Rift Valley fever virus (RVFV) is a tri-segmented single-stranded RNA arbovirus belonging to the genus Phlebovirus, family Phenuiviridae, order Bunyavirales3). RVFV is the causative virus of Rift Valley fever (RVF), an emerging mosquito-borne zoonotic disease that infects both humans and ruminants4).
RVF was first reported in 1930 in the Rift Valley of Kenya5). It subsequently spread to East Africa, South Africa, West Africa, Egypt, and Madagascar, and in 2000, the first major outbreak occurred in the Arabian Peninsula (Saudi Arabia and Yemen)4). During the 2000 outbreak in Saudi Arabia, approximately 883 human infections were reported, with 124 deaths4).
The majority (90–98%) of human RVF infections are asymptomatic or mild2). Symptomatic cases primarily present with influenza-like symptoms such as fever, headache, myalgia, and arthralgia1). Severe cases occur in 8–10% of symptomatic patients and are classified into three forms: hemorrhagic fever, encephalitis, and ocular disease2). Ocular symptoms appear in 0.5–15% of symptomatic cases, but during the 2000 Saudi Arabia outbreak, visual symptoms were observed in 15% of infected individuals4). The case fatality rate among hospitalized patients is reported as 21% (95% CI 14–29)1).
The male-to-female ratio is 3.5:1, with a predominance in males. Risk factors include direct contact with infected animals (farmers and livestock handlers) and exposure to mosquito bites.
There have been no reports of RVF in Japan. However, if you have traveled to an endemic area, caution is needed for onset after returning. Climate change may also expand the distribution of vector mosquitoes5).
Ocular symptoms of RVF appear unilaterally or bilaterally 5 to 14 days after the onset of systemic symptoms.
In a systematic review, blurred vision or partial blindness was observed in 24% (95% CI 7–45; 11 studies, 225 cases)1).
Ocular findings in RVF appear in both the anterior and posterior segments.
Anterior Segment Findings
Acute hemorrhagic conjunctivitis: Conjunctival hyperemia and petechiae.
Anterior uveitis: Transient inflammation with non-granulomatous keratic precipitates (KP, +1 to +3) and anterior chamber flare. Usually resolves spontaneously within 2–3 weeks.
Posterior Segment Findings
Macular and perimacular retinitis: The most specific and frequent ocular finding. Observed as well-defined necrotic lesions surrounded by ill-defined milky white patches. Associated with retinal hemorrhages.
Retinal vasculitis: Primarily phlebitis. Arteritis is rarely observed. May be accompanied by arterial occlusion and vascular sheathing.
Vitreous opacity: Due to infiltration of vitreous cells.
Optic disc edema/pallor: Observed in severe cases.
Fluorescein angiography (FA) shows early hypofluorescence of retinitis areas, delayed filling of venules and arterioles, and late staining of vessels and lesions during the active phase. Follow-up FA reveals occluded macular vessels, vascular occlusion, vasospasm, and window defects after several months.
RVFV is primarily transmitted by mosquitoes of the genera Aedes and Culex3). 73 species of mosquitoes are considered capable of transmitting RVFV5).
The routes of infection in humans are as follows.
During El Niño-Southern Oscillation (ENSO) events, mosquito breeding sites increase, leading to widespread epidemic cycles.
The following tests are used for the definitive diagnosis of RVF as recommended by the WHO5).
| Test method | Target | Remarks |
|---|---|---|
| RT-PCR | Viral RNA | Effective during viremia |
| ELISA (IgM/IgG) | Antibody | Used for serological confirmation |
| Virus isolation | Live virus | BSL3 facility required |
RT-PCR targets the L, S, and M segments, and RT-LAMP has been reported to have a detection sensitivity of 10 copies/reaction 5). Because the period of viremia is transient, it is difficult to confirm cases with molecular diagnosis alone, and combined serological testing is recommended 5).
The plaque reduction neutralization test (PRNT) is the standard for detecting neutralizing antibodies 5).
Ophthalmic evaluation is performed using the following tests.
