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Mycopathologia (2017) 182:297–303 DOI 10.1007/s11046-016-0094-4

Successful Posaconazole Therapy of Disseminated Alternariosis due to Alternaria infectoria in a Heart Transplant Recipient Pavlina Lyskova . Milos Kubanek . Vit Hubka . Eva Sticova . Ludek Voska . Dana Kautznerova . Miroslav Kolarik . Petr Hamal . Martina Vasakova

Received: 20 April 2016 / Accepted: 14 November 2016 / Published online: 19 November 2016 Ó Springer Science+Business Media Dordrecht 2016

Abstract We report a case of phaeohyphomycosis caused by Alternaria infectoria in a 61-year-old heart transplant recipient with multiple skin lesions and pulmonary infiltrates. The infection spread via the haematogenous route from the primary cutaneous lesions into the lungs. The diagnosis was based on the histopathological examination, direct microscopy, skin lesion cultures and detection of Alternaria DNA in the bronchoalveolar lavage fluid using molecular methods. The treatment consisted of a combination of surgical excision and systemic antifungal therapy.

P. Lyskova (&) Laboratory of Medical Mycology, Department of Parasitology, Mycology and Mycobacteriology Prague, Public Health Institute in Usti nad Labem, Sokolovska 60, 186 00 Prague 8, Czech Republic e-mail: [email protected] P. Lyskova P. Hamal Department of Microbiology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Hnevotinska 3, 775 15 Olomouc, Czech Republic M. Kubanek Department of Cardiology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague 4, Czech Republic V. Hubka M. Kolarik Department of Botany, Faculty of Science, Charles University in Prague, Benatska 2, 128 01 Prague 2, Czech Republic

Voriconazole was the first agent used but had a weak effect. Posaconazole was subsequently used to achieve a successful response. The isolate was identified as A. infectoria by sequencing of the rDNA ITS region and the partial b-tubulin gene. Keywords Heart transplantation Phaeohyphomycosis Pulmonary infection Alternariosis

V. Hubka M. Kolarik Laboratory of Fungal Metabolism, Institute of Microbiology of the AS CR, Videnska 1083, 142 20 Prague 4, Czech Republic E. Sticova L. Voska Department of Pathology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague 4, Czech Republic D. Kautznerova Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague 4, Czech Republic M. Vasakova Department of Respiratory Medicine, Thomayer Hospital, 1st Medical School and Charles University, Prague Videnska 800, 140 59 Prague 4, Czech Republic

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Introduction Filamentous fungi are common pathogens in immunocompromised individuals and may cause severe opportunistic infections [1–3]. The term phaeohyphomycosis is used to describe cutaneous, subcutaneous and systemic fungal infections caused by representatives of a heterogeneous group of melanized (‘‘dark’’, ‘‘dematiaceous’’) fungi that belong to various genera, such as Scedosporium, Cladophialophora and Exophiala, whose morphological characteristics in tissue include melanized hyphae, yeast-like cells or a combination of these characteristics [4, 5]. Melanized fungi are frequently considered ubiquitous saprotrophs that inhabit living and dead plant material and, for the most part, reside in the soil [4]. The incidence of phaeohyphomycosis is increasing, mainly in transplant centres [3, 6, 7]. The genus Alternaria encompasses, in particular, plant pathogenic fungi that are occasionally implicated in opportunistic human disease—alternariosis [4, 8–10]. The most frequently reported causal agent of different clinical forms of alternariosis is A. alternata, followed by A. infectoria and A. tenuissima [11]. Traumatic implantation of the fungus is likely responsible for majority of cases of disseminated [8]. Disseminated alternariosis with the involvement of the visceral organs is very rare. The diagnosis of such infections is not easy, and proper antifungal therapy is required to cure the patient. To date, a limited number of case series have been reported. We aimed to describe the clinical signs, diagnostic process and successful treatment of disseminated pulmonary infection caused by Alternaria infectoria in a heart transplant recipient.

