2. Natural clinical evolution

Dengue virus infections encompass a range of well-described clinical illnesses ranging from an asymptomatic infection to a self-limiting febrile illness, dengue fever, to severe dengue (shock and death), a clinical syndrome that typically presents with capillary permeability and can lead to dengue shock syndrome and dengue hemorrhagic fever. Among less common presentations of severe dengue are encephalitis, hepatitis, and renal dysfunction [4]. Infection by any dengue virus requires a 4- to 8-day incubation period and can produce a wide spectrum of illnesses, the majority of these being asymptomatic or subclinical. Although most patients are able to recover after a self-limiting (yet debilitating) illness, a small proportion develops a severe form of the disease, which is mainly characterized by plasma leakage with or without bleeding [3]. The acute illness is usually benign and self-limiting. Moreover, a secondary infection, corresponding to a subsequent infection with a different serotype is also characterized by acute fever and several other nonspecific signs and symptoms, usually indistinguishable from a range of other illnesses. However, in 2–3% of secondary infections with another serotype there is a higher risk of increased disease severity, causing life-threatening Dengue with Warning Signs (DWS+) and Severe dengue (SD), according to the revised WHO dengue case classification (DENCO) [2, 5]. Serotype-cross-reactive antibodies facilitate DENV infection in Fc-receptor-bearing cells by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE) [6, 7]. Dengue without Warning Signs (DWS) is more often observed in adults and adolescents and can manifest with only a mild fever only or a more disabling disease. This latter form is characterized by symptoms occurring mainly in the early febrile stage, such as the sudden onset of high fever, severe headache, retroorbital pain, myalgia, arthralgia, and rash. In the critical phase, the skin is flushed with the appearance of a petechial rash, occurring predominantly around the time of defervescence, when an increase in capillary permeability accompanied by increased hematocrit can occur, leading to hypovolemic shock that can result in organ impairment, metabolic acidosis, disseminated intravascular coagulation, and severe hemorrhage. If untreated, mortality can be as high as 20%, whereas appropriate case management and intravenous rehydration can reduce mortality to less than 1% [3]. SD usually affects children younger than 15 years of age, although it can occur in adults. SD is characterized by a transient increase in vascular permeability resulting in plasma leakage with high fever, bleeding, thrombocytopenia, and hemoconcentration, which can lead to shock [5]. Two factors, namely, antibody-dependentenhancement (ADE) and inherent virulence of the DEN viruses, appear to contribute the most to disease pathogenesis [2].
