Aetiology
Dengue infection is caused by 4 antigenically distinct dengue virus serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. They are RNA viruses that belong to the Flavivirus genus/Flaviviridae family, which also includes the yellow fever virus, West Nile virus, Japanese encephalitis virus, Zika virus, and the St Louis encephalitis virus.[1]
Co-infection with more than one serotype has been reported in 48% of outbreaks. The DENV-2 serotype was the predominant serotype in outbreaks before the year 2000, with DENV-3 the predominant serotype between 2000 and 2009, and DENV-1 the predominant serotype after 2010.[18] The DENV-2 serotype was the most prevalent serotype in Southeast Asia, accounting for 41% of cases, followed by DENV-1 (22%), DENV-3 (15%), and DENV-4 (6%).[19] All 4 subtypes have the capacity to cause severe disease; however, there is evidence that specific serotypes may increase the risk for severe infection.[20]
The primary vector for spread of infection is the Aedes aegypti mosquito, a highly domesticated, day-biting (most active during dusk and dawn) mosquito. However, another species, Aedes albopictus, is also responsible for the spread of the dengue virus. Although the mosquito is of Asian origin, it has now spread to Africa, Europe, and the US. International travel and transportation of goods has helped the spread of both the vector and the virus, making dengue a global infection.[1] The Aedes mosquito is also a vector for Zika and chikungunya viruses.[Figure caption and citation for the preceding image starts]: The Aedes aegypti mosquito, which spreads the dengue virusFrom the collection of N. Samarasinghe, Department of Zoology, University of Peradeniya, Sri Lanka [Citation ends].
The evolution, adaptation, and changing virulence of the dengue virus has happened over centuries. There is no clear evidence about the origin of the virus; however, it is believed to be from either Africa or Asia. It has been reported that some serotypes have sylvatic cycles (i.e., part of a pathogen's lifespan spent cycling between wild animals and the vector), but it is essentially a human virus.[17] The virus has a development cycle in the epithelial cell lining of the midgut of a mosquito before transmission to humans.[21]
A considerable genetic variation occurs within each viral serotype, thereby forming phylogenetically distinct genotypes. The virion consists of 3 structural proteins plus a lipoprotein envelope and 7 non-structural proteins, of which non-structural protein 1 (NS1) has diagnostic and pathological importance. Infection with any one serotype confers lifelong immunity to that specific serotype; however, cross-protection to other serotypes lasts only a few months.[1][2][22] Some studies have shown that infection with either the DENV-1 or DENV-2 serotype may result in more severe infection.[23][24]
As well as mosquito-borne transmission, dengue virus may also be transmitted via blood products, mucocutaneous exposure, or needlestick injury.[25][26] One study estimates dengue transmissibility to be around 37% via blood products.[27]
Pathophysiology
Pathogenesis is linked to the host immune response, which is triggered by infection with the dengue virus.[28] Primary infection is usually benign in nature; however, secondary infection with a different serotype or multiple infections with different serotypes may cause severe infection that can be classified as either dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS), depending on the clinical signs. The incubation period is 4 to 10 days.
