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Open Access Case Report

Bilateral Corneal Perforation in a Patient with Chronic Ocular Graft-Versus-Host Disease: A Case Report and Literature Review

Ginevra G Adamo 1, Sergio D’Angelo 1, Angeli Christy Yu 1, Marco Pellegrini 1, Federico Bernabei 2, Vincenzo Scorcia 3, Giuseppe Giannaccare 3,*

  1. Department of Translational Medicine, University of Ferrara, Ferrara, Italy

  2. Department of Ophthalmology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France

  3. Department of Ophthalmology, University Magna Græcia of Catanzaro, Catanzaro, Italy

Correspondence: Giuseppe Giannaccare

Academic Editor: Nidhi Sharma

Special Issue: Haploidentical Stem Cell Transplantation

Received: June 17, 2022 | Accepted: July 27, 2022 | Published: August 02, 2022

OBM Transplantation 2022, Volume 6, Issue 3, doi:10.21926/obm.transplant.2203164

Recommended citation: Adamo GG, D’Angelo S, Yu AC, Pellegrini M, Bernabei F, Scorcia V, Giannaccare G. Bilateral Corneal Perforation in a Patient with Chronic Ocular Graft-Versus-Host Disease: A Case Report and Literature Review. OBM Transplantation 2022; 6(3): 164; doi:10.21926/obm.transplant.2203164.

© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Graft-versus-host disease (GVHD) is a serious complication that may occur in patients receiving allogeneic hematopoietic stem cell transplant (HSCT). GVHD occurs because of the immunological reaction between the donor’s T cells and the recipient’s antigens; GVHD may develop in different tissues, including the eye. Corneal perforation is an uncommon but vision-threatening manifestation of GVHD. We reported the case of a 65-year-old male patient who developed corneal perforation sequentially in both eyes 3 years after receiving HSCT. Conservative treatment with topical steroids and lubricants, bandage contact lens, and lacrimal punctal occlusion surgery resulted in the successful resolution of the corneal perforation with satisfactory visual recovery in the right eye. Therefore, corneal perforation can occur as the presenting manifestation of ocular GVHD. Regular ophthalmological examinations are recommended after HSCT to enable the early diagnosis of ocular GVHD and prompt treatment initiation.

Keywords

Graft-versus-host disease; ocular graft-versus-host disease; allogeneic stem cell transplant; hematopoietic stem cell transplant; bone marrow transplant; dry eye; corneal perforation

1. Introduction

Hematopoietic stem cell transplant (HSCT) is the standard of care for a wide spectrum of hematological diseases, solid tumors, and immune disorders [1,2]. However, despite undergoing immunoprophylaxis, patients receiving allogeneic HSCT often have the complication of graft-versus-host-disease (GVHD), which affects up to 70% of such patients and is the major cause of late morbidity and mortality. GVHD is a complex interplay of immune-mediated reactions caused by the recognition of recipient antigens by the donor immune cells. The most accepted conceptual model of GVHD involves three phases: recipient tissue damage from the pretransplant conditioning regiment with the activation of antigen-presenting cells; donor T-cell activation and differentiation; and target tissue damage and fibrosis [3,4].

Ocular GVHD primarily affects the ocular surface, which is a complex morpho-functional unit consisting of the surface and glandular epithelia of the cornea, conjunctiva, eyelid margin, and lacrimal and meibomian glands. Ocular GVHD results in meibomian gland loss, symblepharon formation, cicatricial conjunctivitis, limbal stem cell deficiency, corneal epithelial defects leading to ulceration, neovascularization, conjunctivalization, corneal scar, and corneal opacification. In severe cases, the ocular surface impairment can lead to corneal blindness [5,6,7]. Dry eye disease (DED) is the clinical hallmark of this condition; however, the clinical manifestations of ocular GVHD can be heterogenous and can infrequently include corneal perforation, microvascular retinopathy, scleritis, and intraretinal and vitreous hemorrhage [8,9,10,11,12,13,14,15].

We reported an atypical case of ocular GVHD presenting with sequential bilateral corneal perforation without any previous ocular signs or symptoms. The patient provided his verbal and written consent for the publication of his data anonymously.

