A Unique Clinicopathological Manifestation of Fungal Infection: A Case Series of Deep Dermatophytosis in Immunosuppressed Patients

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1 Am J Clin Dermatol DOI /s y SHORT COMMUNICATION A Unique Clinicopathological Manifestation of Fungal Infection: A Case Series of Deep Dermatophytosis in Immunosuppressed Patients Ruben Kershenovich 1 Shany Sherman 1 Ofer Reiter 1 Shiran Reiss Huss 1 Elena Didkovsky 2,3 Daniel Mimouni 1,3 Emmilia Hodak 1,3 Rina Segal 1,3 Ó Springer International Publishing Switzerland 2017 Abstract Background Dermatophytes are the most common cause of superficial fungal infections in humans. Deep dermatophytosis, however, is rare, described to date only in isolated case reports, usually in the setting of systemic immunosuppression. Objective To present the 15-year experience of a tertiary dermato-mycology clinic with the diagnosis and treatment of deep dermatophytosis. Methods Patients were identified by database search. Clinical, mycological, histological, and treatment data were collected from the medical files. Results Ten patients were identified: nine after solid-organ transplantation and one undergoing chemotherapy, all diagnosed within 3 years after beginning immunosuppression (average 7.5 months). The infective agent in nine cases was Trichophyton rubrum. All patients presented with concurrent superficial fungal infections. Complete resolution was noted in response to systemic antifungal agents. There was no histological evidence of hair-follicle involvement. Limitations The limitations of the study were the retrospective design and the small cohort size. Conclusion This case-series study suggests that deep dermatophytosis is a separate entity, distinct from Majocchi s granuloma. It occurs only in immunocompromised patients and is characterized by discrete nodules, an indolent course, the absence of follicular invasion, and proximity to a superficial dermatophyte infection. Systemic antifungal treatment leads to complete resolution. The urgent need for the treatment of superficial fungal infections in immunocompromised patients is emphasized. Key Points Deep dermatophytosis is very rare, exclusively affecting immunocompromised patients. It is characterized by an indolent course, an association with superficial fungal infection, and the absence of hair-follicle involvement and responds to systemic antifungal medication. The difference between Majocchi s granuloma and deep dermatophytosis is highlighted. Early treatment for superficial dermatophytosis is mandatory. & Shany Sherman shanyshnush@gmail.com Department of Dermatology, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., Petach Tikva , Israel Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 1 Introduction Dermatophytes are the most common cause of superficial fungal infections in humans [1]. They have an affinity for keratin and as such parasitize the cornified layer of the epithelium (skin, hair, and nails) causing superficial dermatophyte infestation [2]. In the immunocompetent host, deeper invasion by dermatophytes is prevented by several factors, including physical barriers (epidermal

2 R. Kershenovich et al. keratinization, epidermal keratinocyte turnover, ph, fatty acids from sebaceous glands, body temperature) [3], innate and adaptive immunity [4], and serum components [5]. However, in special circumstances, such as kerion and Majocchi s granuloma (nodular granulomatous perifolliculitis) [6], dermatophytes are able to enter deeper into the dermis through hair follicles. In extremely rare cases, in patients with either a specific genetic predisposition or specific immune defects, lymphatic spread was documented, causing mycetoma/pseudomycetoma [7, 8] and even dissemination to extra-cutaneous sites [9 11]. The growing population of immunocompromised patients has led to an increase in cases of deep (dermal/subcutaneous) dermatophytosis [5]. However, the current data are based on isolated case reports. This study presents the 15-year experience of a tertiary dermato-mycology clinic with the diagnosis and treatment of deep dermatophytosis. 