Dengue is caused by a flavivirus and is the most important mosquito-borne viral infection of humans. Some 40 million symptomatic infections are estimated to occur annually. The disease is hyper-endemic in many large Asian cities, and is also a significant problem in the Pacific region and in the Americas. The primary mosquito vector is Aedes aegypti. Infection can be caused by any one of four closely related but serologically distinct dengue viral serotypes. Following infection with a single serotype there is life-long immunity to that serotype but the possibility of more severe disease during a subsequent infection with a different serotype.
Clinical features and diagnosis—symptomatic disease ranges from a nonspecific febrile illness through to a syndrome characterized by plasma leakage that may, if severe, result in the development of potentially fatal dengue shock syndrome. Thrombocytopenia and deranged haemostasis also occur, but clinically significant bleeding is unusual except it patients with profound shock. Severe hepatic and neurological complications are also seen in some patients. Diagnosis depends on viral isolation, detection of viral antigen or viral RNA, or serological testing.
Management and prevention—treatment is supportive, with particular emphasis on careful fluid management. Prompt volume resuscitation is essential for patients with shock, with regular monitoring of the pulse rate, blood pressure, and haematocrit to minimize the risk of fluid overload. No vaccine is available as yet but a number of candidates are entering clinical trials. Currently prevention relies on elimination of potential vector breeding sites, biological and chemical vector control strategies, and avoidance of mosquito bites.
Introduction and aetiology
Dengue is the most important mosquito-borne viral infection of humans. ‘Dengue’ is a West Indian Spanish word derived from Ki Swahili ‘ka dinga pepo’ (‘a kind of cramping plague’) that was brought from Africa to the Caribbean. In the British West Indies it was called ‘dandy fever’ because of the stiff posture of its victims, and in Cuba dengue was later termed ‘quebranta huesos’ or ‘break-bone fever’ because of the severe myalgias and arthralgias. Infection can be caused by any one of the four closely related but serologically distinct dengue viral serotypes (DEN-1, -2, -3, and -4) that together constitute one subgroup of the genus Flavivirus, family Flaviviridae. Since there is only transient cross-protective immunity between the four serotypes, people living in a dengue-endemic area can be infected up to four times during their lifetime.
Humans are infected with dengue viruses by the bite of a mosquito. Aedes aegypti, the principal vector, is a highly domesticated tropical mosquito that lays its eggs in artificial water containers commonly found in and around homes. The adult mosquitoes rest indoors and prefer to feed on humans during daylight hours, with peak biting activity in the early morning and late afternoon. The adult female mosquitoes are nervous feeders and, if their feeding is interrupted, will return to the same person or different persons to continue feeding. Thus, during a single blood meal several persons may become infected, making Ae aegypti a highly efficient epidemic vector. The transmission cycle of most importance is Ae aegypti–human–Ae aegypti in large urban centres of the tropics. Multiple virus serotypes often cocirculate within the same city causing periodic epidemics. Epidemics of febrile illness attributed to dengue have been reported at intervals over the last 200 years across Asia, Africa, and North America, likely reflecting progressive expansion in the global distribution of the Aedes mosquito vectors. However, from the 1950s onwards a new clinical syndrome, characterized by vascular leakage and bleeding and given the name dengue haemorrhagic fever (DHF), began to emerge in south-east Asia. The first epidemic of DHF in the Americas appeared in 1981 in Cuba, associated with the arrival of a new Asian strain of DEN-2 virus of different genotype from the American strain.
Dengue is now hyperendemic in most Asian cities, with epidemics occurring every 3 to 5 years superimposed on background endemic transmission. Progressive geographical expansion of the disease has also become apparent, attributable to the effects on mosquito ecology of urbanization and climate change. Dengue is now established as a significant problem in the Pacific Region and in the Americas, and outbreaks have also been reported from Africa, the Arabian Peninsula, and even the warmer parts of Europe. More than 3 billion people now live in areas of risk and approximately 40 million symptomatic infections are estimated to occur each year, with some 2 million severe enough to require hospitalization. In parallel with the changing epidemiology and transmission dynamics it is also apparent that different clinical presentations are emerging. Thus in regions with relatively low endemicity, clinical disease tends to be reported among adults rather than children, and the frequency and pattern of complications seen reflects age-related differences in intrinsic physiology as well as the greater likelihood of older patients’ having underlying comorbidities. Although low mortality rates (0.1–0.2% for severe disease) are usual in experienced hands, much higher rates are still reported from some regions, and among infants and elderly people.
