We searched PubMed for articles pertaining to dengue and each of the topics discussed in the Review. Search terms included “dengue” and “epidemiology”, “modeling”, “phylogenetic”, “clinical”, “diagnosis”, “vaccine”, “antiviral”, “pathogenesis”, “immunopathogenesis”, “innate immunity”, “antibody”, “T cell”, and “vector control”, among others. The most relevant and recently published references were then selected to comply with the reference number limitation.
SeminarDengue
Introduction
Dengue is an arthropod-borne viral disease caused by the four dengue virus serotypes (DENV 1–4), which are transmitted by Aedes mosquitoes. Dengue has evolved from a sporadic disease to a major public health problem with substantial social and economic effect because of increased geographical extension, number of cases, and disease severity.
Dengue is endemic in more than 100 countries in southeast Asia, the Americas, the western Pacific, Africa and the eastern Mediterranean regions (figure 1), and its incidence has increased 30-fold in the past 50 years.4 Recent estimates made in 2013 cite that 390 million people have dengue virus infections with 96 million cases annually worldwide, more than three times WHO's 2012 estimate.1 However, the true disease burden is not well known, especially in India, Indonesia, Brazil, China, and Africa.1 Prospective cohort studies5, 6 in Nicaragua and Thailand indicate an incidence of dengue virus infection of 6–29% per year. Other studies7, 8 calculate that 2–28-fold more dengue cases occur than are reported by national surveillance systems and support use of expansion factors for estimations.
Dengue activity in Africa has increased substantially, although lack of clinical suspicion and diagnostic tests probably underestimated dengue prevalence in the past.9 Dengue outbreaks in India and the eastern Mediterranean region have progressively increased, with recent reports of cases in Pakistan, Saudi Arabia, Sudan, Yemen, and Madagascar; cases of dengue haemorrhagic fever/dengue shock syndrome, and circulation of several serotypes have also been reported.9 Resurgent dengue activity has been documented in Hawaii, the Galapagos islands, Easter Island, Hong Kong, and Buenos Aires. Dengue introductions have also been reported in Florida, southeastern France, and Madeira island.9, 10 The presence of Aedes albopictus and Aedes aegypti mosquitoes in Europe, together with increasing travel and pathogen introduction, poses a risk for transmission.11 Increasingly, co-infections of dengue occurring with leptospirosis, malaria, HIV/AIDS, and chikungunya are reported, as well as potential dengue transmission by blood transfusion.12 Lastly, travellers play an important role in global dengue epidemiology, carrying viruses from one region to another.9, 11
Dengue exacts a high economic burden on both governments and individuals. Dengue illness in the Americas costs US$2·1 billion per year on average, excluding vector control, exceeding costs of other viral illnesses.7 In southeast Asia, 2·9 million dengue episodes and 5906 deaths were estimated annually, with an annual economic burden of $950 million.13 Its rapid global emergence is related to demographic and societal changes of the past 50–60 years, including unprecedented population growth, increasing movement of people (and consequently viruses), uncontrolled urbanisation, climate change, and breakdown in public health infrastructure and vector control programmes.
Dengue transmission results from interactions between people, mosquitoes, viruses, and environmental factors. Local human movement is a spatiotemporal driver of transmission dynamics important for dengue virus amplification and spread.14 House-to-house human movements define spatial patterns of dengue incidence, causing marked heterogeneity in transmission rates.14 Fine-scale spatiotemporal clustering of dengue transmission exists, with houses with high dengue virus transmission risk contributing disproportionately to virus amplification and spread.15
The implications of inapparent dengue virus infection in dengue transmission, disease pathogenesis, and vaccine assessment needs careful consideration. Viral characteristics, the host's immune and genetic background, and epidemiological factors lead to variable ratios of symptomatic to inapparent infections.5, 6, 16, 17 Inapparent infections and under-reporting of cases should be considered in estimation of the disease and economic burden.8
The use of mathematical models to help understand multiple aspects of dengue transmission has greatly increased. Some models define patterns of spatiotemporal dependence consistent with the expected effects of homotypic and heterotypic immunity and immune enhancement of disease.18 Other models suggest that the shift of dengue cases in Thailand towards older age groups is attributable to a shift in the age distribution of the population and its effect on the force of infection.19 By contrast, the shift of dengue haemorrhagic fever cases to children in Brazil is explained by an accumulation of multitypic immunity in adults, with reduced probability of remaining susceptible to infection and decreased mean age of secondary infection.20 These factors should be considered in the design of prevention strategies.
