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Clinicopathologic case reports of Alternaria and Fusarium keratitis in Canada

      Fungal keratitis is prevalent in tropical environments, making up 35% of all keratitis cases in Florida.
      • Hassan H.M.
      • Papanikolaou T.
      • Mariatos G.
      • et al.
      Candida albicans keratitis in an immunocompromised patient.
      However, few cases have been reported in more temperate regions such as Canada.
      • Hassan H.M.
      • Papanikolaou T.
      • Mariatos G.
      • et al.
      Candida albicans keratitis in an immunocompromised patient.
      • Jurkunas U.
      • Behlau I.
      • Colby K.
      Fungal keratitis: changing pathogens and risk factors.
      • Zahra L.V.
      • Mallia D.
      • Hardie J.G.
      • et al.
      Case report. Keratomycosis due to Alternaria alternata in a diabetic patient.
      In this article, we present 2 Canadian farmers who experienced keratitis involving a dematiaceous fungus, Alternaria alternata, and a Fusarium species, respectively.

      Case 1

      In a farming accident, a 49-year-old male sustained a severe alkali injury to his left eye (OS), reducing his visual acuity to 20/120 (Fig. 1A). He developed a hypopyon, which slowly improved on topical 1% prednisolone acetate and oral prednisone (50 mg daily) while continuing with prophylactic topical moxifloxacin and tobramycin. His corneal opacification progressed to an inferior descemetocele. Four months after presentation, he received a Boston keratoprosthesis (k-pro). Routine cultures were negative. One month later, he returned with a wound leak and an infiltrate into the graft, which cultured positive for A. alternata (Fig. 1B). He was treated with intracameral amphotericin B, along with topical amphotericin B, moxifloxacin, and vancomycin, and oral itraconazole and ciprofloxacin. Collagen cross-linking (CXL) with 0.1% riboflavin was administered 3 days later. The infection continued, causing melting around the k-pro beyond the limbus. Two months after transplant, he underwent sclerokeratoplasty. Cultures of the k-pro isolated A. alternata. Despite continued topical and oral antimicrobials, the eye experienced development of culture-negative endophthalmitis 1 month postoperatively and became phthisical.
      Figure thumbnail gr1
      Fig. 1A, Corneal ulceration after alkaline chemical burns to the left eye. B, One month after k-pro implantation with the infectious process infiltrating into the graft material. C, The corneal specimen is severely necrotic with irregular thinning of the inflamed stroma (hematoxylin and eosin, ×25 original magnification). D, The Grocott–Gomori methenamine silver stain (GMS) shows numerous filamentous fungi at all levels predominantly anteriorly in the necrotic central stroma (×200 original magnification). E, Higher magnification of septated fungi (GMS, ×640 original magnification). F, Tease mount of a 72-hour culture growth that has been stained with lactophenol cotton blue, showing large, brown pigmented, muriform macroconidia occurring in short chains that is characteristic of Alternaria species (×640 original magnification).
      Examination of the initial corneal specimen showed extensive necrosis and a severe nongranulomatous inflammatory infiltrate (Fig. 1C). The epithelium, Bowman layer, endothelium, and most of Descemet membrane were absent. Numerous septated filamentous fungi (Fig. 1D, 1E) extended to 1 specimen margin. The tease mount showed large, brown, muriform macroconidia occurring in short chains, characteristic of Alternaria species (Fig. 1F).

      Case 2

      A 40-year-old male soft contact lens (CL) wearer presented with hand-motion vision and a 10-day history of a left central corneal ulcer (Fig. 2A). The patient was a farmer who had been combating a Fusarium infection in his wheat crop. Corneal cultures yielded Fusarium species, which was treated with 0.15% drops amphotericin B hourly, moxifloxacin drops every 2 hours, and oral ketoconazole 200 mg twice daily. The corneal ulcer persisted and a repeat culture 4 weeks after presentation isolated Fusarium species. The cornea was collagen cross-linked with 0.1% riboflavin 1 week later. The patient returned 6 days later with pain and a hypopyon, at which time voriconazole drops were instilled followed by a short course of topical 1% prednisolone acetate. The hypopyon improved, but the ulceration failed to stabilize and the cornea perforated centrally 4 weeks later, which was managed by a sclerokeratoplasty with perioperative intracameral voriconazole. At 3 months of follow-up, the patient’s visual acuity improved to 20/60. He subsequently experienced graft rejection with no evidence of infection reactivation.
      Figure thumbnail gr2
      Fig. 2A, Corneal ulceration from Fusarium infection of more than 10 days’ duration in the left eye. B, The cornea is markedly thinned and inflamed centrally with superficial ulceration and a central perforation (hematoxylin and eosin, ×25 original magnification). C, The Grocott–Gomori methenamine silver stain (GMS) shows fungi mainly paracentrally with a large patch superficially (arrow) toward one side (×25 original magnification). D, Large aggregates of filamentous septated fungi in the superficial stromal in the region of the arrow in C (GMS, ×640 original magnification).
      Histopathologic examination of the necrotic cornea showed marked central thinning with perforation (Fig. 2B, 2C). There were extensive acute and chronic nongranulomatous inflammatory infiltrates throughout, especially paracentrally. The epithelium and Bowman layer were absent. Descemet membrane was fragmented centrally and the endothelium was severely attenuated. Septated filamentous fungi were found full thickness centrally and in the anterior half of the cornea peripherally, consistent with Fusarium species (Fig. 2C, 2D).