All four serotypes can cause disease. Infection with one serotype elicits immunity to that serotype but does not provide long-term cross-protective immunity to the remaining serotypes. Severe disease occurs predominantly in patients experiencing a second or subsequent infection with a dengue serotype different from their first infection, or else in infants with transmitted maternal antibody experiencing their first infection. The generally accepted antibody-dependent enhancement (ADE) hypothesis suggests that residual heterotypic non-neutralizing antibodies bind to the new virus enhancing its infectivity by increasing the efficiency of binding and uptake of virus–antibody complexes through Fc receptors on blood monocyte or tissue macrophage cells, thus amplifying viral replication. The resulting increase in viral load drives an immunopathogenic cascade that alters microvascular function in some way, resulting in capillary leakage and coagulopathy. Rapid mobilization of serotype cross-reactive memory T cells has been suggested as an alternative mechanism to trigger the inflammatory cascade. Other factors considered to influence disease severity include differences in viral virulence, molecular mimicry, and immune complex and/or complement-mediated dysregulation, as well as age and genetic predisposition. However, the pathogenesis of the vascular leakage and coagulopathy associated with severe infections remains poorly understood and, so far, no mechanism has been identified that links the established immunological derangements with a definitive effect on microvascular structure or function.
Dengue virus infection in humans causes a wide variety of illnesses ranging from inapparent infection to mild febrile illness to severe and fatal disease. Most infections are asymptomatic. In the past, symptomatic disease was conventionally separated into two major clinical syndromes, dengue fever (DF) and dengue haemorrhagic fever (DHF), with case definitions and management guidelines for these entities published by the World Health Organization (WHO). The pathognomonic feature of DHF is increased vascular permeability, which may be severe enough to result in hypovolaemic shock; in addition, to qualify for a diagnosis of DHF, a patient must have some evidence of bleeding and a platelet count below 100 x 109/litre. Due to practical difficulties in using the old WHO scheme a revised classification system has recently been developed, based on prospective data collected from over 2000 children and adults with dengue from endemic areas around the world, and this has now been adopted in the latest WHO guidelines for dengue published in 2009. The new scheme classifies the disease into dengue and severe dengue, in line with several other complex diseases such as malaria and pneumonia. It is hoped that in the future this will prove to be a simpler system that will be useful for triage, aid clinical management, and improve the quality of surveillance and epidemiological data.
Symptomatic dengue is primarily a disease of older children and adults. After an incubation period of c.4 to 7 days symptoms start suddenly and typically follow three phases—an initial febrile phase, a critical phase around the time of defervescence, and a spontaneous recovery phase.
There is sudden onset of high fever often accompanied by facial flushing, headache, retro-orbital pain, lumbosacral pain, severe malaise, myalgias, bone pain, anorexia, altered sense of taste, mild sore throat, nausea, and vomiting. Younger children experience high fever, but are generally much less symptomatic. Some patients may have a transient rash or skin mottling in early illness (Fig. 22.214.171.124a). Other findings associated with infection may include generalized lymphadenopathy, mild haemorrhagic manifestations (e.g. petechiae or easy bruising, Fig. 126.96.36.199a,b), and palpable hepatomegaly but rarely splenomegaly. Haematuria is uncommon and jaundice is rare. Clinical laboratory findings during the first week include thrombocytopenia and leukopenia, often with moderate elevation of hepatic transaminases.
Most patients recover around the time of defervescence, usually between days 3–7 of illness, but in a small proportion an increase in capillary permeability becomes apparent at this time, marking the onset of the critical phase for complications. A capillary leak syndrome manifests with increasing haemoconcentration, hypoproteinaemia, pleural effusions and ascites, and, if severe, may compromise the circulating plasma volume so that the patient develops the potentially life-threatening dengue shock syndrome (DSS) (Fig. 188.8.131.52a,b). When the pulse pressure narrows to less than 20 mmHg with a rapid weak pulse and impaired peripheral perfusion, or if hypotension develops, the patient is defined as having DSS. If fluid resuscitation is not instituted promptly the ongoing depletion of plasma becomes critical, the systolic pressure falls rapidly, and irreversible shock and death may follow. However, with judicious fluid management the majority of patients make a full recovery. Warning signs that the patient may be at risk for severe disease include severe vomiting, intense abdominal pain, and increasing tender hepatomegaly.
