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Late-onset recurrent Acremonium fungal keratitis after therapeutic penetrating keratoplasty

Published:March 09, 2021DOI:https://doi.org/10.1016/j.jcjo.2021.02.006
      Fungal keratitis is a prominent cause of blindness worldwide. Therapeutic penetrating keratoplasty (TPK) has been demonstrated as an effective treatment for fungal keratitis that does not respond to antifungal medications. Recurrent fungal infection after TPK is uncommon but occurs typically within 2 weeks after surgery.
      • Gong Y
      • Xin M.
      Incidence of recurrent fungal keratitis after primary keratoplasty and visual outcome and prognosis after intervention for the recurrence.
      Acremonium species are a group of filamentous fungi isolated from vegetation matter and are a rare cause of fungal keratitis. We present here an unusual, delayed case of recurrent fungal keratitis with Acremonium species that recurred over 2 months after successful treatment with TPK.

      Case Report

      An 86-year-old woman presented with increased pain and foreign body sensation in her right eye for several weeks. Her past medical history was significant for Sjögren syndrome, for which she had been taking azathioprine 50 mg daily for many years. She had no history of previous eye trauma. Past ocular history was significant for wet age-related macular degeneration for which she was undergoing regular treatment with intravitreal bevacizumab. On presentation, visual acuity in the right eye was light perception. Slit lamp examination showed moderate conjunctival injection with a subtotal corneal ulcer overlying a corneal infiltrate located paracentrally, with 50% corneal thinning centrally and 80% corneal thinning inferotemporally. The anterior chamber was deep with a 1-mm hypopyon (Fig. 1A).
      Fig 1
      Fig. 1(A) Patient at presentation, with multifocal diffuse corneal infiltrates, large corneal ulceration, and hypopyon. (B) Progressive resolution of the infiltrates, ulcer, and hypopyon. (C) Recurrence of the multifocal infiltrates, ulceration, and hypopyon upon suspension of antifungal medications. (D) Rapid worsening of the clinical picture, with increase in size of corneal infiltrates and hypopyon. (E) Patient 1 month after therapeutic penetrating keratoplasty. Note peripheral neovascularisation with loosening of interrupted sutures secondary to withheld use of topical steroids. Central cornea remained relatively transparent. (F) Recurrence of inferotemporal ulcer with superficial infiltrates at the graft-host junction of therapeutic penetrating keratoplasty graft.
      Corneal scraping revealed presence of oval conidia noted on Gram stain, and the patient was diagnosed with fungal keratitis. She was started on topical antifungal amphotericin B 0.15% every 1–2 hours in the right eye. Two weeks later, the microbiological report of the culture from a national mycology reference laboratory identified the presence of Acremonium species. The patient started a tapering course of topical voriconazole 1% along with the amphotericin B 0.15% and progressively improved (Fig. 1B), with ultimate healing of the ulcer in 3 months’ time. Topical loteprednol 0.5% was used sparingly for control of inflammation only upon disappearance of the ulcer and infiltrate.
      Four months after her initial presentation, upon suspension of the antifungal medications, the patient presented with large, recurrent multifocal infiltrates and corneal ulcer (Fig. 1C), with precipitous worsening of the clinical picture (Fig. 1D) and rapid evolution towards perforation. Uncomplicated TPK was performed. Postoperatively, she continued topical amphotericin B 0.15% daily and topical voriconazole 1% daily hourly for 1 week and then 4 times daily, along with topical tacrolimus 0.1% 4 times daily to prevent graft rejection (Fig. 1E). No topical or systemic steroids were used to reduce the chance of recurrence of the infection. While still on antifungal medications, the patient developed endothelial rejection with corneal edema and neovascularization 2 months postoperatively. Topical prednisolone 1% was added 6 times daily, with resolution of the rejection in 1 week. The topical antifungals were suspended 1 week after starting topical steroids because there were no signs of any active fungal infection at that time. The patient remained on tacrolimus 4 times daily throughout this period.
      Two weeks after starting steroid medication and 76 days after the TPK, a 1-mm epithelial defect was noted on the patient's temporal cornea. Two days later, the epithelial defect increased in size, and an ulcer was noted on the patient's temporal corneal (Fig. 1F). A positive culture confirmed the recurrence of Acremonium species. The patient was started again on topical amphotericin B 0.15% and topical voriconazole 1% 6 times daily. Prednisolone eyedrops were reduced to twice daily. These medications were continued for 1 month, at which point the epithelial defect healed. The amphotericin B was discontinued, and the tacrolimus and voriconazole were eventually discontinued over the next 2 months, with the prednisolone reduced to once daily. One year after discontinuing all antifungal medication and 21 months after her initial presentation, there continued to be no recurrence of a fungal infection.

