Cutaneous fungal infections in solid organ transplant recipients

Transplantation Reviews xxx (2017) xxx–xxx

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Transplantation Reviews journal homepage: www.elsevier.com/locate/trre

Cutaneous fungal infections in solid organ transplant recipients☆ Muneeb Ilyas ⁎, Amit Sharma Department of Dermatology, Mayo Clinic Arizona, 13400 E. Shea Blvd. Scottsdale, AZ 85259

a b s t r a c t Although there is an abundance of information on cutaneous malignancies in transplant recipients, information on cutaneous infections in solid organ transplant recipients is underrepresented in dermatologic and transplant literature. Our paper provides a comprehensive review of fungal cutaneous infections within the solid organ transplant population. We compiled literature specific to the solid organ transplant population, reviewing cutaneous manifestations owing to fungal infections. Furthermore, we discuss the diagnosis and treatment of such infections. The following is a list of some of the fungi that we will discuss:

Yeast -

Candida Malassezia Cryptococcus Trichosporon

Endemic dimorphic fungi - Coccidioides - Histoplasma - Blastomyces

Filamentous fungi -

Dermatophytes (T. rubrum, M. canis, etc.) Aspergillus Mucor Rhizopus Rhizomucor Fusarium Dematiaceous Fungi (Curvularia, Alternaria)

© 2017 Elsevier Inc. All rights reserved.

1. Introduction A large spectrum of cutaneous diseases afflicts the transplant recipient population. Although cutaneous malignancies in solid organ ☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author. Tel.: +1 602 327 5087. E-mail address: [email protected] (M. Ilyas).

transplant recipients (SOTRs) are well defined, there is an underrepresentation of literature on the diagnosis and treatment of fungal cutaneous infections. Infections from fungi can cause an array of symptoms from solitary benign skin lesions to widespread systemic infections with high morbidity (Tables 1 and 2). The groups of fungi discussed in this review include yeast, endemic dimorphic fungi, and filamentous fungi. It is of great benefit for care providers of SOTRs to quickly recognize and appropriately manage fungal cutaneous infections to improve patient outcomes.

http://dx.doi.org/10.1016/j.trre.2017.03.001 0955-470X/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Ilyas M, Sharma A, Cutaneous fungal infections in solid organ transplant recipients, Transplant Rev (2017), http:// dx.doi.org/10.1016/j.trre.2017.03.001

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Table 1 Sources of fungal infection and their associated cutaneous manifestations in SOTRs. Fungus

Diagnoses

Yeasts Candida

Oral thrush Angular cheilitis Stomatitis Onychomycosis Systemic candidiasis Pityriasis versicolor Pityrosporum folliculitis Focal cutaneous infection Disseminated cryptococcosis White piedra Disseminated trichosporonosis

Malassezia Cryptococcus Trichosporon

Endemic Dimorphic Fungi Coccidioides, Histoplasma, Blastomyces

Non-specific cutaneous findings with disseminated infection

Filamentous Fungi Dermatophytes (Trichophyton rubrum, Microsporum canis, etc.)

Aspergillus Mucormycosis (Lichtheimia, Rhizopus, Mucor, Rhizomucor) Fusarium

Dematiaceous Fungi (Curvularia, Alternaria, etc.)

2. Yeasts Opportunistic yeast species such as Candida, Malassezia, Cryptococcus, and Trichosporon may cause infections in SOTRs. 2.1. Candidiasis Transplant recipients have higher rates (45%–84%) of oropharyngeal Candida colonization and of disseminated disease when compared to the immunocompetent patients [1]. Oral candidiasis is the most common fungal infection in SOTRs within the first post-transplant year, afflicting up to 64% of transplant recipients [2–5]. Other sites of Candida infection include the nails and skin folds. Oral candidiasis can present as oral thrush, angular cheilitis (perlèche), and stomatitis. Oral thrush presents with thick, curd-like white papules and plaques upon an erythematous base that can be removed with rubbing. Angular cheilitis effects the corners of the mouth, leading to cracking, fissuring, and crusting with underlying erythema. Candidal stomatitis presents with a bright, erythematous, glossy palate. Patients on corticosteroid or antibacterial