Non-neutralising, cross-reactive antibodies elicited by a previous primary infection are involved in the phenomenon of antibody-dependent enhancement (ADE), which causes a heavy viral burden. Cells of the monocyte-macrophage lineage are the major sites of viral replication, but the virus can infect other tissues in the body such as the liver, brain, pancreas, and heart.[29][30][31]
Antigen-presenting dendritic cells, the humoral immune response, and the cell-mediated immune response are involved in the pathogenesis. Proliferation of memory T cells and the production of pro-inflammatory cytokines leads to vascular endothelial cell dysfunction, which results in plasma leakage. There is a higher concentration of cytokines such as interferon-gamma, tumour necrosis factor (TNF)-alpha, and interleukin-10, as well as reduced levels of nitric oxide and some complement factors. NS1 is a modulator of the complement pathway and plays a role in low levels of complement factors.[29][32] After infection, specific cross-reactive antibodies, as well as CD4+ and CD8+ T cells, remain in the body for years.[2]
Vascular leak is the hallmark of DHF and DSS, and causes an increase in haematocrit, hypoalbuminaemia, and the development of pleural effusions or ascites. Preliminary data suggest that transient dysfunction of the endothelial glycocalyx layer leads to vascular leak.[33] There is also a tendency towards haemorrhage associated with severe thrombocytopenia and coagulation disorders.[1][29]
In severe infection, loss of intravascular fluid leads to tissue hypoperfusion, resulting in lactic acidosis, hypoglycaemia, hypocalcaemia, and, finally, multiple organ failure.[1] Multiple organ dysfunction including myocarditis, encephalopathy, and liver cell necrosis can also result from direct viral damage to, and subsequent inflammation in, tissues.[1][30][31]
Infants can develop severe dengue infection during a primary infection (which is usually benign in nature) due to transplacental transfer of maternal antibodies from an immune mother, which subsequently amplifies the infant's immune response to the primary infection.[29]
Co-infection with chikungunya or Zika virus (or both) is possible.[34][35] Co-infection with malaria is also possible, and patients with malaria co-infection may develop either severe malaria or severe dengue with bleeding complications.[36][37]
TNF-alpha (-308) polymorphism has been linked with dengue susceptibility.[38][39]
Classification
World Health Organization (WHO): case definition (2009)[2]
The 1997 dengue case definition (below) is limited in terms of its complexity and applicability. This limitation led to a new WHO classification in which dengue severity is divided into dengue without warning signs, dengue with warning signs, and severe dengue. While WHO still support both case definitions, there is a move towards using the 2009 case definition due to its ease of use. One study found that the revised classification had a high potential for facilitating dengue case management and surveillance, and that it was more sensitive than the 1997 case definition for timely recognition of disease.[3]
Dengue without warning signs:
Fever and 2 of the following:
Nausea/vomiting
Rash
Aches and pains
Leukopenia
Positive tourniquet test.
Dengue with warning signs:
Dengue (as defined above) with any of the following:
Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation (e.g., ascites, pleural effusion)
Mucosal bleeding
Lethargy/restlessness
Liver enlargement >2 cm
Laboratory: increase in haematocrit concurrent with rapid decrease in platelet count.
Warning signs require strict observation and medical intervention.
Severe dengue:
Dengue with at least 1 of the following:
Severe plasma leakage leading to shock (dengue shock syndrome) or fluid accumulation with respiratory distress
Severe bleeding (as evaluated by a clinician)
Severe organ involvement (i.e., aspartate aminotransferase [AST] or alanine aminotransferase [ALT] 1000 or greater, impaired consciousness, organ failure).
World Health Organization (WHO): case definition (1997)[2]
The traditional classification is divided into dengue fever, dengue haemorrhagic fever, and dengue shock syndrome.
Dengue fever (DF):
Defined by the presence of fever and 2 or more of the following (but not meeting the case definition of dengue haemorrhagic fever):
Retro-orbital or ocular pain
Headache
Rash
Myalgia
Arthralgia
Leukopenia
Haemorrhagic manifestations (e.g., positive tourniquet test, petechiae, purpura/ecchymosis, epistaxis, gum bleeding, blood in vomit/urine/stool, vaginal bleeding).
Dengue haemorrhagic fever (DHF):
Fever lasting from 2 to 7 days
Evidence of haemorrhagic manifestation or a positive tourniquet test
Thrombocytopenia
Evidence of plasma leakage shown by haemoconcentration, pleural effusion, or ascites.
Dengue shock syndrome (DSS):
Has all the criteria of DHF plus circulatory failure as evidenced by:
Rapid and weak pulse and narrow pulse pressure, or
Age-specific hypotension and cold, clammy skin and restlessness.
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