Dengue

ESSENTIALS OF DIAGNOSIS

• Incubation period 7–10 days.

• Sudden onset of high fever, chills, severe myalgias and arthralgias, headache, and retroorbital
pain.
• Severe dengue is defined by the presence of plasma leakage, hemorrhage, or organ
involvement.
• Signs of hemorrhage such as ecchymoses, gastrointestinal bleeding, and epistaxis appear later in
the disease.

General Considerations
Dengue virus belongs to the genus Flavivirus. It has four distinct serotypes that can cause infection.
Infection with one serotype does not confer immunity to the other serotypes. Dengue is transmitted
primarily from human to human by the bite of the Aedes (mostly A. aegypti but also A. albopictus)
mosquito. Healthcare-associated transmission (needlestick or mucocutaneous exposure) and vertical
transmission occur rarely. WHO reports that dengue is currently endemic in more than 100 countries,
mostly in tropical and subtropical regions. Up to 100 million cases of dengue fever occur annually (with
500,000 severe) and the surge of cases is associated with climatic factors, travel, and urbanization. Thus,
along with malaria, dengue is one of the two most common vector-borne diseases of humans.

There are several factors that contribute to intermittent outbreaks in these regions, including the season
of the year when rainfall is optimal for mosquito breeding, large population with no previous immunity to
the specific serotype, and frequent contact between the people and the vector.

Pathogenesis

Dengue virus (DENV) is an enveloped positive-strand RNA flavivirus. Its genome encodes three structural
proteins and seven nonstructural proteins. There are four serotypes (DENV-1, DENV-2, DENV-3, and
DENV-4).

The incubation period is usually 7–10 days. When the virus is introduced into susceptible populations,
usually by viremic travelers, epidemic attack rates may range from 50% to 70%.

Infection by one serotype (primary dengue infection) causes homotypic long-term immunity with
development of neutralizing antibodies, but only transiently protective cross-immunity to the three other
serotypes. Over time, falling cross-reactive antibodies are unable to prevent infection by heterotypic
serotypes. When subsequent heterotypic infection occurs (secondary dengue infection), there is a greater
risk of severe illness. Secondary dengue infection is associated with antibody-dependent enhancement
(ADE): The binding of non-neutralizing heterotypic antibody to DENV creates virus-antibody complexes
that activate the complement and bind to Fc-receptor-bearing monocytes and macrophages, resulting in
increased phagocytosis and intracellular replication with prolonged viremia. This induces imbalanced pro-
and anti-inflammatory responses.
The action of the non-structural protein 1 (NS1) on the vascular endothelium, triggering the release of
vasoactive cytokines from immune cells, both of which result in endothelial hyperpermeability and
vascular leak, has also been implicated. The pathogenesis of severe dengue also involves cross-reactive
activated memory T lymphocytes, proinflammatory cytokines (IFN-γ, TNF-α, and IL-10) that mediate
increased endothelial permeability and the interval between primary and secondary dengue infections.

Several host factors (young age, female sex, non-African ancestry, and specific HLA alleles) predict severe
dengue. Viral factors are relevant: The serotypes DENV-2 and DENV-3 are most often found in severe
dengue. Virulent DENV genotypes cause epidemics of DHF and severe primary dengue.

Clinical Findings
A. Symptoms and Signs
Most infected patients are asymptomatic, only 20% develops symptoms ranging from mild disease
(dengue fever) to severe hemorrhagic fever to fatal shock (dengue shock syndrome). The 1997 WHO
classified symptomatic dengue into dengue fever, dengue hemorrhagic fever, and dengue shock
syndrome. A recent (2009) WHO classification defines dengue without danger signs, dengue with danger
signs, and severe dengue.

After the incubation period, febrile phase begins abruptly with nonspecific symptoms, high fever
(40C/104F), chills, severe headache, facial flushing, malaise, retroorbital eye pain, generalized body pain,
and arthralgia. Some patients might have maculopapular rash, sore throat, and conjunctival injection. Not
all patients have all symptoms or fever. Mild hemorrhagic manifestations can be seen. Most of the
patients will recover and fever is usually cleared by day 8.