2 Methods The database of the Department of Dermatology at Rabin Medical Center, a tertiary university-affiliated hospital in Israel, was searched for all patients with deep dermatophytosis who attended the dermato-mycology clinic in Only patients with nodular lesions ([1 cm) were included. The medical records of the eligible patients were reviewed, and the following data were collected: demographics; medical and dermatological history; immunosuppression status, including duration of immunosuppression until presentation and immunosuppressive medications; presence and location of concurrent superficial dermatophyte infections; isolation of the infecting pathogen; histologic and microbiologic findings on deep incisional or deep punch biopsies; anti-fungal treatment; and follow-up findings. All diagnoses, treatments, and follow-up evaluations were performed at the dermato-mycology clinic, and photographs of the lesions were taken. The histology and microbiology samples were analyzed by the institute s mycology laboratory technician and dermatopathologist, respectively. The slides were reexamined at the time of data collection for the study by a dermatopathologist at our medical center. Included were only cases with positive microbiologic findings of superficial fungal infections from a deep tissue biopsy, and correspondent pathological findings of intradermal fungal elements, confirming the presence of deep fungal infection. Recently, another patient was included in the study (15 November, 2016); therefore, follow-up evaluations are incomplete. 3 Results Ten patients with a histologically and microbiologically proven diagnosis of deep dermatophytosis were identified. Their characteristics are summarized in Table 1. The maleto-female ratio was 7:3. The mean patient age at presentation was 60 years (range years). All patients were immunocompromised. Nine were receiving immunosuppressive medications following kidney (n = 8) or lung (n = 1) transplantation, and one was undergoing chemotherapy for sigmoid cancer. The average number of immunosuppressive medications was 2.3. The immunosuppressive agents included prednisone, administered to all the organ-transplant recipients, in addition to, sirolimus, mycophenolate mofetil, cyclosporine, and mycophenolic acid. The patient with sigmoid cancer was treated with capecitabine. In all cases, a concurrent superficial dermatophyte infection was documented at admission: onychomycosis in seven patients, tinea cruris in two patients, and tinea corporis in one patient. Superficial tissue cultures were positive for Trichophyton rubrum in eight patients. In two patients (nos. 2 and 8), culture results were negative, but the potassium hydroxide smear revealed hyphae. The deep dermatophytosis occurred during the first 3 years after initiation of immunosuppressive treatment; seven patients (70%) presented within the first year. The average time elapsed was 8.8 months (range 3 27 months). The most frequent clinical manifestation consisted of nodules, which in seven patients were located on the lower s (Figs. 1, 2). Involvement of the neck/trunk/groin was documented in the remaining patients. Biopsy studies demonstrated histologic features of reactive epidermal changes in most biopsies: epidermal acanthosis (eight patients) and even pseudoepiteliomatous hyperplasia (three patients). Dermal infiltrates comprised acute infiltrates, including neutrophils with frequent formation of microabscesses, and of chronic infiltrates, including numerous histiocytes, some of which were forming multinucleated giant cells. Periodic acid-schiff and methenamine silver stains demonstrated spores and hyphae within the deep dermis in all biopsy samples (Fig. 3). Hair follicles were not involved in the infectious process in all biopsies in serial sections. Deep tissue cultures were positive for Trichophyton rubrum in nine patients and for Microsporum audouini in one, while mycological examination of skin scales overlying the nodules were negative. All patients were given oral antifungal agents. Treatment was selected following consultation with the patients physicians responsible for the immunosuppressive protocols (nephrologists, pulmonologists, and oncologists), with

