Elsevier

American Journal of Ophthalmology

Volume 233, January 2022, Pages 227-242
American Journal of Ophthalmology

AOS Thesis
Molecular and Clinical Characterization of Human Adenovirus E4–Associated Conjunctivitis

https://doi.org/10.1016/j.ajo.2021.10.028Get rights and content

Purpose

To determine the characteristics of conjunctivitis associated with human adenovirus E4 (AdV E4).

Methods

Samples and outcomes from 500 patients with conjunctivitis were obtained from the NVC-422 randomized controlled clinical trial comparing auriclosene to placebo. Molecular typing identified 36 cases associated with AdV E4. Signs and symptoms at presentation and at the day 18 endpoint were compared with the larger cohort of 262 subjects with conjunctivitis caused by due to AdV D8. Full viral genomes of 22 AdV E4 isolates were reconstructed.

Results

AdV E4 was the most frequently identified adenoviral type in conjunctivitis cases from the United States. Signs and symptoms at presentation were comparable to those associated with AdV D8. Viral load at presentation was comparable between groups but resolution was more rapid in the AdV E4 group. Clinical signs were fully resolved by day 18 in 26 of 36 (72%) patients with AdV E4. Subepithelial infiltrates developed in 12 of 36 (33%) patients with AdV E4 compared with 98 of 215 (45%) patients with AdV D8 (P = .0001). One hundred twenty-four polymorphisms were observed among 22 whole viral genome sequences, which clustered into 3 clades. Patients in each clade developed subepithelial infiltrates. Neither single nucleotide polymorphism analysis nor machine learning approaches identified specific sequence features predictive of presenting signs or outcome.

Conclusions

AdV E4 conjunctivitis may be indistinguishable at presentation from AdV D8–associated disease. Resolution of viral load for AdV E4 appears more rapid than for AdV D8, and the risk for subepithelial infiltrates appears lower. Multiple substrains of AdV E4 are in circulation but all appeared equivalently pathogenic for conjunctivitis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Section snippets

PARTICIPANTS

This prospective study was conducted with Goodwin University Institutional Review Board approval (Cincinnati, Ohio, USA). In addition, local approval at all sites was obtained (including Drug Controller General in India, Scientific and Ethical Review Board, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka, and National Ethics Committee in Research review in Brazil). All research was conducted in accord with to the tenets of the Declaration of Helsinki, applicable privacy laws,

PATIENT DEMOGRAPHICS AND PRESENTING SIGNS AND SYMPTOMS

Overall demographics of patients in the NVC-422 clinical trial have been presented previously.13 In the current study, we focused on those patients with PCR evidence for AdV E4 compared with those with AdV D8 (Table 1). A total of 36 subjects were PCR-positive for Adv E4 compared with 262 who tested positive for AdV D8. The mean age was similar between groups (33.6 ± 16.8 years for AdV E4, 34.2 ± 11.7 years for AdV D8, P = .81). Only 4 subjects among the 298 were <18 years of age, 3 of 36 in

DISCUSSION

Human adenovirus was first isolated from adenoid tissue (hence the name) by Rowe and associates in 1953.22 Adenoviruses are double-stranded, nonenveloped DNA viruses in the Mastadenovirus family. Adenoviruses are largely confined to humans23 and are believed to be the causative agent for a wide range of diseases, including mucosal diseases of the respiratory, genitourinary, and gastrointestinal tracts, neurologic infections, as well as ocular surface infections.

Viral typing has traditionally

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