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Distinguishing Between Infectious Endophthalmitis and Noninfectious Inflammation Following Intravitreal Anti-VEGF Injection

Endophthalmitis is a severe, vision-threatening condition associated with intravitreal injections as well as other surgical and nonsurgical etiologies. As the number of intravitreal injections performed increases, postinjection infectious endophthalmitis becomes an increasingly important clinical problem. However, some patients develop noninfectious inflammation following intravitreal injection that may resemble infectious endophthalmitis. Distinguishing between these 2 entities is a practical challenge for the clinician. The rate of infectious endophthalmitis following intravitreal injection is low and may be decreasing over time. For example, the rate of clinically suspected infectious endophthalmitis (including both culture-positive and culture-negative cases) following injections of antivascular endothelial growth factor (antiVEGF) agents at a single large referral institution between 2005 and 2017 was recently reported as 0.013% (24/183,898). In the subgroup of patients injected between 2014 and 2017, the rate was 0.0038% (3/79,056). There were no significant differences in the rates between the 3 most commonly injected agents (aflibercept, bevacizumab, and ranibizumab). These rates are comparable to data calculated by the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry. Based on IRIS Registry data, a 0.025% rate (approximately 9 million anti-VEGF injections) of clinically suspected infectious endophthalmitis was described (written communication, David W. Parke II, MD, chief executive officer, AAO, July 2018). There were also no significant rate differences between the 3 anti-VEGF agents. The rate of noninfectious inflammation is unknown but is also low. Noninfectious inflammation has been reported with all 3 agents but may be more common with aflibercept. A prospective, open-label, nonrandomized phase 4 clinical study of 100 eyes treated with aflibercept or ranibizumab reported that a maximum anterior chamber reaction of at least 0.5 (according to Standardization of Uveitis Nomenclature grading) occurred in 19% of eyes treated with aflibercept compared with 2% of eyes receiving ranibizumab, which was statistically significant. The rates of vitreous reaction of the 2 agents were not significant. In addition, aflibercept has been associated with at least 2 major clusters of noninfectious inflammation. The first cluster occurred shortly after aflibercept achieved United States Food and Drug Administration approval in November 2011, and the second was reported by the manufacturer (Regeneron Pharmaceuticals Inc, Tarrytown, NY) in February 2018. The manufacturer subsequently reported that in the second cluster, certain batches of syringes were associated with inflammation. According to a letter from Ned Braunstein, MD, senior vice president, regulatory affairs and pharmacovigilance, Regeneron (May 2018), the “base” rate of inflammation associated with aflibercept averages approximately 1-4 cases per 10,000 injections (approximately 0.025%), but during the more recent cluster, the rate increased to 8-12 cases per 10,000 injections