2. Case Report

A 65-year-old male patient with a history of allogeneic HSCT for myelodysplastic syndrome 3 years prior presented to our Cornea clinic (Department of Ophthalmology, University “Magna Græcia,” Catanzaro, Italy) with acute onset of ocular pain and blurring of vision in the right eye. The patient had no prior history of DED, and previous ophthalmological examinations were unremarkable. Upon presentation, the patient’s visual acuity (VA) was limited to counting fingers at 1 foot. Slit lamp examination revealed severe inferior corneal ulceration associated with perforation (Figure 1A). Anterior segment optical coherence tomography (AS-OCT) confirmed full-thickness perforation with complete iridocorneal adhesion and a flattened anterior chamber (Figure 1C). The slit lamp examination of the left eye was unremarkable, except for mild conjunctival hyperemia. Oral doxycycline (20 mg twice a day), topical dexamethasone eye drops (four times a day), and topical lubricants were prescribed. A bandage contact lens was applied, and lacrimal punctal occlusion surgery was performed to improve tear retention. Both clinical picture and ocular symptoms improved gradually over the following weeks. However, 3 months from the initial presentation, the patient presented at the clinic with pain and blurry vision in the contralateral eye. The VA of the left eye was limited to hand motion, and the slit lamp examination revealed a corneal perforation involving the visual axis (Figure 1B). AS-OCT revealed marked corneal thinning and a shallow anterior chamber (Figure 1D).

Click to view original image

Figure 1 A. Slit lamp image of the right eye revealing inferior corneal perforation. B. Slit lamp image of the left eye revealing central corneal perforation. C. AS-OCT of the right eye revealing a full-thickness perforation with complete iridocorneal adhesion and a flattened anterior chamber. D. AS-OCT of the left eye revealing marked corneal thinning with a shallow anterior chamber.

The aforementioned treatment was also prescribed in the left eye and resulted in gradual spontaneous healing. Doxycycline was suggested to be taken for 6 months, whereas topical dexamethasone was tapered off in 12 months until discontinuation. At the last follow-up 12 months after the initial presentation, the VA was 20/50 in the right eye and counting fingers at 1 foot in the left eye (Figure 2).

Click to view original image

Figure 2 12-month follow-up visit. A. Slit lamp image of the right eye revealing healed corneal perforation. B. Slit lamp image of the left eye revealing healed central corneal perforation. C. AS-OCT of the right eye. D. AS-OCT of the left eye.

3. Discussion

We described a case of severe ocular GVHD initially presenting with spontaneous corneal perforation in one eye, which rapidly progressed to corneal perforation in the other eye. The patient did not present with the typical manifestations of GVHD or any other ocular symptoms. This severe and atypical presentation indicates the importance of periodical hematological and ophthalmological examinations in patients who have undergone HSCT to promptly diagnose GVHD and initiate appropriate treatment.

Corneal perforation is a rare and severe complication of ocular GVHD, resulting not only in functional visual impairment but also in the loss of the globe [16]. In a large retrospective case series conducted by Lin et al. (n = 249), Stevenson et al. (n = 243), and Pellegrini et al. (n = 283), the rates of corneal perforation in patients with GVHD were exceedingly low, ranging from 0.7% to 1.2% [17,18,19] (Table 1). A few cases of bilateral corneal perforation, usually associated with advanced chronic ocular GVHD, have been reported in the literature [20,21,22,23]. Lin et al. described one case of bilateral corneal perforation secondary to infectious keratitis in which penetrating keratoplasty was ultimately required [17]. Mohammadpour et al. reported a case of recurrent corneal perforation in both eyes in a patient with severe DED secondary to chronic GVHD. Corneal perforation recurred twice in the patient following cyanoacrylate gluing and amniotic membrane transplant, and penetrating keratoplasty was eventually performed [24]. Yoshida et al. described the occurrence of sequential bilateral corneal perforations in a patient with severe chronic GVHD [25].

Table 1 Large case series on ocular GVHD.