Tinea cruris Tinea corporis Tinea unguium Tinea pedis Majocchi's granuloma Onychomycosis Cutaneous aspergillosis Disseminated aspergillosis Cutaneous mucormycosis — due to inoculation or disseminated disease. Onychomycosis Cellulitis Intertrigo Disseminated fusariosis Phaeohyphomycosis Chromoblastomycosis Mycetoma

therapy, diabetics, and denture wearers are at increased risk of oral candidiasis [1]. Candidiasis of the nail presents with edema and discoloration at the lateral proximal nail fold, along with occasional pus formation. C. albicans is a common cause of candidiasis, but species including C. tropicalis, C. krusei, C. glabrata, C. parapsilosis are additional sources [6–8]. Systemic Candida infection usually develops in the early post-transplant period due to heavy immunosuppression [8]. Cutaneous manifestations of systemic Candida infections are reported in up to 13% of SOTRs [9]. Systemic candidiasis may present with skin findings, and patients may decompensate rapidly with fever and myalgia. Skin manifestations of systemic candidiasis present as small scattered macules, small papules, and subcutaneous nodules on the trunk and extremities. Ulcers that simulate EG and intradermal bullae have also been reported [9,10]. Although blood culture is the gold standard for disseminated infection, it takes up to 5 days to finalize, leading to substantial delays in the initiation of therapy [11]. Additionally, patients with disseminated candidiasis have negative blood cultures 50% of the time [12]. The Beta-D-glucan antigen assay has higher efficacy than blood culture alone [13–16]; however, this assay has low specificity, leading

Table 2 Cutaneous lesions and their possible fungal etiology. Lesion

Fungi

Papules or nodules

Candida, Malassezia, Cryptococcus, Trichosporon, Coccidioides, Histoplasma, Blastomyces, Trichophyton, Microsporum, Aspergillus, Fusarium, Alternaria, Chromoblastomycosis Malassezia, Cryptococcus, Coccidioides, Blastomyces, Trichophyton, Microsporum, Aspergillus, Alternaria Candida, Cryptococcus, Trichosporon, Coccidioides, Histoplasma, Alternaria, Chromoblastomycosis Malassezia, Histoplasma, Blastomyces, Aspergillus Candida, Cryptococcus, Aspergillus, Curvularia, Alternaria Cryptococcus, Aspergillus, Lichtheimia Rhizopus, Mucor, Rhizomucor, Fusarium Cryptococcus, Coccidioides, Histoplasma, Curvularia, Alternaria Coccidioides, Histoplasma, Blastomyces, Chromoblastomycosis Candida Trichosporon, Lichtheimia, Rhizopus, Mucor, Rhizomucor, Fusarium

Pustules Ulcers Plaques Subcutaneous nodules Cellulitis Abscesses Erythema nodosum Verrucous lesions Intradermal bullae Necrotic lesions

Please cite this article as: Ilyas M, Sharma A, Cutaneous fungal infections in solid organ transplant recipients, Transplant Rev (2017), http:// dx.doi.org/10.1016/j.trre.2017.03.001