Case Report A 61-year-old man underwent heart transplantation (HTx) at the Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic, in 2011. He was a mountain climber, non-smoker, abstinent from ethanol and otherwise healthy except for his cardiac disease (dilated cardiomyopathy) and impaired glucose tolerance. The post-transplantation maintenance immunosuppression consisted of tacrolimus with an initial target trough level of 10–15 ng/ ml, mycophenolate mofetil 2000 mg daily and

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prednisone. The initial dose of prednisone was 1 mg/ kg/day, with subsequent tapering to 20 mg daily at 1 month and 7.5 mg daily at 12 months after transplantation. Six months after the HTx, the patient experienced a cytomegalovirus infection, which was treated with valganciclovir and a dose reduction of mycophenolate mofetil to 1000 mg daily due to leucopoenia. Twelve months after the HTx, a regular follow-up in the outpatient department revealed several cutaneous nodules on his left elbow. Additionally, a scheduled chest X-ray detected an inflammatory infiltrate in the basal portion of the left lung. Empiric treatment with cefuroxime 500 mg twice daily was initiated, and the patient was referred for an excision of the cutaneous lesions. Based on the histopathology of the lesions (periodic acid–Schiff and Grocott’s staining), a diagnosis of profound cutaneous mycosis caused by filamentous fungi was made. Shortly after the excision of the skin nodules, the patient experienced acute decompensation of right heart failure and was admitted to the transplant centre. Upon admission, the patient was afebrile, with increased filling of the jugular veins, ascites and swollen legs. His immunosuppressive regimen at the time consisted of tacrolimus (1.5 mg twice daily), mycophenolate mofetil (500 mg twice daily) and prednisone (7.5 mg once daily). A chest X-ray and subsequent chest computed tomography (CT) identified a large nodule attached to the pleura (the largest diameter of 25 mm) in the left lower pulmonary lobe. Antibiotic treatment with cefuroxime was initiated. The second opinion CT reading revealed, in addition to the previously described nodule in left lower lobe (S9) with suspect central necrosis surrounded by ground glass opacity directed towards the pulmonary hilum, two small opacities in the right lung (Fig. 1a). These findings suggested a mycotic aetiology of the lung disease. This had progressed compared to the previous finding despite the antibiotic treatment. The treatment was switched from cefuroxime to oral voriconazole (200 mg twice daily). Woodworking was revealed in the patient’s history. Specifically, the patient cut sculptures from wooden blocks (logs), which were visibly affected by mould. A bronchoalveolar lavage was performed, and the bronchoalveolar lavage fluid (BALF) and the tissue from the remaining subcutaneous nodules of the left forearm were sent for histopathology, mycological investigation including direct microscopy, culture and PCR detection. The


Fig. 1 CT scan with subpleural nodule in the segment 9 of the left lung, oval-shaped, 2.5 9 2 cm in size with relatively sharp borders, with suspected small decomposition centrally and with adjacent ground glass opacity leading to the pulmonary hilum

histopathological analysis (Grocott’s staining) revealed dark pigmented filamentous and oval-shaped fungal elements with septate hyphae with irregular or rectangular branching in the dermis and the subcutaneous tissue (Fig. 2). Fluorescence microscopy of the tissue revealed the septate hyphae as well, and Alternaria sp. grew in culture (Fig. 3). PCR detection directly from the collected skin and BALF sample material (18S rDNA) was positive for the presence of Alternaria sp. [12]. Alternaria grew in the pure culture from the subcutaneous nodules of the left forearm. The disc diffusion test showed sufficient zones for amphotericin B and posaconazole (Fig. 3) [13]. Due to the slow growth and reluctant sporulation of the culture, the susceptibility test result was known ten weeks after the biopsy. The isolated strain was identified as a member of the Alternaria infectoria species group by sequence data of the ID region of the rDNA (ITS1, 5.8S, ITS2 and partial LSU rDNA) and the partial btubulin gene. The DNA was isolated, and the genetic loci were amplified as described previously [14, 15]. The obtained sequences were deposited into the EMBL database under accession numbers HG324079 and HG324082. The case isolate was deposited into the Culture Collection of Fungi (CCF), Department of Botany, Charles University, Prague, as CCF 4380. The patient remained afebrile with low CRP levels (5.3 mg/l). An immunological examination showed marked immunodeficiency with CD4 ? T lymphocytes of 302 9 106/L, a CD4/CD8 ratio of 0.67, CD19 lymphocytes of 83 9 106/L and NK cells 117 9 106/

