Antiviral response in vernal keratoconjunctivitis may be protective against COVID‐19
Authors: Andrea Leonardi, Umberto Rosani, Fabiano Cavarzeran, Philippe Daull, Jean‐Sebastien Garrigue, Brun Paola
Journal: Allergy (2021)

Vernal keratoconjunctivitis (VKC) is a severe type 2 ocular eosinophilic inflammation with a proven IgE sensitization in about 50% of patients. Many Th2-type and proinflammatory cytokines have been found to be locally overexpressed in VKC patients, recalling a sort of local cytokine storm. Conjunctivitis is a common, self-limiting manifestation of COVID-19 with an incidence of 11% in affected patients,1 but can be the first or the unique manifestation of SARS-CoV-2 infection. As a referral center for the diagnosis and treatment of VKC, so far, we observed only two VKC patient affected by COVID-19 without any ocular symptoms or consequences. The prevalence of VKC is estimated in our area 4/10.000 under 15 years of age.2 Knowing that the prevalence of COVID-19 in pediatric population (0–14) in Padova great area is 6.4%, we calculated that the odds ratio (OR) for VKC to be associated with COVID-19 is OR = 0.88 (95% CI, 0.66–1.16), therefore, with a tendency for VKC to be protective. It has been suggested that a Th2-skewed immunity may be protective against severe COVID-19 disease.3 For this reason, we investigated the conjunctival expression of genes related to the local defense immunity to virus that may play a relevant role in the response to SARS-CoV-2. Conjunctival samples were collected from 15 VKC patients and 5 healthy age-matched control subjects (CTRL) using the EyeprimTM device (OPIA Technologies SAS). Samples were immediately treated and stored at −80℃ for subsequent RNA isolation and Affymetrix assay (see Appendix S1). Over the 21,448 tested expression probes, using the Gene Ontology Biological Process (GOBP) term "defense response to virus," 237 genes were selected (Figure S1). In addition, using bibliographic elements, we selected genes with SARS-CoV-2 receptor function and antiviral activity. The receptor angiotensin-converting enzyme 2 (ACE2), cellular transmembrane serine protease 2 (TMPRSS2), Basigin/CD147/EMMPRIN (BSG), cathepsin L (CTSL), and dipeptidyl peptidase (DPP4) were not overexpressed in VKC compared to CTRL. Conversely, FURIN (FC = 2.73, p = 0.001) and ADAM-17 (FC = 1.61; p = 0.01) were significantly higher in VKC. Thirty-eight genes involved in the defense response to virus, including bone marrow stromal antigen (BST2)/tetherin and MX Dynamin Like GTPase 2/myxovirus resistance protein 2 (MX2) and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) were overexpressed in VKC (Table 1 and Figure 1). Even though several members of the interferon regulatory and inducible proteins (Table 1) were overexpressed in VKC, genes encoding for interferons were not. Notably, interferon receptors IFNAR1 (FC = 1.88; p = 0.003), IFNGR2 (FC = 2.6; p = 0.04) were significantly overexpressed in VKC. The meaning of the upregulation of all these antiviral genes in VKC is not clear. It has been shown that ACE2 is overexpressed in diseased conjunctiva compared to normal tissues and that conjunctival inflammation can enhance its expression.4 Our results show that this is not the case for allergic inflammation. It has been suggested that type 2 immune response can provide certain protective effects against COVID-19 since asthma patients do not have increased susceptibility or severity of SARS-CoV-2 infection than others.5 Although the presence of SARS-CoV-2 in tears has rarely been detected in infected individuals, the conjunctiva is a potential gateway for the SARS-CoV-2 and conjunctivitis may be a sign of COVID-19 prior to or after the onset of respiratory symptoms. In our study, we suggest that the overexpression of multiple antiviral factors in severe allergic inflammation and the low ACE2 expression in the conjunctiva might explain to the low prevalence of COVID-19 in VKC. In addition, it has been shown that having eosinophilia and a Th2 phenotype (which are typical of VKC) may be an important predictive factor for reduced COVID-19 morbidity and mortality in asthma.6 We cannot translate this statement for VKC patients, but we suggest that having a local persistent allergic inflammation might be protective for ocular viral infections. Open Access Funding provided by Universita degli Studi di Padova within the CRUI-CARE Agreement. [Correction added on 21 May 2022, after first online publication: CRUI-CARE funding statement has been added.] Authors have no conflict of interest, only Philippe Daull and Jean-Sébastien Garrigue are employees of Santen SAS. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.