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to high rates of false positives in at-risk populations [12]. A new method of diagnosing Candida infection using manual T2 magnetic resonance shows high specificity and sensitivity, with results available within 5 h [17]. Superficial Candida skin infections are treated with topical antifungals such as imidazoles, allylamines or nystatin [18]. Universal prophylaxis for Candida is not routinely used in renal, heart or lung transplant recipients; however, prophylactic fluconazole therapy is recommended for 1–2 weeks' post-transplant in pancreatic transplant recipients [19]. Additionally, high-risk liver transplant recipients on prophylactic liposomal amphotericin-B or echinocandins for 3–4 weeks' posttransplant had reduced rates of invasive candidiasis [20–22]. Candidal onychomycosis is managed with oral antifungals including fluconazole, itraconazole, or terbinafine [23]. The first-line agents for invasive candidiasis are the echinocandins as these drugs show improved survival when compared to triazoles or amphotericin B [24]. Intravenous (IV) caspofungin therapy begins with one dose at 70 mg/day, followed by doses of 50 mg/day until infection is resolved [25]. IV liposomal amphotericin-B, dosed at 3 to 6 mg/kg/day may be used as a secondline alternative [25–27]. 2.2. Malassezia Malassezia is a yeast genus that colonizes healthy human skin but is also capable of causing infection when skin flora is altered [28]. Immunosuppression allows for Malassezia overgrowth and studies [29,30] on SOTRs show that Malassezia colonization on the upper back occurred twice as frequently in SOTRs compared to healthy controls [29,30]. Malassezia infection may lead to the development of pityriasis versicolor (PV) or pityrosporum folliculitis (PF). PV presents as numerous oval macules, patches, or plaques with a fine scale that may be hypopigmented or hyperpigmented. These lesions are commonly distributed over the chest, back and upper arms. PF is associated with sebaceous inflammation owing to M. furfur converting triglycerides into free fatty acids [28]. PF appears as an acneiform eruption with erythematous papules and pustules on the upper back, scalp, neck, and arms [31]. Diagnosis of Malassezia is made by examining skin scrapings under a microscope with KOH preparation. Fungal culture is not utilized when diagnosing Malassezia spp. as these fungi cannot grow on conventional media. Biopsy is reserved for cases with a high degree of doubt. Treatment of PF or PV infections involves the use of topical antifungal creams including imidazoles, ciclopirox, and ketoconazole shampoo [32]. When these infections have extensive spreading, or show resistance to topical antifungals, oral fluconazole or itraconazole are used in SOTRs [31,33]. 2.3. Cryptococcosis Cryptococcus spp., particularly C. neoformans, is an opportunistic fungus that causes mild pulmonary disease in the immunocompetent and may cause severe disseminated disease in the immunocompromised. AIDS patients are commonly afflicted, but disseminated infection in SOTRs has been reported [34–38]. Cryptococcosis is reported in up to 2.8% of SOTRs [39]. Cutaneous symptoms occur in up to 15% of cryptococcosis patients and are often the first sign of underlying systemic infection [34,40]. However, there are reports of localized primary cutaneous cryptococcal disease in SOTRs [37,41,42]. Cutaneous manifestations of cryptococcosis present as non-specific polymorphic lesions including papules, pustules, vesicles, nonhealing ulcers, cellulitis, subcutaneous nodules, ecchymoses, gummas, abscesses, and granulomata [9,42,43]. Lesions suspicious for Cryptococcal infection must be biopsied and cultured to confirm disease. Disease confirmation should be followed with a thorough work-up for systemic infection, including blood cultures and cryptococcal antigen titers of the serum and cerebrospinal fluid (CSF), a marker for disease severity. Treatment of primary cutaneous cryptococcal lesions in SOTRs has been successful using fluconazole [41,42]. SOTRs with disseminated disease are treated with combination therapy of amphotericin B and flucytosine, followed by a long course of