3 A Unique Clinicopathological Manifestation of Fungal Infection Table 1 Characterization of patients with deep dermatophytosis Patient no. Age (years)/sex Type of IS Time from IS to dx (months) IS medication Superficial mycosis 1 65/M Kidney 3 Prednisone 4mg9 1/day 2 41/M Kidney 3 59/M Kidney 4 45/M Kidney 5 69/F Colon cancer 3 Prednisone sirolimus 4mg9 1/day 27 Prednisone sirolimus 1mg9 2/day, MPA 360 mg 9 2/day 13 Prednisone, cyclosporine (dosage unknown) 4 Capecitabine 500 mg 9 3/day Tinea cruris Tinea cruris 6 61/F Lung 24 Prednisone 10 mg 9 1/day, 1.5 mg/day 7 64/M Kidney 8 50/F Kidney 2 Prednisone 10 mg 9 1/day, 2mg9 1/day, MMF 1.5 g 9 1/day 4 Prednisone 15 mg 9 1/day, 7 mg/day, MPA 360 mg 9 2/day Tinea corporis Nodule site Histology a,b,c Culture Oral treatment Response Acanthosis; acute and chronic dermal infiltrates, multinuclear giant cells; dermal spores and hyphae; PAS, silver? Neck Acanthosis; focal acute and chronic dermal infiltrates, abscess; a few eosinophils; a few spores and hyphae; PAS, silver? Trichophyton rubrum Terbinafine 250 mg/week for 1 month (until hospitalized) T. rubrum Terbinafine 250 mg/day for 6 weeks Groin Acanthosis; acute and chronic dermal infiltrates; a few hyphae; PAS, silver? T. rubrum Fluconazole 150 mg/week for 3 months Trunk, lower s Groin, pubis Right shin Acanthosis; acute and chronic dermal infiltrates, microabscesses, multinuclear giant cells; spores and hyphae; PAS, silver? Acanthosis; acute and chronic dermal infiltrates, microabscesses, multinuclear giant cells; spores and hyphae in abscesses; PAS, silver? No epidermis; focal acute and chronic infiltrates with involvement of subcutaneous tissue; no granulomas; spores and hyphae in dermis; PAS, silver? Pseudoepitheliomatous hyperplasia; acute and chronic dermal infiltrates, with no involvement of subcutaneous tissue, multinuclear giant cells; spores and hyphae in dermis; PAS, silver? T. rubrum Fluconazole 150 mg/week for 3 months T. rubrum Terbinafine 250 mg/day for 4 weeks T. rubrum Itraconazole 100 mg twice daily for 16 weeks T. rubrum Terbinafine 250 mg/day for 8 weeks Normal epidermis; focal acute and heavy chronic superficial and mid-dermal infiltrates, with no involvement of subcutaneous tissue; spores and hyphae in dermis; PAS, silver? Microsporum audouinni Terbinafine 250 mg/day for 8 weeks

4 R. Kershenovich et al. Table 1 continued Patient no. Age (years)/sex Type of IS Time from IS to dx (months) IS medication Superficial mycosis Nodule site Histology a,b,c Culture Oral treatment Response 9 77/M Kidney 10 70/M Kidney 3 Prednisone 2.5 mg 9 1/day, MPA 360 mg 9 2/day 5 Prednisone 2mg9 1/day Epidermal hyperplasia; acute and chronic dermal infiltrates, microabscesses, multinuclear giant cells; many plasma cells with involvement of upper subcutaneous tissue; spores and hyphae in dermis; PAS, silver? Pseudoepitheliomatous hyperplasia; acute and chronic dermal infiltrates, microabscesses; multinuclear giant cells; numerous plasma cells with involvement of upper subcutaneous tissue; spores and hyphae in dermis; no involvement of hair follicles T. rubrum Fluconazole 150 mg/week for 6 months T. rubrum Terbinafine 125 mg once daily N/A d complete response, dx diagnosis (of deep dermatophytosis), F female, IS immunosuppression, M male, MMF mycophenolate mofetil, MPA mycophenolic acid, N/A not available, PAS periodic acid-schiff (stain), transplantation Acute infiltrates: neutrophils, formation of small abscesses; chronic infiltrates: lymphocytes, histiocytes, formation of multinucleated giant cells a b In patient nos. 1 4, the biopsy did not reach the subcutaneous tissue In no case was hair follicle involvement noted c d The patient was identified in November 2016, and the outcome data were still incomplete at the time of submission of this manuscript

5 A Unique Clinicopathological Manifestation of Fungal Infection Fig. 2 Clinical findings, patient no. 10. An asymptomatic eruption involving the ankle and left lower shin. Note the indurated nodule (2 9 1 cm) separated by normal-appearing skin from an infiltrated plaque on which several small cauliflower-shaped nodules, some ulcerated, may be seen. Nail dystrophy was present Fig. 1 Clinical findings, patient no. 6. An asymmetric rash with a sporotrichoid pattern is seen involving the right lower. The rash is made up of erythematous to purple nodules; some are ulcerated and covered with a thick crust. There are two large vegetative nodules on the dorsum of the leg and proximal fourth finger. The distal lesions appear to be more infiltrated than the proximal lesions. Nail dystrophy is observed as well consideration of possible interactions with current immunosuppressive treatments and renal and/or hepatic