Monkeypox-Associated Disciform Keratitis

Purpose:

The purpose of this study was to describe a case of monkeypox (MPX)-associated disciform keratitis.

Methods:

This is a case report.

Results:

A 36-year-old male patient presented to the infectious diseases clinic with a 1-week history of disseminated pustular skin lesions, a 4-day history of constitutional symptoms, and redness in the left eye. Testing of blood, 2 skin lesions, and a conjunctival swab confirmed the presence of MPX virus by polymerase chain reaction. On ophthalmologic examination on the 17th day of illness, there was a corneal epithelial ridge that stained with fluorescein with disciform corneal edema and underlying keratic precipitates. The patient was treated with oral tecovirimat 600 mg twice a day for 14 days and topical prednisolone acetate 1% 4 times daily, starting 2 days later. On completion of oral treatment, his corneal findings had resolved except for a small subepithelial scar at which time topical steroids were tapered.

Conclusions:

MPX may cause disciform keratitis and scarring that closely resembles other ocular viral infections. Clinical trials are urgently needed to define the optimal management of human MPX infections and reduce vision loss.

Monkeypox (MPX) infection is caused by MPX virus, which is part of the Poxviridae family, Orthopoxvirus genus. The virus is endemic in central and western Africa, with the first case reported in Congo in 1970.¹ The systemic manifestations of MPX may seem similar to smallpox, another orthopoxvirus,² and include a constellation of signs and symptoms that permit clinical diagnosis in the absence of laboratory testing. In this case report, we describe a case of MPX-associated disciform keratitis proven by real-time multiplex polymerase chain reaction (PCR).

CASE REPORT

A 36-year-old male patient presented to the infectious diseases clinic of a quaternary care academic hospital on day 7 after onset of a disseminated skin rash, including the staggered development of papular and pustular lesions on the face, scalp, torso, genitals, arms, and legs. He was also noted to have conjunctival injection of the left eye but attributed this to overuse of contact lenses for over 2 weeks. Four days before presentation (day 3), he had developed fever, chills, myalgias, joint pain, back pain, fatigue, and night sweats. On day 5, he had developed a sore throat. He was otherwise healthy, and his only medication was daily oral tenofovir disoproxil fumarate/emtricitabine as HIV pre-exposure prophylaxis. He had no significant ocular history and was not immunocompromised. Two days before his symptom onset, he had engaged in oral sex, giving and receiving, with a semiregular male partner who had subsequently been diagnosed with MPX infection. Four days before his symptom onset, he had engaged in unclear sexual activities with a different male partner for whom no further health information was available. He was advised to self-isolate according to public health guidance and use analgesia and antipyretics for supportive care and discontinue use of contact lenses.

Swabs of a lip lesion, torso lesion, and the left conjunctiva, as well as a blood sample were collected at the initial day 7 visit and were reported 3 days later to show evidence of MPX virus by PCR (Table 1). Despite multiple attempts, the patient could not be reached for follow-up until 10 days after the initial assessment, on day 17, and he reported that he had been sleeping excessively because of his illness and not answering his telephone. By that point, his systemic symptoms and skin lesions had improved significantly, but his red eye persisted and he described ongoing blurred vision and photophobia. Repeat swabs of multiple cutaneous sites, the nasopharynx, and the left conjunctiva from day 17 were again positive for MPX by PCR (Table 1). Conjunctival swab of the left eye from day 17 was negative for herpes simplex virus (HSV) types 1 and 2, varicella zoster virus, and cytomegalovirus by PCR. He was urgently referred to ophthalmology and initiated on oral tecovirimat 600 mg twice daily on day 18.

TABLE 1.