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fluconazole therapy [38,44,45]. It's important for care providers to educate patients on sources of Cryptococcus infections such as pigeon excrement. 2.4. Trichosporonosis Trichosporon spp. is a yeast commonly found in soil, water, and human mucosa. Trichosporon species including T. inkin, T. cutaneum, T. ovoides, T. loubieri may cause white piedra, tan or brown nodules on terminal hair shafts distributed on hair throughout the body, usually sparing the scalp [46]. T. asahii may cause disseminated infection in the immunosuppressed, particularly in neutropenic patients [47]. Although disseminated infection is most common in bone marrow transplant recipients, cases in SOTRs have been reported [46,48]. Disseminated Trichosporon infection is usually fatal, presenting with high fever and rapid multiorgan failure [48]. One-third of patients with disseminated trichosporonosis develop cutaneous lesions. Lesions may present anywhere on the body, usually as violaceous papules and nodules with central necrosis or ulceration [46,49]. SOTRs treated with echinocandins are at a particular risk of Trichosporon infection, as this fungus demonstrates intrinsic resistance to this drug class [50]. The gold standard for diagnosing disseminated trichosporonosis is blood culture, although the fungus has previously been isolated in urine, CSF, tissue, and sputum samples [51,52]. Treating white piedra involves shaving off hair within the infected region and applying a 2% ketoconazole shampoo daily until infection is resolved. Persistent cases of white piedra are managed with 100 mg/day oral itraconazole in addition to topical therapy. Treating Trichosporon can be challenging, as cases of multi-drug resistant disseminated trichosporonosis in liver transplant recipients have been reported [53–55]. The first line therapy for SOTRs with disseminated trichosporonosis is voriconazole [56–59]. Additional treatment options include reducing immunosuppression, cytokines to improve neutrophil counts, and combination therapy using voriconazole and a lipid formation of amphotericin B. 3. Endemic dimorphic fungi Disseminated infections with endemic dimorphic fungi including Coccidioides, Histoplasma, and Blastomyces have been reported in SOTRs. These infections are due to either reactivation of dormant infection or acquisition of fungi from the environment [60]. Dermatologic manifestations are a consequence of disseminated disease. Coccidioidomycosis due to C. immitis or C. posadasii is most common in the Southwestern United States and Northern Mexico. Cutaneous lesions with disseminated coccidioidomycosis include papules, pustules, abscesses, ulcers (Fig. 3), nodules, pruritic exanthem, urticarial papules, and erythema nodosum (EN), tender nodules usually restricted to the lower extremities [7,61]. The most frequently utilized assays for diagnosing coccidioidomycosis involve serologic testing for IgM and IgG anti coccidioidal antibodies [62]. Additional techniques include in situ hybridization and PCR. Treatment of primary and disseminated coccidioidomycosis involves the use of 400 mg/day of fluconazole or itraconazole therapy for up to 12 months; however, combination therapy with liposomal amphotericin B in indicated in cases that are severe are rapidly progressing [63]. Although histoplasmosis is most common in regions including the Ohio/Mississippi River Valley and Central America, cases throughout the world have been reported [64–66]. Acute lung disease due to H. capsulatum infection is associated with development of EN [8]. Disseminated histoplasmosis may present with limited or diffuse cutaneous lesions, including ulcers, papules, nodules, oral ulcers, abscesses, plaques, and purpuric lesions [8]. Serum and urine antigen testing on all patients suspected of histoplasmosis is recommended, as 95% of immunocompromised patients afflicted have a positive urine antigen test [67]. Blood cultures should always be conducted, although they have a lower sensitivity than antigen testing [68]. Fungal isolator tubes improve blood culture sensitivity for detecting H. capsulatum,

Please cite this article as: Ilyas M, Sharma A, Cutaneous fungal infections in solid organ transplant recipients, Transplant Rev (2017), http:// dx.doi.org/10.1016/j.trre.2017.03.001

