Purpose
To report the presenting features and clinical outcomes of a series of patients with noninfectious inflammation after intravitreal aflibercept injection.
Design
Noncomparative consecutive case series.
Methods
Medical records of patients who presented with noninfectious inflammation after intravitreal aflibercept injection between November 18, 2011 and June 30, 2013 were retrospectively reviewed.
Results
A total of 20 cases of postinjection inflammation were identified in 5356 aflibercept injections. The patients presented 1–13 days after aflibercept injection (median 3 days); all noted decreased vision, while 3 of 20 (15%) had pain and 2 of 20 (10%) had conjunctival injection. One patient had a hypopyon (0.5 mm), and the average anterior chamber cell was 1.8+ (range 0 to 4+). All eyes had some degree of vitritis (average 1.8+; range 0.5+ to 4+). Patients on average had received 6 prior aflibercept injections (range 0–16). Only 1 patient—the first to present with inflammation in this series—received an intravitreal tap (culture negative) and injection of antibiotics. All patients were managed with frequent topical steroids and were followed closely for signs of improvement. All but 1 patient regained their preinjection visual acuity (average: 33 days; range: 7–73 days). Four patients were subsequently rechallenged with aflibercept, and 1 developed inflammation again after 5 additional aflibercept injections. The overall incidence of inflammation after intravitreal aflibercept injection was 20 of 5356 injections (0.37%) or 19 of 844 patients (2.25%). However, a disproportionate number of cases clustered around 1 provider (17/20, 85%; P < .001 vs all other providers) and around the 2 office locations where this physician primarily worked (16/20, 75%; P < .001 vs 5 other offices).
Conclusions
Noninfectious inflammation after intravitreal aflibercept injection typically presents without pain, conjunctival injection, or hypopyon, and responds to topical steroid therapy. The visual outcomes are generally favorable, though the return to baseline acuity can take many weeks.
Approved in November 2011, aflibercept (Eylea; Regeneron, Tarrytown, New York, USA) has been widely adopted for the treatment of neovascular age-related macular degeneration (AMD) and, more recently, retinal vein occlusion (RVO). In the pivotal phase III studies leading to US Food & Drug Administration approval, intravitreal aflibercept injection was well tolerated and associated with a low overall complication rate.
Since then, however, cases of noninfectious inflammation after aflibercept injection have surfaced, prompting a pharmaceutical surveillance committee of the American Society of Retina Specialists to investigate further. Differentiating inflammation from infectious endophthalmitis, a feared complication of intravitreal injection, is critical for patients and clinicians alike. To that end, we herein report a large series of noninfectious inflammation after aflibercept injection, including a description of its clinical presentation and course. We also estimate its incidence and describe investigative efforts into its cause.
Methods
Institutional review board exemption was granted from Chesapeake Research Review, Inc, Columbia, Maryland, USA, which waived the requirement for informed consent. This report is compliant with the Health Insurance Portability and Accountability Act requirements, the Declaration of Helsinki, and all state and federal laws.
The medical records of all patients treated by the retina service at Ophthalmic Consultants of Boston (Boston, Massachusetts, USA) who developed noninfectious inflammation after intravitreal aflibercept injection between November 18, 2011 and June 30, 2013 were retrospectively reviewed.
The data collected include the age and sex of each patient, the affected eye and its lens status, the date of the inciting intravitreal aflibercept injection, the number of prior aflibercept injections and other anti–vascular endothelial growth factor (VEGF) injections, the underlying diagnosis and clinical indication for intravitreal injection, and the preinjection visual acuity. The lot number, office location, injecting physician, and preparation technique, as well as use of postinjection antibiotics, were recorded. Presentation and diagnostic data were collected as well, including the date of presentation, the visual acuity and intraocular pressure, the pain score, the presenting symptoms and signs, and the initial management. The patients’ clinical courses, including the visual acuity over time and response to additional intravitreal aflibercept injections, were documented.
An estimate of incidence was obtained by determining the total number of aflibercept injections between November 18, 2011, and June 30, 2013. All eyes were prepared for injection with subconjunctival or topical anesthesia and povidone-iodine antisepsis. The practice includes 6 retina providers and 7 office locations.
Results
A total of 20 cases in 19 eyes of 19 patients were included in this study. The average age at the time of presentation with noninfectious inflammation after intravitreal aflibercept injection was 79.3 (range 70–93) years; 19 of 20 cases were being treated for neovascular AMD, the other for RVO. Preinjection visual acuities ranged from 20/25 to count fingers. All but 1 patient had received prior aflibercept injection without incident (average 6 prior injections, range 0–16). No patient had a history of uveitis or inflammation after intravitreal injection with another agent.
