Adenoviral conjunctivitis is one of the most common conditions in all of medicine. Despite being a common cause of morbidity world-wide, there are no known host or pathogen factors that predict clinical outcomes in adenoviral keratoconjunctivitis (AdV KC). A recent, large, international clinical study of adenovirus-related KC revealed that approximately 10% of patients suffer from sustained visual loss. Preliminary deep DNA sequencing of AdV has revealed an unexpected sequence diversity in the viral genome, with ~8% sequence divergence even amongst samples with the same hexon-defined molecular type. Remarkably, 20% of the patients in this study lacked any polymerase chain reaction (PCR) or deep DNA sequencing evidence for adenovirus. Given the unexpected molecular variation of adenovirus and a large spectrum of clinical outcome in KC, we propose to analyze host and viral factors contributing to poor outcome (Aim 1). Using next generation DNA sequencing, we propose to catalog the molecular variants of adenovirus and correlate these with clinical outcomes as well (Aim 2). The results of these studies will expand our understanding of the molecular pathogenesis of viral conjunctivitis, and may provide biomarkers for predicting outcomes from this condition. These advances will facilitate future efforts toward developing therapies for this common condition.
Viral conjunctivitis is one of the most common conditions in all medicine. At present, there are no known molecular or pathogenic factors that can predict poor clinical outcomes in adenoviral keratoconjunctivitis. Data from a recent clinical trial in epidemic keratoconjunctivitis (EKC, trial for NV-422) has shown that a significant portion of subjects suffered sustained visual loss for several weeks after presentation. Preliminary molecular data from this trial revealed unexpected diversity of adenoviral species and types, and high genomic variability even within the same type. Additionally, approximately 20% of patients had no evidence of adenoviral infectioin by PCR, which was validated by next generation whole genome sequencing (WGS). We propose to examine the host and viral factors predictive of poor visual or anatomic outcomes in viral keratoconjunctivitis. The available dataset for this trial constitutes over 100,000 discrete data elements, and the molecular dataset includes over 5,000 clinical swab samples. In our first aim, we propose a comprehensive analysis for host and viral factors predictive of outcomes in the disease. In our second aim, we propose fully sequencing the viral genome of 180 subjects and correlating specific variants with outcomes. At the conclusion of this study, we will have significantly advanced knowledge of the factors influencing visual and anatomic outcomes following adenoviral conjunctivitis.
| Lee, Cecilia S; Lee, Aaron Y; Akileswaran, Lakshmi et al. (2018) Determinants of Outcomes of Adenoviral Keratoconjunctivitis. Ophthalmology 125:1344-1353 |
