Concomitant protothecosis and Corynespora cassiicola infection: A case report

Dear Editor, We present the case of a 72-year-old male with a past medical history of hypertension who presented to our clinics with complaints of progressively pruritic and painful skin changes over 1 year. The clinical examination demonstrated multiple, well-demarcated, large erythematous plaques with erosions and purulent discharge. These were primarily located on the bilateral upper extremities, originating as itchy, red plaques on both forearms [Figure 1a].Figure 1: Clinical presentation of cutaneous Corynespora cassiicola infection in our patient (a) well-demarcated, extensive, erosive erythematous plaques accompanied by purulent discharge prominently on bilateral upper extremities (b) remarkable improvement after 3 months of itraconazole and cortisone supplement.His initial contact with local medical services led to a provisional diagnosis of eczema, and treatment was initiated with topical and oral steroids. Despite this intervention, the condition progressed, with an expansion of plaques to the upper arms and exacerbation of pruritus. The patient did not report fever but did exhibit progressive malaise and poor appetite. The patient's history included cultivating pineapples and guavas in Kaohsiung Chi Shan. He could not recall any traumatic incidents occurring before the onset of skin changes. Chronic eczema, protothecosis, and deep fungal infections were among the provisional diagnoses considered before performing a skin biopsy. Histopathologic evaluation showed epidermal pseudoepitheliomatous hyperplasia and an abscess populated by fungal hyphae, spores, and a neutrophilic infiltrate in the dermis. A periodic acid-Schiff stain corroborated the presence of fungal hyphae and spores. A fungal culture yielded Corynespora cassiicola, characterized by a gray-olive, velvety colony on a potato dextrose agar plate [Figure 2a]. Microscopic examination revealed the fungus to contain pale brown, catenated cylindrical conidia with distosepta [Figure 2b]. The minimum inhibitory concentrations of the isolate were determined: amphotericin B = 4 μg/mL, itraconazole = 8 μg/mL, posaconazole = 2 μg/mL, terbinafine = 1 μg/mL, and voriconazole = 1 μg/mL.Figure 2: (a) Fungal culture of skin tissue has gray-olive velvety surface on potato dextrose agar. (b) The morphology showed the pale brown and cylindrical-shaped conidia with distosepta microscopically.Treatment was initiated with itraconazole 100 mg twice daily. However, after 2 weeks, the patient returned to our clinic with a swollen right hand, a large tense blister, and progressive erythematous plaques with crusting. A culture of the purulent discharge from the bullae identified Prototheca wickerhamii. Given the patient's extensive infection and limited response to antifungal therapy, we initiated a comprehensive immunity assessment and modified his treatment plan to include voriconazole based on antifungal susceptibility testing. After 4 weeks, due to the onset of delirium, we reverted the antifungal regimen to itraconazole. Tests for anti-interferon-γ autoantibody, CARD9 gene mutation, and HIV were all negative. Considering his prolonged history of oral steroid use, we evaluated his cortisol and Adrenocorticotropic hormone (ACTH) levels, which suggested adrenal insufficiency (cortisol 0.5 μg/dL and ACTH <1.5 μg/dL). This adrenal insufficiency could have contributed to the extensive infection and poor response to antifungal therapy. In light of these findings, we concurrently supplemented the patient's treatment regimen with cortisone (administered postprandially, twice daily) with the antifungal therapy. After 3 months of this combined therapeutic approach, we observed a substantial improvement in the lesions [Figure 1b]. C. cassiicola, a prominent phytopathogen within the Pleosporales order, is known to affect rubber plants worldwide.[1] First isolated in Sierra Leone in 1936, this pathogen has since been identified in tropical and subtropical regions, including Taiwan, where it has been documented to cause leaf spot disease in cucumber, tomato, and papaya.[2] Despite its ubiquitous presence in plants, human infections attributable to C. cassiicola remain exceedingly rare, with only eleven reported cases in medical literature. A commonality among these patients is underlying immunosuppression, frequently associated with conditions such as diabetes mellitus, immunodeficiency diseases, or prolonged use of corticosteroids.[3] Skin lesions are usually localized at exposed sites and demonstrate varied clinical presentations, including verrucous plaques, subcutaneous nodules, mycetoma, and purulent ulcers. Four of these patients also had occupational exposure to agricultural activities.[3] This suggests that subtle skin trauma and contact with plants in agrarian settings may enhance susceptibility to opportunistic infections by C. cassiicola.[3] This case presented as well-demarcated elevated plaques on both forearms, which were not initially considered an infection. However, the clinical presentation, characterized by elevated, well-demarcated plaques with ulcerative lesions, exhibited progressive changes following oral steroid use, raising suspicion of infection. Further examination to obtain cultures from either discharge or tissue should be arranged if the clinical situation described above occurs. Our patient presented with extensive lesions and poorly responded to antifungal therapy. It is crucial to consider evaluating for immunodeficiencies such as anti-interferon-γ autoantibody, CARD9 gene mutation, and HIV infection. Anti-interferon-γ autoantibody-associated immunodeficiency is a late-onset immunodeficiency, increasing susceptibility to severe mycobacterial infections and certain bacterial and fungal infections.[4] CARD9 deficiency reduces T helper 17 cell counts and impairs neutrophilic activity, predisposing otherwise healthy individuals to a broad spectrum of fungal infections.[5] Among patients diagnosed with CARD9 deficiency, three reported severe and persistent infections, two demonstrating limited response to antifungal therapy.[3,6] Due to the rarity of C. cassiicola infections, there is currently no consensus on its treatment. Various therapeutic approaches, including amphotericin B, voriconazole, terbinafine, and other potential antifungal agents such as micafungin, have shown efficacy against C. cassiicola. Photodynamic therapy has recently been reported to manage a patient with renal failure successfully.[7] In our case, the patient was engaged in pineapple cultivation, during which he could have sustained occult skin injuries, potentially enhancing susceptibility to opportunistic infections by C. cassiicola. Furthermore, prolonged oral steroid use combined with his advanced age could have led to an immunocompromised state, culminating in an extensive cutaneous infection. Evaluations for anti-interferon-γ autoantibody, CARD 9 gene mutation, and HIV were all negative in this patient. The dosage and duration of the patient's corticosteroid use remain undetermined. However, medical literature implies that secondary adrenal insufficiency can occur following glucocorticoid discontinuation, regardless of dosage, administration form, treatment duration, or underlying disease.[8] This case underscores the importance of considering CARD9 gene mutations in the context of poor therapeutic response and the potential for secondary adrenal insufficiency, particularly in patients with a history of steroid use, to achieve improved treatment efficacy clinically. Ethical approval The study was approved by the Institutional Review Board of Chang Gung Medical Foundation (IRB# 202300809B0) on 2023/07/13. Data availability statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest Dr. Pei-Lun Sun, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.