMENT

 Provide a comfortable, dim, and quiet room for rest;

 Watch out for bleeding manifestations;
 Full diet / DAT EXCEPT DARK-COLORED FOODS;
 “Avoid ASPIRIN”;
 Correction of fluid and electrolyte imbalance;
 Advise screening and environmental sanitation;
 Clean all stagnant water and water containers and make sure to cover these;

Prevention and control

At present, the only method of controlling or preventing dengue virus transmission is to
combat the vector mosquitoes.
In Asia and the Americas, Aedes aegypti breeds primarily in man-made containers like
earthenware jars, metal drums and concrete cisterns used for domestic water storage, as
well as discarded plastic food containers, used automobile tyres and other items that
collect rainwater. In Africa the mosquito also breeds extensively in natural habitats such
as tree holes, and leaves that gather to form "cups" and catch water.
In recent years, Aedes albopictus, a secondary dengue vector in Asia, has become established in
the United States, several Latin American and Caribbean countries, parts of Europe and Africa.
The rapid geographic spread of this species is largely attributed
to the international trade in used tyres, a breeding habitat.

Vector control is implemented using environmental management and chemical methods.

Proper solid waste disposal and improved water storage practices, including covering
containers to prevent access by egg-laying female mosquitoes are among methods that
are encouraged through community-based programmes.

The application of appropriate insecticides to larval habitats, particularly those that are
useful in households, e.g. water storage vessels, prevents mosquito breeding for several
weeks but must be re-applied periodically. Small, mosquito-eating fish and copepods
(tiny crustaceans) have also been used with some success.

During outbreaks, emergency vector control measures can also include broad application
of insecticides as space sprays using portable or truck-mounted machines or even aircraft.
However, the mosquito-killing effect is transient, variable in its effectiveness because the
aerosol droplets may not penetrate indoors to microhabitats where adult mosquitoes are
sequestered, and the procedure is costly and operationally difficult. Regular monitoring
of the vectors' susceptibility to widely used insecticides is necessary to ensure the
appropriate choice of chemicals.