Determinants of Outcomes of Adenoviral Keratoconjunctivitis

Abstract

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.

Figure 1. Score and viral load reductions on days 1, 3, 6, 11, and 18 by adenoviral species. A, Mean composite scores of symptoms in adenoviral keratoconjunctivitis. B, Mean composite scores of signs. C, Mean adenoviral load (copy numbers/mL in log₁₀)

Cases with AdV-D infection are significantly slower in improving signs and symptoms compared to the rest of AdV species or AdV-negative group. No significant difference in viral load exists among AdV species on day 1. The viral load of AdV-D remains elevated on day 11 and 18 compared to other species. Colors represent different adenoviral species and adenoviral negative group. Bars represent 95% confidence intervals. AdV, adenovirus. *p-value <0.05 indicates a significant difference in scores between different AdV species by Analysis of Variance (1C includes AdV-positive species only).

Figure 2. Hazard ratios of resolution of signs and symptoms in patients infected with AdV-D compared to other species (AdV-B, C, and E)

Left of the dotted line represents that patients with AdV-D are less likely to resolve a sign or symptom compared to AdV-nonD infection.