Hantavirus is an enveloped, negative-sense single-stranded RNA virus belonging to the family Hantaviridae. It is broadly divided into Old World and New World types.
Old World (Puumala, Hantaan, Dobrava, Seoul viruses): cause hemorrhagic fever with renal syndrome (HFRS)
New World (Sin Nombre, Andes viruses): cause hantavirus cardiopulmonary syndrome (HCPS)
Rodents are the main reservoir hosts. They shed the virus in saliva, urine, and feces, and humans become infected by inhaling aerosolized excreta. Rarely, infection occurs through rodent bites. Human-to-human transmission has been reported for Andes virus.
HFRS progresses through five stages: febrile, hypotensive, oliguric, diuretic, and convalescent. In HCPS, headache and myalgia are followed by rapid progression of respiratory failure, sometimes requiring mechanical ventilation.
Ocular symptoms are not as widely recognized as systemic symptoms. However, various ophthalmic findings have been reported, especially in nephropathia epidemica (NE), a mild form of HFRS. Ocular symptoms may precede systemic symptoms and are important as clues for early diagnosis.
QCan hantavirus be transmitted from person to person?
A
Most hantaviruses do not cause human-to-human transmission. However, human-to-human infection has been reported only for the Andes virus. The main route of infection is inhalation of rodent excreta.
Ocular findings are broadly divided into anterior segment and posterior segment findings.
Anterior Segment Findings
Transient myopia: The most frequent ocular finding, observed in up to 78% of cases [1,3]. It is accompanied by lens thickening (over 80%) and shallowing of the anterior chamber [1,5].
Intraocular pressure changes: Both elevation and reduction have been reported [1,2]. Some cases develop angle-closure glaucoma [2].
Conjunctival edema: Reported in up to 87% of affected eyes [1]. It is caused by increased capillary permeability due to endothelial dysfunction [6].
Subconjunctival hemorrhage: Occurs due to increased vascular permeability and coagulation disorders [5].
Eyelid edema and hyperemia: Occur through the same mechanism as systemic edema.
Uveitis-like findings: Anterior chamber inflammation has been reported, but whether it is true uveitis is debated.
Posterior segment findings
Retinal hemorrhage: Punctate or blot hemorrhages in the macula and linear hemorrhages around the optic disc. Associated with thrombocytopenia.
Retinal edema: Unilateral retinal edema with hemorrhage has been reported.
Posterior necrotizing retinitis: Accompanied by retinal vasculitis, with confluent whitening around the optic disc. Flame-shaped hemorrhages and venous sheathing may also be present.
Note: Posterior segment findings are rare; in one cohort, they were observed in only 1 of multiple cases [4].
Regarding uveitis-like findings, two case series reported a total of 11 cases of anterior uveitis that resolved spontaneously. In contrast, a prospective study of 92 eyes found no uveitis [1]. Because it resolves without treatment, it has been suggested that it may reflect transient vascular leakage rather than true inflammation [2].
QDo ocular symptoms of hantavirus infection leave sequelae?
A
Most ocular findings are transient and resolve during the recovery phase of systemic infection. Long-term sequelae are rare, but follow-up is recommended to confirm resolution of rare retinal lesions.
Ocular symptoms of hantavirus are due to systemic vascular endothelial damage caused by the virus. It is not an eye-specific infection but a consequence of systemic pathophysiology affecting ocular tissues.
The main factors associated with the development of ocular symptoms are as follows:
Increased vascular permeability: Endothelial cell infection via β3 integrin leads to excessive VEGF sensitivity [6]. This causes capillary leakage, resulting in conjunctival edema, eyelid edema, and subconjunctival hemorrhage.
Platelet dysfunction: Viral binding to platelets reduces circulating platelet count, inducing a bleeding tendency. Involved in retinal hemorrhage and subconjunctival hemorrhage [4].
Effect on the ciliary body: Ciliary body edema and zonular relaxation cause anterior displacement and thickening of the lens, leading to myopic shift and shallowing of the anterior chamber [5].
The risk of infection depends on the opportunity for contact with rodents. Agricultural work, outdoor activities, and cleaning in environments contaminated with rodent urine and feces are the main risk behaviors.
QWhy do eye symptoms occur?
A
The main mechanism is that hantavirus binds to β3 integrin on vascular endothelial cells, increasing vascular permeability. Plasma leakage from ocular microvessels causes conjunctival edema and eyelid edema, and changes in the ciliary body lead to myopia and intraocular pressure fluctuations. For details, see the “Pathophysiology” section.
The diagnosis of hantavirus infection is primarily based on systemic serological testing. Ophthalmic evaluation is used to identify and follow up on ocular complications.
