Mosquito-Borne Uveitis

Mosquitos are the most common vector for arthropod-borne (arbo-) infections, the most prevalent being malaria, which infects over 200 million people and produces more than half a million deaths globally each year.^1,2 While retinal vascular occlusions and their associated complications are well-described in the setting of malaria, uveitis per se is not a common complication of this particular parasitosis.³ In contrast, mosquito-borne viral infections can and do cause uveitis.^4–7 Among the arboviral infections, dengue virus is by far the most frequent, with 40–50% of the global population at risk of infection, resulting in an estimated annual incidence of infection between 50 and 100 million.^8,9 Although dengue virus infection is asymptomatic in the vast majority of cases, the complications of infection can be severe in some, with over 20,000 global dengue-associated deaths reported each year. Under 10% of patients with symptomatic infection caused by dengue virus have ocular complications - the most common of which are conjunctivitis and anterior uveitis.^10,11 Other mosquito-borne viruses known to cause ocular inflammation include Zika virus,^12–14 chikungunya virus,¹⁵ West Nile virus,^16,17 and Phlebovirus – the causative agent in Rift Valley fever.¹⁸ One review,¹⁹ two original articles^20,21 and five letters^22–26 in this issue of Ocular Immunology & Inflammation (OII) address various aspects of the diagnosis, clinical characteristics, management and outcome of eyes with uveitis following a mosquito-borne viral infection.

Agrawal et al¹⁹ reviewed ocular infection by Zika virus infection, an RNA arbovirus transmitted in the vast majority of cases by Aedes species of mosquitos indigenous to the tropics and subtropics, and less frequently among adults through sexual contact or from mother to infant via the placenta. Time from infection to onset of symptoms, which develop in about 20% of acutely infected patients, is typically one week. Symptoms, which tend to last seven to 10 days and are often non-specific, include headache, fever, myalgias, arthralgias and a maculopapular rash. Conjunctivitis occurs in more than half of all symptomatic patients. Acute infection may be confirmed with Real Time-Polymerase Chain Reaction (RT-PCR)-based analysis of body fluids, most typically serum, during the symptomatic phase, or through detection of neutralizing antibodies after the first week as constitutional symptoms abate. Since cross-reactivity of neutralizing antibodies against the related arboviruses Zika, dengue, chikungunya, and West Nile viruses is common, antibody-based support for infection by a specific virus requires the demonstration of either a four-fold higher single titer against that virus, Zika vs dengue or chikungunya, for example, or a four-fold rise in the anti-arbovirus antibody of interest. Treatment of acute infection should be symptomatic and supportive. In addition to conjunctivitis, less common ocular complications of Zika virus infection seen in adults include anterior or anterior with intermediate uveitis, and focal infection of the retinal pigment epithelium (RPE) producing Unilateral Acute Idiopathic Maculopathy (UAIM). As is common for acute infectious uveitis,²⁷ some subjects with active Zika-associated anterior uveitis also had acutely elevated Intraocular Pressure (IOP). Singh et al described a single subject with perifoveal microaneurysms, localized photoreceptor disruption, and a small pigment epithelial detachment in the setting of acute Zika infection.²⁸ Intraocular complications identified in up to two-thirds of all newborns infected in utero have included areas of RPE disruption, retinochoroidal atrophy, optic disc abnormalities – including hypoplasia, and retinal vascular telangiectasis. Abnormalities of ocular alignment and motility are also common. Risk factors for ocular involvement appear to include symptomatic first trimester infection and associated microcephaly.^12–14 Infants suspected of being infected in utero should undergo a dilated fundus examination shortly after birth and again at three months of age.^25,26

Lima et al²⁰ described two patients in Brazil with dengue fever who developed Purtscher-like retinopathy, including peripapillary and macular cotton-wool spots and small intraretinal hemorrhages in each eye. Localized areas of intraretinal and subretinal fluid were also seen. Spectral Domain-Optical Coherence Tomography (SD-OCT) revealed changes consistent with these findings. Vision improved and the fundus findings resolved in both patients following four to five months of supportive care.

Ng et al²¹ described two patients in Malaysia with dengue fever who developed fibrinous macular detachment with layering of the fibrinous and inflammatory material at the dependent, inferior edge of the detachment space – a finding the authors called “pseudohypopyon” formation. One patient also had moderate vitritis and retinal vasculitis. The macular detachments resolved in both patients, leaving unilateral subretinal scarring and moderate vision loss in one patient. The authors suggested that a concurrent choroidopathy may have produced the fibrinous macular detachment, but provided little direct evidence to support that hypothesis.

Akanda et al²² used multimodal imaging to characterize macular changes in a 43-year-old patient in America who developed acute dengue fever following a trip to Mexico. The patient, who described multiple scotomas in her vision, was found to have bilateral mottling of the fovea on clinical examination and localized disruptions of the photoreceptor in each eye on SD-OCT imaging. These changes improved with convalescence. Both fluorescein and indocyanine green angiographic studies were generally unremarkable. Numerous other ocular findings have been reported in patients with dengue fever, including subconjunctival and intraocular hemorrhage, anterior chamber inflammation, vitritis, retinal vasculitis, often with edema and hemorrhage. Localized thickening of the central macula producing a yellow-orange appearance to the outer fovea has been termed “foveolitis.” Inflammation of the optic nerve has also been described.^10,11

Rocha et al²³ described a 57-year old man in Brazil who developed, conjunctival injection, bilateral anterior uveitis and focal iris atrophy in each eye in the setting of acute chikungunya virus infection associated with meningoencephalitis in the setting of fever, arthralgias, myalgias, and a pruritic maculopapular rash. A single cotton-wool spot was also present. The findings resolved following treatment with topical and systemic corticosteroids, and a topical cycloplegic/mydriatic agent.

Lin et al²⁴ described a 44-year-old Dominican woman living in New York City who developed chikungunya virus infection associated with unilaterally blurred vision following a trip to the Dominican Republic. Ocular findings in the affected right eye included fine, inferior keratic precipitates, mild anterior chamber inflammation, Koeppe nodules at the iris margin, and moderate vitritis with snowball vitreous opacities. Vision improved and the inflammation resolved following a three month treatment and taper of topical and systemic corticosteroids. Other ocular findings associated with chikungunya virus infection include retinochoroiditis, retinal vasculitis, neuroretinitis, and optic neuritis.¹⁵

Together, these studies highlight the occurrence and diversity of arboviral-associated ocular complications. While conjunctivitis and anterior uveitis are the most common findings, posterior segment involvement may also occur, including vitritis, retinal vasculitis, retinochoroiditis, serous retinal detachment, and involvement of the RPE. Undoubtedly, other ocular complications will be described – including complications caused by arboviruses not yet reported to affect the eye or cause ocular inflammation. Yellow fever virus is perhaps one such example. The oldest and best-known arboviral pathogen, yellow fever virus infected large numbers of people for millennia prior to the introduction of an effective, live-attenuated vaccine in 1937. In fact, the flavivirus family draws its name from yellow fever, as “flavus” means “yellow” in Latin.²⁹ Yet, descriptions of yellow fever virus-induced ocular inflammation are not readily found in the literature. This may soon change, however, as oral reports appear to be emerging from referral centers in or near areas experiencing epidemic outbreaks (R. Belfort, Jr, personal communication).

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

FINANCIAL CONFLICTS

The authors have no financial conflicts.

Additional information

Funding

Supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).