Haemorrhagic manifestations are common during this period but often limited to the presence of skin petechiae or bruising, or a positive tourniquet test. Mucosal bleeding (e.g. epistaxis, gastrointestinal bleeding, haematuria, menorrhagia) may occur, but is rarely clinically significant in children except in association with profound or prolonged shock. However, adults tend to experience more severe bleeding problems than children (Fig. 184.108.40.206a,b); gastrointestinal bleeding and menorrhagia may be significant even in patients with little evidence of vascular leakage. Moderate to severe thrombocytopenia is usual, with nadirs below 20 × 109 /litre often observed during the critical period followed by rapid improvement during the recovery phase. An increase in the activated partial thromboplastin time and a reduction in fibrinogen levels are also frequently noted. However, these findings are not indicative of classic disseminated intravascular coagulation and the true nature of the coagulopathy remains unknown. Other laboratory investigations show similar but usually more profound abnormalities to those seen in uncomplicated cases.
The increase in permeability is transient and reverts to normal after approximately 24–48 h. Fluid is reabsorbed quite rapidly, often with an obvious diuresis, and the patient improves. A second rash, varying in form from scarlatiniform to maculopapular, may appear around day 6 to 7 of illness, typically on the extremities although sometimes involving the trunk and face (Fig. 220.127.116.11b). The rash blanches on pressure, may be accompanied by intense pruritus, and often resolves with desquamation.
Unusual manifestations, including acute liver failure and encephalopathy/encephalitis, may be noted, even in the absence of severe plasma leakage or shock. Myocarditis has also been reported in a few cases.
Under the new scheme, patients who recover without complications are classified as having dengue, while those who experience any one of the following problems are classified as having severe dengue: plasma leakage resulting in shock and/or fluid accumulation sufficient to cause respiratory distress; severe bleeding; severe organ impairment, e.g. liver failure, myocarditis etc. However, most deaths from dengue occur in patients with profound shock, particularly if the situation is complicated by fluid overload.
The differential diagnosis during the acute phase of illness includes influenza, Epstein–Barr virus, measles, rubella, typhoid, leptospirosis, rickettsial infection, malaria, other arboviral infections with rash, other viral haemorrhagic fevers, and meningococcaemia.
During the early febrile stage (up to about day 5 of illness) laboratory confirmation of dengue infection relies on viral isolation or detection of viral antigen or viral RNA by reverse transcription–polymerase chain reaction (RT-PCR) in blood. After this time IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is the most widely used serological test for dengue diagnosis; seroconversion or a rising titre of dengue-specific IgM or IgG in paired samples indicates acute infection. Patients with secondary infection (either dengue or another flavivirus infection) often develop high levels of IgG antibodies in the acute phase and the IgM response may be less intense. Serological diagnosis is also complicated by the existence of flavivirus cross-reactivity, making it necessary to perform tests for other locally prevalent flaviviruses in parallel with dengue serology. Because antidengue antibodies persist for several months, diagnosis based on a single positive MAC-ELISA result should be considered provisional. Bedside rapid serological tests are now available but, in common with conventional serological tests, may not become positive until the end of the first week of illness. ELISA tests to detect circulating dengue nonstructural protein 1 (NS1) during the first few days of fever may be a promising tool for early diagnosis.
Good supportive care, with a particular focus on careful fluid management, is critical for a favourable outcome. For patients with mild disease, oral rehydration is usually sufficient. Fever should be controlled with tepid sponging and paracetamol. Aspirin and nonsteroidal anti-inflammatory drugs are contraindicated.
Persistent vomiting, severe abdominal pain, mucosal bleeding or severe skin bleeding, a rapidly rising haematocrit, or a marked drop in the platelet count indicate the need for close observation and frequent monitoring of vital signs and haematocrit. Judicious parenteral fluid therapy is indicated for those with a rapidly rising haematocrit. For patients with established DSS, prompt but careful restoration of circulating plasma volume is crucial, followed by maintenance fluids to support the circulation at a level just sufficient to maintain critical organ perfusion until vascular permeability reverts to normal. However, fluid overload with respiratory compromise is a common complication and one of the major contributors to mortality. Thus the volume of parenteral fluid given must be kept to the minimum required to maintain cardiovascular stability and adequate urine output during the phase of active leakage, and as soon as reabsorption begins, usually about 1 to 2 days later, intravenous fluids should be stopped. Isotonic crystalloid solutions should be used initially. Colloid solutions should be reserved for patients presenting with severe DSS and those who fail to improve with crystalloid therapy. Correction of metabolic acidosis, electrolyte imbalance, and hypoglycaemia are also essential. Platelet concentrates are not indicated, even for profound thrombocytopenia unless there is overt bleeding, as the thrombocytopenia improves rapidly during the recovery phase without intervention. However, in the event of significant bleeding transfusion of fresh blood, platelets, and other blood products may be indicated, but should be undertaken with great care because of the risk of fluid overload.