functional status. No adaptation of the immunosuppressive protocols was necessary, and in no case was topical antifungal treatment added. Six patients received terbinafine, at a full dose (250 mg once daily) in four patients and a halfdose (125 mg once daily, for a prolonged period) in two patients. The average duration of treatment with terbinafine was 7 weeks (range 4 12 weeks). Three patients received fluconazole 150 mg once weekly for an average of 16 weeks (range weeks). One patient (no. 6) received two courses of 4 months of oral itraconazole (100 mg twice daily), owing to a relapse, but relapsed once more and was subsequently switched to a half-dose of terbinafine (125 mg one daily) with a dosage adjustment for reduced renal function (glomerular filtration rate 34 ml/min). Treatment resulted in complete clinical resolution of the lesions. There were no relapses during follow-up. Two patients died during follow-up for reasons unrelated to the fungal infection or its treatment. Patient no. 10 was recently included in the study (15 November, 2016); therefore, the outcome data are still incomplete. 4 Discussion Deep dermatophytosis is a very rare disease, with only a few case reports published to date. Therefore, to clarify the characteristics and course of deep dermatophytosis, we identified all new cases diagnosed in the last 15 years at Rabin Medical Center, constituting the largest solid-organ transplantation department in Israel (average [250/year) and accounting for more than 70% of all renal and liver transplants and 100% of all lung transplants nationwide [12]. Dermatophytes are obligate parasites of the stratum corneum. In the setting of profound immunosuppression along with superficial fungal infection, dermatophytes can invade deeper into the dermis and subcutaneous tissues [5, 6, 9, 13 16]. Very rarely, they may cause a lifethreatening infection by invading the lymph nodes [17, 18] or internal organs [19]. Primary immunodeficiency with a genetic origin is also recognized as a predisposition to deep dermatophytosis [11]. Recently, there has been a great interest in the caspase recruitment domain-containing protein gene (CARD9) and its role in human antifungal immunity. Since the first report in 2009, in recent years, we have witnessed a handful of reports of patients, otherwise

6 R. Kershenovich et al. Fig. 3 Histologic findings, patient no. 10. Punch biopsy from a nodule on the inner shin. a Hematoxylin and eosin stain shows a multinucleated giant cell surrounded by neutrophils, with nuclear dust, histiocytes, lymphocytes, and extravasated erythrocytes (magnification 9200). b Periodic acid-schiff stain demonstrates several multinucleated giant cells intermingled with neutrophils and nuclear dust. Few spores and hyphae are present in the cytoplasm of the multinucleated giant cells (magnification 9200). Insert A Multinucleated giant cell engulfing spores and hyphae (magnification 9400). c Methenamine silver stain demonstrates hyphae and spores within the dermal infiltrate (magnification 9400) immunocompetent with the spontaneous development of persistent and severe fungal infections that primarily localize to the skin and subcutaneous tissue, with occasional dissemination to lymph nodes, bone, and the central nervous system. Most of the patients had concurrent tinea corporis and onychomycosis. Those patients all had in common a specific immunodeficiency caused by mutations in the gene CARD9. Candida and phaeohyphomycosis infections were also reported in CARD9-deficient patients [10, 11, 20, 21]. The rarity of deep dermatophytosis and the frequent failure of clinicians to recognize the disease have led to some ambiguity regarding its distinction from the better known Majocchi s granuloma. Majocchi s granuloma is not sine qua non to deep dermatophytosis. Rouzaud et al. in their review of severe dermatophytosis also highlighted the distinction between the two entities [11]. It usually affects immunocompetent patients sometimes with local immunosuppression (e.g., during topical corticosteroid application) [5, 22]. Clinically, the lesions manifest as pruritic papules, pustules, and small nodules (up to 0.5 cm in diameter) in areas involved in a pre-existing dermatophytic infection. A potassium hydroxide smear of overlying skin scales is positive, and histopathology demonstrates perifollicular