      Discussion

      Alternaria and Fusarium species are opportunistic pathogens commonly found in the soil and in plants,
      • Zahra L.V.
      • Mallia D.
      • Hardie J.G.
      • et al.
      Case report. Keratomycosis due to Alternaria alternata in a diabetic patient.
      • Thomas P.A.
      Current perspectives on ophthalmic mycoses.
      with individuals in the agricultural industry being especially at risk for acquiring these infections after trauma. Geographic location greatly influences the prevalence of fungal keratitis, decreasing to 2% in more temperate areas such as New York.
      • Hassan H.M.
      • Papanikolaou T.
      • Mariatos G.
      • et al.
      Candida albicans keratitis in an immunocompromised patient.
      Candida species are the major causative agent in the northern United States, whereas Fusarium species are more frequent in warmer regions.
      • Hassan H.M.
      • Papanikolaou T.
      • Mariatos G.
      • et al.
      Candida albicans keratitis in an immunocompromised patient.
      To our knowledge, Case 1 is the first report of A. alternata keratitis in Canada.
      A number of factors increased the risk for fungal infection in Case 1. This patient was a poor candidate for lamellar and penetrating keratoplasty because of the extensive chemical damage with resultant cicatrizing conjunctivitis and limbal stem cell deficiency. K-pro is well tolerated in these unfavourable post–chemical injury corneas.
      • Zerbe B.L.
      • Belin M.W.
      • Ciolino J.B.
      Results from the Multicenter Boston Type 1 Keratoprosthesis Study.
      • Basu S.
      • Taneja M.
      • Narayanan R.
      • et al.
      Short-term outcome of Boston Type 1 keratoprosthesis for bilateral limbal stem cell deficiency.
      However, the combination of a poor ocular surface and the synthetic k-pro optic likely encouraged formation of a fungal biofilm and invasion into and around the graft leading to inflammation-mediated stromal melting. Thus, in these high-risk cases, prophylactic antifungal therapy also may be considered. Chan and Holland
      • Chan C.C.
      • Holland E.J.
      Infectious keratitis after Boston type 1 keratoprosthesis implantation.
      found that in patients with k-pro, CL and systemic immunosuppression were not predisposing factors to infection. Moreover, collagenase and proteinases are released after an alkaline injury, promoting corneal melting. Melting may have been further compounded by the use of topical corticosteroids, which may promote collagenases activity.
      • Davis A.R.
      • Ali Q.K.
      • Aclimandos W.A.
      • et al.
      Topical steroid use in the treatment of ocular alkali burns.
      Fungal infections are best controlled with early treatment. Case 2 presented 10 days after the onset of infection. This late presentation is associated with an increased requirement for penetrating keratoplasty (PKP).
      • Rautaraya B.
      • Sharma S.
      • Kar S.
      • et al.
      Diagnosis and treatment outcome of mycotic keratitis at a tertiary eye care center in eastern India.
      Furthermore, in Fusarium keratitis involving the deeper stroma, meta-analysis found that 70% were unsuccessful on medical therapy alone.
      • Thomas P.A.
      Current perspectives on ophthalmic mycoses.
      CXL has been reported to yield good outcomes in infectious keratitis, controlling and preventing emergency PKP.
      • Anwar H.M.
      • El-Danasoury A.M.
      • Hashem A.N.
      Corneal collagen crosslinking in the treatment of infectious keratitis.
      CXL increases corneal integrity, making the collagen matrix more resistant to digestive enzymes released by infectious pathogens, as well as promoting a direct antimicrobial effect.
      • Anwar H.M.
      • El-Danasoury A.M.
      • Hashem A.N.
      Corneal collagen crosslinking in the treatment of infectious keratitis.
      • Spoerl E.
      • Wollensak G.
      • Seiler T.
      Increased resistance of crosslinked cornea against enzymatic digestion.
      However, CXL also may reduce drug penetration.
      • Tschopp M.
      • Stary J.
      • Frueh B.E.
      • et al.
      Impact of corneal cross-linking on drug penetration in an ex vivo porcine eye model.
      In a porcine model of CXL, the reduction in penetration for voriconazole was 15.6%.
      • Tschopp M.
      • Stary J.
      • Frueh B.E.
      • et al.
      Impact of corneal cross-linking on drug penetration in an ex vivo porcine eye model.
      It is important to consider that CXL in Case 2 may have been unsuccessful because the tissue was extensively infiltrated with fungi. CXL-mediated fungal death may have triggered an inflammatory response, and in combination with inadequate drug penetration after CXL treatment, led to complications resulting in an emergent PKP for corneal perforation.
      Although in Case 2 the PKP failed because of rejection, PKP is effective for controlling fungal keratitis.
      • Xie L.
      • Dong X.
      • Shi W.
      Treatment of fungal keratitis by penetrating keratoplasty.
      Case 2 was maintained on antifungal medication following the control of the infection after the PKP. It is unclear whether the use of voriconazole along with the PKP significantly contributed to the initial successful outcome, but it also has been suggested that the PKP promotes the absorption of topical voriconazole.
      • Jurkunas U.V.
      • Langston D.P.
      • Colby K.
      Use of voriconazole in the treatment of fungal keratitis.
      Despite its relative rarity in the cooler Canadian environment, ophthalmologists should maintain a high index of suspicion toward fungal keratitis, especially in traumatic or CL-related keratitis that does not improve on broad-spectrum antibiotics. Furthermore, both Fusarium and Alternaria species are common North American crop pathogens.
      • Lacey J.
      • Ramakrishna N.
      • Hamer A.
      • et al.
      Grain fungi.
      It is important that both farmers and physicians are aware of the potential hazard of fungal keratitis to minimize its occurrence and initiate appropriate therapy in a timely manner.

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