The four dengue virus serotypes are genetically diverse and share limited identity (around 60–75%) at the aminoacid level. Viruses within the same serotype have about 3% difference at the aminoacid level and 6% difference at the nucleotide level and are phylogenetically divided into genotypes and clades. Genetic variations between serotypes and clades are important determinants of differential viral fitness, virulence, and epidemic potential.21, 22, 23, 24 For example, strains with a replicative advantage in both humans and mosquitoes can spread more rapidly and successfully than can strains with lower replicative abilities, and might eventually displace strains with lower fitness.21, 22, 23, 24 Viral genetics also influence interactions of the virus with the host's pre-existing immune response,24 as well as the overall efficacy of host anti-viral immune responses. Consequently, particular serotypes and clades have been associated with differential clinical manifestations and disease severity.24, 25 In addition, the population structure of dengue virus genomes within an individual during acute disease (ie, intrahost diversity) could have a role in determination of disease outcome. With the use of deep sequencing technologies, the study of intrahost diversity is actively evolving, and recent reports suggest that the extent of dengue virus diversity during acute infection is lower26 than previous estimates suggest.27 The association between intrahost diversity and disease outcome is an area of active investigation.
In terms of serotype and strain introductions, studies in Iquitos, Peru, suggest that the establishment of a new serotype requires a period during which environmental conditions are favourable for virus amplification, with three phases: amplification, replacement, and epidemic transmission.28 Substantial genetic diversity among circulating viruses indicates that dengue virus is frequently introduced into both semiurban and rural areas from other populations.29 Accordingly, invasion and establishment of viruses from outside of an area reduces the extent of lineage persistence. Lastly, the implications of sylvatic human infections also deserve careful study.30
Section snippets
New dengue case classification
After an incubation period of 4–8 days, infection by any dengue virus can produce a wide spectrum of illness, with most infections asymptomatic or subclinical. Most patients recover after a self-limiting (although debilitating) illness, while a small proportion progress to severe disease, mostly characterised by plasma leakage with or without bleeding. Illness begins abruptly, followed by three phases: febrile, critical, and recovery. The critical period occurs around defervescence, when an
Dengue diagnosis
Diagnosis is important for clinical management, surveillance, and research. Diagnostic options include assays to detect the virus or its components (genome and antigen) or the host response to the virus. Assay choice depends on the timing of sample collection and the purpose of testing (appendix).9 Viraemia is detectable for roughly 4–5 days after fever onset and correlates closely with fever duration. In a primary infection, anti-dengue-virus IgG evolves relatively slowly, with low titres 8–10
Dengue virus and the immune response
Dengue virus enters target host cells via clathrin-dependent receptor-mediated endocytosis.52 Numerous putative receptors have been identified on human and mosquito cells, while dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) serves as a dengue virus attachment factor on dendritic cells.54 In secondary infections, pre-existing antibodies bind to DENV virions and enable Fcγ receptor-mediated uptake by target Fcγ receptor-bearing cells, a process known as
Dengue pathogenesis
The pathophysiological basis for severe dengue is multifactorial. Protective versus pathological outcome depends on the balance among the host genetic and immunological background and viral factors (figure 3).77
Vaccines
Concern about antibody-dependent enhancement and its role in dengue haemorrhagic fever/dengue shock syndrome supports the necessity for tetravalent dengue vaccines that stimulate balanced immune responses to the four serotypes (panel). However, development of multivalent dengue vaccines has been hampered by difficulties in induction of a balanced immune response. Live attenuated and inactivated viruses, recombinant proteins, and DNA vaccines are under development as vaccine candidates (table 1).
Future directions
Basic and translational research in the past decade has substantially improved our knowledge about dengue; however, to contain the global pandemic, new efforts are needed. Application of nanotechnology and omics is expected to improve knowledge of virus-host and virus-vector interactions, aiding development of diagnostic techniques, therapeutic approaches, prognostic markers, new insecticides, and vaccines. Mathematical modelling should improve our understanding of transmission dynamics, vector
Search strategy and selection criteria
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