inflammation and hyphae within or around hair follicles. By contrast, deep dermatophytosis occurs exclusively in immunosuppressed patients. The clinical picture consists of large ([1 cm), mostly asymptomatic nodular lesions, occasionally ulcerative, without an overlying superficial dermatophytic infection. In most cases, there is a concurrent, usually precedent, superficial fungal infection located elsewhere. A superficial potassium hydroxide smear from a nodular lesion surface is negative. The clinical differential diagnosis may include subcutaneous fungal infections (e.g., sporotrichosis, chromoblastomycosis), opportunistic fungal infections, or proliferative processes such as cutaneous lymphoma or Kaposi s sarcoma. Histopathology demonstrates hyphae surrounded by an acute infiltrate (neutrophils, microabscesses), a chronic infiltrate (lymphohistiocytic infiltrate frequently leading to granuloma), or a combined infiltrate (Table 1). Unlike Majocchi s granuloma, which develops consequent to invasion of hair follicles [22, 23], the pathway of fungal spread to the dermis in deep dermatophytosis remains unclear. In none of our cases was there, clinically or histologically, invasion or disruption of the hair follicles or, so far as could be discerned, known trauma to the skin. Because all superficial cultures and potassium hydroxide smears were negative, we speculate that the underlying mechanism of deep dermatophytosis was through a lymphatic spread (i.e., sporotrichoid pattern), or less unlikely as a result of an unnoticed micro-

7 A Unique Clinicopathological Manifestation of Fungal Infection trauma to the skin (as during shaving) in the presence of deep immunosuppression, which maintains the survival of the hyphae in the dermis. In all our cases, the deep infection occurred a relatively short time after initiation of immunosuppression, mostly during the first year (average 7.5 months, range 3 27 months). The timing appeared to be analogous to the well-recognized time frame of invasive opportunistic fungal infections (e.g., invasive candidiasis, cryptococcosis, invasive aspergillosis, phaeohyphomycosis) [24, 25], which are known to increase in incidence in the first 6 months after transplantation, when immunosuppression is more intense [25]. However, previous data on the interval from posttransplant immunosuppression to the appearance of deep dermatophytosis are mixed. Some studies reported similar latency periods to ours [12, 14], whereas others reported a latency of more than 3 years [9] and even up to 14 years [20]. Late manifestations may be associated with the initiation of salvage treatment for allograft rejection and an increased dose of immunosuppressive treatments [22, 23]. The most prevalent dermatophyte species isolated in our cohort (nine of ten patients) was the anthropophilic Trichophyton rubrum. This finding is in accordance with previous reports [5, 6, 9, 13 16]. Because all our patients had an adjacent concurrent localized superficial fungal infection (caused by T. rubrum in all eight patients with available culture results), we assume the organism responsible for the superficial infection was also responsible for the deep infection. Therefore, the isolation of Microsporum audouinii in one patient (no. 8, Table 1) from a lesion on the lower was surprising. Microsporum audouinii is an unusual pathogen in Israel (unpublished data presented at the First Israeli Dermato-Mycology Convention, Israel, 2011), and it has been found so far in the literature to be responsible for only two cases of deep mycosis, in the form of mycetoma [7] or generalized invasive dermatophytosis [19]. In the second report, defective lymphocyte transformation was associated with an uncharacterized plasma factor [19]. The first patient was not reported to have an immunodeficiency [7]. In 2011, Romero et al. [22] reviewed 22 reported cases of Majocchi s granuloma in organ-transplant recipients. Their cohort had many similar clinical characteristics to ours, including male predominance, mostly renal transplants, average age almost 50 years, lesion localized mostly to the lower extremities, and indolent disease course. On analysis of the clinical and laboratory findings, several of the reports appeared to be actually describing deep dermatophytosis, i.e., histopathologic findings of a granulomatous infiltrate, with