Summary
- Up to 350 million infections annually, 500 thousand cases of severe dengue, mortality approximately 20,000.
- Vector: mosquitoes, Aedes species
- Flavivirus, 4 main serotypes (DEN 1-4)
- Infection with one serotype produces lifelong immunity against this serotype, but only short-lasting cross-protection to other serotypes.
- Main clinical presentations: fever, artralgia/aash, haemorrhagic syndrome (FD, AR, HS)
- Plasma leakage is the hallmark of severe dengue
- WHO 2009 classification: Dengue and Severe Dengue (D/SD); Warning signs (WS) help clinicians identify cases in need of closer surveillance (dengue with warning signs [D +/- WS]).
- WHO 1997 classification: Dengue fever, dengue haemorrhagic fever and dengue shock syndrome (DF/DHF/DSS).
- No antiviral treatment is available at present, but mortality is greatly reduced by appropriate supportive treatment.
- A vaccine (CYD-TDV) was approved, but interpretation of efficacy and protection of individuals vaccinated is complicated.
Virus
Dengue viruses belong to the Flaviviridae (yellow viruses). The virus has a positive sense single-stranded RNA genome. It is translated into a large precursor protein, which is then cleaved by host-cell and viral proteases into three structural and seven non-structural proteins (See Figure 5).
Dengue virus has 4 main serotypes. Infection with one serotype results in lifelong immunity to subsequent infection with that particular serotype (homologous immunity). There is no lasting cross-protection between the serotypes (heterologous immunity).
In 2013, a 5th serotype (DEN-5) has been described, of which the clinical significance is not yet understood. Contrary to DEN 1-4 it has a sylvatic transmission cycle, which may hamper current dengue control efforts.
Epidemiology and transmission
Dengue prevalence increased over 15 fold over the last two decades attributable to three principal drivers: urbanization, globalization and lack of effective mosquito control. Dengue viruses have fully adapted to a human-Aedes aegypti-human transmission cycle in large, crowded urban centres in the tropics. In rapidly developing suburbs, running tap water is often lacking and people depend on fetching water in small reservoirs. Sewage systems are often open and are ideal breeding sites for mosquitoes. Increased mobilization with more car tyres together with a surge in the use of plastics contributes to mosquito propagation since water is often retained in these structures. International travel can transport the virus to new regions where there is little mosquito control. Transported rubber car tyres and lucky bamboo plants have been shown to carry Aedes spp. larvae.
Dengue virus infects an estimated 300-530 million cases worldwide annually, of which almost 100 million manifest clinically. The estimated annual death rate of 5000 deaths due to dengue virus is relatively low, but high numbers of less sick dengue patients can overburden health structures. Dengue occurs in 129 countries and 70£ of the actual burden is in Asia. As with other arboviruses, geographic distribution of dengue is determined by the distribution of its vectors (See Figure 6). The main reservoir of the dengue serotypes 1-4 is probably man.
Dengue is transmitted by the bite of infected female Aedes mosquitoes. The virus develops a life-long non-cytocidal infection in the mosquito. It may infect the mosquito ovaries and offspring (transovarial transmission). Aedes eggs can withstand dehydration for several months, and eggs of some Aedes species survive for several years. This cycle can be repeated for multiple generations and drive new outbreaks. It takes at least one week from the hatching of the egg to the adult stage of the mosquito. This is an important piece of information for understanding the “dry day” principle (see below). Infection of humans occurs when dengue virus is introduced into the skin via the insect’s saliva during a bite of female mosquitoes. Aedes albopictus is a less competent vector for dengue virus, but survives in a more temperate climate. Global warming might therefor increase the population at risk for dengue.
Clinical aspects
Three-quarters of the estimated 390 million dengue virus (DENV) infections annually are clinically unapparent. These asymptomatic cases have the potential to contribute significantly more to virus transmission to mosquitoes than previously recognized, as high levels of viremia have been detected in infected people who do not have interruption to their daily routine and who continue to have exposure to the virus’ vectors.
Symptomatic dengue infection begins with a sudden onset of a flu-like syndrome. Fever is common and lasts 2-7 days and is frequently biphasic (saddleback fever). Skin rash, headache and arthralgia are frequent symptoms. The rash may have a dengue-specific appearance of “white isles in a red sea” (Figure), but this finding has low sensitivity (up to 20%).
There may be marked muscle pain (breakbone fever), especially in the back and in the extraocular eye muscles (pain around and behind the eyes when looking sideways).
