Dengue Virus

Dengue virus (DENV) is a small, positive-sense, single-stranded RNA virus of the

genus Flavivirus. The infection can be transmitted to humans by the bite of female
Aedes mosquitoes. The majority of infections are asymptomatic. Symptomatic
individuals may progress through 3 stages of the disease, with severe
manifestations occurring in those with previous infections. The febrile phase
includes a high fever, headache and retro-orbital pain, severe myalgias and
arthralgias (“breakbone” pain), and macular or maculopapular rash. The critical
phase includes more severe manifestations of capillary leakage, hemorrhage, and
shock. A resolution of signs and symptoms occurs in the convalescent phase. The
diagnosis is made based on the clinical history, examination, serology, antigen
testing, or PCR. Management is supportive.

Last updated: October 5, 2022

CONTENTS

Classification
General Characteristics and Epidemiology
Pathogenesis
Clinical Presentation
Diagnosis and Management
Comparison of Similar Flavivirus Species
Differential Diagnosis
References:

Classification
RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed
by either DNA or RNA. RNA genome viruses can be further characterized by either a single-
or double-stranded RNA. "Enveloped" viruses are covered by a thin coat of cell membrane
(usually taken from the host cell). If the coat is absent, the viruses are called “naked”
viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is
directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-
sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to
transcribe their genome into messenger RNA.
Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and

Epidemiology
Basic features of dengue virus (DENV)
 Taxonomy:
Family: Flaviviridae
Genus: Flavivirus
RNA virus
Single stranded
Positive sense
Linear
Spherical
Icosahedral symmetry
Enveloped
Size: 40–60 nm

Transmission electron microscopic image of a tissue specimen depicts a number of round

dengue virus (DENV) particles.

Image: “Transmission electron microscopic image of a tissue specimen depicts a number of round, dengue
virus particles.” by CDC. License: Public Domain

Clinically relevant species

Clinically relevant species
Four distinct serotypes (DENV 1–4) cause dengue infection.

Epidemiology
The leading cause of arthropod-borne viral disease in the world
> 100 million humans affected annually
The incidence is increasing.
Found in > 100 countries
Mortality:
Causes 20,000–25,000 deaths annually (primarily in children)
Untreated severe dengue fever: 10% to 20%
Treated severe dengue fever: 1%
Geographic distribution:
Southeast Asia
Australia and Oceania
Central and South America
Caribbean
Africa
Middle East

Pathogenesis
Reservoir
Humans (primary reservoir)
Primates

Transmission
Vector: female Aedes mosquitoes (primary mode of transmission)
Rare:
Vertical
Blood transfusions
Breast milk
Organ transplantation

Host risk factors

 For dengue infection:
Living in an endemic area
Travel to an endemic region
For severe disease:
Previous dengue infection with a different serotype
Young children

Viral replication cycle

Virus attaches to receptors on a cell’s surface (facilitated by the viral
envelope (E) glycoprotein) → endocytosis
Acidification of endosome → fusion of cell and viral membranes → viral RNA
released into cytoplasm
Translation of RNA into viral proteins
Assembly and budding of new virions (mechanism is poorly understood)

Pathophysiology
Mosquito bite → subcutaneous injection of DENV into a human
Replication occurs in local cells (target cells not yet identified, but potentially
macrophages and dendritic cells)
Spread to lymphatic system → viremia → dissemination to organs
Innate and adaptive immune response
Infection with one serotype (primary infection) → lifelong immunity to the
same serotype
Individuals with a history of prior infection to one serotype can still be
infected by another dengue serotype (secondary infection):
Secondary infection has increased risk of more severe disease (e.g.,
dengue hemorrhagic fever, dengue shock syndrome).
Contributing factors:
Antibody-dependent enhancement (enhancing antibodies do not
neutralize the virus)
↑ Immune complexes
↑ T-lymphocyte response

Clinical Presentation
The majority of patients will be asymptomatic. Those with symptomatic
disease may experience 3 phases: febrile, critical, and convalescent.

Febrile phase
Febrile phase
This phase occurs after an incubation period of 3–14 days and lasts 2–7 days.
General:
Sudden high fever
Lymphadenopathy
Pain:
Headache
Retro-orbital pain
Lumbar back pain
Severe myalgias and arthralgias (“breakbone” pain)
Rash:
Transient
Macular or maculopapular
May be pruritic
Distribution:
Face
Thorax
Abdomen
Extremities
Respiratory:
Pharyngitis
Cough
Nasal congestion
Abdominal:
Nausea and vomiting
Abdominal pain
Hepatomegaly

