Determinants of Outcomes of Adenoviral Keratoconjunctivitis

doi:10.1016/j.ophtha.2018.02.016

Ophthalmology

Volume 125, Issue 9, September 2018, Pages 1344-1353

Presented in part at: Association for Research in Vision and Ophthalmology Annual Meeting, 2015; Ophthalmology Microbiology and Immunology Group Annual Meeting, October 2016, Chicago, Illinois.

https://doi.org/10.1016/j.ophtha.2018.02.016 Get rights and content

Purpose

To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis.

Design

Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694).

Participants

Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus.

Methods

Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression.

Main Outcome Measures

The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign.

Results

Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non–adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age.

Conclusions

A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non–adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.

Section snippets

Participants and Procedures

Participants were recruited at 58 ophthalmology centers in United States, Brazil, Sri Lanka, and India. Informed consent was obtained, and the work complied with the Health Insurance Portability and Accountability Act. Institutional review board approval for this study was obtained, and the research adhered to the tenets of the Declaration of Helsinki (US: Goodwin IRB (Cincinnati, OH); India: Drug Controller General (DCGI) with local Ethics committees; Sri Lanka: Scientific and Ethical Review,

Demographic Characteristics of the Participants and Distribution of Adenoviral Species and Types

Participants were recruited from the United States (n = 111), India (n = 200), Sri Lanka (n = 84), and Brazil (n = 103) were randomized to auriclosene or vehicle arm at a 1:1 ratio (Table 1). Mean age was 35 years (range, 1–90 years) and 290 were male (58%); 428 participants (86%) completed 18 days of follow-up. Participants from India (18%; n = 35) and Brazil (27%; n = 27) had the highest rate of missing the day 18 visit. In contrast, less than 5% of participants from United States and Sri

Discussion

In this large study of keratoconjunctivitis, several findings were notable. First, we found an unexpected diversity of types and species associated with keratoconjunctivitis, particularly in the United States compared with other parts of the world. Second, we found that a substantial proportion of keratoconjunctivitis cases do not seem to be associated with a detectable adenovirus. Third, we found that the outcomes of adenoviral keratoconjunctivitis depended on the species. Specifically,

Acknowledgments

The authors thank Jiaqi Yin, PhD, and Hyunju Son, MA, for their assistance with statistical analyses and all the investigators who contributed to the study.

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The D-species adenoviruses, specifically D8, D19, (recently reclassified D64), and D37, have been thought to underlie most EKC. The NovaBay NVC-422 study76 was a large, multi-national, randomized controlled clinical trial testing the antiseptic and antiviral compound auricloscene for treatment of EKC-type conjunctivitis. The study enrolled 500 subjects with typical conjunctivitis from India, Brazil, Sri Lanka, and the United States.
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: Financial Disclosure(s): The author(s) have made the following disclosure(s): A.Y.L.: Financial support – Novartis, Microsoft

: D.S.: Employee – NovaBay Pharmaceuticals, Inc.

: K.N-T.: Employee – NovaBay Pharmaceuticals, Inc.

: S.K.: Employee – Viracor Eurofins Clinical Diagnostics

: A.W.: Consultant – Aicuris, Amgen, Merck, GSK; Financial support – Genocea, Vical, Admedus; Royalties – Uptodate

: Supported by the National Institutes of Health, Bethesda, Maryland (grant nos.: K23EY02492, P30EY001730, and R21EY027453, and K24 AI071113 [A.W.]); the Latham Vision Science Innovation Award, Seattle, Washington (C.S.L.); Research to Prevent Blindness, Inc., New York, New York (C.S.L., A.Y.L., R.N.V.G.); the Mark J. Daily, MD, Research Fund (R.N.V.G.). The University of Washington received a research grant from NovaBay Pharmaceuticals, Inc., Emeryville, California. The sponsor or funding organization participated in the design, conduct, and data collection of the trial (NV-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). However, they had no role in the design or conduct of the research presented on the manuscript.

: HUMAN SUBJECTS: Human subjects were included in this study. The institutional review board approved the study (US: Goodwin IRB (Cincinnati, OH); India: Drug Controller General (DCGI) with local Ethics committees; Sri Lanka: Scientific and Ethical Review, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka; Brazil: National Ethics Committee in Research (CONEP) plus local ethic committees), and informed consent to participate in the study was obtained from all patients. The study was performed in accordance with the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability (HIPAA) Act of 1996.

: No animal subjects were used in this study.

: Author Contributions:

: Conception and design: C.S.Lee, Akileswaran, Stroman, Najafi-Tagol, Kleiboeker, Wald, Van Gelder

: Analysis and interpretation: C.S.Lee, A.Y.Lee, Stroman, Najafi-Tagol, Kleiboeker, Chodosh, Magaret, Wald, Van Gelder

: Data collection: C.S.Lee, A.Y.Lee, Akileswaran, Stroman, Najafi-Tagol, Kleiboeker, Magaret, Wald, Van Gelder

: Obtained funding: None

: Overall responsibility: C.S.Lee

: Supplemental material available at www.aaojournal.org.

^∗: A complete list of contact research organizations and principal investigators of BAYnovation Study Group are listed in the Appendix, available at www.aaojournal.org.

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Original articleDeterminants of Outcomes of Adenoviral Keratoconjunctivitis

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Participants and Procedures

Demographic Characteristics of the Participants and Distribution of Adenoviral Species and Types

Discussion

Acknowledgments

Am J Med Sci

Ophthalmology

Am J Infect Control

Virology

J Clin Virol

Braz J Infect Dis

Ophthalmology

Ophthalmology

A comparison of eye problems in primary care and ophthalmology practices

Fam Med

Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States

BMC Ophthalmol

Epidemic kerato-conjunctivitis—do outbreaks have to be epidemic?

Eye

Adenovirus-associated epidemic keratoconjunctivitis outbreaks in four states, 2008–2010

MMWR Morb Mortal Wkly Rep

Epidemic keratoconjunctivitis at a U.S. military base: Republic of the Philippines

Mil Med

Virology and epidemiology analyses of global adenovirus-associated conjunctivitis outbreaks, 1953–2013

Epidemiol Infect

New paradigms in infectious eye disease: adenoviral keratoconjunctivitis

Archivos de la Sociedad Española de Oftalmología

Adenoviral keratoconjunctivitis in a tertiary care eye clinic

Cornea

Adenovirus advances: new diagnostic and therapeutic options

Curr Opin Ophthalmol

Broad-spectrum virucidal activity of (NVC-422) N,N-dichloro-2,2-dimethyltaurine against viral ocular pathogens in vitro

Invest Ophthalmol Vis Sci

Original article
Determinants of Outcomes of Adenoviral Keratoconjunctivitis