ReviewKyasanur forest disease
Highlights
► Kyasanur forest disease (KFD), caused by a tick-borne flavivirus, is seen in a limited area of India. ► The disease affects both wild primates and humans living near forested areas. ► KFD is characterized by hemorrhagic fever, with a case fatality rate in the range of 1–3%. ► Viruses related to KFDV have been identified in China and Saudi Arabia. ► A formalin-inactivated vaccine is in use, but no effective therapies have been identified.
Introduction
In February, 2012, ProMED cited reports in The Hindu (http://www.thehindu.com) of an on-going outbreak of Kyasanur forest disease (KFD) in Tirhahalli and Hosanager taluks (counties) in the Shimoga district of India, with 176 suspected and 38 confirmed cases since the beginning of the year. These reports serve as a reminder that KFD is a significant public health problem in that region, and that outbreaks occur with some frequency. It has been estimated that an average of 400–500 cases of KFD occur per year in India (Pavri, 1989, Work et al., 1957). From 2003 through late March 2012 there were 3263 suspected cases, with 823 confirmed cases and 28 deaths, a 3.4% case fatality rate (CFR) (Table 1). Similar diseases have been reported in China and Saudi Arabia since 1995, and there is serological evidence of KFDV infection in other parts of India.
Despite the frequent occurrence of KFD in its endemic area, relatively little is known about its pathogenic mechanisms or the host response to infection. There is also some debate regarding its typical manifestations, beyond an acute febrile illness. As discussed below, KFD was initially described as a type of viral hemorrhagic fever, but overt bleeding does not occur in all cases. Also, in contrast to related flaviviruses in the tick-borne encephalitis virus (TBEV) serocomplex, KFDV rarely causes severe neurologic illness. Because many virologists are unfamiliar with the disease, the goal of this article is to review the history of KFD and highlight the importance of the disease and others caused by closely related flaviviruses.
Section snippets
History
KFDV was first isolated during an outbreak of febrile disease in 1957 in people living in the Kyasanur forest area of the Shimoga district in the Karnataka (then Mysore) state of India (Work and Trapido, 1957, Work et al., 1957) (Fig. 1). Reports of a large number of deaths among local nonhuman primates (NHPs) provided the first evidence of an epizootic of unknown etiology. When investigators from the Virus Research Center in Pune arrived, district health officials reported that there had been
Clinical features
Initial descriptions of KFD focused largely on its hemorrhagic component, and did not identify significant signs of neurological disease (Work et al., 1957). The presumption that KFD was a type of viral hemorrhagic fever was based on findings in two fatal cases, which showed hemorrhage and consolidation in the lungs and significant bleeding in the gastrointestinal tract (see first KFD case summary in Appendix A) (Work, 1958). These observations suggested that the new disease resembled some
Pathologic findings
Gross and microscopic examination of tissues from fatal KFD cases have found evidence of a largely non-specific disease process, with prominence of macrophages and lymphocytes in the liver and spleen, moderate parenchymal degeneration in the liver and kidneys and evidence of erythrophagocytosis in the spleen. Some have shown hemorrhagic pneumonia (Iyer et al., 1959, Pavri, 1989). As indicated previously, in the few reports that describe neurological disease, it may best be described as aseptic
Natural infection
The evaluation of KFDV infection in NHPs has only been performed through necropsies of animals found sick or dead in the forest; no studies have described the natural course of illness. Postmortem findings resembled the nonspecific disease seen in humans (Work, 1958). The liver architecture was well preserved, but areas of necrosis were more pronounced than in humans; infiltrates of inflammatory cells, including hypertrophic or multinucleated cells of reticuloendothelial origin, and
Related viruses
Kyasanur forest disease virus is member of the family Flaviviridae, genus Flavivirus. The flaviviruses are genetically divided into two major clades, those transmitted by mosquitoes and those transmitted by ticks. The mosquito-vectored viruses are further subdivided into three serocomplexes of closely related viruses: yellow fever, dengue and Japanese encephalitis, which includes West Nile virus (Gubler et al., 2007). Tick-borne viruses in the TBEV serocomplex are closely related, with less
Vaccines
The first KFD vaccine was a formalin-inactivated, mouse-brain preparation of RSSEV produced by the Walter Reed Army Institute of Research at the request of the Indian Council of Medical Research, with the assistance of the Rockefeller Foundation (Aniker et al., 1962). RSSEV was known to be closely related antigenically to KFDV, and was therefore hypothesized to provide cross-protection. The RSSEV vaccine protected mice against KFDV challenge, and was more efficacious than another vaccine
Summary
KFD is a historically understudied tick-borne disease that affects hundreds of people each year in India. Seroprevalence studies and the identification of the closely related AHFV in Saudi Arabia suggest that the geographic range of KFD-like viruses may be much broader than previously thought, raising the possibility that the transport of infected ticks by birds or in shipments of infected animals could introduce KFDV into new environments. Fortunately, deaths from KFD are relatively rare, and
Acknowledgements
The author appreciates the willingness of Dr. Sulochana of the Virus Diagnostic Laboratory, Shimoga, India to provide data on the recent incidence of Kyasanur forest disease, and the assistance of Dr. Sudhanshu Vrati, Dean of the Translational Health Science and Technology Institute in Gurgaon, India. He also thanks Dr. D.T. Mourya of the National Institute of Virology, Pune, India for his careful reading of the final manuscript, and Fabian de-Kok Mercado for preparing Fig. 1, Fig. 2.
MRH is an
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