**1. Introduction**

90 Current Topics in Tropical Medicine

World Health Organization.Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention

The geographic distribution and genetic diversity of dengue virus is deeply rooted in Asia suggesting its origin from this region, with first reported out-break of DHF from Philippine in 1953 (Halstead, 1980). One of the characteristics notable in Asian regions, where the disease is endemic is that dengue hemorrhagic fever outbreaks occur in repetitive cycles of 3-5 years, (Ferguson et al, 1999). The incidence of disease and its severity varies across different dengue virus serotypes and also between primary and secondary infections of same serotypes(Vaughn DW et al).

Due to lack of in-vivo study models, there is little information about factors contributing to disease severity and its variation across dengue virus genotypes and the cyclical nature of dengue outbreaks. It is however critical to study these factors particularly in the South East Asian region where incidence of dengue cases is thought to be associated with variables such as water, sanitation, population density and rate of literacy as opposed to developed countries where ambient temperature, moisture and rainfall perhaps plays the major role. A better understanding of disease epidemiology and pathogenesis will help identify optimum control measures in the region. It will also develop systems for predicting the outcome of mass vaccination when the vaccine becomes available in this region.

The chapter has been divided in three parts: the first part will discuss the historical evolution of the dengue virus in the region its spatial and temporal distribution. It will also look at the effects of covariates such as poverty, water supply, sanitation and global warming on expansion of the dengue endemic regions. .

The second part of the chapter will focus on the genetic evolution of the viral isolates circulating in the region. Phylogenetic studies of dengue viruses have uncovered genetic variation within each serotypes, these variations have been organized in discrete clusters on dendograms. Analyses of such studies have broadened our horizon to relate the mutational changes with disease evolution and factors like seasonality and incidence variability. This part of chapter will focus on the common mutational variations that have been reported so far and how these relate with the disease dynamics in the endemic region.

In the third and final part of the chapter an attempt has been made to relate the mutational changes of dengue genotypes with disease severity. Vast array of literature has been published investigating relationship of genetic variation with disease severity. The structure

Genetic Diversity of Dengue Virus and

transmission season in temperate regions.

(anonymous 2006).

**2.3 Dengue fever and dengue hemorrhagic fever** 

Associated Clinical Severity During Periodic Epidemics in South East Asia 93

acclimatized to urban set-up, once established the density of this mosquito is directly proportional to density of human population and artificial breeding sites (Merril S.A *et al* 2005), it feeds almost exclusively on humans. Moreover A. aegypti is considered to be more competent vector for dengue virus. Genetic traits that determines successful midgut infection by DEN virus have been mapped on several loci on A. aegypti chromosomes (Benedict, M.Q, *et al* 2007) indicating that vector competence is genetically determined. The extent to which these mosquitoes compete with each other in the environment is not clear, nonetheless the balance of two species in the region is important, and the socioeconomic factors in SEA appear to be displacing *A.albopictus* in favour of *A.aegypti* leaving the population more susceptible. The poor socioeconomic conditions are major contributing factor to sustained vector activity with severe form of disease in the South East Asia. The breeding habitats of A.aegypti have been strongly associated with squatter settlements, inadequate piped water supply and sewage facilities (Halstead, S.B. 1966). In addition, there are impacts of higher environmental temperature in the region. High temperature is inversely related to the mosquito gonotropic cycle and viral extrinsic incubation period; this increases the egg laying episodes resulting in more blood meals and increased risk for viral transmission. In addition shorten extrinsic viral incubation period culminate to increase virus load at time of inoculation (Focks D.A. et al 1993). These effects have been proven for dengue vectors in simulation studies conducted by (Cox J et al 2001) and it has been projected that increase in global temperature would increase the length of

The word dengue is believed to have originated from Swahili language "*ki denga pepo"*, which describes sudden cramp like seizure. The clinical symptoms suggestive of dengue virus infection can be traced back to Chinese Chin Dynasty (265-420 AD) where disease was considered as water poison and was known to be associated with water and insects

Emergence of the disease in the new world can be traced back to the transmigration of the vector in the 17th century. There are reports that suggest possible epidemics of dengue like illness in three major continents (Asia, Africa and North America) as early as 1779 and 1780, within Asia Batavia (now known as Jakarta) was affected by this outbreak (Halstead,S.B. 1966). By early nineteenth century Dengue fever was known to be endemic in the rural areas of South East Asia probably due to the indigenous vector *A.albopictus*. It manifested as self limiting disease to which native population developed immunity at early age. With the advent of *A. aegypti* at Asian ports, the disease spread to the main inland cities and towns. It is assumed that unlike rural population, the urban populations of South East Asia remained susceptible to dengue virus and were then infected by newly imported vector. Dengue epidemics progressively became less frequent as urban population became immune to the disease, until 1953 when a new form of dengue fever was reported from Thailand and Manila, where children suffered from fever followed by bleeding diathesis; the disease was then called as *Philippine Fever* (Aiken, S.R. 1978). By 1960's the hemorrhagic form of disease had spread to Malaysia, Vietnam, Sri Lanka, Singapore and Indonesia (Halstead, S.B. 1966). The disease epidemiology extended and outbreaks of dengue hemorrhagic fever (DHF) were reported from India 1988) French Polynesia (1990), Pakistan (1992) and Bangladesh (2000).Until recently, DHF was considered to be disease of childhood, especially in South

of virus E- protein that confers the viral infectivity and host immune response of the virus (E.Descloux,2009) remains the focus of such studies. Sequence variation at different loci such as CprM, E/NS1, preM/E, C/prM/M and untranslated regions etc. have been investigated for its association with disease severity. This part of chapter will throw some light on our current understanding of disease severity and it relation with genetic variation.
