Comparative Immunology, Microbiology and Infectious Diseases
Dengue hemorrhagic fever with special emphasis on immunopathogenesis
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Dengue viruses
Dengue viruses are transmitted to humans by infected mosquitoes, mainly Aedes aegypti and Aedes albopictus [1]. Humans are natural hosts of dengue viruses, and dengue viruses are maintained between mosquitoes and humans in nature. Dengue viruses belong to the family Flaviviridae, the genus Flavivirus. There are four serotypes, dengue virus types 1, 2, 3, and 4 [2]. Although dengue virus types 1, 2, 3, and 4 are called four serotypes of dengue virus, it is generally accepted that these four
Dengue fever (DF) and dengue hemorrhagic fever (DHF); two types of clinical manifestation of dengue virus infection
Dengue virus infection can be asymptomatic or causes two forms of illness, DF and DHF [4], [5] (Table 1), although the majority of dengue virus infections are asymptomatic. DF is a self-limited febrile illness [4], [5]. After an incubation period of 2–7 days, a sudden onset of fever occurs. The fever is usually accompanied with retro-orbital or frontal headache. Myalgia and bone pain occur soon after the onset of fever. A transient macular rash that blanches under pressure, nausea, vomiting,
Epidemiological features of DF and DHF
Dengue virus infections are a serious cause of morbidity and mortality in most tropical and subtropical areas of the world: mainly Southeast and South Asia, Central and South America, and the Caribbean [1], [4] (Fig. 1). There are approximately 2.5 billion people at risk in the world for infection with dengue viruses. Nearly 100 countries and areas have a risk for domestic dengue virus infections. Dengue cases are estimated to occur in up to 100 million population annually. A total of
Pathogenesis of DHF
Major manifestations of DHF include (i) plasma leakage through elevated vascular permeability, (ii) hemorrhage, and (iii) thrombocytopenia. Some of the patients infected with dengue virus develop DHF, while most with symptomatic infections end up as DF. The pathogenesis of DHF has been explained by two theories. One theory is based on the virulence of infecting dengue viruses; virulent dengue virus strains cause DHF, while avirulent dengue virus strains cause DF. The other is based on
Role of non-neutralizing antibodies in the pathogenesis of DHF
Epidemiologic data have suggested that DHF is mediated by host immune responses. The studies done in Thailand demonstrated that up to 99% of DHF cases had heterotypic antibody to the serotype of dengue virus that caused DHF. These DHF cases were divided into two groups. Nearly 90% of them were children who were older than 1 year and in a secondary infection with a serotype of dengue virus different from that which caused the primary infection. The other 10% were less than 1 year old and
Virulence of viruses as a cause of DHF
Although DHF occurs more frequently in secondary infection than in primary infection, DHF also occurs in primary infection. This suggests that virulence of the virus contributes to the development of DHF. It has been assumed that virulent dengue virus strains cause DHF, while avirulent dengue virus strains cause DF. There are multiple genotypes in each of four dengue viruses.
The introduction of the Southeast Asian genotype coincided with the appearance of DHF in different countries in the
Role of cytokines in the pathogenesis of DHF
A series of studies have suggested that plasma leakage, which differentiates DHF from DF, is caused by malfunction of vascular endothelial cells induced by cytokines or chemical mediators rather than by destruction of the small vessels [20], [21], [22]. Plasma levels of various cytokines are significantly higher in DHF than in DF. The cytokines elevated in patients with DHF include TNF-α, IL-2, IL-6, IL-8, IL-10, IL-12, and IFN-γ. The levels of IL-8 and MCP-1 are also elevated in the pleural
Complement activation in patients with DHF
Activation of complement is another important clinical manifestations in DHF. It was reported that the levels of C3a and C5a, complement activation products, are correlated with the severity of DHF and the levels of C3a and C5a reached the peak at the time of defervescence when plasma leakage becomes most apparent [27]. This is consistent with the assumption that complement activation is also responsible for the pathogenesis of DHF.
The mechanism of complement activation in DHF is not completely
Further researches
There have been many studies that target the pathogenesis of DHF (Table 2). However, our understanding is not complete yet. In this section some questions and projects that remain to be addressed toward a fuller understanding of DHF pathogenesis are listed.
Final remark
DF/DHF is one of the most important infectious diseases in tropical and subtropical countries. The areas where DF and DHF are a serious health concern have been expanding, and the number of DHF patients has been increasing. New findings of dengue viruses are accumulating, and a dengue vaccine may be available in the near future. However, understanding of the pathogenesis of DHF still remains a challenge. Better understanding of DHF pathogenesis will lead us to developing better strategies to
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