Our patient presented with new onset erythema and telangiectasia of the lid margin, conjunctival hyperemia, and superficial punctate keratopathy which are the common signs of ocular GVHD. However, prominent anterior uveitis, which is a very rare (< 1%) ocular manifestation of GVHD, was also observed[5].
There are several pieces of evidence that support the possible existence of a causal relationship between COVID-19 vaccination and GVHD and anterior uveitis, despite a lack of definitive proof, including a temporal association, the occurrence of acute exacerbation of GVHD in a well-controlled case without the use of immunosuppressant for a long period, and the exclusion of common causes of anterior uveitis. Furthermore, the patient did not have a previous attack of uveitis according to his medical history, even during the period of acute GVHD.
Both uveitis and GVHD have been reported after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[6, 7]. Nevertheless, to the best of our knowledge, this is the first case report of acute exacerbation of ocular GVHD and anterior uveitis occurring concurrently in recipients of HSCT after COVID-19 vaccination.
Recipients of HSCT are at risk of infection from various pathogens and therefore vaccination is a crucial protection for these patients. The immune response generated by vaccination in patients with HSCT is usually weaker than that in healthy individuals during the initial months or years after transplantation and gradually improve over the next 2–3 years[8]. In the recipients of HSCT, the use of immunosuppressants or conditioning regimen, and the occurrence of GVHD both affect the recovery of the immune systems. As a result of the COVID-19 pandemic, novel vaccines based on mRNA technique, including the Pfizer-BioNTech BNT162b2 vaccine and Moderna mRNA-1273 vaccine were developed. Nevertheless, there are no large-scale studies of these vaccines to the recipients of HSCT.
The association between vaccination and the occurrence of GVHD is not well investigated. New or exacerbation of GVHD was reported after adjuvanted recombinant zoster vaccine and adjuvanted influenza vaccine[9, 10]. Molecular mechanisms of inflammatory triggers in GVHD include sterile damage associated molecular pattern (DAMP) molecules and pathogen-associated molecular pattern (PAMP). The former implicates that molecules release into extracellular space where tissue damage, immune activation could be stirred. The latter involves microbe such as bacteria, viruses, etc[11]. Immunological mechanisms of mRNA vaccines and DAMP/PAMP had been discussed as well. Cytokines can be induced by DAMP/PAMP and result in reactogenicity and immunogeniticy of vaccination. The components of vaccines may serve as PAMP/DAMP, which may trigger the immune response and lead to GVHD subsequently[12].
In addition, current studies on the association between vaccination against SARS-CoV-2 and the occurrence of GVHD were reported but limited. Andrew et al reported that in allogeneic HSCT recipients with chronic GVHD, the occurrence of symptom exacerbation following COVID-19 vaccination was relatively common (26.5%)[13]. Ali, H., et al. reported the incidence of adverse events following Pfizer-BioNTech BNT162b2 vaccine and Moderna mRNA-1273 vaccine[6]. Among the 113 cases, worsening of chronic GVHD occurred in 3.5% cases and new chronic GVHD occurred in 9.7% cases. The onset of GVHD after vaccination ranged from 3 to 55 days. Only three of the 13 cases with new or worsening GVHD had ocular symptoms and signs, but ocular manifestations were not documented in detail. 3 cases were treated with either systemic prednisone, tacrolimus, sirolimus or prednisolone 1% eye drops and achieved well-controlled or resolved disease status. Ram, R., et al. prospectively evaluated the efficacy and safety of Pfizer-BioNTech BNT162b2 vaccine in allogeneic HSCT recipients[4]. Exacerbation of GVHD, including oral, liver, gastrointestinal tract and skin manifestations occurred in three cases (4.5% of total cases) within the first week after vaccination.
With regard to uveitis, rare occurrence of anterior uveitis has been reported as a manifestation of GVHD[14]. Rabinovitch, T., et al. reported uveitis following Pfizer-BioNTech BNT162b2 vaccination, including 21 anterior uveitis cases[7]. The majority of cases with anterior uveitis completely resolved after treatment with topical corticosteroid. The clinical course differed from our case, which presented with chronic anterior uveitis despite systemic, local and topical corticosteroids treatment. Also, the aforementioned case series did not include recipients of HSCT, which may have contributed to the different clinical presentation. The special immune system of recipients of HSCT may contribute to the completely different manifestation in our case. Uveitis in our case didn't subside until intravitreal corticosteroid injection 6 months after vaccination. Intravitreous steroid injection was considered to be effective and important in refractory or chronic uveitis. On the other hand, humoral response diminished progressively 4–6 months after COVID-19 vaccination, which was indicated by previous systemic review[15]. The resolution of uveitis in our case occurred 6 months after vaccination, that might be contributed to either intravitreous steroid injection or diminished immune response. Further investigation is required to determine whether anterior uveitis is a manifestation of ocular GVHD or an independent manifestation after vaccination.
Clinicians should be alert to the possibility of acute exacerbation of ocular GVHD and anterior uveitis following vaccination against SARS-CoV-2 in patients who have undergone allogeneic HSCT. Under the condition that immunogenicity could be different in this group of patients, disease activity may be recurrent and refractory, and a more chronic course should be expected. Early diagnosis, close monitoring, and aggressive treatment, including intravitreal corticosteroid injection, in addition to topical or systemic steroid in usual cases, should be considered due to the possibility of severe complications. We did not use systemic immunomodulatory therapy because of the risk of infection and attenuation of the vaccination. Further studies and case reports are required to determine the role of systemic immunomodulatory therapy in patients with anterior uveitis and ocular GVHD following COVID-19 vaccination.