The National Institutes of Health diagnostic criteria were developed in 2005 and revised in 2014 to standardize the diagnosis and grading of chronic GVHD. The diagnosis of GVHD requires either one diagnostic clinical sign or one distinctive manifestation confirmed by pertinent biopsy or other relevant tests, including biopsy or laboratory confirmation in the skin or another organ. According to these criteria, ocular involvement alone is not sufficient to confirm chronic GVHD [1]. Nevertheless, because eye involvement is common, patients with ocular manifestations alone might not fit these diagnostic criteria. Therefore, Shikari et al. and Ogawa et al. have suggested that the presence of ocular GVHD should be sufficient to establish a diagnosis of chronic GVHD [26,27]. In 2007, the International Chronic Ocular GVHD Consensus Group proposed alternative diagnostic criteria specifically for ocular GVHD on the basis of the Ocular Surface Disease Index score, Schirmer test, corneal staining, and conjunctival redness. However, ocular GVHD can manifest with a wide range of presentations that may not meet these diagnostic criteria. As demonstrated by the present case, corneal ulceration and perforation can occur in the absence of ocular surface symptoms or other manifestations of systemic GVHD [20,28]. Thus, ophthalmologists should maintain a high degree of suspicion for ocular GVHD in patients who have undergone HSCT.

Corneal perforation management in the setting of GVHD includes different medical and surgical treatments, such as topical anti-inflammatory drugs, autologous serum tears, bandage contact lenses, amniotic membrane transplant, cyanoacrylate gluing, and tectonic keratoplasty [29,30,31,32,33,34,35,36,37]. Systemic immunosuppression plays an important role in multisystemic GVHD; however, the risk-to-benefit ratio in localized diseases remains undetermined [29,30,31,32,33]. Oral doxycycline is particularly highly effective in inhibiting pro-inflammatory cytokines, including matrix metalloproteinases (e.g., MMP-6 and MMP-9); such cytokines typically infiltrate epithelial and stromal matrix in eyes with ocular GVHD [22,38,39]. Previous studies have reported the successful use of cyclosporine eye drops for the treatment of noninfectious corneal ulcers [40]. Because of its ability to reduce the number of activated T cells on the ocular surface, topical cyclosporine may represent a valid option for the treatment of corneal ulceration in patients with ocular GVHD [14].

Our patient was managed conservatively with a bandage contact lens, topical dexamethasone, lubricants, lacrimal punctal occlusion surgery, and oral doxycycline. This approach resulted in the successful resolution of the corneal perforation with satisfactory visual recovery in the right eye. Some authors have reported that compared with patients receiving nonsurgical interventions, patients receiving keratoplasty exhibit superior visual rehabilitation [35,36]; however, keratoplasty results in an overall poor prognosis in eyes with intense inflammation, dryness, and neovascularization [41]. Therefore, we reserve keratoplasty for nonhealing corneal perforations following failed medical treatment or for late visual rehabilitation once the ocular surface status has improved.

In conclusion, corneal perforation is a rare but vision-threatening manifestation of ocular GVHD. In the presented patient, the perforation occurred sequentially in both eyes without any prior evidence of ocular GVHD. Therefore, regular ophthalmological examinations are recommended following HSCT to enable the prompt diagnosis, prevention, and appropriate treatment of GVHD and ocular complications. Conservative medical treatment resulted in the successful resolution of the corneal perforation with satisfactory visual recovery.

Author Contributions

All authors contributed equally to this work.

Competing Interests

The authors have declared that no competing interests exist.

