In December 2019, a new strain of coronavirus identified as acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses caused the coronavirus disease 2019 (COVID-19) (Gorbalenya et al. 2020). The epidemic rapidly spread around the world and was declared a pandemic by the World Health Organization in March 2020. Since then, descriptions of the ocular manifestations associated with SARS-CoV-2 have been published (Nasiri et al. 2021; Cunha et al. 2020). Systematic reviews and meta-analyses suggest that the virus can be detected on the ocular surface and produce conjunctivitis as a sign of COVID-19 infection (Aiello et al. 2020; Loffredo et al. 2020). The clinical spectrum and corneal manifestations of COVID-19 disease are largely unknown, with few case reports of corneal involvement in the form of keratoconjunctivitis and, more recently, in the form of late corneal stromal deposits (Guo et al. 2020; Cheema et al. 2020; Pareja-Ríos and Bonaque-González 2021).
We present what we believe is a bilateral ocular complication related to COVID-19 disease, possibly due to an immune stromal reaction.
A 46-year-old male with no relevant medical or ophthalmological history apart from contact lens wear for myopic astigmatism, (no history of herpetic keratitis, adenoviral keratoconjunctivitis, or contact lens-related keratitis) had routine ophthalmologic evaluations until January 2018, with a corrected distance visual acuity (CDVA) of 20/20 and unremarkable ophthalmic evaluation in both eyes.
In April 2021, he was diagnosed with COVID-19 disease with a clinical course complicated by bilateral pneumonia that required hospitalization but not intubation or intensive care admission. In May 2021, he presented to the Ophthalmology clinic with a history of photophobia, mild ocular pain, and blurred vision that started 4-weeks after the COVID-19 diagnosis. His CDVA was 20/25 in both eyes and intraocular pressure (IOP) was normal. He had mild conjunctival hyperemia with no conjunctival or corneal staining, the corneal sensation was preserved, and no vestibular-auditory symptoms were present. Bilateral linear corneal stromal infiltrates that resembled the shape of a LASIK-flap were seen biomicroscopically (Fig. 1A) and depth of involvement was assessed using anterior segment optical coherence tomography (AS-OCT, Cirrus 5000 HD-OCT; Carl Zeiss Meditec, Dublin, CA) (Fig. 1B). There was no anterior chamber reaction, and funduscopic evaluation was normal.
Treatment with topical dexamethasone sodium phosphate (1 mg/ml) was prescribed every 4 hours while awake until symptoms improved and then tapered slowly. Four months after presentation his CDVA was 20/20 in both eyes, IOP remained stable and no stromal infiltrates were seen (Fig. 2A-B).
In this report, we present the case of a patient who developed bilateral ocular symptoms 1-month after COVID-19 disease. Although we cannot prove that these infiltrates were caused by or directly related to SARS-CoV-2, because conjunctival swabs were not performed, we did not find a cause that could explain these ophthalmic manifestations. Differential diagnoses such as Herpetic keratitis, syphilitic keratitis, adenoviral keratoconjunctivitis, contact lens-induced infiltrative keratitis, or Epstein Barr keratitis were considered, however, ophthalmologic history and clinical presentation were not consistent with any of these diagnoses. Also, there were no associated constitutional symptoms, no epidemiological history suggestive of other infectious etiologies, and VDRL and FT-ABS tests were negative. Since no other findings suggesting systemic reasons for the stromal keratitis were found, we can only cautiously suggest that it may be related to SARS-CoV-2.
Recent findings suggest that angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) which are known to be viral entry factors for the SARS-CoV-2 are found in corneal, limbal, and conjunctival epithelium (Roehrich, Yuan, and Hou 2020; Zhou et al. 2020). Thus implying the possibility of affection and transmission through the ocular surface. Several systematic reviews and meta-analyses have found that the virus can be detected in the ocular surface in 3 – 3.5% of patients and ocular manifestations such as conjunctivitis, ocular pain, discharge, and redness can be seen in up to 12%. Moreover, ocular manifestations can be the first symptom of COVID-19 in 2% of affected individuals, and the presence of conjunctival signs can be associated with a more severe form of the disease (Aiello et al. 2020; Loffredo et al. 2020).
Until now, most ocular findings related to COVID-19 have been described as signs and symptoms related to conjunctivitis. Only a few case reports regarding corneal involvement in the form of keratoconjunctivitis have been published (Guo et al. 2020; Cheema et al. 2020). Also, one case report of SARS-CoV-2 RNA found in the corneal epithelium of a patient with unilateral keratouveitis, and one report of late stromal deposits after COVID-19 disease were found (Pareja-Ríos and Bonaque-González 2021; Kuo and Mostafa 2021).
It is known that SARS-CoV-2 can elicit a form of immune dysregulation characterized by the overproduction of pro-inflammatory cytokines (IL-6, IL-1, IL-2, TNF amongst others) and changes in the activity of T lymphocytes (particularly CD4+ T cells) (Singh and Mathur 2021). These may increase susceptibility for corneal immune reactions.
Although the SARS-CoV-2 conjunctival swab was not performed, we hypothesize that the findings described in our case were a result of virus-induced immune dysregulation, taking into account factors such as the confirmed severe COVID-19 infection (with the consequent pro-inflammatory state), the timeline of corneal manifestations (which is highly suggestive), and the outstanding response to topical corticosteroids.
Therefore, we suggest that corneal manifestations must be considered when evaluating patients with known or suspected COVID-19. This may be particularly important in the subacute stages of the disease and should be suspected in any patient presenting with corneal stromal infiltrates, blurred vision, ocular pain, and photophobia without apparent cause and previous history of COVID-19 disease.
Ophthalmologists should be aware of subacute corneal manifestations in COVID-19 patients to treat them accordingly and prevent sequelae.
DECLARATION OF CONFLICTING INTEREST
None. No conflicting relationship exists for any author.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CONSENT FOR PUBLICATION
Written informed consent was obtained from the patient for the publication of the images in this case report.
Study concept and design (RP, JG); data collection (IM-R); analysis and interpretation of data (RP, JG, NM-C); writing the manuscript (RP, NM-C); critical revision of the manuscript (JG, IM-R, NA); supervision (JG)