Fever after intravitreal anti-VEGF injections

Dear Editor: Multiple periodic intravitreal injections of various antivascular endothelial growth factor (anti-VEGF) drugs, including Ranibizumab (Lucentis, Genentech, Inc., San Francisco, CA, USA) and Bevacizumab (Avastin, Genentech), to treat different retinal or choroidal diseases have gained great popularity among ophthalmologists and they are currently part of everyday practice around the world. Multiple intravitreal injections of both drugs seem to be well-tolerated and safe over a long period of time. We would like to report on four peculiar cases of transient fever development in two of our patients after anti-VEGF intravitreal injections. The first patient (76-year-old female, no systemic diseases) had neovascular age-related macular degeneration (ARMD) in both eyes, and had been treated with multiple intravitreal injections of bevacizumab (12 in the right eye and ten in the left, up to now). Two to 4 days after the third and eighth injection in the right eye, as well as the fourth injection in the left she developed fever (38.5–39.5°C) and chills. Her visual acuity was stable during the episodes, while no signs of intraocular inflammation were detected. The patient was referred to an internist (after the first and the third episode), and the clinical and laboratory evaluation was negative. No other systemic findings were revealed, and the fever dropped within the following 2 or 3 days without any treatment. The second patient (73-year-old male, no systemic diseases) had also neovascular ARMD in the right eye. The second day after the first intravitreal injection of ranibizumab, he developed fever (38.5–39°C) and chills. His visual acuity was stable during the episode, without any sign of intraocular inflammation. The patient was referred to an internist and, as for the first patient, the clinical and laboratory evaluation was negative. No other systemic findings were revealed, and the fever dropped after 2 days without any treatment. The explanation of this transient development of fever after intravitreal injection of anti-VEGF drugs is unclear. The lack of any other symptoms, the negative clinical and laboratory evaluation, and the regression of the fever within a few days without any medical treatment make the hypothesis of an infection less likely. It is known that both drugs may enter the systemic circulation after an intravitreal injection [1, 2]. Even though their serum concentration is low, we could hypothesize that a reaction to the drug provides a possible explanation for the development of fever in our cases. The reported mild, probably drug-related, systemic adverse event was very uncommon, as it was noted only in two among our total 700 patients (four among our 3,000 intravitreal injections) treated with ranibizumab or bevacizumab. The purpose of our letter is to report this peculiar event. It would be very interesting for us to know, if other ophthalmologists noted a similar event after intravitreal injections of bevacizumab or ranibizumab, as this has never been reported in the literature so far. Since the incidence of this probable adverse event seems to be very low, and the mild to moderate fever is developed I. D. Ladas :A. I. Kotsolis Retina Service, 1st Department of Ophthalmology, Athens University School of Medicine, Athens, Greece