References

  1. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015; 21: 389-401.e1. [CrossRef]
  2. Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe, 2019. Bone Marrow Transplant. 2019; 54: 1525-1552. [CrossRef]
  3. Choi SW, Levine JE, Ferrara JL. Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am. 2010; 30: 75-101. [CrossRef]
  4. Hess NJ, Brown ME, Capitini CM. Gvhd pathogenesis, prevention and treatment: Lessons from humanized mouse transplant models. Front Immunol. 2021; 12: 723544. [CrossRef]
  5. Gipson IK. The ocular surface: The challenge to enable and protect vision: The Friedenwald lecture. Invest Ophthalmol Vis Sci. 2007; 48: 4391-4398. [CrossRef]
  6. Nosrati H, Ashrafi-Dehkordi K, Alizadeh Z, Sanami S, Banitalebi-Dehkordi M. Biopolymer-based scaffolds for corneal stromal regeneration: A review. Polim Med. 2020; 50: 57-64. [CrossRef]
  7. Nosrati H, Alizadeh Z, Nosrati A, Ashrafi-Dehkordi K, Banitalebi-Dehkordi M, Sanami S, et al. Stem cell-based therapeutic strategies for corneal epithelium regeneration. Tissue Cell. 2021; 68: 101470. [CrossRef]
  8. Munir SZ, Aylward J. A review of ocular graft-versus-host disease. Optom Vis Sci. 2017; 94: 545-555. [CrossRef]
  9. Ogawa Y, Kawakami Y, Tsubota K. Cascade of inflammatory, fibrotic processes, and stress-induced senescence in chronic GVHD-related dry eye disease. Int J Mol Sci. 2021; 22: 6114. [CrossRef]
  10. Berchicci L, Rabiolo A, Marchese A, Iuliano L, Gigliotti C, Miserocchi E, et al. Ocular chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in an Italian referral center. Ocul Surf. 2018; 16: 314-321. [CrossRef]
  11. Giannaccare G, Bernabei F, Pellegrini M, Arpinati M, Bonifazi F, Sessa M, et al. Eyelid metrics assessment in patients with chronic ocular graft versus-host disease. Ocul Surf. 2019; 17: 98-103. [CrossRef]
  12. Pellegrini M, Bernabei F, Moscardelli F, Vagge A, Scotto R, Bovone C, et al. Assessment of corneal fluorescein staining in different dry eye subtypes using digital image analysis. Transl Vis Sci Technol. 2019; 8: 34. [CrossRef]
  13. Giannaccare G, Pellegrini M, Taroni L, Bernabei F, Senni C, Grendele A, et al. Corneal biomechanical alterations in patients with chronic ocular graft versus-host disease. PLoS One. 2019; 14: e0213117. [CrossRef]
  14. Giannaccare G, Pellegrini M, Bernabei F, Scorcia V, Campos E. Ocular surface system alterations in ocular graft-versus-host disease: All the pieces of the complex puzzle. Graefes Arch Clin Exp Ophthalmol. 2019; 257: 1341-1351. [CrossRef]
  15. Nosrati H, Abpeikar Z, Mahmoudian ZG, Zafari M, Majidi J, Alizadeh A, et al. Corneal epithelium tissue engineering: Recent advances in regeneration and replacement of corneal surface. Regen Med. 2020; 15: 2029-2044. [CrossRef]
  16. Ferrete T, Rocher F, Elmaleh V, Loschi M, Tieulie N, Baillif S, et al. Eye amputation following lifitegrast treatment for ocular graft-versus-host disease: First case report. J Fr Ophtalmol. 2021; 44: 652-657. [CrossRef]
  17. Lin X, Cavanagh HD. Ocular manifestations of graft-versus-host disease: 10 years' experience. Clin Ophthalmol. 2015; 9: 1209-1213. [CrossRef]
  18. Stevenson W, Shikari H, Saboo US, Amparo F, Dana R. Bilateral corneal ulceration in ocular graft-versus-host disease. Clin Ophthalmol. 2013; 7: 2153-2158. [CrossRef]
  19. Pellegrini M, Bernabei F, Barbato F, Arpinati M, Giannaccare G, Versura P, et al. Incidence, risk factors and complications of ocular graft-versus-host disease following hematopoietic stem cell transplantation. Am J Ophthalmol. 2021; 227: 25-34. [CrossRef]
  20. Hessen M, Akpek EK. Ocular graft-versus-host disease. Curr Opin Allergy Clin Immunol. 2012; 12: 540-547. [CrossRef]