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(a); follow-up CT scan after 5 months of treatment with voriconazole. There is modest regression of the lesion in segment S9 (b); disappearance of the subpleural lesion after 2 months of treatment with posaconazole (c)

Fig. 2 Histopathology of cutaneous lesions shows dermal suppurative granulomatous infiltrates (haematoxylin and eosin, original magnification 910) (a); detection of dark pigmented yeast forms and hyphal elements using Grocott’s staining (original magnification 940) (b)

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The posaconazole therapy was completed after 8 weeks of treatment. Serum galactomannan (GM; Platelia Aspergillus test, Bio-Rad, Marnes-la-Coquette, France) was repeatedly assessed during the treatment with negative results. The subsequent period was uneventful. The patient is now enjoying a good quality of life.

Discussion

Fig. 3 Branched, septate hyphae and spores identified by the use of the chitin-binding stain Blankophor (Bayer, Leverkusen, Germany) with a fluorescent microscope on potassium hydroxide wet mounts in cutaneous and subcutaneous tissue of the left forearm (bar 50 lm) (a); three test tubes with Sabouraud dextrose agar with chloramphenicol and thiamine (SDA; Trios, Prague, Czech Republic); A. infectoria cultured from cutaneous and subcutaneous tissue of the left forearm at 35 °C (4-day-old sterile white culture—not pigmented yet) (b); disc diffusion test on Muëller-Hinton agar (MHA; Trios, Prague, Czech Republic) by Neo-Sensitabs tablet (Rosco Diagnostics, Taastrup, Denmark), 48 h at 35 °C (c)

L. Due to the presence of the opportunistic infection, the mycophenolate mofetil therapy was discontinued. The patient was discharged after 2 weeks of voriconazole treatment with stable findings on a chest X-ray. However, repeated chest CT scans after 1 and 5 months of voriconazole treatment showed persistence of the nodule in the 9th segment of the left lung (Fig. 1b). The therapy was, therefore, changed from voriconazole (after 5.5 months) to oral posaconazole (200 mg four times daily for the first week, then 200 mg three times daily), according to the in vitro susceptibility results (Fig. 3). After 6 weeks of posaconazole treatment, a complete regression of the pulmonary lesion was visible on a chest CT (Fig. 1c).

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Several review articles have been published on phaeohyphomycosis and/or alternariosis [4, 8, 10]. Alternaria spp. cause a broad spectrum of clinical manifestations in humans, including disseminated diseases, hypersensitivity pneumonitis, allergic fungal sinusitis, paranasal infections, ocular infections, palatal ulcers, cutaneous and subcutaneous infections and onychomycosis [4, 8, 16]. A localized mucocutaneous disease is the most common clinical manifestation of alternariosis [17–21]. It seems that disseminated alternariosis is not unusual because remote secondary cutaneous foci are found relatively frequently. In contrast, visceral involvement is very rare, and published cases were caused by A. infectoria and A. alternata [24–26]. The disseminated alternariosis usually primarily develops as a cutaneous (trauma) or sinus (inhalation) infection with subsequent dissemination to other parts of the body (e.g. lungs, brain) [5, 16, 24–26]. The infection mostly affects patients after solid organ transplantation and may also develop in other immunocompromised patients (bone marrow transplants, chronic granulomatous disease) [6, 21–23, 26–28]. Disseminated infection by A. malorum in an immunocompetent patient was also described [5]. Our patient fulfilled the aforementioned risk factors, as he received an HTx and was immunocompromised [11, 18, 19]. He worked with wood and most likely obtained a splinter in his left forearm, which resulted in a primary cutaneous site. Clearly, the fungus spread via the bloodstream to form secondary foci in the lungs. There was also a tendency to form other new cutaneous nodules on his left arm (above the elbow). In general, melanized fungi have a tendency to disseminate from the primary site of the infection (most often cutaneous), and positive blood cultures were recorded in some genera (e.g. Scedosporium spp., Exophiala spp., Cladophialophora spp.,