Anti-hantavirus IgM/IgG ELISA: This is the gold standard for definitive diagnosis. IgM peaks about one week after infection. IgG peaks during the convalescent phase.
Slit-lamp examination: Used to assess shallow anterior chamber, anterior chamber inflammation (cells, flare), conjunctival edema, and injection.
Tonometry: Continuous measurement to monitor both low intraocular pressure and elevated intraocular pressure.
Autorefractor: Measurement under cycloplegia to quantify transient myopic shift. A myopic change of -0.50 diopters or more is a diagnostic indicator.
Dilated fundus examination: Detects posterior segment lesions such as retinal hemorrhage, edema, and necrotizing retinitis.
Anterior segment OCT/ultrasound biomicroscopy: Useful for evaluating ciliary body edema and choroidal detachment. In some cases, elevated intraocular pressure with choroidal detachment has been reported.
Most ocular findings in hantavirus infection are transient and self-limiting. They often resolve with supportive care and observation. Systemic management is the priority, and multidisciplinary collaboration with infectious disease, nephrology, and pulmonology specialists is essential.
Systemic Treatment
Supportive care: ICU management is fundamental for close monitoring of hemodynamic and respiratory status.
Fluid management: Correct hypotension but avoid excessive fluid due to risk of pulmonary edema.
Respiratory support: In HCPS, mechanical ventilation or ECMO may be required. Early ECMO initiation has been reported to have an 80% survival rate.
Ribavirin: Intravenous administration in early HFRS has shown a reduction in viral load. Evidence in HCPS is insufficient.
Coagulopathy management: For bleeding, maintain platelet count ≥50×10⁹/L with platelet transfusion.
Ophthalmic Treatment
Refractive changes: Usually no intervention is needed; they resolve spontaneously as the systemic infection recovers.
Persistent elevated intraocular pressure: Rarely requires treatment. Prostaglandin analogs are first-line, but in cases with active uveitis, aqueous suppressants are preferred.
Uveitis-like findings: If anterior chamber inflammation is confirmed, consider steroid eye drops and cycloplegics. Monitor intraocular pressure changes.
Follow-up: Short-term ophthalmic follow-up after recovery is recommended.
QIs specific treatment for ocular symptoms necessary?
A
Most ocular findings resolve spontaneously with recovery from systemic infection, so no specific ophthalmic treatment is needed. However, if persistent intraocular pressure elevation or significant anterior chamber inflammation is present, consider using antiglaucoma medications or steroid eye drops.
Hantavirus binds to β3 integrin, which is highly expressed on microvascular endothelial cells, and enters the cells. β3 integrin normally regulates the endothelial response to VEGF. Viral binding disrupts this regulation, leading to excessive VEGF sensitivity and increased vascular permeability [6].
Furthermore, infected cells show increased activity of factor XII and kallikrein. This enhances bradykinin production, promoting vasodilation and leakage.
CD8-positive T cells release inflammatory cytokines such as TNF-α and IFN-γ. These cytokines destabilize intercellular junctions of endothelial cells, further increasing vascular permeability.
Viral binding to platelets via β3 integrin promotes platelet sequestration. While circulating platelet count decreases, infected endothelium becomes hyperadhesive, and platelets coat the vessel wall. These changes impair hemostatic function, contributing to mucosal bleeding, subcutaneous hemorrhage, and coagulation disorders.
Similar permeability mechanisms operate in ocular tissues.
Myopia and shallow anterior chamber: Ciliary body edema and zonular relaxation cause the lens to move forward and thicken. Lens thickening has been confirmed in over 80% of cases [1]. This leads to refractive myopia [5].
Increased intraocular pressure: Caused by ciliary body edema/hemorrhage, anterior uveitis, and angle closure due to forward lens movement. Cases with choroidal detachment have also been reported.
Decreased intraocular pressure: Presumed to be due to a temporary reduction in aqueous humor production caused by ciliary endothelial dysfunction.
Conjunctival edema and subconjunctival hemorrhage: Caused by leakage of plasma and red blood cells from ocular microvessels.
Retinal hemorrhage: Bleeding tendency due to thrombocytopenia and coagulopathy extends to retinal vessels.
All of these conditions reflect temporary changes in vascular integrity rather than direct structural damage to ocular tissues. Therefore, they resolve during the recovery phase.
7. Latest Research and Future Perspectives (Investigational Reports)
Currently, there is no hantavirus vaccine approved by the FDA or WHO. Inactivated orthohantavirus vaccines have been developed and introduced in China and South Korea, with good safety and protective efficacy reported in endemic areas. However, large-scale randomized data are limited, and the long-term durability of protection is under evaluation.
As a future prevention strategy, DNA vaccines targeting viral subunit antigens are in preclinical and early clinical stages.
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