No specific drugs are available as yet for the treatment of dengue. Current research is focused on two main therapeutic approaches: first, reduction in viraemia through use of antiviral drugs, and second, immune modulation to suppress the immunopathogenic cascade that is considered to be ultimately responsible for the severe manifestations. Several viral inhibitors are in preclinical trials, and chloroquine, a cheap, safe drug that is known to have modest antiviral effects in vitro, was recently assessed in a formal randomized blinded trial in adults with confirmed dengue. However, no effect was seen on the duration of viraemia or NS1 antigenaemia, and use of chloroquine was associated with a higher frequency of adverse events compared to placebo although these were generally mild. Corticosteroid therapy showed no convincing benefit on mortality from shock in several small clinical trials during the 1980s, but whether deployment before the development of shock influences outcome remains unknown. A recent safety study of early prednisolone use indicated that immune modulation during the viraemic phase did not interfere with viral clearance mechanisms. However,although the study was not powered to assess efficacy, there was no reduction in the incidence of shock or other recognized complications of dengue, suggesting that any protective effect of early steroid use is small.
The lead dengue vaccine candidate, ChimeriVax-Dengue, is a tetravalent formulation of attenuated yellow fever 17D vaccine strains expressing dengue envelope proteins. Multicentre clinical trials to establish the efficacy of this vaccine are ongoing, but long-term follow-up of vaccinees will be essential to determine if waning vaccine-elicited immunity predisposes recipients to more severe outcomes during any subsequent natural infection. Other candidates in clinical development include live attenuated virus vaccines and recombinant subunit vaccines.
The majority of patients with dengue make a full recovery. Those with DSS and/or significant bleeding usually do well provided they receive appropriate supportive care from experienced health care personnel during the critical phase of the illness. Adults may go on to experience several weeks of extreme tiredness, weakness, skin desquamation, pruritus, and depression during convalescence after infection, but there are no permanent sequelae. In general, children recover more rapidly and do not experience such problems.
Although major efforts are being directed towards development of safe and effective dengue vaccines, it seems unlikely that a suitable candidate will be available for large-scale deployment for some years. Until then prevention of epidemics will continue to rely on elimination of potential vector breeding sites together with biological and chemical vector control strategies. Community control of Ae aegypti by eradication of mosquito larvae from stagnant water sources is recommended but has been difficult to achieve in contemporary tropical urban settings. Insecticide-treated bednets have limited use since Ae aegypti mosquitoes are primarily daytime feeders. Avoidance of mosquito bites in areas infested with Ae aegypti by using repellents containing N,N-diethyl-3-methylbenzamide (DEET) or picaridin and protective clothing are the most effective preventive measures for the traveller.
Deen JL, et al. (2006). The WHO dengue classification and case definitions: time for a reassessment. Lancet, 368, 170–3.Find this resource:
Durbin AP, Whitehead SS (2010). Dengue vaccine candidates in development. Curr Top Microbiol Immunol, 338, 129–43.Find this resource:
Halstead SB (1965). Dengue and hemorrhagic fevers of Southeast Asia. Yale J Biol Med, 37, 434–54.Find this resource:
Halstead SB, Nimmannitya S, Cohen SN (1970). Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med, 42, 311–28.Find this resource:
Kay B, Vu SN (2005). New strategy against Aedes aegypti in Vietnam. Lancet, 365, 613–7.Find this resource:
Mackenzie JS, Gubler DJ, Petersen LR (2004). Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med, 10 Suppl, S98–109.Find this resource:
Mongkolsapaya J, et al. (2003). Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med, 9, 921–7.Find this resource:
Screaton G, Mongkolsapaya J (2006). T cell responses and dengue haemorrhagic fever. Novartis Found Symp, 277, 164–71.Find this resource:
Tricou V, et al. (2010). A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis, 10, e785.Find this resource:
Wilder-Smith A, Schwartz E (2005). Dengue in travelers. N Engl J Med,353, 924–32.Find this resource:
Wills BA, et al. (2005). Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med, 353, 877–89.Find this resource:
World Health Organisation (1997). Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. World Health Organisation, Geneva.Find this resource:
World Health Organisation (2009). Dengue: Guidelines for diagnosis, treatment, prevention and control. World Health Organisation, Geneva.Find this resource: