Ocular Manifestations of Mpox

Abstract

Purpose of review:

To highlight the clinical features of mpox with an emphasis on ocular manifestations and to review treatment options for this re-emerging infectious disease.

Recent Findings:

Ocular involvement of mpox varies by clade. The most recent 2022 outbreak appears to be associated with fewer conjunctivitis cases compared to previous outbreaks. However, the ocular findings occurring during this newly emerging clade can be visually threatening and include cases of keratitis, rapidly progressing scleritis, and necrotizing periorbital rashes.

Summary:

Ocular mpox is an important clinical feature of systemic mpox virus (MPXV) infection. Heightened clinical suspicion allows for a timely diagnosis and the initiation of anti-viral treatment, when appropriate. Randomized clinical trials for mpox systemic and ocular treatment efficacy are lacking. Prior clinical experience with smallpox and in-vitro mpox data support the use of systemic antivirals such as tecovirimat, cidofovir, brincidofovir and topical use of trifluridine in ocular mpox management, though treatment-resistant infection can occur and portend a poor prognosis.

Introduction

Mpox is one of several re-emerging infectious diseases. Similar to other emerging and re-emerging infectious diseases (e.g. COVID-19, Ebola, Zika) ocular involvement contributes to the overall clinical burden of disease.

This review will summarize the virology and epidemiology of mpox. We will review the systemic manifestations of this disease. Ocular manifestations and treatment options will be highlighted.

Virology

Mpox is the preferred term for the viral illness caused by the mpox virus (MPXV). MPXV is an enveloped double-stranded DNA virus belonging to the Orthopoxvirus genus in the Poxviridae family. Other members of the Orthopoxvirus genus include the cowpox and smallpox viruses. Mpox binds to surface cell glycosaminoglycans and enters host cells by endocytosis. MPXV DNA replication progresses within cytoplasmic structures called factories[1] During the rapid viral replication cycle, mature virions are produced, fuse to the host cytoplasmic membranes and exit the cell[2].

The MPXV genome is approximately 197 kb and encodes 200 proteins[3]. Like other poxviridae, genes responsible for transcription, replication, and assembly, are located in a relatively conserved central coding region. The sequences located at the ends of the genome are more variable and contain genes attributable to pathogenicity and immunomodulation[4].

MPXV genetic sequences are classified into clades. Clade is nomenclature for a group of organisms that include a common ancestor. Clade I describes the virus transmitted originally in Central Africa/Congo Basin. Clade II describes the virus initially transmitted in West Africa. The genome from the most recent outbreak is being classified and is often referred to as Clade IIB and/or Clade III[5–7].

Epidemiology

The first human case of mpox was reported in 1970 in a 9 month old boy from the Democratic Republic of the Congo in 1970.[8] Over the next several decades, mpox occurred sporadically in Central and East Africa (Clade I) and West Africa (Clade II). Clade I is associated with a higher case fatality rate (10.6 %) than the Clade II (3.6 %) [9].The first human case of mpox outside of Africa was in 2003 in the USA and was associated with infected animal contact from the exotic animal trade[10]. Since 2018 and escalating rapidly since 2022, mpox has been diagnosed in numerous countries across the globe. In July 2022, the World Health Organization declared mpox a public health emergency of international concern [11]. From January 2022 through April 2023, over 87,000 laboratory-confirmed cases from 111 countries/territories of mpox had been reported to the WHO. This report included 130 deaths [12] This estimate underestimates the true global burden of disease as not all cases are laboratory confirmed.

Mpox can affect all humans of any age who have had exposure to the MPXV. The median incubation period after virus contact to the development of systemic symptoms is 7 days[13]. In the most recent outbreak, mpox has been more commonly identified in men who have sex with men communities [14, 15]. Spread of MPXV can occur with close contact skin-to-skin contact, (including sexual contact), through saliva, mucous membrane exposure, respiratory droplets, environmental contamination, contact with infected animals, or vertical (maternal–fetal) transmission[16, 17]. MPXV is detectable in semen[18]. Semen to eye[19] and hand to eye MPXV transmission can occur. As with prevention of any infectious disease, handwashing and avoidance of hand-eye contact are key in prevention of disease.

Systemic Findings of Mpox

Mpox shares many similar clinical features with infections caused by other pox viruses[20]. The natural history of mpox is described in phases. The first phase is characterized by prodromal symptoms including fever, lymphadenopathy, myalgia, headache, as well as mild respiratory illness and usually lasts for 1–2 weeks[21, 22]. An umbilicated vesicular rash is the predominant finding of the next phase, which spreads from the face down. Unlike chickenpox, skin lesions usually appear simultaneously and follow a centrifugal distribution at each site[23]. MPXV can stimulate the development of any number of skin pox lesions range from a few to thousands. Occasionally the pox lesions can be painful enough to require hospitalization for pain control until crusting over occurs [21]. Identification of lymphadenopathy, in particular inguinal lymphadenopathy, and anogenital rash are helpful in distinguishing between mpox and smallpox[14].

