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.

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Classification

RNA Viruses Flowchart 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
dengue fever virus particles Flaviviridae

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

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 → 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

Clinical Presentation

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

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
    • Edema
    • Ascites
    • Pleural effusion

Dengue hemorrhagic fever:

  • Petechiae, purpura, or ecchymosis 
  • Mucosal bleeding
  • Hematemesis or melena
  • Heavy menstrual bleeding
  • Disseminated intravascular coagulation (DIC)
  • Abdominal pain
  • Altered mental status

Dengue shock syndrome:

  • Shock
  • Organ dysfunction 
  • Can be lethal
Bilateral periorbital ecchymosis dengue virus Flaviviridae

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
    • 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
OrganismYellow fever virusHepatitis C virus (HCV)Dengue virus (DENV)
Characteristics
  • 1 serotype
  • 40–60 nm
  • 2 serotypes
  • 55–65 nm
  • 4 serotypes
  • 40–60 nm
TransmissionMosquitoBlood-borneMosquito
Clinical presentation
  • Fever
  • Flu-like symptoms
  • Jaundice
  • Multiorgan dysfunction
  • Hemorrhage
  • Shock
  • Asymptomatic
  • Hepatitis
  • Cirrhosis
  • Hepatocellular carcinoma
  • Fever
  • Flu-like symptoms
  • Skin flushing/rash
  • Severe pain
  • Multiorgan dysfunction
  • Hemorrhage
  • Shock
Diagnosis
  • Serology
  • PCR
  • Viral culture
  • Serology
  • PCR
  • Serology
  • PCR
  • Antigen testing
ManagementSupportiveDirect-acting antiviralsSupportive
Prevention
  • Mosquito-avoidance measures
  • Vaccine
  • Avoid sharing needles.
  • Proper sharps and waste disposal
  • Testing donated blood
  • Mosquito-avoidance measures
  • Vaccine

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. Patients 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 penicillin.

References:

  1. World Health Organization. (2021). Dengue and severe dengue fact sheet. WHO. http://www.who.int/mediacentre/factsheets/fs117/en/
  2. Bhatt, S, Gething, PW, Brady, OJ, Messina, JP, Farlow, AW, Moyes, CL, et al. (2013). The global distribution and burden of dengue. Nature. 496 (7446):504–7.
  3. Baak-Baak, CM, et al. (2019). Entomological and virological surveillance for dengue virus in churches in Merida, Mexico. Rev Inst Med Trop Sao Paulo. 14;61:e9.
  4. Sharma, M, et al. (2020). Magnitude and functionality of the NS1-specific antibody response elicited by a live-attenuated tetravalent dengue vaccine candidate. J Infect Dis. 02;221(6):867–77.
  5. Gubler, DJ. (2004). Cities spawn epidemic dengue viruses. Nat Med. 10(2):129–30.
  6. Wilder-Smith, A, Gubler, DJ. (2008). Geographic expansion of dengue: The impact of international travel. Med Clin North Am. 92(6):1377–90, x.
  7. Maia, LMS, et al. (2019). Natural vertical infection by dengue virus serotype 4, Zika virus and Mayaro virus in Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus. Med Vet Entomol.;33(3):437–42.
  8. Wharton-Smith, A, Green, J, Loh, EC, Gorrie, A, Omar, SFS, Bacchus, L, Lum, LCS. (2019). Using clinical practice guidelines to manage dengue: A qualitative study in a Malaysian hospital. BMC Infect Dis. 11;19(1):45.
  9. Thomas, SJ, and Rothman, AL. (2021). Dengue virus infection: Epidemiology. UpToDate. Retrieved May 14, 2021, from https://www.uptodate.com/contents/dengue-virus-infection-epidemiology
  10. Thomas, SJ, and Rothman, AL. (2019). Dengue virus infection: Pathogenesis. UpToDate. Retrieved May 14, 2021, from https://www.uptodate.com/contents/dengue-virus-infection-pathogenesis
  11. Thomas, SJ, Rothman, AL, Srikiatkhachorn, A, and Kalayanarooj, S. (2021). Dengue virus infection: Clinical manifestations and diagnosis. UpToDate. Retrieved May 14, 2021, from https://www.uptodate.com/contents/dengue-virus-infection-clinical-manifestations-and-diagnosis
  12. Thomas, SJ, Rothman, AL, Srikiatkhachorn, A, and Kalayanarooj, S. (2020). Dengue virus infection: Prevention and treatment. UpToDate. Retrieved May 14, 2021, from https://www.uptodate.com/contents/dengue-virus-infection-prevention-and-treatment
  13. Smith, DS, Mariano, DJ, and Trautwein, ML. (2019). Dengue. In Bronze, M.S. (Ed.), Medscape. Retrieved May 14, 2021, from https://emedicine.medscape.com/article/215840-overview
  14. Yuill, TM. (2020). Dengue. [online] MSD Manual Professional Version. Retrieved May 14, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/dengue
  15. Schaefer, TJ, Panda, PK, and Wolford, RW. (2020). Dengue fever. [online] StatPearls. Retrieved May 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK430732/

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