Epidemiology

Dengue is the most widely distributed mosquito-borne viral infection of humans, affecting an estimated 100 million people worldwide each year, with 40% (2.5 billion) of the world’s population estimated to be at risk of infection.⁴ It is endemic in parts of Asia and the Americas and has been reported increasingly from many tropical countries in recent years.^4,⁵ It is now classified by the World Health Organization (WHO) into dengue fever and severe dengue (Box 149-1). The most important feature of severe dengue is increased capillary permeability, leading to DSS (Figure 149-1). It is among the leading causes of hospitalization in Asia during the rainy season, with 500,000 cases reported annually to the WHO. When shock becomes established, mortality rates of 12% to 40% have been reported, although this can be less than 1% when patients are looked after by experienced clinical teams.

Figure 149-1 Acute skin manifestations of dengue. A, Characteristic minor bleeding near injection sites. B, Rash in established dengue shock syndrome. C, Severe bleeding following IV injection. Staff should press after IV injections for five minutes to ensure bleeding stops.

The dengue virus is a single-stranded, positive sense RNA virus of approximately 11 kb in length and encodes 3 structural and 7 nonstructural genes.⁶ It is a member of the Flavivirus genus, which also includes yellow fever, Japanese encephalitis, West Nile virus, and hepatitis C virus.⁷ There is considerable genetic diversity in the dengue virus family, with four serotypes (Den-I, Den-II, Den-III, and Den-IV), all of which may produce a nonspecific febrile illness, dengue fever, or may result in the more severe manifestation of severe dengue.

The dengue viruses are transmitted from viremic individuals to susceptible hosts by mosquitoes of the subgenus Stegomyia; the major global vector is Aedes aegypti, although other species may be more important in restricted geographic areas. A. aegypti lays individual eggs in the damp walls of artificial and natural water containers, and these eggs can remain viable for months. The adult mosquito is strongly anthropophilic, prefers resting in sheltered dark areas inside houses, and has a diurnal feeding pattern, usually peaking in the midmorning and late afternoon. The female usually feeds twice during a single gonotrophic cycle, and the average life span is 8 to 14 days.

Pathophysiology

Severe dengue is characterized by increased vascular permeability and plasma leakage, thrombocytopenia, and hemorrhage (see Figure 149-1). Vascular permeability is the most important parameter determining the severity of dengue, and the plasma leak that occurs can precipitate DSS through circulatory failure (reduced pulse pressure and hypotension).⁵ The capillary leak predisposes to pulmonary edema, pleural effusion, ascites, intravascular compromise, and hemoconcentration. Dengue is characterized by only mild hemorrhage, as indicated by spontaneous petechiae and a positive tourniquet test, whereas in severe dengue, mucosal bleeding (including that associated with peptic ulceration and menorrhagia) and other clinically important manifestations of hemorrhage can be present. These are usually associated with prolonged shock.

The most widely cited hypothesis to explain the vascular leak and hemorrhage associated with dengue is increased viral replication due to enhanced infection of monocytes in the presence of preexisting antidengue antibodies at subneutralizing levels, leading to antibody-dependent immune enhancement.⁸ This observation, which has strong epidemiologic and in vitro experimental evidence to support it, argues that in asymptomatic dengue infection, the moderate viremia is controlled. The host immune system develops long-lasting immunity to the serotype of the infecting strain and short-lived cross-protection against heterologous serotypes. After a few months, the levels of cross-protective antibodies directed against the heterologous serotypes fall below neutralizing levels, however, and from this stage onward infection with a second heterologous strain may result in increased viral uptake via Fcγ receptors into monocytes and enhanced viral replication. Severe disease has been reported during primary infections, however, and not all secondary infections lead to severe disease, so other theories (viral and host genetic factors) have been suggested to explain the complex epidemiologic and immunopathogenetic features.⁹^–¹²

Clinical Features

Dengue fever is a mild, self-limited febrile episode that is commonly associated with a rash. It usually begins with fever, respiratory symptoms (sore throat, coryza, cough), anorexia, nausea, vomiting, diarrhea, and headache. Back pain, myalgias, arthralgias, and conjunctivitis also may occur. The initial fever usually resolves within 1 week, and a few days later a generalized morbilliform or maculopapular rash may develop. Fever may return with the rash. As noted, dengue is now classified into dengue and severe dengue by the WHO (see Box 149-1). These two groups form part of a continuous spectrum of severity, with the most important clinical features of severe dengue being capillary permeability leading to DSS (see Figure 149-1). Other complications include severe mucosal (and less commonly, intracerebral and pulmonary hemorrhage) bleeding, pleural effusions, encephalopathy, pneumonia, and liver dysfunction. The differential diagnosis is extensive and varies depending on where the patient is seen, but would include malaria, typhoid, leptospirosis, scrub and murine typhus, septicemia, other viral hemorrhagic fevers (e.g., Ebola, Lassa fever), chikungunya, West Nile fever, o’nyong-nyong fever, and Rift Valley fever (usually without a rash).

A pulse pressure of less than 20 mm Hg is one of the earliest manifestations of shock and usually occurs before the onset of systolic hypotension. The mainstay of treatment is prompt but careful fluid resuscitation. If appropriate volume resuscitation is instituted at an early stage, shock is usually reversible; in certain severe cases and in patients who are inappropriately resuscitated, patients may progress to irreversible shock and death. Careful clinical judgment is required throughout the patient’s stay in the hospital to maintain an effective circulation while assiduously avoiding fluid overload. During the critical phase of illness, regular review (every 15-30 minutes) of vital signs—pulse rate, blood pressure (BP), respiratory rate (RR), and peripheral temperature—as well as measurement of hematocrit (Hct) at least every 2 hours (more frequently if very severe or unstable).^13,^14,¹⁵ It is imperative that these measurements be made, the patients assessed, and the treatment modified in light of the clinical situation and results. Ideally the Hct should be measured on the ward (or the results be made available immediately). Dengue has a very dynamic clinical progression, and it is not acceptable to define therapy on the basis of blood results taken hours earlier. For patients with DSS, the WHO recommends immediate volume replacement with isotonic crystalloid solutions, followed by the use of plasma or colloid solutions, specifically dextrans, for profound or continuing shock.⁴

Thrombocytopenia is a very common feature in dengue, and platelet function is abnormal. Mild prolongation of the prothrombin and partial thromboplastin times with reduced fibrinogen levels is common, but fibrin degradation products have not been found to be elevated to a degree consistent with classic disseminated intravascular coagulation (DIC). Patients with DSS have significant abnormalities in all the major pathways of the coagulation cascade.¹⁶

Diagnosis

Classic dengue illness can be an easy diagnosis to make in endemic regions with experienced clinical staff and a high prior probability that a febrile illness with rash and thrombocytopenia is caused by dengue. Most of the symptoms and signs accompanying dengue infection are common to many febrile illnesses, with few features that reliably discriminate dengue, especially at early stages.^17,¹⁸ The differential diagnosis invariably is large; it is region, country, and season specific. The differential diagnosis includes measles, rubella, enterovirus, influenza, typhoid, chikungunya, scarlet fever, malaria, leptospirosis, hepatitis A, rickettsiosis, bacterial sepsis, Hanta virus infection, viral hemorrhagic fevers (including Ebola, Lassa fever), West Nile virus, o’nyong-nyong fever, and Rift Valley fever (usually without a rash). Because of the variation in clinical findings and the multiplicity of possible causative agents, the descriptive term dengue-like disease may be used until the clinical picture becomes clearer or the laboratory provides a specific diagnosis (Figure 149-2).