Elsevier

Antiviral Research

Volume 96, Issue 3, December 2012, Pages 353-362
Antiviral Research

Review
Kyasanur forest disease

https://doi.org/10.1016/j.antiviral.2012.10.005Get rights and content

Abstract

In the spring of 1957, an outbreak of severe disease was documented in people living near the Kyasanur forest in Karnataka state, India, which also affected wild nonhuman primates. Collection of samples from dead animals and the use of classical virological techniques led to the isolation of a previously unrecognized virus, named Kyasanur forest disease virus (KFDV), which was found to be related to the Russian spring-summer encephalitis (RSSE) complex of tick-borne viruses. Further evaluation found that KFD, which frequently took the form of a hemorrhagic syndrome, differed from most other RSSE virus infections, which were characterized by neurologic disease. Its association with illness in wild primates was also unique. Hemaphysalis spinigera was identified as the probable tick vector. Despite an estimated annual incidence in India of 400–500 cases, KFD is historically understudied. Most of what is known about the disease comes from studies in the late 1950s and early 1960s by the Virus Research Center in Pune, India and their collaborators at the Rockefeller Foundation. A report in ProMED in early 2012 indicated that the number of cases of KFD this year is possibly the largest since 2005, reminding us that there are significant gaps in our knowledge of the disease, including many aspects of its pathogenesis, the host response to infection and potential therapeutic options. A vaccine is currently in use in India, but efforts could be made to improve its long-term efficacy.

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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