The differential diagnosis of RVF retinitis is broad. Major infectious differentials include cytomegalovirus retinitis, herpetic retinal necrosis, syphilitic retinitis, toxoplasmic retinochoroiditis, and retinitis caused by West Nile virus, dengue virus, and chikungunya virus. Travel history from endemic areas is an important clue for differentiation.
Ocular symptoms typically appear 5 to 14 days after the onset of systemic RVF symptoms. Some reports indicate onset between 4 and 20 days. Anterior uveitis usually resolves spontaneously within 2 to 3 weeks.
Currently, there is no specific treatment for RVF approved by the FDA. Treatment is primarily supportive care.
Anterior uveitis usually resolves spontaneously within 2 to 3 weeks. Active retinitis, retinal hemorrhage, and vitreous reaction also often resolve within 10 to 12 weeks. However, scarring can result in permanent visual impairment, and vision loss has been reported in 40–50% of cases with retinal complications.
The pathogenesis of ocular complications in RVFV infection remains unclear, whether due to immune-mediated reactions or direct viral cytotoxicity.
Postmortem examination has reported localized retinal necrosis along with perivascular cuffing and degeneration of the retinal pigment epithelium (RPE) accompanied by inflammatory infiltration of round cells. However, the presence of the virus within ocular tissues has not been demonstrated.
In experimental studies using Sprague-Dawley rats, the virus was isolated from the retina, ciliary body, choroid, and optic nerve after subcutaneous infection. This study showed that RVFV has tropism for the posterior segment of the eye and demonstrated virus-mediated increases in inflammatory cytokines and leukocyte counts in ocular tissues.
The RVFV genome consists of three segments: L (large), M (medium), and S (small)3). The S segment has an ambisense polarity and encodes the N protein (nucleocapsid) and the NSs protein. The M segment encodes the glycoprotein precursor (Gn and Gc) and the NSm protein. The L segment encodes the RNA-dependent RNA polymerase3).
The NSs protein is a major virulence factor that functions as an antagonist of type I interferon (IFN)6). NSs suppresses the transcription of host IFN-β mRNA and also induces post-translational degradation of PKR (dsRNA-dependent protein kinase), enabling efficient viral protein synthesis6). This immune evasion mechanism is considered a contributing factor to disease severity.
RVFV targets dendritic cells early in infection and may affect their maturation and migration 4). Hepatocytes are the main target cells in acute RVF. RVFV shows strong neurotropism in many host species, causing encephalitis in mice, rats, hamsters, non-human primates, and humans 4).
Neutralizing antibodies target Gn and Gc glycoproteins and become detectable within one week after infection 5). RVFV has a single serotype, and cross-protection occurs between different genetic lineages 4).
WHO has designated RVFV as a priority disease with high epidemic potential, but currently no vaccine is approved for humans 4). Several animal vaccines are licensed in endemic countries.
Alkan et al. (2023) provided a comprehensive review of RVF vaccine development, outlining next-generation live attenuated vaccine candidates 4). Live attenuated vaccines based on MP-12 and Clone 13 strains, as well as ChAdOx vector vaccines, are being considered as promising candidates. Vaccination with MP-12 or arMP12-ΔNSm21/384 achieved over 80% plaque reduction against different genetic lineages of RVFV strains.
Wichgers Schreur et al. (2023) reported on the prospects of next-generation live attenuated vaccines, including a four-segment genome RVFV vaccine based on BunyaVax technology 7). These vaccines are being developed for use in both animals and humans.
Newman-Gerhardt et al. (2013) reported the possibility of an autoimmune mechanism in the development of RVF retinitis 1). The delayed onset of retinitis after systemic symptoms and the absence of virus detection in ocular tissues suggest the involvement of immunological mechanisms.
Lapa et al. (2024) reviewed the current status of RVFV diagnostic methods 5). RT-LAMP showed high sensitivity of 19 RNA copies/reaction and has potential as a point-of-care diagnostic tool. Due to the short duration of viremia, combined use of molecular diagnostics and serological tests is recommended. Applications of multiplex RT-qPCR and next-generation sequencing are also being explored.