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but often take weeks to grow [69]. As an alternative to antigen testing, rapid diagnosis of histoplasmosis can be made using histopathological identification of budding yeasts with a methenamine silver or periodic acid-Schiff (PAS) stain [69]. Despite the use of antibody testing for Histoplasma in the immunocompetent population, SOTRs cannot mount a significant antibody response and antibody testing cannot be relied upon to make a diagnosis in SOTRs. In SOTRs, treatment starts with 3–5 mg/kg of IV lipid amphotericin B given daily for 1–2 weeks followed by either itraconazole, voriconazole or posaconazole [69–73]. Itraconazole is the drug of choice after lipid amphotericin B therapy in SOTRs and recommended therapy includes a loading dose of 200 mg three times daily for three days, followed by maintenance therapy with 200 mg twice daily for 12 months [69]. The fungus B. dermatitidis is endemic to most of North America, Southern Africa and the Middle East. Although blastomycosis most commonly involves the lungs, up to 18% of infected individuals show cutaneous symptoms [74]. The characteristic finding of cutaneous blastomycosis is the presence of verrucous lesions with irregular borders, ranging in color from violet to gray. Other presentations include ulcerated lesions developing from pustules, nodules, or plaques with punctate microabscesses [75]. Diagnosis of Blastomyces spp. requires a positive culture from a clinical specimen, although visualization of the organism on histology using a methenamine silver or PAS stain is sufficient to make a presumptive diagnosis [69,75]. Antigen assays are useful as a rapid test to diagnose Blastomyces, but due to cross-reactivity with H. capsulatum, diagnosis requires histologic or cultural confirmation [69]. The utility of PCR for diagnosing blastomycosis has not yet been proven [76,77]. Blastomycosis is treated similarly to Histoplasma infection and treatment is initiated with 3–5 mg/kg IV liposomal amphotericin B daily until several weeks after resolution of clinical symptoms. This is followed by itraconazole therapy with a loading dose of 200 mg three times daily for three days and maintenance therapy with 200 mg itraconazole twice daily for 12 months [69]. Voriconazole is the second line azole, followed by fluconazole. It is essential to start treatment immediately in SOTRs as disseminated blastomycosis is associated with a 40% mortality rate in this population [78,79]. 4. Filamentous fungi 4.1. Dermatophytes Dermatophyte infection is a common cutaneous infection in SOTRs, occurring in up to 5.6% of patients [80]. The most common dermatophyte infection in both the SOTR and immunocompetent population is Trichophyton rubrum, a fungus linked with the development of tinea cruris, tinea corporis, tinea unguium and tinea pedis [81]. Dermatophytes spare deep cutaneous structures and normally infect superficial keratinized structures including the stratum corneum, nails, and hair. However, in SOTRs, decreased host defense may allow dermatophyte infection to extend into deeper cutaneous structures. Dermatophyte infection within the hair follicle by T. rubrum or Microsporum canis can lead to Majocchi's granuloma, which presents with multiple erythematous follicular pustules, papules, or nodules (Fig. 1) [82,83]. Tinea capitis is a common dermatophyte infection in SOTRs that presents with scaly macules or patches and sometimes alopecia. In the immunocompromised, tinea infections tend to be diffuse, non-specific, and recur frequently [84,85]. Onychomycosis is characterized by nail thickening, yellowing, and subungual debris. This condition usually afflicts toenails and is associated with concurrent tinea pedis infection. Onychomycosis involving multiple toes or fingernails is common in the SOTR population. Proximal subungual onychomycosis (PSO) is a dermatophyte infection extending from the proximal nail fold to the ventral nail plate, and is pathognomonic of immunosuppression (Fig. 2) [81,86]. It is important to note that dermatophytosis, even in SOTRs, is a benign infection. Diagnosis of a dermatophyte infection is made using

Fig. 1. Majocchi's granuloma presenting as a violaceous nodule on the lower extremity of a renal transplant recipient. Reprinted from “Majocchi's Granuloma and Posttransplant Lymphoproliferative Disease in a Renal Transplant Recipient,” by Kai-Chung Tse, et al., 2001, American Journal of Kidney Diseases, 38(6), p. 2. Copyright 2001 by National Kidney Foundation. Reprinted with permission.