In most cases, the infection is self-limiting, and the rash resolves within 2 weeks[24]. However, pediatric, pregnant, and immunocompromised patients may progress to severe, disseminated disease with sepsis, pneumonia, encephalitis, and globe-threatening eye infections[25–30]. Mortality occurs at a rate of 0.1–10% and varies with each clade [30, 31] The 1988 mpox outbreak in Zaire (now present day Democratic Republic of Congo) reported a 10% mortality rate (33 deaths among 338 mpox patients). In that outbreak, all deaths occurred in unvaccinated children between 3 months and 8 years old[32]. Between May 2022 and March 2023, the CDC reported 38 deaths among 30,235 cases (0.1%), with the majority fatalities (93.9%) occurring in immunocompromised patients with HIV infections[33].

Ocular Findings of Mpox

Mpox ophthalmic disease can be subcategorized into external and ocular infections. The external infection is characterized by the presence of a vesicular rash on the skin of the eyelids and periorbital region. [32, 34]. These lesions are identical to the cutaneous pox lesions elsewhere on the body (Figure 1) [35–37]. A retrospective review of 40 patients hospitalized for mpox in Nigeria between September 2017 and December 2018 demonstrated 25% developed a pox rash around the eye [38].

Figure 1.

Mpox Eyelid Vesicles. Active umbilicated pox lesions (left). Healing and crusted mpox lesions(right).[37]

Ocular disease represents MPXV infections of the globe with or without a pox rash on the surrounding periorbital skin. Pox lesion may develop directly on the conjunctiva. Mpox related conjunctivitis, scleritis, keratitis and uveitis have all been reported [25]. In the 2014 Clade I outbreak, conjunctivitis was the most common ocular complication, reported in 23.1%. In this outbreak, the presence of conjunctivitis was associated with more severe systemic disease[39]. The 2022 outbreak appears to be associated with fewer cases of conjunctivitis. In 528 cases diagnosed in 16 countries between April and June 2022, conjunctivitis was reported in only 3 patients (0.6%)[21]. Another series of 197 cases in London between May and July 2022 reported 2 patients with conjunctivitis (1.0%)[40]. Mpox related conjunctivitis can take a variety of forms including follicular, serpiginous (described as white, infiltrative, and thickened conjunctiva), nodular, ulcerative, pseudomembranous, and can occur with and without conjunctival pox lesions.[41–44] (FIGURE 2). Conjunctivitis and/or conjunctival pox lesions may develop before eyelid skin pox lesions are noted[42]. A subconjunctival nodule with only mild sectoral hyperemia has been reported[45].

Figure 2.

Mpox Associated Serpiginous Conjunctivitis[42]

Corneal involvement can occur with mpox. Ulcerative keratitis can cause corneal scarring leading to significant visual morbidity. Clade I reported a 4.1% incidence of keratitis and corneal ulceration[32]. Ulcerative keratitis is also occurring in this most recent outbreak[24, 34, 46, 47]. Blepharoconjunctivitis can accompany keratitis [48]. Some corneal ulcers are non-healing or slow to heal suggesting a neurotrophic component to the mpox keratitis [19, 49]. Of note, corneal ulceration, perforation, and disciform keratitis are also known visually threatening complications of smallpox[50].

Mpox associated uveitis can occur as anterior uveitis [49, 51], disciform keratitis with endothelial plaques and keratic precipitates, [19, 52] and scleritis[19, 53]. Notably, prolonged use of cidofovir for any indication, including for the treatment of mpox, can result in drug induced uveitis and hypotony.

In general, ocular involvement occurs with systemic symptoms and pox lesions. However ocular-only mpox, with no systemic symptoms or skin lesions, has been described [19]. Here (FIGURE 3), a vaccinated patient with no pox lesions presented with episcleritis which progressed to vision-threatening scleritis, keratitis and uveitis. In this case, MPXV was detected in the anterior chamber. In addition, repeat ocular surface swabs for MPXV PCR remailed positive for several months. This patient ultimately lost vision despite aggressive and long-term topical and systemic anti-viral treatment.

Figure 3.

Ocular only mpox. No skin lesions with nasal episcleritis (upper left) progresses to necrotizing sclerokeratitis with a neurotrophic cornea and persistently positive MPXV detection from the ocular surface[19].

Unvaccinated and immunocompromised individuals experienced more severe and frequent ocular manifestations compared to their vaccinated counterparts[54]. Systemically and visually devastating pan-facial gangrene with ocular rupture has been described in immunocompromised patients with both mpox and AIDS. Both patients died secondary to mpox systemic complications[54].

