DOI: https://doi.org/10.21203/rs.3.rs-2678809/v1
Background: To report a case of acute exacerbation of ocular graft-versus-host disease (GVHD) and anterior uveitis following coronavirus disease 2019 (COVID-19) vaccination.
Case presentation: A 60-year-old man with primary myelofibrosis and GVHD after receiving allogeneic hematopoietic stem cell transplantation (HSCT), developed acute exacerbation of ocular GVHD and anterior uveitis after receiving first dose of COVID-19 vaccine. Erythema of the eyelids, conjunctival hyperemia, superficial punctate keratopathy, and prominent anterior chamber inflammation in both eyes were revealed. Ocular GVHD and anterior uveitis were managed with mainly topical corticosteroid, antibiotics, and systemic corticosteroid, but were difficult to control. Successful treatment was achieved with intravitreal injection of dexamethasone 6 months later.
Conclusions: Clinicians should beware of the rare refractory anterior uveitis and acute exacerbation of ocular GVHD after COVID-19 vaccination in patients undergoing HSCT. Early diagnosis and aggressive treatment should be considered to reduce the likelihood of severe complications.
Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT). Grafted immune cells attack the host tissue, including skin, mouth, eyes, lungs, liver, gastrointestinal tract, genitalia, hematopoietic and the immune systems[1]. GVHD can be classified as acute or chronic type and most ocular complications occur in chronic GVHD. Cicatricial conjunctivitis and keratoconjunctivitis sicca are the main manifestation of chronic GVHD. Late complications include limbal stem cell deficiency and corneal scaring.
Because of the coronavirus disease 2019 (COVID-19) pandemic, over half of the world’s population has received at least one dose of vaccine to prevent morbidity and mortality. Two mRNA vaccines, Pfizer-BioNTech BNT162b2 vaccine and Moderna mRNA-1273 vaccine received Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) for the prevention of COVID-19[2, 3]. However, the safety and efficacy of these vaccines in patients after allogeneic HSCT are still under investigation[4].
Here, we present a case of acute exacerbation of ocular GVHD and anterior uveitis following Moderna mRNA-1273 vaccination.
A 60-year-old male presented with acute onset of bilateral blurred vision, pain, and redness 3 days after receiving a first dose of Moderna mRNA-1273 vaccine. He was diagnosed with primary myelofibrosis and underwent allogeneic HSCT in 2014. Grade IV acute GVHD and subsequent chronic GVHD, which manifested mainly as skin and ocular lesion were diagnosed. The disease activity of GVHD became stable after treatment with systemic corticosteroids and immunosuppressants. All corticosteroids and immunosuppressants have been discontinued since 2019. Since then, his ocular condition became stable. Moderate corneal opacity and band keratopathy in the right eye was noted; severe corneal opacity and pannus was noted in the left eye, with baseline intraocular pressure around 18 to 20mmHg in bilateral eyes, and visual acuity of 20/100 in the right eye and hand motion in the left eye. The patient was treated for keratoconjunctivitis sicca with artificial tears. In addition, no previous attack of uveitis was recorded.
At presentation, his uncorrected visual acuity was 20/200 in the right eye and hand movements in the left eye. Ocular examination showed erythema of the eyelids, telangiectasia of lid margin, conjunctival hyperemia, superficial punctate keratopathy, prominent anterior chamber inflammation (cells 4+), posterior synechiae in both eyes, and hypopyon in the left eye (Fig. 1A, 1B. 1C). New central corneal perforation with iris incarceration of his left eye was documented. Posterior segment was obscured by the severe posterior synechiae and corneal perforation. Ultrasonography showed a clear vitreous cavity in both eyes. Physical examination revealed new erythematous skin eruptions over his back (Fig. 1D). He did not report gastrointestinal symptoms.
Blood analysis reported thrombocytopenia, and a slightly elevated erythrocyte sedimentation rate. Human leucocyte antigen (HLA) B27 typing, rheumatoid factor and syphilis serologic test were negative. Aqueous sample for polymerase chain reaction of herpes simplex virus, varicella zoster virus, and cytomegalovirus were negative.
Treatment with topical 1% prednisolone acetate 2 hourly, levofloxacin 4 times daily, 1% atropine twice daily, and oral doxycycline 2 times daily were initiated. At follow-up four weeks later, oral prednisolone 10 mg three times daily and 0.05% topical cyclosporine twice daily were started because of only minimal improvement of symptoms and signs, and dosage was tapered gradually according to clinical condition. Besides, intravitreal corticosteroid injection was recommended, but the patient was concerned about the invasive procedure and refused initially. Therefore, sub-tenon injection of triamcinolone for both eyes was administered 2 times for management of anterior uveitis, which resulted in partial resolution of anterior chamber inflammation (to cell 1+); however, it rebounded 4 weeks later (to cell 3 + in the right eye and cell trace in the left eye). The patient still refused intravitreal injection, and topical 1% prednisolone acetate hourly and oral prednisolone 10 mg daily were administered over the following 2 months that dosage was adjusted based on ocular condition. Due to progressive blurred vision, persistent anterior uveitis and cataract, the patient accepted to receive intravitreal dexamethasone injection for right eye. The conjunctival hyperemia and anterior chamber inflammation subsided after only one intravitreal injection. The anterior chamber remained silent and topical prednisolone acetate was gradually tapered to once daily.
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.
COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; GVHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; DAMP: damage-associated molecular pattern; PAMP: pathogen-associated molecular pattern
Ethics approval and consent to participate
The study received ethics approval from the Institutional Review Board (IRB) of Taichung Veterans General Hospital. All study protocols adhered to the principles outlined in the Declaration of Helsinki.
Consent for publication
Written informed consent for publication was obtained from the patient.
Availability of data and materials
All relevant findings are contained within this manuscript.
Competing interests
All authors report there are no competing interests to declare.
Funding
The authors received no funding in this study.
Authors' contributions
Hung-Jen Chien contributed to the acquisition and investigation of the patient
information. Chen-Yu Lin and Hung-Jen Chien wrote the initial draft, and both reviewed and edited the manuscript with equal contributions. All authors have read and approved the final manuscript.
Acknowledgements
Not applicable.
Statement on human and animal rights
Our study is descriptive and non-interventional, which is in accordance with the principles stated in the Declaration of Helsinki.