A subset of patients may progress to severe dengue, which is defined by the presence of plasma leakage,
hemorrhage, or organ involvement. Hematocrit rise could be the earliest sign and an indicator of the
severity of plasma leakage. Pleural effusion and ascites develop and are detected first by lateral decubitus
chest radiograph and ultrasound before clinical detection. Increasing liver size, persistent vomiting and
severe abdominal pain are indications of plasma leakage. Signs of hemorrhage such as ecchymoses,
gastrointestinal bleeding, and epistaxis appear. Severe organ involvement may develop such as severe
hepatitis, encephalitis, and myocarditis.

Shock develops in patients when a critical volume of plasma is lost through leakage. Decrease in the level
of consciousness, hypothermia, hypoperfusion resulting in metabolic acidosis, progressive organ
impairment, and disseminated intravascular coagulation leading to severe hemorrhage should raise
concern about shock. Acute kidney injury in dengue largely occurs with shock syndrome and shows a high
mortality.

After the critical phase, the patient enters the recovery phase, where extravascular compartment fluid is
reabsorbed and the bleeding stops. Vital signs and laboratory abnormalities normalize.
Warning Signs and Severe Dengue

Warning Signs Severe Dengue

Abdominal pain or tenderness Severe plasma leakage: shock or fluid accumulation with
respiratory distress
Persistent vomiting Severe bleeding
Clinical fluid accumulation Severe organ impairment: liver, CNS, heart
Mucosal bleeding
Lethargy or restlessness
Liver enlargement >2cm
Increased hematocrit concurrent
with a rapid decrease in platelets

B. Laboratory Findings
Leukopenia is characteristic, and elevated transaminases are found frequently in dengue fever.
Thrombocytopenia, fibrinolysis, and hemoconcentration occur more often in the hemorrhagic form of the
disease. The erythrocyte sedimentation rate is often normal in most cases.

The choice of diagnostic tests to use should be governed by the time from illness onset: virus PCR or
antigen detection is more useful in the first week after illness onset, while antibody assays are more
informative after the first week of illness. IgM antibodies can be detected as early as 5–7 days after onset
of fever and persist for 3–5 months.

Differential Diagnosis
Distinguishing between dengue and other causes of febrile illness in endemic areas is difficult. Fevers due
to dengue are more often associated with neutropenia and thrombocytopenia and with myalgias,
arthralgias/arthritis, and lethargy among adults. Chikungunya is more apt to develop a chronic arthritis.
The arboviral encephalitides require additional epidemiologic information and serologic data to make the
diagnosis. Influenza and malaria are easily confused early in disease although the rhinitis and malaise
should help distinguish influenza, and the cyclicity of fevers and presence of splenomegaly should suggest
malaria.

Complications
Usual complications include pneumonia, bone marrow failure, hepatitis, iritis, retinal hemorrhages and
maculopathy, orchitis, and oophoritis. Neurologic complications (such as encephalitis, Guillain-Barré
syndrome, phrenic neuropathy, subdural hematoma, and transverse myelitis) are less common. Bacterial
superinfection can occur.

Maternal infection poses a risk for premature birth and hemorrhage in both the mother and the infant if
infection occurs near term.

Treatment
There are no specific therapeutic options for the clinical management of dengue besides supportive care.
Treatment entails the appropriate use of volume support, blood products, and vasopressors.
Acetaminophen is recommended for analgesic and antipyretic treatment. NSAID usage should be
minimized and preferably avoided to decrease the risk of gastritis and bleeding, particularly in patients
with a predilection for hemorrhage or when there are abnormalities in platelet, liver function, or clotting
factors.

Platelet counts do not usefully predict clinically significant bleeding. Platelet transfusions may be
considered for severe thrombocytopenia (less than 10,000/mcL) or when there is evidence of bleeding.
However, benefit in the absence of bleeding may not be observed, and harm may be caused by delay in
count recovery. Monitoring vital signs and blood volume may help in anticipating the complications of
dengue hemorrhagic fever or shock syndrome.