      Discussion

      Fungal keratitis can unfortunately recur after TPK. A retrospective analysis of 1148 cases of fungal keratitis treated with TPK reported that recurrence typically appeared within 2 weeks after surgery in 7.7% of eyes,
      • Gong Y
      • Xin M.
      Incidence of recurrent fungal keratitis after primary keratoplasty and visual outcome and prognosis after intervention for the recurrence.
      consistent with previous reports.
      It has also been shown that recurrence rates for fungal keratitis in patients who have been given steroids before surgery are significantly higher than those who were not treated with any steroids prior to surgery.
      • Shi W
      • Wang T
      • Xie L
      • et al.
      Risk Factors, clinical features, and outcomes of recurrent fungal keratitis after corneal transplantation.
      To note, the patient in our case had been administering loteprednol sparingly to manage corneal edema a week before her TPK. Additionally, recurrence rates are higher for patients with a preoperative hypopyon,
      • Shi W
      • Wang T
      • Xie L
      • et al.
      Risk Factors, clinical features, and outcomes of recurrent fungal keratitis after corneal transplantation.
      corneal perforation,
      • Shi W
      • Wang T
      • Xie L
      • et al.
      Risk Factors, clinical features, and outcomes of recurrent fungal keratitis after corneal transplantation.
      and larger infiltrates
      • Mundra J
      • Dhakal R
      • Mohamed A
      • et al.
      Outcomes of therapeutic penetrating keratoplasty in 198 eyes with fungal keratitis.
      —all of which were present in our patient. Our patient had also been taking azathioprine, a known immunosuppressant, for many years, which could have played a role in the recurrence of the fungal infection. This medication was not changed during the course of her fungal keratitis treatment. A common postoperative treatment after fungal keratitis outlined by Shi et al. involves 0.5% fluconazole and 0.25% amphotericin B or 5% natamycin. If no signs of recurrence are present for 2 weeks, low concentration topical steroids are administered twice daily.
      • Shi W
      • Wang T
      • Xie L
      • et al.
      Risk Factors, clinical features, and outcomes of recurrent fungal keratitis after corneal transplantation.
      In our case, tacrolimus 0.1% was started as an immunosuppressive medication to prevent graft rejection on postoperative day 1, although steroids were withheld until 2 months postoperatively and only when corneal edema and neovascularization owing to presumed graft rejection were noted. Our patient succumbed to a recurrence of Acremonium keratitis more than 2 months after TPK upon initiation of topical steroid treatment and without any prior signs of lingering or recalcitrant infection. In retrospect, perhaps it would have been beneficial to maintain the antifungal treatment for a longer period once the steroids were started. Another option would have been to use topical cyclosporin drops, which also have an antifungal effect.
      • Perry HD
      • Doshi SJ
      • Donnenfeld ED
      • Bai GS.
      Topical cyclosporin A in the management of therapeutic keratoplasty for mycotic keratitis.
      This case reports the longest latency between TPK and recurrent fungal infection described to date, with recurrence on the 76th day after TPK. The second longest delay in recurrence we could find in the literature was the 66th day after TPK.
      • Chatterjee S
      • Agrawal D.
      Recurrence of infection in corneal grafts after therapeutic penetrating keratoplasty for microbial keratitis.
      Our case highlights the particular difficulty in treating Acremonium keratitis, demonstrating its ability to remain quiescent in the cornea and reactivate months after TPK. One previous similar case has been documented, occurring in a 65-year-old man.
      • Wang MX
      • Shen DJ
      • Liu JC
      • Pflugfelder SC
      • Alfonso EC
      • Forster RK.
      Recurrent fungal keratitis and endophthalmitis.
      In this case, the patient underwent a corneoscleral keratoplasty and began prednisolone 1% acetate drops 2 weeks after the procedure. Seven weeks after the corneoscleral keratoplasty, the patient was diagnosed with recurrent Acremonium keratitis and ultimately required a second TPK.
      In summary, our present case demonstrates the potential for Acremonium keratitis to reoccur months after TPK in the absence of clinical signs of persistent infection and encourages clinicians to exercise caution in their use of immunosuppressive medication during postoperative management of this fungal species.

      Footnotes and Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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