Detection of Monkeypox Virus DNA by Polymerase Chain Reaction in a Patient With Disciform Keratitis

Day of Illness	Anatomic Site	Monkeypox Virus PCR Result (Cycle Threshold)	West African Clade Monkeypox Virus PCR Result (Cycle Threshold)	On Tecovirimat Therapy?
7	Conjunctiva	Detected (26.83)	Detected (26.84)	No
7	Back ulcer	Detected (22.77)	Detected (22.84)	No
7	Lip ulcer	Detected (30.06)	Detected (29.94)	No
7	Blood	Detected (33.67)	Detected (32.49)	No
17	Conjunctiva	Detected (31.18)	Detected (31.02)	No
17	Hand ulcer	Detected (15.8)	Detected (15.73)	No
17	Foot: ulcer	Detected (28.44)	Detected (28.15)	No
17	Nasopharynx	Detected (33.28)	Detected (33.41)	No
20	Conjunctiva	Not detected	Not detected	Yes
26	Conjunctiva	Not detected	Detected (36.98)	Yes
26	Back papule	Detected (36.90)	Detected (37.91)	Yes
33	Back papule	Detected (37.52)	Not detected	No
34	Conjunctiva	Not detected	Not detected	No
40	Back papule	Detected (35.39)	Detected (36.24)	No

On his initial day 17 ophthalmic examination, no skin lesions were noted on the eyelids or the face. The best-corrected visual acuity was 20/20 and 20/50 in the right and left eyes, respectively. The intraocular pressure was 10 mm Hg in the right eye and 12 mm Hg in the left eye. On slitlamp examination, there was diffuse conjunctival injection of the left eye and a corneal epithelial ridge that stained with fluorescein, disciform corneal edema, and underlying keratic precipitates (Fig. 1). There was a 1+ grade of anterior chamber cellular reaction with no flare. Dilated fundus examination was normal. Examination of the fellow eye was within normal limits. On day 20, given the persistent disciform keratitis appearance and minimal fluorescein staining, topical prednisolone acetate 1% 4 times a day was added.

FIGURE 1.

A slitlamp photograph of patient's left eye showing an irregular corneal epithelial ridge, which stained with fluorescein and disciform keratitis (stromal edema with underlying keratic precipitates).

Over the ensuing 2-week interval, between days 18 to 31, his systemic and dermatologic symptoms nearly completely resolved, but his complaints of blurred vision and photophobia worsened despite full adherence to the prescribed regimen. Repeat conjunctival swabs for MPX PCR were negative on day 20, weakly positive on day 26, and negative on day 34 (Table 1). Despite therapy, new, painless papules were noted on physical examination of the patient's back (Fig. 2), which were positive for MPX PCR on days 26 and 33.

FIGURE 2.

Photograph of papules noted on physical examination of the patient's back on day 26 which were positive for monkeypox polymerase chain reaction and emerged while receiving tecovirimat 600 mg twice daily.

At the patient's most recent visit (day 34), his symptoms were improved. The best-corrected pinhole vision in the left eye was 20/40, the conjunctival injection and corneal edema had resolved, but a small subepithelial corneal opacity remained (Fig. 3). The topical prednisolone acetate 1% was tapered.

FIGURE 3.

A slitlamp photograph of patient's left eye demonstrating subepithelial corneal scarring (3 weeks after initiation of oral tecovirimat and topical steroids).

DISCUSSION

To the best of our knowledge, this is the first reported case of PCR-positive MPX corneal involvement, with endothelial disease, keratic precipitates, disciform stromal edema, and iritis. Our patient was treated with oral tecovirimat and topical steroids and achieved resolution of corneal findings with mild visual compromise due to residual small subepithelial scar. Between 2010 and 2014, MPX was reported to cause conjunctivitis in 23.1% (68/294 cases) in the Democratic Republic of Congo, a country in which MPX is endemic.³ In a study on 282 people with MPX in the Democratic Republic of Congo during 1980 to 1985, conjunctival and eyelid margin lesions were noted among 17% and 13% of unvaccinated and vaccinated patients, respectively.⁴ By contrast, in the most current global outbreak of MPX, afflicting over 16,000 individuals as of 25 JUL 2022,⁵ reports of ocular involvement have been rare; a recent international case series found that only 3/217 individuals with available data had eye involvement.⁶ This difference may reflect differences in data ascertainment, early self-isolation periods during which time patients are not being seen, early treatment, or a difference in viral tropism. This is not currently understood. Recently, 2 cases of PCR-proven MPX eyelid and conjunctival vesicular infection were published.^7,8

