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Current Medical Diagnosis and Treatment 2020

32-04: Viral Hemorrhagic Fevers

eFigure 32–3.

3. 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 and 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 mosquito. Healthcare-associated transmission (needlestick
or mucocutaneous exposure) and vertical transmission occur rarely. WHO reports that dengue is currently
endemic in 128 countries, mostly in tropical and subtropical regions with 3.9 billion persons at risk for
infection. An estimated 390 million cases of dengue fever occur annually (with 96 million manifesting clinical
disease including at least 500,000 with severe disease and up to 20,000 deaths). 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. Dengue is also the second overall cause of a febrile illness
(a er malaria and excluding common upper respiratory viral infections) in travelers returning from
developing countries.

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, presence of a large population with no previous
immunity to the specific serotype, and frequent contact between people and the vector.

In the United States, even though dengue is endemic in Northern Mexico and the Aedes mosquito is common
in the southern states, outbreaks are uncommon. Most cases occur in travelers, immigrants, or inhabitants of
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US territories that are endemic to the dengue virus. Puerto Rico experiences periodic large outbreaks. In 2015
and 2016, an outbreak of locally acquired cases of dengue fever was reported from Hawaii where 264 dengue
patients were identified with 46 (17.4%) of the cases among children; all cases were serotype 1.

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

Clinical Findings

A. Symptoms and Signs

A history of travel to a dengue-endemic area within 14 days of symptom onset is helpful in establishing a
diagnosis. Most infected patients are asymptomatic. Only 20% develop symptoms ranging from mild disease
(dengue fever) to severe hemorrhagic fever to fatal shock (dengue shock syndrome). In 1997 the WHO
classified symptomatic dengue into dengue fever, dengue hemorrhagic fever, and dengue shock syndrome.
In 2009, the WHO classified dengue as the following: dengue without warning signs; dengue with warning
signs; and severe dengue. This classification was criticized for lacking clarity and mixing distinct disease
phenotypes within each category and was not adopted by all countries.

A er the incubation period, the febrile phase begins abruptly with nonspecific symptoms, high fever, chills,
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, especially those with suboptimally controlled type 2 diabetes, may progress to severe
dengue, which is defined by the presence of plasma leakage, hemorrhage, or organ involvement. Hematocrit
drop may be the earliest sign and an indicator of the severity of plasma leakage. Pleural e usion and ascites
can develop and may be detected by lateral decubitus chest radiograph or 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 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 for shock.
Acute kidney injury in dengue largely occurs with shock syndrome and shows a high mortality.

A er 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.

B. Laboratory Findings

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Leukopenia is characteristic, and elevated transaminases are found frequently in dengue fever.
Thrombocytopenia, fibrinolysis, and hemoconcentration occur more o en in the hemorrhagic form of the
disease. In other forms of disease, especially in children, anemia is more common. The erythrocyte
sedimentation rate (ESR) is o en normal in most cases.

The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG
ELISAs a er the febrile phase. Virus is recovered from the blood by PCR or detection of the specific viral
protein NS1 by ELISA during the first few days of infection. Immunohistochemistry for antigen detection in
tissue samples and dried blood spots can also be used. Thrombocytopenia in remote settings can be
assessed with a tourniquet cu test.

Di erential Diagnosis

Distinguishing between dengue and other causes of febrile illness in endemic areas is di icult. Fevers due to
dengue are more o en 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, cerebral vasculitis, and transverse myelitis) are less
common. Acute disseminated encephalomyelitis has been linked with infection and vaccination. Bacterial
superinfection can occur. Oral complications include acute gingivitis, palatal bleeding, tongue plaques,
xerostomia, and rarely osteonecrosis of the jaw.

Maternal infection poses a risk of hemorrhage in both the mother and the infant if infection occurs near term.
Severe dengue is a risk factor for obstetric complications, cesarean delivery, fetal distress, and maternal
morbidity

Treatment

There are no specific therapeutic options for the clinical management of dengue besides supportive care.
Treatment entails the appropriate use of volume replacement, 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.

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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.

Repurposed drugs, such as chloroquine, statins, and balapiravir, are being explored for the treatment of
dengue, although none has shown clear therapeutic benefit. New research is focusing on monoclonal
antibodies as a therapeutic option as well as drugs including peptide agents that target structural and
nonstructural proteins of dengue virus essential to its replication.

Prognosis

Although fatalities occur with severe disease, the estimated mortality (2.5% of severe cases) appears to be
diminishing, likely due to improved recognition of the disease and wider availability of supportive treatment.
Causes of death include hemorrhagic fever (seen with recurrent disease) and occasionally fulminant
hepatitis. Thrombocytopenia and acute hepatitis are predictors of severe dengue and higher mortality. Acute
kidney injury in dengue shock syndrome portends poor prognosis. In general, the more advanced forms of
disease (hemorrhagic fever and shock) occur more o en in Asia than in Americas. Comorbidities of
cardiovascular disease, diabetes, stroke, pulmonary disease, kidney disease, and older age are associated
with more severe dengue.

Prevention

Preventive measures should be encouraged, such as control of mosquitoes by screening and insect
repellents including long-lasting insecticides, particularly during early morning and late a ernoon
exposures. Screening blood transfusions for dengue is of increasing importance, especially in endemic areas.

Dengvaxia, a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), is the first vaccine to be
approved and is now licensed for use by 19 regulatory authorities. Trials evaluating the e icacy of this
vaccine reported overall 60% e icacy; however, e icacy was lower in younger age groups, seronegative
individuals at the time of vaccination, and those infected with dengue serotype 2. The vaccine is given as a 0-,
6-, and 12-month series. Serious side e ects were no more common than in placebo recipients. Vaccination is
indicated for those between ages 9 and 45 years. Some investigators recommend limiting the vaccine to
those who have prior exposure because of immune enhancement, and recommend community vaccination
only when serosurveys document seropositivity levels of at least 70%. Pregnant women and
immunosuppressed persons should not be vaccinated.

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