  21. Inagaki E, Ogawa Y, Matsumoto Y, Kawakita T, Shimmura S, Tsubota K. Four cases of corneal perforation in patients with chronic graft-versus-host disease. Mol Vis. 2011; 17: 598-606.
  22. Suzuki M, Usui T, Kinoshita N, Yamagami S, Amano S. A case of sterile corneal perforation after bone marrow transplantation. Eye (Lond). 2007; 21: 114-116. [CrossRef]
  23. Yen PT, Hou YC, Lin WC, Wang LJ, Hu FR. Recurrent corneal perforation and acute calcareous corneal degeneration in chronic graft-versus-host disease. J Formos Med Assoc. 2006; 105: 334-339. [CrossRef]
  24. Mohammadpour M, Maleki S, Hashemi H, Beheshtnejad AH. Recurrent corneal perforation due to chronic graft versus host disease; a clinicopathologic report. J Ophthalmic Vis Res. 2016; 11: 108-111. [CrossRef]
  25. Yoshida A, Kawano YI, Kato K, Yoshida S, Yoshikawa H, Muta T, et al. Apoptosis in perforated cornea of a patient with graft-versus-host disease. Can J Ophthalmol. 2006; 41: 472-475. [CrossRef]
  26. Shikari H, Antin JH, Dana R. Ocular graft-versus-host disease: A review. Surv Ophthalmol. 2013; 58: 233-251. [CrossRef]
  27. Ogawa Y, Kim SK, Dana R, Clayton J, Jain S, Rosenblatt MI, et al. International chronic ocular graft-vs-host-disease (GVHD) consensus group: Proposed diagnostic criteria for chronic GVHD (part I). Sci Rep. 2013; 3: 3419. [CrossRef]
  28. Arafat SN, Robert MC, Abud T, Spurr-Michaud S, Amparo F, Dohlman CH, et al. Elevated neutrophil elastase in tears of ocular graft-versus-host disease patients. Am J Ophthalmol. 2017; 176: 46-52. [CrossRef]
  29. Ramachandran V, Kolli SS, Strowd LC. Review of graft-versus-host disease. Dermatol Clin. 2019; 37: 569-582. [CrossRef]
  30. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015; 125: 606-615. [CrossRef]
  31. Nair S, Vanathi M, Mukhija R, Tandon R, Jain S, Ogawa Y. Update on ocular graft-versus-host disease. Indian J Ophthalmol. 2021; 69: 1038-1050. [CrossRef]
  32. Tung CI. Current approaches to treatment of ocular graft-versus-host disease. Int Ophthalmol Clin. 2017; 57: 65-88. [CrossRef]
  33. Couriel D, Carpenter PA, Cutler C, Bolaños-Meade J, Treister NS, Gea-Banacloche J, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary therapy and supportive care working group report. Biol Blood Marrow Transplant. 2006; 12: 375-396. [CrossRef]
  34. Sabti S, Halter JP, Braun Fränkl BC, Goldblum D. Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GVHD. Bone Marrow Transplant. 2012; 47: 981-984. [CrossRef]
  35. Zhang CY, Farooq AV, Harocopos GJ, Sollenberger EL, Hou JH, Bouchard CS, et al. Corneal perforation in ocular graft-versus-host disease. Am J Ophthalmol Case Rep. 2021; 24: 101224. [CrossRef]
  36. Di Zazzo A, Kheirkhah A, Abud TB, Goyal S, Dana R. Management of high-risk corneal transplantation. Surv Ophthalmol. 2017; 62: 816-827. [CrossRef]
  37. Busin M, Giannaccare G, Sapigni L, Testoni N, Leon P, Versura P, et al. Conjunctival and limbal transplantation from the same living-related bone marrow donor to patients with severe ocular graft-vs-host disease. JAMA Ophthalmol. 2017; 135: 1123-1125. [CrossRef]
  38. Dang DH, Riaz KM, Karamichos D. Treatment of non-infectious corneal injury: Review of diagnostic agents, therapeutic medications, and future targets. Drugs. 2022; 82: 145-167. [CrossRef]
  39. Nissinen L, Kähäri VM. Matrix metalloproteinases in inflammation. Biochim Biophys Acta. 2014; 1840: 2571-2580. [CrossRef]
  40. Gottsch JD, Akpek EK. Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers. Trans Am Ophthalmol Soc. 2000; 98: 81-90.
  41. Sinha S, Singh RB, Dohlman TH, Taketani Y, Yin J, Dana R. Prevalence and risk factors associated with corneal perforation in chronic ocular graft-versus-host-disease. Cornea. 2021; 40: 877-882. [CrossRef]
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