According to the 2009 WHO guidelines for diagnosis, treatment, prevention and control of dengue, a positive tourniquet test (aka. Rumpel-Leede or capillary fragility test) increases the probability of dengue in acute febrile illness. The sphygmomanometer is inflated around the upper arm to midsystolic blood pressure. After the cuff is left in place for 5 minutes, more than 20 petechiae in a 3 cm diameter circle in the crease of the elbow indicate a positive test. Recent literature suggests that the tourniquet test is more effective in detecting true negative than true positive cases and the test should not be used for diagnosing dengue.
Severe dengue
Severe dengue may rapidly be fatal. An estimated 500 000 people with severe dengue require hospitalization each year, a large proportion of whom are children.
Complications may develop after 3 to 5 days, when the first fever subsides (defervescence) and endothelial dysfunction may lead to haemoconcentration. Patients may develop haemorrhage (ranging from petechiae, ecchymosis and purpura to overt bleeding from mucosal surfaces (epistaxis, melena), injection sites and cerebrovascular accidents. They may develop shock with plasma leakage; clinically, pleural or pericardial effusion or ascites can be observed by ultrasonography. Detection of an oedematous gallbladder wall by serial ultrasonography may identify patients at risk for development of severe dengue.
Prediction of severe dengue remains a challenge, mainly because the determinants of a complicated course of dengue virus infection are poorly understood. Severe dengue was observed to occur more frequently in secondary dengue infections. In 1977, this led to development of the concept of ‘Antibody Dependent Enhancement’ (ADE). Secondary dengue infections were found to be correlated with higher levels of viraemia. A molecular model to support the ADE hypothesis was described by Dejnirattisai et al. Briefly: Dengue infection leads to the development of homologous neutralising and protective antibodies. Upon subsequent infection with a different serotype, these antibodies may enhance replication of even immature virus particles. This results in higher levels of viraemia (replication of both mature and immature virions), thereby increasing the release of pro-inflammatory cytokines and thus the severity of disease.
The prevailing dengue serotype may be a determinant of severe dengue. This should probably also be evaluated against existing population immunity to previous dengue serotypes. In a recent meta-analysis, Soo et al. compared the percentage of severe cases of both primary and secondary infections with different serotypes of dengue virus. They found that the presence of certain serotypes, including primary infection with DENV-3 from the SEA region and secondary infection with DENV-2, DENV-3, and DENV-4 also from the SEA region, as well as DENV-2 and DENV-3 from non-SEA regions, increased the risk of severe dengue infections.
There is no specific treatment for dengue/ severe dengue, but early detection and access to proper medical care lowers fatality rates below 1%. To facilitate clinical management of patients with dengue virus infections, a new classification system was introduced by the WHO in 2009.
WHO dengue classification
Recognizing Severe Dengue remains a challenge for the clinician. In 2009, WHO adopted a new classification of symptomatic dengue infections i.e.. dengue with or without warning signs (WS +/-). While the performance of the triage based on the presence of warning signs (WS) need further validation across different clinical settings, this practical classification helps clinicians identify those patients in need of closer surveillance and/or hospitalization. Warning signs of Severe Dengue include spontaneous or provoked bleeding, severe abdominal pain, persistent vomiting, painful hepatomegaly, dyspnoea, lethargy and effusions (see Figure 8).
The former WHO classification (1975, revised in 1997) was derived from a paediatric population. It identified Dengue fever, dengue haemorrhagic fever and dengue shock syndrome (DF/ DHF/ DSS). It was used to classify disease severity for surveillance purposes. The main criticisms are summarized below:
- poorly related to disease severity
- misdirecting clinicians identifying severe disease
- difficult to use (tests required are often not available/difficult to apply)
- does not help for triage in outbreaks
- leads to different reporting globally as a result of the difficulties in using the classification for reporting clinicians.
Further comparison of the usefulness of the 1997 and 2009 WHO Dengue Case Classifications can be found in recent publications.
Diagnosis
(see also the section: Laboratory diagnosis of arboviral infections).
Common haematological abnormalities include leukopenia and thrombocytopenia. Both are poor predictors of disease severity. Increased haematocrit (≥20% increase) is an indication of severe disease since it can point towards plasma leakage syndrome and evolution to shock syndrome.
Biochemical abnormalities correlate with disease severity and organ failure. Increased transaminase levels and hypoproteinaemia are observed in severe dengue. Proteinuria, where proteins up as large as albumin are lost, occurs and is consistent with disruption in the function of the endothelial glycocalyx layer. Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances and may reflect macrophage activation.
