Kyasanur Forest Disease (KFD) is a tick-borne zoonotic disease caused by the Kyasanur Forest Disease virus (KFDV), a single-stranded positive-sense RNA virus belonging to the genus Flavivirus in the family Flaviviridae. It is also known as “monkey fever.”
First identified in 1957 in the Kyasanur Forest of Karnataka, India 1). Since then, approximately 400–500 cases are reported annually as an endemic disease in South India 3). Traditionally confined to Karnataka, it has recently spread to Kerala, Tamil Nadu, Goa, and Maharashtra 1).
KFD follows a biphasic clinical course.
The case fatality rate is reported as 3–5%, but ranges from 2–10% depending on the report 1)2). Human-to-human transmission has not been reported.
This section focuses on the ocular findings associated with KFD.
KFD is endemic in South India and has not been reported in Japan. It should be considered as a differential diagnosis if there is a history of travel to endemic areas.
Ocular subjective symptoms in KFD are as follows.
Systemic symptoms include sudden high fever, frontal headache, myalgia, and gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea)2). Hemorrhagic symptoms (epistaxis, gingival bleeding) are observed in about 10-15% of cases2).
Ocular findings in KFD are presumed to result from viral hemorrhagic diathesis or immune-mediated reactions, but the pathophysiology in the eye has not been fully elucidated.
Anterior segment findings
Conjunctival hyperemia: the most common finding. Accompanied by palpebral conjunctival hyperemia and serous discharge.
Subconjunctival hemorrhage: a finding reflecting hemorrhagic diathesis.
Punctate superficial keratitis: Punctate erosion of the corneal epithelium.
Iritis: Mild to moderate anterior chamber inflammation may be present.
Posterior segment findings
Retinal hemorrhage: Superficial and deep retinal hemorrhages are observed.
Hard exudates: Lipid deposits within the retina.
Vitreous hemorrhage: May occur in severe cases.
Papilledema: May be observed secondary to increased intracranial pressure following encephalitis.
Characteristic systemic laboratory findings include leukopenia, thrombocytopenia, and elevated liver enzymes1)2). Lymphopenia can be severe.
Khalid et al. (2025) reported oral candidiasis in 7 patients with KFD phase 15). All patients had lymphopenia, and no other immunosuppressive factors were identified. This finding suggests transient immunosuppression and opportunistic infection in KFD.
In most patients, recovery begins 14 days or more after infection. Ocular symptoms also often resolve spontaneously, but in some cases, decreased vision, photophobia, and eye pain persist longer. Long-term sequelae are considered rare.
KFDV primarily infects humans through the bite of the tick Haemaphysalis spinigera1). Other ticks such as H. turturis and H. kinneari may also transmit the virus. Humans are dead-end hosts, and human-to-human transmission does not occur.
Contact with infected animals (especially monkeys shortly after onset or death) is also a route of infection.
Main risk factors are as follows.
Human-to-human transmission of KFD has not been reported. Infection occurs only through tick bites or contact with infected animals (mainly monkeys)1).
Diagnosis of KFD is difficult due to symptom overlap with other febrile illnesses such as dengue fever and malaria. Suspect the disease based on exposure history in endemic areas and clinical presentation; laboratory confirmation is required1).
The main tests are shown below.
| Test | Features | Notes |
|---|---|---|
| Real-time RT-PCR | High sensitivity and specificity | Useful in early stage of disease |
| IgM capture ELISA | Detection of acute infection | Positive for about 4 months |
| Truenat KFD | Point-of-care test | Usable in remote areas |
Blood tests reveal the following abnormalities:
The following diseases with ocular findings and hemorrhagic fever are considered in the differential diagnosis:
There is no FDA-approved specific treatment for KFD1). Treatment is mainly supportive.
There is no specific treatment for ocular complications; symptomatic therapy is the mainstay. For iritis, mydriatics and steroid eye drops may be considered.
Since 1990, a formalin-inactivated tissue culture vaccine has been administered in KFD-endemic areas1).
A formalin-inactivated tissue culture vaccine is used in endemic areas, but its efficacy after two doses is only about 67% 1). A third booster dose increases efficacy to 82.9%, but the duration of protection is short, and improvements are needed.
KFDV enters the human body through the skin when an infected tick bites. The virus is taken up by macrophages and antigen-presenting cells and transported to organs throughout the body 1).
The progression mechanism of infection is as follows:
The pathogenesis of ophthalmic findings is thought to involve vascular damage due to viral hemorrhagic diathesis and immune-mediated inflammatory reactions, but the detailed pathophysiology in the eye remains unclear. Thrombocytopenia and coagulation disorders are believed to contribute to subconjunctival hemorrhage, retinal hemorrhage, and vitreous hemorrhage. Papilledema is presumed to result from increased intracranial pressure associated with meningoencephalitis in the second phase.
KFDV has been reported to induce neuronal apoptosis in experimental animals, causing brain tissue damage in the cerebellum, cerebral cortex, and hippocampus 1). This neural damage may contribute to visual disturbances in the second phase.
Development of specific therapeutic drugs is being explored. The main candidate drugs are shown below.
| Drug Name | Mechanism of Action | Development Stage |
|---|---|---|
| Sofosbuvir | NS5 RdRp inhibition | In vitro activity confirmed |
| NITD008 | Nucleoside analog | Computational model / in vitro |
| EGCG | NS3 helicase inhibition | In silico |
Sofosbuvir and its active metabolite have been reported to inhibit the RNA-dependent RNA polymerase activity of the nonstructural protein NS5 of KFDV1). However, in vivo studies have not been conducted.
NITD008 is a nucleoside analog inhibitor widely used for flavivirus infections, and computational models and in vitro studies have shown activity against KFDV4). In vivo validation is essential for clinical application.
Because the current vaccine has limited efficacy, development of next-generation vaccines is underway.
A live attenuated vaccine using the VSV (vesicular stomatitis virus) platform has shown efficacy in primate models, preventing the onset of KFD with a single dose1). It has also been confirmed to induce cross-protection against Alkhurma hemorrhagic fever virus (a variant of KFDV).
Other candidates, such as subunit vaccines based on envelope protein, NS1, and NS5 proteins, as well as banana-based oral vaccines, are also in the exploratory stage1).
Development of RT-LAMP assays and multi-pathogen simultaneous detection methods using viral metagenomics is underway1). Machine learning-based outbreak prediction models are also being considered1).