potassium hydroxide (KOH) preparation on skin scrapings. Dermatophytes under light microscopy appear as segmented hyphae. However, KOH preparation is not specific for dermatophyte infection, and definitive diagnosis requires fungal cultures and species identification; although, cultures are often negative. Superficial dermatophytosis in SOTRs can be treated aggressively with topical or oral antifungal agents including azoles, allylamines, ciclopirox and butenafine [87,88]. Topical clotrimazole 1% cream applied twice daily is the drug of choice for superficial dermatophytosis [89]. Oral terbinafine 100 mg daily for two to four weeks is the therapy of choice for Majocchi's granuloma or severe superficial dermatophyte infections refractory to topical therapy [90–92]. 4.2. Aspergillosis Aspergillosis due to Aspergillus spp. is the second most common opportunistic fungal infection in SOTRs [93]. Invasive aspergillosis usually occurs within 6 weeks post-transplant and is associated with a high mortality rate [94,95]. Primary cutaneous aspergillosis is rare, but has been reported in conjunction with contaminated devices such as catheters or IV devices [96,97]. The majority of cutaneous manifestations are due to systemic infection or extension from a contiguous site, most commonly due to A. fumigatus [98–100]. Cutaneous aspergillosis can present as widespread papules, subcutaneous nodules, cellulitis, solitary plaques, and pustules. Aspergillus tends to invade vasculature, leading to purpuric and necrotic changes to lesions over time [101]. Definitive diagnosis of aspergillosis is made via culture. Histopathology of biopsy samples is an effective method

Fig. 2. Proximal subungual onychomycosis. Reprinted from “Proximal Subungual Onychomycosis in a Patient with Classic Kaposi Sarcoma Caused by Trichophyton rubrum,” by Lee KJ, Lee YB, Lee JY, Cho BK, Choi JS, and Park HJ, 2011, Annals of Dermatology, 23(1), p.S11. Copyright 2011 by Korean Dermatological Association; The Korean Society for Investigative Dermatology. Reprinted with permission.

Please cite this article as: Ilyas M, Sharma A, Cutaneous fungal infections in solid organ transplant recipients, Transplant Rev (2017), http:// dx.doi.org/10.1016/j.trre.2017.03.001

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Fig. 3. Coccidioiodomycosis presenting with a lower lip ulceration. Reprinted from “Lip Lesion in a Solid Organ Transplant Recipient,” by Philip A. Mackowiak, 2012, Clinical Infectious Diseases, 54(9), p.1332. Copyright 2016 by Infectious Diseases Society of America. Reprinted with permission.

to aid in diagnosis, but is not always attainable due to bleeding risk [102]. Detecting serum biomarkers for Aspergillus such as galactomannan and beta-D-glucan is a less invasive method, albeit with lower sensitivity [103–105]. Semi-nested PCR used on formalin-fixed and paraffinembedded tissues is a new, promising tool for diagnosing Aspergillus [106]; however, PCR alone is not sufficient for diagnosis and current recommendations suggest additional confirmation tests [105]. Cutaneous manifestations of invasive aspergillosis are rare, therefore chest computed tomographic scan is recommended whenever there is a strong clinical suspicion for invasive aspergillosis [105]. Treating SOTRs with disseminated aspergillosis is commonly initiated with voriconazole therapy for 12 weeks, although clinical response should determine duration of therapy [107,108]. It is important to reduce calcineurin-inhibitor doses when combining these agents with voriconazole to prevent immunosuppressantassociated toxicity [109]. The use of prophylactic voriconazole for 90 days in high-risk liver transplant recipients has led to greatly reduced rates of invasive aspergillosis in this population [110,111]. Prophylactic treatment for aspergillosis in lung transplant recipients is recommended using voriconazole or itraconazole for 3–4 months posttransplant [105].

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Fig. 4. Mucormycosis on the glans penis. Reprinted from “First case report of isolated penile mucormycosis in a liver transplantation recipient,” by Ming-Chun Lai et al., 2014, International Journal of Infectious Diseases, 29, p.208. Copyright 2014 by Lai MC et al. Reprinted with permission.