Critical phase
This phase is not seen in all cases and usually presents in patients who have
had a previous dengue infection.
General features:
 ↓ Fever
Systemic capillary leakage (secondary to ↑ vascular permeability) occurs
between days 3–7:
Edema
Ascites
Pleural effusion
Hemoconcentration (hematocrit ↑ of 20% or more above baseline)
Dengue hemorrhagic fever:
Hemorrhagic manifestations:
Petechiae, purpura, or ecchymosis
Mucosal bleeding
Hematemesis or melena
Heavy menstrual bleeding
Positive tourniquet test:
Inflate the BP cuff on the arm midway between the systolic and
diastolic pressures for 5 minutes.
≥ 10 petechiae per 2.5 cm² (below the cuff)
Disseminated intravascular coagulation (DIC)
Abdominal pain
Altered mental status
Dengue shock syndrome:
Shock
Extreme abdominal pain, vomiting, lethargy/restlessness occurring with
defervescence indicate impending shock syndrome.
Weak pulse
Hypotension
Organ dysfunction
Can be lethal
 Bilateral periorbital ecchymosis in a patient with dengue hemorrhagic fever

Image: “Bilateral periorbital ecchymosis in a case with dengue fever” by Kumar V et al. License: CC BY 2.0

Convalescent phase
Gradual resorption of extravascular fluid
Stabilization of vital signs
Resolution of hemorrhage
Pruritic, confluent erythematous rash may occur
Profound fatigue (may last from days to weeks)

Diagnosis and Management

Diagnosis
The diagnosis should be suspected in people living in or traveling from
endemic areas.
 Confirmatory lab tests include:
Serology (ELISA)
Viral antigen detection
PCR for viral RNA
Viral culture (rarely useful)
Supporting evaluation:
Leukopenia
Thrombocytopenia
↑ Liver enzymes
↑ PT and PTT
↓ Fibrinogen
↓ Proteins (hypoproteinemia)
Ultrasound → ascites
X-ray → pleural effusion

Management
There is no effective antiviral therapy, so management is supportive. This may
include:
Rehydration
Blood transfusions (as needed)
Analgesia (avoid NSAIDs due to bleeding risk)

Prevention
Prevent mosquito bites
Insecticide/repellents
Protective clothing
Sleeping under a mosquito net
Eliminating stagnant water around the home
Vaccine
Decreases the risk of severe disease in previously infected patients
Can increase the risk of severe disease in seronegative children
Not approved for travelers to endemic regions

Comparison of Similar Flavivirus Species

Table: Comparison of Flavivirus species

Organism Yellow fever Hepatitis C Dengue virus

virus virus (HCV) (DENV)

Characteristics 1 serotype 2 serotypes 4 serotypes

40–60 nm 55–65 nm 40–60 nm

Transmission Mosquito Blood-borne Mosquito

Clinical Fever Asymptomatic Fever

presentation Flu-like Hepatitis Flu-like
symptoms Cirrhosis symptoms
Jaundice Hepatocellular Skin
Multiorgan carcinoma flushing/rash
dysfunction Severe pain
Hemorrhage Multiorgan
Shock dysfunction
Hemorrhage
Shock

Diagnosis Serology Serology Serology

PCR PCR PCR
Viral culture Antigen
testing

Management Supportive Direct-acting Supportive

antivirals

Prevention Mosquito- Avoid sharing Mosquito-

avoidance needles. avoidance
measures Proper sharps measures
Vaccine and waste Vaccine
disposal
Testing
donated
blood
 Differential Diagnosis
Zika virus: a Flavivirus that causes fever, conjunctivitis, and headache. An
infection during pregnancy can result in microcephaly and developmental
impairments in newborns. Diagnosis is established with serology or PCR.
Management is supportive.
Chikungunya virus: a virus belonging to the family Togaviridae and
transmitted by Aedes mosquitoes. Affected individuals present with abrupt
onset of fever and myalgias. A symmetrical, bilateral polyarthralgia can occur
in distal joints, as well as a generalized maculopapular rash. Diagnosis
includes serology and PCR. Management is supportive.
Malaria: mosquito-borne infectious disease caused by Plasmodium species.
Malaria often presents with fever, rigors, diaphoresis, jaundice, abdominal
pain, hemolytic anemia, hepatosplenomegaly, and renal impairment. A
blood smear shows a single pleomorphic ring. Rapid testing for Plasmodium
antigens can also be performed. Management requires a prolonged course
of multiple antimalarial drugs.
Leptospirosis: a disease caused by the gram-negative spirochete Leptospira
. Bacteria shed in the urine of rodents and other animals can be transmitted
to humans via contaminated water. A mild flu-like illness occurs in a majority
of cases. In a minority of patients, icterohemorrhagic leptospirosis develops,
manifesting as hemorrhage, renal failure, and jaundice. A bacterial culture
takes weeks, so other diagnostic tests, such as serology and
dark-field microscopy, are used. Treatment is primarily with antibiotics (e.g.,
doxycycline, azithromycin, penicillin).

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