New research is focusing on monoclonal antibodies as therapeutic option as well as drugs that target
structural and nonstructural proteins of dengue virus essential to its replication.

Prognosis
Fatalities are rare but do occur, especially during epidemic outbreaks with hemorrhagic fever (seen with
recurrent disease), and with occasional patients dying of fulminant hepatitis. Thrombocytopenia and
acute hepatitis are predictors of severe dengue and higher mortality. Acute kidney injury in dengue shock
syndrome portends poor prognosis.

Prevention
Preventive measures should be encouraged, such as vector control, prevention from mosquito bites by
screening and insect repellents including long-lasting insecticides, particularly during early morning and
late afternoon exposures. Screening blood transfusions for dengue is of increasing importance, especially
in endemic areas.

Dengue vaccines:
 a. Dengvaxia, a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), is the first
vaccine to be approved and is now licensed for use. Trials evaluating the efficacy of this vaccine
reported overall 80% efficacy which lasts for several years (data still coming on the duration of
protection). It can be given to individuals aged 9-60 years living in dengue-endemic countries who
have a lab confirmed previous dengue infection (seropositive). This vaccine when given to
seronegative individuals, increases the risk of hospitalization and severe illness if they get dengue
after vaccination. Schedule: 3 doses, 6 months apart (at 0, 6 & 12 months). Because of the
requirement of pre-vaccination screening, this vaccine is currently not being widely used.
b. Qednga (TAK-003), live, attenuated, tetravalent dengue vaccine. Given to children 6-16 years
living in high dengue transmission settings. Persons with comorbidities (e.g. sickle cell disease,
diabetes, hypertension, renal, and cardiovascular diseases) with documented severe dengue
outcomes in that subpopulation in a country may be offered vaccination (age range 6-60 years).
Schedule: 2 doses 3 months apart (at 0 & 3 months). High dengue transmission areas: A
seroprevalence rate of more than 60% by the age of 9 years or a mean age of peak dengue-
associated hospitalizations below the age of 16 years could be considered as indicators of high
dengue transmission.
c. Another vaccine is under late stages of clinical development in USA.

Vector control:

1. Targeted residual spraying of resting sites of Aedes spp. mosquitoes primarily inside and, to a
lesser extent, around houses as the primary vector control intervention for immediate response.
2. Space spraying is effective inside buildings where Aedes spp. mosquitoes rest and bite. It has no
residual effect. Its application outdoors only suppresses vector populations temporarily and is not
as effective as indoor space spraying.
3. Larval control including source reduction and larvicide should be applied where appropriate
through community mobilization.
4. Personal protection measures should be used to protect against day biting mosquitoes. These
include the use of appropriate repellents and wearing of light-coloured loose-fitting clothing.

There are a number of challenges in implementing existing vector control interventions. These include:
unplanned urbanization; inadequate programme implementation; lack of human, financial and
infrastructural capacity; and political will. The strength and rigour of implementation of vector control
must be improved to reduce infected vector populations and transmission of Aedes-borne diseases. All of
these interventions should be well targeted, guided by local conditions, and entomological and
epidemiological data, including insecticide susceptibility. WHO-recommended insecticides, to which
mosquitoes are susceptible, should be used for vector control.

Biocontrol studies have shown that Ae. aegypti mosquitoes infected with the wMel strain of the
endosymbiotic bacterium Wolbachia pipientis are less susceptible than wild-type Ae. aegypti to dengue
virus infection. A trial in Indonesia demonstrated an efficacy of 77% (95% CI: 65–85) in preventing cases.
The efficacy was similar across all 4 serotypes and lower dengue hospitalization rates were observed.
Another effectiveness study conducted in Brazil demonstrated a 69% reduction in dengue incidence (95%
CI: 54–79); a 56% reduction in chikungunya incidence (95% CI: 16–77); and a 37% reduction in Zika
incidence (95% CI: 1–60), in the aggregate release area, compared with the pre-defined control area.