infections afflict the immunocompromised, particularly those who are T-cell deficient or neutropenic [134]. Common presentations of localized cutaneous fusariosis include onychomycosis, cellulitis, or intertrigo [135]. Cutaneous findings associated with disseminated fusariosis include erythematous papular or nodular lesions that may be tender. Distinctive “target” lesions, with a rim of erythema surrounding papules or nodules are present in some cases. These lesions may involve any skin site, rapidly evolve to become necrotic, and individual lesions may be in different stages of progression [135,136]. All skin lesions suspicious for fusariosis in immunocompromised patients should be biopsied and sent for histopathology and microbiological studies. Blood cultures are commonly positive in disseminated fusariosis and differentiating hyphae of Fusarium spp. from Aspergillus spp. relies on analysis of the macroscopic and microscopic morphology in culture. In cases of disseminated fusariosis, IV voriconazole and IV liposomal amphotericin B have shown efficacy, and combination therapy in the severely immunocompromised is recommended [137–140]. 4.5. Dematiaceous fungi

Mucormycosis is a fungal infection most commonly associated with Lichtheimia, Rhizopus, Mucor, and Rhizomucor spp. [112–114]. Mucormycosis usually afflicts patients with risk factors including hematologic malignancy, chemotherapy, corticosteroids, diabetes mellitus and trauma [115]. Up to 2% of invasive fungal infections in SOTRs are attributed to mucormycosis [113,116–120]. Cutaneous mucormycosis occurs with inoculation of fungal spores into the dermis from trauma or due to disseminated disease. Mucormycosis at a trauma site presents as a single, indurated region of cellulitis that progresses to a black, necrotic eschar with an erythematous or violaceous border (Fig. 4). Deep tissue or systemic infection is an extremely rare complication of cutaneous mucormycosis [121–124]. Diagnosing mucormycosis involves identification of the organism in tissue and confirmation with culture. Upon direct examination of clinical samples, the presence of non-septate hyphae, with right-angle branching suggests mucormycosis. The use of PCR in culture negative cases has been utilized to establish diagnosis [125–129]. Treating mucormycosis involves urgent surgical debridement, correction of metabolic abnormalities, reducing immunosuppression, and antifungal therapy. Liposomal amphotericin B followed by oral posaconazole or isavuconazole step-down therapy shows efficacy in the SOTR population; although, patient prognosis still remains poor [130–133].

Phaeohyphomycosis, chromoblastomycosis and mycetoma are associated with more than 100 saprophytic dark-pigmented fungal species. Skin infections are most commonly associated with Curvularia and Alternaria spp. [141,142]. In SOTRs, 65% of infections with dematiaceous fungi occur around 2 years after transplant, most commonly due to traumatic inoculation [143]. Phaeohyphomycosis most frequently presents on the extremities as a subcutaneous asymptomatic nodule with a central cyst that may evolve into an abscess. Phaeohyphomycosis due to Alternaria spp. in SOTRs has presented as individual or multiple pustules, plaques, papulonodules, and ulcers [144–146]. Patients with a history of gardening or cutaneous trauma with soil exposure are particularly prone to Alternaria infection; although, Alternaria infections are typically benign. Chromoblastomycosis is relatively rare, endemic to particular regions of the world, and presents with localized purple nodules that may be verrucous, ulcerated, or crusted. These lesions are often difficult to clinically differentiate from squamous cell carcinoma or Kaposi's sarcoma [147–149]. Diagnosis of dematiaceous fungal infection is made by histopathology and culture of biopsy samples. Biopsy of a chromoblastomycosis lesion shows Medlar bodies, thick-walled, globe shaped bodies which confirm the diagnosis. Surgical excision or cryotherapy may be sufficient treatment in SOTRs, but the addition of systemic therapy with voriconazole, posaconazole, fluconazole, terbinafine or liposomal amphotericin B is recommended [150–153].

4.4. Fusariosis

5. Conclusion

Fusariosis can present in SOTRs as a local superficial cutaneous infection or an invasive infection. The vast majority of invasive Fusarium spp.

Transplant recipients may present with a wide variety of cutaneous findings. Infection, drug toxicity, and malignancy can all be sources of

4.3. Mucormycosis

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Please cite this article as: Ilyas M, Sharma A, Cutaneous fungal infections in solid organ transplant recipients, Transplant Rev (2017), http:// dx.doi.org/10.1016/j.trre.2017.03.001