As mpox related ocular involvement can be visually threatening, any patient with mpox-related periocular pox lesions should be seen by an ophthalmologist. Immunocompromised patients with periocular involvement, especially when associated with a red eye should be referred for urgent evaluation.

Eye Treatment

Currently there are no definitively established antiviral regimens for the treatment of ocular mpox[55]. Trifluridine 1% is effective against herpetic keratitis and was the preferred treatment for ocular vaccinia following exposure to smallpox ACAM2000 vaccinees in 2004 [56–58]. Because of this and due to the fact that mpox is a DNA virus, the CDC recommends consideration of topical trifluridine 1% in cases of mpox ocular infections[55]. When combined with appropriate systemic antiviral therapy, topical trifluridine may help clear mpox associated conjunctivitis[24, 59]. Topical trifluridine is limited by drug-induced corneal epithelial toxicity[60] and long term use is generally avoided. As with other ocular viral infections, when corneal epithelial defects are present, it is important to consider a topical antibacterial agent to prevent or treat a bacterial superinfection. In isolated cases of ocular mpox, topical ganciclovir gel and povidone iodine drops (0.6–1%) have been trialed[42, 61]. Frequent topical lubrication is also recommended to improve ocular comfort[62]. Topical corticosteroids are contraindicated, as use was associated with treatment resistance and keratoplasty graft failure in corneal cowpox infections[63].

Systemic Treatment

There is no systemic treatment approved specifically for mpox. However, because mpox and smallpox share similarities in viral structure and clinical presentation, anti-virals effective against smallpox are commonly used to treat mpox. Examples of theses anti-virals include tecovirimat, cidovovir, and brincidofovir [64]. Several of these anti-virals have also shown efficacy against MPXV in vitro [65]. Tecovirimat works by preventing viral replication and release. It can be administered orally or intravenously. Cidofovir and brincidofovir both work by interfering with viral DNA polymerase. Cidofovir is only available as an intravenous infusion and carries a risk of nephrotoxicity [66]. Systemic cidofovir can also be associated with hypotony and drug-induced uveitis, so special consideration and monitoring must be made in patients with mpox related uveitis. Brincidofovir is the prodrug of cidofovir, is available both orally and intravenously, is reported to be less nephrotoxic[67] and may carry some risk of hepatotoxity[68]. As with many viral illnesses, systemic treatment is not always indicated. The vast majority of patients infected with MPXV have mild systemic symptoms and recover without specific treatment. In some cases, supportive care for nausea, vomiting, dehydration or local pain is required. However, anti-viral systemic treatment is typically recommended for immunocompromised patients[69] because this population is high risk for the development of severe disease. Here, tecovirimat commonly being used as a first line systemic antiviral therapeutic. Administration of a smallpox vaccine has protection against the development of mpox[70]. This vaccine is recommended for adults who are at high-risk for exposure to MPXV[71].

Other Eye-Specific Mpox Considerations

To date there are no known cases of mpox transmission after solid organ or corneal transplant. To reduce the theoretical risk of mpox transmission via transplanted ocular tissue, the Eye Bank Association of America issued an informal guidance in July 2022 advising a twenty-one day avoidance period of any donated eye tissue associated with donors with new pox lesions, or who tested positive for any Orthopoxvirus including MPXV, or who had close contact with mpox-infected individuals[72]. However, in rare cases, MPXV can continue to be detected on the ocular surface for several months [19][44]. It is up to the discretion and risk benefit analysis of the eye surgeon to accept tissue beyond this recommended, but not data-driven, 21-day hold period.

Conclusion

Ophthalmology continues to have an important role in the identification of emerging and re-emerging infectious diseases. Mpox, as with other orthomyxovirdae can present with ocular manifestations. Mpox related eye findings range from self-resolving conjunctivitis to blinding keratitis and scleritis. Clinical suspicion for mpox should be considered in all high-risk groups.

Familiarity with the epidemiology and systemic manifestations of mpox will allow ophthalmologists to consider mpox in the differential diagnosis any patient with skin lesions and a red eye. Particularly heightened clinical suspicion for mpox is important in all immunocompromised individuals with ocular inflammation.

Key points:

• An umbilicated vesicular skin rash and inguinal lymphadenopathy are important systemic features of mpox.

• Ocular mpox may be characterized by periorbital skin lesions with or without conjunctivitis, conjunctivitis with or without skin pox lesions, scleritis, keratitis and anterior uveitis.

• Populations at risk for severe, life-threatening mpox related systemic disease and visual-threatening eye infections include young children, and immunocompromised and unvaccinated individuals.

• For immunocompromised patients and patients with severe mpox, systemic treatment (tecovirimat, cidofovir or brincidofovir) and ocular (trifluridine 1%) can be used. However, recalcitrant disease does exist and can result in devastating systemic and visual outcomes.