The ophthalmic presentation of this case resembles ocular vaccinia and herpes simplex keratitis type-1 disciform keratitis^9,10 and the former typically occurring because of accidental inoculation of the eye by live attenuated smallpox virus during vaccination¹¹ and the latter which is related to the ocular immune system's response to latent virus residing in the trigeminal ganglion.¹⁰ Ocular vaccinia and HSV-1 are both reported to cause conjunctivitis, epithelial keratitis, disciform stromal keratitis, interstitial keratitis, endothelial keratitis, and iritis.^9,10 After treatment, our patient's best-corrected pinhole vision reached 20/40, with a subepithelial corneal scar evident on examination. Unfortunately, corneal topography was not performed to assess for astigmatism secondary to corneal scarring. Ocular vaccinia may result in residual stromal scarring and opacification.¹¹ Other sequelae of ocular vaccinia include stromal necrosis, corneal perforation, and neovascularization.⁹ Cowpox, another orthopoxvirus, was reported in one case in Finland to cause corneal melting requiring corneal transplantation.¹² The ability of MPX virus to cause stromal scarring underscores the importance of initiating treatment early in the disease process.

The goal of treatment in our case was to reduce the viral load, lessen severity of the corneal inflammation, and shorten the course of the disease, thus providing a combination of antiviral and anti-inflammatory approaches. However, the optimal antiviral therapy for MPX infection at any anatomic site remains unknown. Topical trifluridine 1% 9x/day is recommended to be used, off-label, in conjunctival and corneal involvement in ocular vaccinia.⁹ However, owing to its unavailability in Canada and potential ocular toxicity, trifluridine was not used in this case. Instead, the patient was treated with oral tecovirimat, the first antiviral that was approved by the US Food and Drug Administration in the treatment of smallpox.¹³ The drug is also approved by Health Canada in the treatment of adults and children (≥13 kg) with smallpox.¹⁴ In smallpox, tecovirimat was shown to reduce skin lesions and viral shedding and shorten the time of PCR positivity.¹⁵ The European Medicines Agency recently approved tecovirimat in MPX infection.¹⁶

Importantly, however, MPX infection is reported to resolve spontaneously without specific therapy,¹⁷ and there are no clinical trial data at this time that demonstrate the superiority of tecovirimat over supportive care alone for the management of human MPX infection. The fact that the patient in the presented case developed new PCR-positive lesions on his back while still receiving tecovirimat raises further uncertainty about the clinical role of this treatment. Owing to the presence of stromal and endothelial involvement in this case, a decision was made to start topical prednisolone acetate 1% to reduce the immune-mediated component of disease. In addition, given the epithelial ridge and fluorescein staining on ophthalmic slitlamp examination, we believe that several days of antiviral therapy to initiate clearing of active MPX and to allow the epithelium to heal would be beneficial before initiating topical steroids to treat the inflammatory findings, using similar principles used when treating HSV keratitis: combined antiviral and topical steroids.¹⁰ In addition, rabbit studies involving inoculation of the vaccinia virus into a corneal epithelial defect created using a trephine blade and treatment using only topical prednisolone acetate, resulted in poor viral clearance and persistent ocular disease.¹⁸

In conclusion, MPX may cause disciform keratitis that closely resembles ocular vaccinia. Patients and physicians should be made aware of the ability of MPX to cause corneal disease with potential scarring and vision loss. Accordingly, consideration should be given to early involvement of ophthalmology in patients presenting with ocular symptoms and a syndrome compatible with MPX infection, with potential treatment initiated even before diagnostic confirmation. Evaluation of potential epithelial compromise and/or patient-specific considerations of the merits of anti-inflammatory eye drops should also be addressed. Further research and clinical trials to determine optimal treatment regimens for MPX ocular disease are urgently needed.