Fellow-eye herpes simplex virus type 1 uveitis after intravitreal bevacizumab: a case report

Abstract

Background

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is widely used for neovascular retinal diseases. Intraocular inflammation is a recognized adverse event and typically occurs in the injected eye. Inflammation in the fellow, uninjected eye is exceptionally rare and may be misinterpreted as sterile immune-mediated inflammation, potentially delaying appropriate treatment. We report a case of polymerase chain reaction (PCR)-confirmed herpes simplex virus type 1 (HSV-1) uveitis presenting in the fellow eye shortly after intravitreal bevacizumab administration.

Case presentation

An 84-year-old man with well-controlled type 2 diabetes mellitus received intravitreal bevacizumab (1.25 mg) in the left eye for neovascular age-related macular degeneration. Three days later, he developed acute granulomatous anterior uveitis with dense vitritis in the right, uninjected eye, while the treated eye remained quiescent. Best-corrected visual acuity decreased to 20/400. Given the severity of inflammation and limited fundus visualization, viral retinitis was suspected. Empirical systemic valacyclovir and topical corticosteroids were initiated. Aqueous humor PCR detected HSV-1 DNA, confirming herpetic uveitis. Inflammation resolved within 40 days with recovery of visual acuity to 20/20 and no progression to acute retinal necrosis. The patient remained recurrence-free under antiviral prophylaxis at last follow-up.

Conclusions

Severe fellow-eye inflammation following intravitreal bevacizumab may reflect viral reactivation rather than sterile inflammation. Early diagnostic evaluation, including aqueous humor PCR when clinically indicated, is essential to guide appropriate therapy and prevent sight-threatening complications.

Background

Intravitreal (IVT) vascular endothelial growth factor (VEGF) inhibitors represent the standard of care for several neovascular retinal diseases and are also widely used in non-neovascular conditions such as diabetic macular edema [1–3]. Although generally safe, these procedures are associated with complications including endophthalmitis, the most feared due to its potential for severe visual loss, as well as intraocular inflammation (IOI), which typically occurs in the injected eye and is most often sterile in nature [4–8].

Inflammation involving the fellow, uninjected eye is exceedingly rare. Only one isolated case has been reported, and the underlying mechanisms remain unclear [9]. While a sterile immune-mediated response has been proposed, infectious etiologies must be carefully excluded, as management strategies differ substantially.

We report a case of polymerase chain reaction (PRC)–confirmed herpes simplex virus type 1 (HSV-1) granulomatous uveitis presenting in the fellow eye shortly after intravitreal bevacizumab injection, highlighting the importance of distinguishing between sterile and viral inflammation.

Case presentation

An 84-year-old male with well-controlled type 2 diabetes mellitus (HbA1c < 7%) on metformin therapy, and a diagnosis of nAMD in the left eye (LE), was referred to the Ocular Immunovirology Unit at Sapienza University of Rome in January 2025 for uveitis of unknown etiology in the right eye (RE). Three days before presentation, the patient had received his fourth IVT injection of 1.25 mg bevacizumab in the LE.

The treatment course in LE included an initial loading phase of three monthly IVT bevacizumab injections, followed by a fourth injection administered five months later. The patient had no prior exposure to anti-VEGF therapy in RE, and no inflammatory reactions had been observed in the treated eye following any injections.

At presentation, the RE exhibited normotensive (14 mmHg), granulomatous anterior uveitis, with large mutton-fat keratic precipitates on the corneal endothelium, 2+ anterior chamber cells (SUN grading [10]), and 3+ vitreous haze (Nussenblatt grading system [11]), obscuring fundus visualization. The LE showed signs of nAMD but no evidence of intraocular inflammation or diabetic retinopathy. Best-corrected visual acuity (BCVA) was 20/400 in the RE and 20/100 in the LE.

B-scan ultrasonography of the RE revealed dense vitritis with an attached retina (Fig. 1). Given the presence of granulomatous anterior uveitis, severe vitritis and the inability to assess the fundus, raising clinical suspicion of possible viral retinitis or acute retinal necrosis, empirical treatment was promptly initiated. The therapeutic regimen included systemic valacyclovir (1 g three times daily, gradually tapered) along with topical corticosteroid drops.

Fig. 1.

Multimodal imaging of the right eye (RE). (A) B-scan ultrasonography shows dense vitritis during the acute phase. (B) fluorescein angiography demonstrates a quiescent eye with complete resolution of inflammation following antiviral therapy

Subsequent laboratory investigations revealed positive serology for HSV-1 IgG. PCR analysis of aqueous humor, obtained via anterior chamber paracentesis, confirmed the presence of HSV-1 DNA.