In these cases, all patients complained of decreased vision and were seen on average 3.25 days after aflibercept injection (median 3 days, range 1–13 days). Lines of visual acuity lost between injection and presentation averaged 3.5 (median 3 lines, range 0–9 lines lost). Pain was not a common presenting symptom—noted in 3 of 20 cases (15%)—and was mild in nature when present. The conjunctiva was rarely injected (2/20, 10%), and hypopyon was seen in only 1 patient (Case 14; 0.5 mm in height). The degree of anterior chamber inflammation ranged from 0 to 4+ cell (median 2+ cell), and vitreous inflammation was noted in all 20 cases (median 2+ cell, range 0.5+ to 4+ cell). The Table summarizes the pertinent clinical findings for each case.
| Case | Age (y) | Office a | MD b | Dx | Eye | No. of Prior IAI | InjVA | Needle Gauge | Days to Pres | Pres VA | Presenting Symptoms and Signs | T&I | VA Return (d) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pain | Conj | AC Cell c | Vitreous Cell | |||||||||||||
| 1 | 79.3 | A | 1 | AMD | OD | 2 | 20/25 | 32 | 3 | 3/200 | No | 0 | 0 | 3+ | Yes d | 73 |
| 2 | 81.9 | B | 2 | AMD | OS | 1 | 20/70 | 32 | 5 | 20/200 | No | 0 | 1 | 1+ | No | 71 |
| 3 | 91.3 | C | 1 | AMD | OS | 2 | 20/50 | 32 | 6 | 20/70 | No | 0 | 1 | 1+ | No | 63 |
| 4 | 88.0 | C | 1 | AMD | OD | 6 | 20/30+ | 32 | 4 | 20/200 | No | 0 | 1.5 | 2+ | No | 34 |
| 5 | 70.1 | B | 3 | AMD | OS | 2 | 20/40 | 32 | 1 | 20/400 | No | 0 | 4 | 4+ | No | 42 |
| 6 | 87.8 | C | 1 | AMD | OS | 8 | 20/200 | 32 | 3 | 20/400 | No | 0 | 1 | 1+ | No | 28 |
| 7 | 80.2 | C | 1 | AMD | OS | 6 | 20/200 | 32 | 3 | 20/300 | No | 0 | 2 | 1+ | No | 34 |
| 8 | 66.7 | C | 1 | AMD | OS | 8 | 20/70 | 30 | 1 | 20/300 | No | 0 | 3 | 2+ | No | 15 |
| 9 | 61.3 | C | 1 | CRVO | OD | 0 | 20/70 | 30 | 13 | 20/60 | No | 0 | 0 | 1+ | No | 13 |
| 10 | 82.1 | A | 1 | AMD | OS | 5 | 20/30 | 30 | 2 | 1/200 | No | 0 | 2 | 3+ | No | 46 |
| 11 | 70.7 | D | 3 | AMD | OD | 7 | 20/30 | 30 | 3 | 20/40 | No | 0 | 2 | 1+ | No | 21 |
| 12 | 75.8 | C | 1 | AMD | OD | 2 | 20/40 | 30 | 1 | 20/100 | Yes | 2+ | 4 | 0.5+ | No | 14 |
| 13 | 87.0 | C | 1 | AMD | OD | 5 | 20/60 | 30 | 4 | 20/200 | Yes | Trace | 4 | 2+ | No | 28 e |
| 14 | 79.1 | A | 1 | AMD | OD | 10 | 20/70 | 30 | 2 | HM | Yes | 0 | 4 c | 3+ | No | 42 |
| 15 | 84.2 | A | 1 | AMD | OD | 10 | 20/50 | 30 | 2 | 2/200 | No | 0 | 3 | 3+ | No | 28 |
| 16 | 85.3 | A | 1 | AMD | OS | 11 | 6/200 | 30 | 4 | 1/200 | No | 0 | Rare | 2+ | No | 14 |
| 17 | 84.6 | A | 1 | AMD | OS | 4 | 6/200 | 32 | 3 | 1/200 | No | 0 | 0 | 3+ | No | 7 |
| 18 | 71.4 | C | 1 | AMD | OD | 5 | 20/25 | 30 | 1 | 20/50 | No | 0 | Rare | 2+ | No | 69 |
| 19 | 81.5 | E | 1 | AMD | OD | 9 | 20/50 | 30 | 1 | 20/70 | No | 0 | 2+ | 1+ | No | 14 |
| 20 | 77.2 | C | 1 | AMD | OD | 16 | 20/30 | 30 | 3 | 20/40 | No | 0 | 2+ | 0.5+ | No | 7 |
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