Phialemonium spp.) [7, 10]. Unfortunately, blood cultures were not obtained from our patient. The isolate, in this case, was first identified at the genus level based on an 18S rDNA sequence obtained by PCR detection from clinical samples of skin and BALF. A more accurate identification was subsequently achieved by sequencing of the ITS rDNA (internal transcribed spacer region of ribosomal DNA) region and the b-tubulin gene. Both genetic loci equally indicated that the pathogen belonged to the Alternaria section Infectoriae [29–31]. The identification of A. alternata and related species (sect. Alternaria) was possible because of the recent revision that clarified the relationships between species and resolved several old names. However, the identification of species in sect. Infectoriae remains challenging due to a lack of similar revisions [32]. We believe that the identification of the case fungus as A. infectoria most accurately reflects the current state of knowledge in taxonomy and current practice in medical mycology. The identification of the causal agent may change after a thorough taxonomic revision of this group is conducted, and the sequence data acquired from this study may serve as re-identification in the future. A. infectoria was demonstrated by microscopy and culture from samples of the cutaneous and subcutaneous tissue. These methods failed in the sample of BALF, where the fungus was detected only by molecular methods. Halaby et al. [25] reported a similar case of an A. infectoria infection involving the skin and lungs. These authors also failed to locate the fungus in the BALF sample using classical methods in their reported case. The successful treatment of the mycotic focus in the lungs with an antifungal agent (liposomal amphotericin B) was evidence of an Alternaria aetiology according to the authors [25]. This fact may imply that proof of the pulmonary infection in BALF would not be possible by classical methods, and it would be necessary to obtain tissue samples for diagnosis. Serum GM was repeatedly tested with negative results. Unfortunately, we did not test another rapid serological method, detection of pan-fungal antigen 1,3-b-D-glucan, which could be useful in the diagnosis of infections caused by black fungi and also seems to be helpful in the diagnosis of alternariosis [33, 34]. According to the medical literature, the recommended therapy is surgery, prolonged antifungal therapy and reduction in immunosuppression

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[11, 22, 35]. Itraconazole was previously successful for systemic therapy of cutaneous and also disseminated alternariosis [18, 19, 22, 26, 36]. An A. infectoria brain abscess was treated by a combination of voriconazole and caspofungin with a clinical improvement, but the abscess could not be completely removed with fatal consequences for the patient [24]. Interestingly, de Sousa Ferreira et al. [23] suggested a possible synergy of liposomal amphotericin B and posaconazole in an A. alternata infection, which developed on posaconazole prophylaxis. In vitro susceptibility data suggest that the susceptibility of Alternaria spp. to antifungals appears to be species dependent, with most species susceptible to amphotericin B, voriconazole and posaconazole [11, 37]. In our case, cutaneous foci were successfully eradicated by surgery. Pulmonary foci were effectively treated with posaconazole in accordance with in vitro antifungal susceptibility results. The isolate, in this case, had limited susceptibility to voriconazole, which is in accordance with previously published results for Alternaria spp. [22, 37, 38]. Derber et al. [16] also reported recovery of a disseminated alternaria infection (paranasal cavities and lungs) with posaconazole despite previous unsuccessful voriconazole therapy. Rammaert et al. [39] observed good efficacy of posaconazole in the treatment of an A. infectoria cutaneous infection. This experience, together with our data, may justify the use of posaconazole in the therapy of A. infectoria infections in the future.

Conclusion Excision of skin lesions, tapering of immunosuppressive treatment and posaconazole therapy appeared to be effective and safe treatments for our heart transplant patient with systemic mycosis caused by Alternaria infectoria, which manifested in multiple skin involvement and pulmonary infiltrates. The molecular detection of the pathogen and in vitro susceptibility results was helpful for the appropriate treatment. Acknowledgements This research was supported by the Ministry of Education, Youth and Sports of the Czech Republic (SVV project), and by the project ‘‘BIOCEV— Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University’’ (CZ.1.05/1.1.00/02.0109) from the European Regional Development Fund. Additional

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support was obtained from a research grant from the Ministry of Health, Czech Republic [MZ 15-27682A] and from the project of the Ministry of Health, Czech Republic, for development of research organization 00023001 (IKEM, Prague, Czech Republic). This work was also supported by grant no. IGA_LF_2016_022 and RVO: 61989592 (Palacky University Olomouc, Czech Republic). All rights reserved.

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Compliance with Ethical Standards

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Conflict of interest The authors declare that they have no conflict of interest.

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