Pulmonary Phaeohyphomycosis Caused by Phaeoacremonium in a Kidney Transplant Recipient: Successful Treatment with Posaconazole

We report a rare case of pulmonary phaeohyphomycosis in a 49-year-old woman 6 years after kidney transplantation. She presented with dyspnea, cough, and fatigue. Her chest CT scan revealed nodular opacities in the right upper lung. A fine needle aspirate biopsy culture yielded Phaeoacremonium and surgical pathology of the biopsy showed chronic inflammation. We successfully treated her with posaconazole and managed drug interactions between posaconazole and tacrolimus. This is the second reported case of biopsy-proven pulmonary infection by Phaeoacremonium in a kidney transplant recipient and successfully treated with posaconazole.


Background
Phaeoacremonium species are well known plant pathogens causing stunted growth and dieback of various woody hosts especially grapevines and have been isolated from necrotic woody tissue of Prunus species [1,2]. Phaeoacremonium species are dematiaceous fungi characterized by the presence of melanin or melanin-like pigments and are widely distributed in the environment particularly in soil, wood, and decomposing plant debris. Phaeohyphomycosis is a collective term for cutaneous, subcutaneous, and systemic disease caused by dematiaceous fungi. Pulmonary phaeohyphomycosis is a rare opportunistic infection of immunocompromised hosts. A review of 34 cases of dematiaceous fungal infections in organ transplant recipients revealed an overall mortality of 57% among patients with systemic disease and 7% among those with skin, soft-tissue, or joint infections [3]. This is only the second case of biopsy-proven pulmonary infection by Phaeoacremonium in a kidney transplant recipient and the first report of successful treatment with posaconazole. Moreover, management of drug interactions between posaconazole and tacrolimus was successfully done, thereby preventing supratherapeutic levels of tacrolimus and avoiding kidney injury.

Case Report
A 49-year-old Caucasian female who underwent a living related kidney transplant 6 years before presented with progressive dyspnea, cough, and fatigue over 6 months that failed to improve after the administration of several antibiotic courses. She had been on tacrolimus and prednisone for maintenance immunosuppression. She lived in a rural area, had exposure to chicken sheds and barns, and was a gardener. A chest CT scan revealed nodular opacities in the right upper lobe (Figure 1(a)), and she underwent bronchoscopy with bronchoalveolar lavage and transbronchial fine needle aspiration biopsy of the right upper lobe nodules.
Phaeoacremonium species grew from the biopsy culture within four days of incubation. Identification was assigned 2 Case Reports in Medicine   based on macroscopic and microscopic morphology. Initially, the surface of the mold was olive in color, becoming greyishblack upon subculture. The texture was velvety, and the reverse was black. Microscopically, pigmented hyphae with tapering, funnel-shaped phialides were observed, and conidia were hyaline and oblong, forming clusters at the tip of the phialides. Macroscopic and microscopic morphology was consistent with Phaeoacremonium species. Surgical pathology of the biopsy showed chronic inflammation but no fungal hyphae. Culture for acid fast bacilli from the biopsy specimen was negative for mycobacteria. Culture of bronchial fluid yielded Dactylaria constricta and few Mycobacterium aviumintracellulare complex. Given that her biopsy culture yielded Phaeoacremonium and showed chronic inflammation, we started oral posaconazole 200 mg QID and reduced her tacrolimus dose from 2 mg BID to 1 mg Q day. A repeat chest CT scan one month after the institution of antifungal therapy showed improvement (Figure 1(b)), and she reported reduced cough and shortness of breath. Two months after commencing treatment, we changed her posaconazole dose to 400 mg BID for greater ease of administration. She received posaconazole for 4 months and her symptoms resolved ( Figure 2).

Discussion
To et al. reported the first case of biopsy-proven Phaeoacremonium parasiticum lung infection in a kidney transplant recipient. In contrast to our case, the patient was severely immunocompromised due to chemotherapy for posttransplant lymphoproliferative disease. He showed initial improvement with voriconazole and caspofungin but succumbed after a prolonged period of neutropenic fever. Shah et al. described a case of probable Phaeoacremonium lung infection in a lung transplant recipient. The patient developed cavitary lung nodules in the native lung a few months after single lung transplantation. Biopsy of one of the nodules showed chronic inflammation with possible granulomatous lesions. Phaeoacremonium parasiticum grew only from the bronchoalveolar lavage culture but not from the biopsy culture. The patient improved after the administration of voriconazole and caspofungin [21,26].  Phaeoacremonium species are typically isolated from thorns, wood, and soil. Human infection can be caused by traumatic implantation or occurs in the setting of immunocompromising conditions. Twenty-seven cases of human infections with Phaeoacremonium species have been reported in the literature. In immunocompetent hosts, Phaeoacremonium has been reported to cause subcutaneous phaeohyphomycosis, osteomyelitis, endophthalmitis, and onychomycosis. Successful outcomes have been achieved with debridement and antifungals (Table 1). In immunocompromised patients, Phaeoacremonium causes more severe disease and has been reported to cause endocarditis, brain abscesses, cavitary lung nodules, and disseminated infections. Disseminated infections in severely immunocompromised hosts are associated with poor outcomes and death ( Table 2).
The other dematiaceous fungus isolated from this patient was Dactylaria constricta. It grew only from culture of bronchial fluid and not from the biopsy. Mycobacterium avium-intracellulare complex (MAC) also grew only from the culture of bronchial fluid. Given our patient's exposure history (gardening, exposure to sheds and barns) and no growth of these organisms from the biopsy specimen, it is likely that these organisms were merely colonizers of her respiratory tract and not pathogens. Moreover, resolution of her illness without treatment for MAC suggests that it was not a pathogen.
There is no standard antifungal regimen described for Phaeoacremonium in the literature. Posaconazole is the most recently approved triazole with an extended spectrum of activity against a wide variety of fungi. Posaconazole was chosen over other azoles because it is well tolerated and has a favorable side effect profile and a low potential of drug interactions compared to other azoles. Posaconazole inhibits the metabolism of calcineurin inhibitors. Failure to adjust tacrolimus dosing can result in supratherapeutic levels of tacrolimus and harm the kidney [28]. Our patient responded well to the treatment with no relapse of infection during 4 years of follow-up. Her kidney allograft continues to function well, with creatinine levels ranging between 1 and 1.3 mg/dL.