Ocular involvement in monkeypox: Description of an unusual presentation during the current outbreak

Dear Editor,

We read with great interest the manuscript by Orviz et al.¹ recently published in the Journal of Infection. In this paper, the authors describe the clinical and virological characteristics of the first 48 cases of monkeypox (MPX) observed in a reference centre for sexual transmitted infections/HIV infection in Spain during the multi-national outbreak started in May 2022 in non-endemic countries.

As discussed by the authors, during the current outbreak, which counts, as of August 4, 2022, 13,022 confirmed cases from 27 EU/EEA countries,² the disease has mainly occurred in men who had sex with men (MSM) who had no epidemiological link to the endemic countries. Additionally, in the above manuscript,¹ consistent with previous reports,³ the clinical presentation of the disease appeared mild and self-limited, with rare severe manifestations or complications. In this regard, in the course of this outbreak, ocular complications of the disease were described rarely (<1%),² compared with reports from endemic areas where ocular involvement, including corneal scarring and endophthalmitis, ranged from 9 to 23%.^{4 , 5}

Here we reported a clinical case of ocular involvement in a MSM, in which MPXV-DNA was detected by real-time PCR both in eyelid and conjunctival swabs, and MPXV was also isolated in cell culture as replication-competent, infective virus. This case highlights some elements that may have implications for the transmission and pathogenesis of this unusual complication.

In May 2022, a 26-year-old Italian male attended the outpatients’ department for the appearance of two papular lesions in the suprapubic area and he was diagnosed as infected by MPXV by real-time PCR performed on skin lesions. He reported a protected sexual intercourse five days before the visit with a male partner who subsequently tested positive for MPXV.

Two days after the first visit, he was admitted to our hospital for fever, general malaise, headache, painful inguinal lymphadenopathy and multiple papular lesions in the right eyelid with progressive periorbital and conjunctival involvement. The ophthalmologist's evaluation ruled out visual impairment and corneal involvement, and, on suspicion of bacterial superinfection, topical steroid therapy was started along with intravenous antibiotic therapy.

Due to the clinical worsening (increased number of lesions in upper and lower eyelids and the eye fornix with periorbital oedema and conjunctival hyperaemia), swabs from periorbital lesions and conjunctiva were collected and tested for MPXV. Viral DNA was extracted by Qiamp Viral RNA mini kit (Qiagen), and two real time PCRs were used to assess the presence of MPXV DNA: Real-Star Orthopoxvirus PCR Kit (Altona Diagnostics GmbH), that recognizes a region common to all Orthopoxviruses without distinction of species, was used as screening PCR; the second PCR (G2R_G assay) published by Li et al. targets the tumour necrosis factor (TNF) receptor gene and was used as confirmatory PCR.⁶ The Rotor-Gene Q (Qiagen) platform was used to run both assays. We also measured the viral quantification cycle (Cq) in positive samples. Both eyelid and conjunctival samples were positive for MPXV DNA by both PCRs. Moreover, the conjunctival swab was successfully inoculated in Vero E6 cells, a clear cytopathic effect was observed 48 h after the inoculum and MPXV replication was confirmed by real-time PCR on DNA purified from cell growth medium collected after 48, 72, and 96 h.⁷

The patient was treated with two doses of intravenous cidofovir (5 mg/kg weekly associated with oral probenecid and fluid support) and anti-inflammatory and vitamin A-based eye drops; steroid local therapy was stopped. Slow clinical improvement was observed with asynchronous evolution of the lesions and their total disappearance at approximately two months after onset (Fig. 1 ).

Fig. 1.

Timeline of clinical evolution and PCR positivity in biological samples collected.

Our case confirms the possibility of ocular involvement during MPXV infection in a non-endemic setting. We detected MPXV-DNA by real time PCR and were able to isolate MPXV as a replication-competent virus from conjunctival swabs. Unlike previously described, in our patient systemic symptoms and ocular involvement were subsequent to the appearance of the first skin lesions by a few days. This time course suggests that eye localization might be related to self-inoculation, rather than conjunctival spread during the early viraemic phase of infection.

Although the passage of the virus into the conjunctival secretion from the plasma compartment has been hypothesized, previously described cases of ocular complications of MPX were mainly related to bacterial superinfection.⁸ In contrast, we showed that both eyelid and conjunctival specimens were positive for MPXV DNA, and a replication-competent MPXV was isolated in culture from conjunctival swab, in absence of bacterial growth.

MPX in the current outbreak had usually mild to moderate and self-limited clinical presentation⁹and observed cases generally did not require specific antiviral therapies.³ However, antivirals may be considered in severe disease, or complicated lesions localized in areas at high risk of sequelae.¹⁰ Tecovirimat is currently the only drug approved by the European Medicines Agency (EMA) for the treatment of MPXV, but it is not yet readily available. Although only data in vitro and from mouse models are available on systemic antiviral therapy with cidofovir,¹¹ we used this drug due to the worsening clinical picture to avert the risk of sequelae on vision. Complete recovery and intraocular viral clearance occurred slowly, suggesting that the antiviral activity of cidofovir only partially contributed to clinical resolution. Finally, our case suggests a pathogenetic mechanism of ocular localization based on the spread from a local inoculum. Therefore, appropriate counselling on hygiene measures to reduce the risk of virus self-spreading should be also carried out.

Author contributions

CP, VM, AM, and AA followed the patients during the diagnostic and therapeutic path, conceived the study, drafted the first manuscript, and revised the final version. FB, MM, SGT, MC, SV, and EN followed the patients during the diagnostic and therapeutic path and discussed the results of the study. FC, SM, CM, GM and FM provided for virological assay on samples. RS performed eye follow-up and obtained eyelid and conjunctival samples. EG and FV reviewed and supervised the manuscript. All authors gave their final approval of the version to be submitted.

Funding

This study was supported by Ricerca Corrente Linea 1 and 2, funded by the Italian Ministry of Health.

Declaration of Competing Interest

The authors declare that no conflicting financial interests or other competing relationships exist.