Patients with dengue or other febrile illness usually seek medical attention within several days of fever onset. Documenting the day of symptom onset (day 0) is essential to choose a single specimen diagnostic approach. DENV viremia occurs for 3–5 days prior to fever onset and continues for approximately 5 days into the febrile illness. Viraemia can be detected by molecular assays targeting DENV RNA (such as RT-PCR) or by immunoassays targeting DENV nonstructural protein 1 (NS1) antigen. An anti-DENV IgM response becomes detectable by IgM-capture immunoassays (Enzyme Linked Immuno Sorbent Assay (ELISA) or Immune Fluorescence Assays (IFA)) 3–5 days after onset of fever. IgM levels peak at 6–10 days after fever onset and may persist for up to 90 days. IgG antibodies can be detected from day 7 onwards and may persist for life. Anti-dengue IgG-antibodies may increase sooner in the event of a secondary dengue infection. In view of these kinetics, routine laboratory diagnostic options in a patient with suspected dengue infection should be considered in function of the day of symptom onset (Figure 9). Performance of testing for dengue should be optimized by developing and evaluating algorithms appropriate to a laboratory’s capacities and specific clinical setting.
Flaviviruses share antigenic epitopes, which elicit cross-reacting antibodies. This cross-reactivity may result in false positive test results. To identify false positive test results or confirm true positives, virus neutralization tests can be performed. Because of costs and technical expertise required, use of these tests is mainly restricted to reference laboratories.
Treatment
No antiviral compounds are available for the treatment of dengue virus infections. There is no evidence in favour of the use of any specific therapeutic agent, including balapiravir, chloroquine, lovastatin and celgosivir. Corticosteroids are not effective.
Most cases can be treated on an out-patient basis. Symptomatic treatment should avoid aspirin and NSAIDs (risk of bleeding), but paracetamol can be used. The patient or the parents of the sick child should be informed of the potential risk of complications. In-patient care is required if warning signs appear as these may predict severe dengue to occur on days 4-7 after symptom onset.
In the case of warning signs, isotonic crystalloid fluids such as Ringer’s lactate should be used to restore circulating blood volume. Fluid resuscitation requires observation in intensive care units; when the endothelial function recovers, fluid overload may cause iatrogenic complications. In patients with severe dengue infection adjuvant therapy, including vasopressor and inotropic therapies, renal-replacement therapy and further treatment of organ impairment may be necessary.
Blood transfusion and fresh frozen plasma may be required to treat severe bleeding. In case of massive bleeding platelet transfusion may be needed in addition to red ell transfusion but there is no evidence for benefit of prophylactic platelet transfusions, even in patients with counts as low as 5*10^9/ l.
Prevention
Personal protection
Contact with Aedes mosquitoes can be reduced with insect repellents. Sleeping at night under a bed net does not give any protection against Aedes that bite during the day but can be useful for e. g. children sleeping during the day.
Vaccination
Immunity to dengue virus infections is complex, and so is the development of dengue vaccines. As discussed under the section ‘Severe Dengue’. Dengue infection with one serotype leads to the development of lasting homologous neutralising and protective antibodies, but it induces only short-term immunity against other (heterologous) serotypes. Because of ADE, infection with a second serotype may lead to more severe illness. Hence there is concern over increasing the risk of severe dengue by vaccinating. After infection with 2 different serotypes, broad immunity is observed.
The first tetravalent dengue vaccine, Denvaxia® (CYD-TDV) is now used in about 20 countries as part of their dengue control programme, after a study had shown a 80.3% efficacy against in hospitalization and a 60,8% efficacy in contraction dengue disease in children. An additional analysis with retrospective determination of serostatus at the time of vaccination showed that children that were seronegative at the time of the first vaccination had a higher risk to develop severe dengue. Vaccination is therefor limited to people living in endemic areas ranging from 9-45 years of age who have had at least 1 documented dengue virus infection previously. This pre-vaccination screening for past dengue disease complicates the roll out of this vaccine in many low resource settings.
In 2019, the first results of a phase 3 trial of the tetravalent dengue vaccine candidate (TAK-003, a live attenuated DENV-2 virus with the premembrane- and envelop genes of the DENV-2 replaced with those from wild-type DENV-1, DENVV-3 and DENV-4 strains) in Asia and Latin America were released. The overall vaccine efficacy in children and adolescent 4 to 16 years of age was 80.9% (95% CI 75.2-85.3) with 78 cases per 13,380 in the vaccine group vs. 199 cases per 6687 in the placebo group and there was a 95% efficacy against hospitalization for dengue. Even in the subgroup that was seronegative at baseline the vaccine efficacy was 75% without increase in severe dengue cases. Since DENV-2 was the backbone of TAK-003, efficacy was highest against DENV-2 with a more moderate efficacy against the other three serotypes. Future monitoring will learn whether protection persists beyond 12 months after vaccination for non-DENV-2 serotypes.
