Dengue hemorrhagic fever with special emphasis on immunopathogenesis

https://doi.org/10.1016/j.cimid.2007.05.010Get rights and content

Abstract

Dengue virus infections are a serious cause of morbidity and mortality in most tropical and subtropical areas of the world; Southeast and South Asia, Central and South America, and the Caribbean. Dengue virus infection can be asymptomatic or causes two forms of illness, dengue fever (DF) and dengue hemorrhagic fever (DHF), which is the severe form of dengue illness and often fatal. Pathogenesis of DHF has been analyzed, and two mechanisms are considered to be responsible. These include dengue serotype cross-reactive immune responses and virulence of the virus. The immunopathological mechanisms include a complex series of immune responses. Rapid increase in the levels of cytokines, especially TNF-α, and chemical mediators play a key role in inducing unique clinical manifestations of DHF such as plasma leakage, shock, and hemorrhagic manifestations. It is understood that the process is initiated by infection with a virulent dengue virus, often in the presence of antibodies that enhance dengue virus infection in secondary infection, and then triggered by rapidly elevated cytokines and chemical mediators that were produced by intense immune activation. However, complete understanding of the entire pathological mechanism is far from complete, and further studies are still needed.

Résumé

Les infections de la fièvre dengue sont une cause sérieuse de morbidité et de mortalité dans la plupart des zones tropicales et subtropicales du monde, l’Asie du sud-est, l’Asie du sud, l’Amérique centrale et du sud, et les Caraïbes. L’infection du virus de la dengue peut être ou asymptomatique, ou causer deux formes de maladies, la fièvre dengue et la fièvre dengue hémorragique (DHF), forme grave de la maladie de la dengue qui peut être mortelle. L’analyse de la pathogénie de la DHF a montré deux mécanismes qui sont considérés responsables. Sont inclus dans ces derniers les réactions croisées des réponses immunitaires entre sérotypes de dengue différents, et la virulence du virus. Les mécanismes immunopathologiques comprennent une série complexe de réponses immunitaires. Une augmentation rapide des niveaux de cytokines, en particulier la TNF, et les facteurs médiateurs jouent un rôle clef dans l’induction de manifestations cliniques spécifiques de la DHF comme la perte de plasma, les manifestations hémorragiques et de choc. Il est entendu que le processus est initié par une infection d’un virus de dengue virulent, parfois en présence d’anticorps qui augmentent l’infection du virus de la dengue en infection secondaire, puis déclenché par l’augmentation rapide de cytokines et de médiateurs chimiques produits par une activation immunitaire intense. Toutefois, le mécanisme pathologique est loin d’être entièrement compris, et des études ultérieures sont nécessaires.

Section snippets

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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