The patient experienced complete clinical resolution within 40 days. Notably, no retinal necrotic lesions or residual scarring were observed after resolution of the vitritis, making acute retinal necrosis unlikely. Follow-up multimodal imaging, including spectral-domain OCT, OCT-angiography and fluorescein angiography, demonstrated a fully quiescent eye, with no residual signs of intraocular inflammation (Fig. 1). At the follow-up in April 2025, BCVA in the RE had returned to 20/20. As of August 2025, the patient remained recurrence-free under prophylactic valacyclovir 500 mg/day.

Discussion and conclusions

IOI is a recognized complication of intravitreal anti-VEGF therapy, typically confined to the injected eye [3–8]. Its pathogenesis remains incompletely understood and is thought to involve a combination of immunogenic and inflammatory mechanisms, including endotoxin contamination, molecular aggregation of the therapeutic agent, and anti-drug antibody formation [6].

Contralateral inflammation is exceedingly rare. The sentinel case reported by Neri et al. described a fellow-eye vitritis following bevacizumab that resolved with corticosteroids, suggesting a sterile immune-mediated mechanism [9]. In contrast, our case represents a more severe presentation, characterized by granulomatous anterior uveitis and dense vitritis in the uninjected eye.

Herpetic uveitis is typically described as a predominantly anterior, often non-granulomatous inflammation. However, the spectrum of herpetic ocular disease is broader. Acute retinal necrosis represents a severe manifestation with a panuveitic presentation, including granulomatous anterior chamber inflammation, dense vitritis, and posterior segment involvement. In this context, the granulomatous nature of the inflammation, together with the marked vitritis and the inability to visualize the fundus, raised suspicion for an infectious rather than sterile etiology [12]. The clinical features, combined with PCR analysis of the aqueous humor, confirmed a herpetic origin of the uveitis.

The pathophysiological link between intravitreal injection and contralateral viral reactivation is likely multifactorial. We propose a “two-hit” hypothesis involving systemic pharmacokinetic effects and host susceptibility. Bevacizumab, a full-length monoclonal antibody with an Fc region and longer vitreous half-life, may result in greater systemic exposure compared to antibody fragments. Previous studies have shown that intravitreal bevacizumab can suppress serum VEGF levels, with measurable effects in the fellow eye [13]. Given the role of VEGF in neuroprotection and immune homeostasis, transient systemic suppression, combined with procedural stress, may alter the latency threshold of HSV-1 within the trigeminal ganglion.

Host-related factors likely contribute to this process. Advanced age and diabetes mellitus are well-recognized risk factors for viral reactivation. Immunosenescence may impair both innate and adaptive immune responses, while diabetes is associated with chronic low-grade inflammation and dysregulated cellular immunity. In this setting, the intravitreal injection may act as a systemic trigger facilitating viral reactivation [14, 15].

Our findings complement those reported by Neri et al. [9]. While their case suggested a sterile immune-mediated mechanism, our report demonstrates a distinct phenotype with granulomatous features and PCR-confirmed viral infection. Together, these observations suggest that contralateral IOI represents a spectrum ranging from sterile inflammation to viral reactivation. This distinction is clinically relevant, as corticosteroid therapy alone may be insufficient or potentially harmful in cases of viral etiology.

From a clinical perspective, distinguishing between anti-VEGF–related sterile intraocular inflammation and viral uveitis is essential. Sterile inflammation typically occurs shortly after injection, is confined to the treated eye, and responds rapidly to corticosteroids. In contrast, viral uveitis may involve the fellow eye, present with granulomatous features and dense vitritis, and requires prompt antiviral therapy. In atypical presentations, aqueous humor PCR plays a key role in guiding diagnosis and management.

This report has inherent limitations. As a single retrospective case, a causal relationship between intravitreal injection and contralateral viral reactivation cannot be established. Although the temporal association is suggestive, coincidental herpetic reactivation cannot be entirely excluded. In addition, the absence of systemic biomarker analysis limits further pathophysiological interpretation.

In conclusion, although sterile inflammation remains the most common adverse event following anti-VEGF therapy, clinicians should be aware that these procedures may also act as systemic triggers for viral reactivation. A high index of suspicion for infectious etiologies is essential, particularly in patients with systemic risk factors such as diabetes. Early diagnostic evaluation, including aqueous humor PCR when clinically indicated, is crucial to guide appropriate management and prevent sight-threatening complications.

Author contributions

MCS drafted the manuscript. OMG, MLC, MA, LA, and FG contributed to data collection and clinical management. DI supervised the study and critically revised the manuscript. All authors read and approved the final manuscript.

Funding

No specific funding was received for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

According to institutional policy, ethical approval was not required for a single retrospective case report.

Consent for publication

Written informed consent for publication of clinical details and images was obtained from the patient.

Competing interests

The authors declare no competing interests.