either no mention of an association with hair follicles or a specific mention of a lack of involvement of hair follicles [16, 23]. Trichophyton rubrum was also the pathogen most often isolated in the earlier study [22], but it accounted for 59% of cases compared with 90% in our cohort. This difference may reflect a geographic variation in dermatophyte species responsible for superficial fungal infections. In Israel, more than 90% of dermatophytic infections are caused by T. rubrum (unpublished data presented at the First Israeli Dermato-Mycology Convention, Israel, 2011). The present series highlights the effectiveness of oral terbinafine or fluconazole in the treatment of deep dermatophytosis. Both drugs were associated with rapid (1 4 months) resolution of the lesions, without evidence of relapse over a long follow-up period. In the review of Romero et al. [22], itraconazole, administered in seven cases, was found to be effective. Other reported treatments include amphotericin B [16], surgery [23], griseofulvin [9], and a multi-modal approach of surgery and fluconazole. The favorable results achieved with terbinafine are attributable to its good penetration and fungicidal action. Additionally, it is preferable to triazoles, which inhibit the cytochrome P450 3A4 enzyme, leading to increased plasma concentrations of the immunosuppressive agents, cyclosporine and. The rank order of potential inhibition is ketoconazole [ itraconazole [ voriconazole [ fluconazole [26]. Therefore, when terbinafine is contraindicated, fluconazole is the least toxic alternative. The risk of opportunistic infections is increasing with the growing population of immunocompromised patients as a result of organ transplantation and malignancy [27]. Approximately 40% of renal-transplant recipients are predisposed to the development of dermatophytosis [23]. A study of Israeli renal-transplant recipients revealed an even higher rate of dermatophytosis of almost 47%, which rose to 71% after more than 3 years post-transplantation. These findings were partially explained by the relatively higher prevalence of dermatophytosis in the general population in Israel [28]. Our experience together with the previously published case reports should alert dermatologists to the possibility of deep dermatophytosis, especially given its association with preceding superficial fungal infections (particularly onychomycosis, tinea pedis, and tinea cruris), which are very common in the general population. Therefore, superficial dermatophytoses, especially in transplant candidates, must be treated promptly, and patients should be kept under close observation by a dermatologist even before immunosuppression is initiated. 5 Limitations The study is limited by the retrospective design and small cohort. Additionally, there might be a selection bias owing to the inclusion of only lesions [1 cm as deep dermatophytosis.

8 R. Kershenovich et al. 6 Conclusion Our findings suggest that deep dermatophytosis is a distinct entity, different clinically and histologically from Majocchi s granuloma and limited to immunocompromised patients. It is characterized by male predominance, early appearance after initiation of immunosuppressive medication (\3 years), a clinical picture of subcutaneous erythematous, often ulcerated, nodules, mainly in the lower s, findings of an acute and/or chronic dermal infiltrate without hair follicle involvement on biopsy study, and a generally indolent course. It responds well to systemic antifungal treatment, especially terbinafine. This study supports the association of deep dermatophytosis with concurrent superficial fungal infection and emphasizes the need for the proper treatment of superficial fungal infections in immunocompromised patients, preferably, if possible, even before immunosuppression is initiated. Author contributions R. Kershenovich and S. Sherman contributed equally to this work. Compliance with Ethical Standards Funding No funding was received for this study. Conflict of interest R. Kershenovich, S. Sherman, O. Reiter, S. Reiss Huss, E. Didkovsky, D. Mimouni, E. Hodak, and R. Segal have no conflicts of interest directly relevant to the content of this study. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent to participate For this type of study, formal consent is not required. References 1. Havlickova B, Czaika VA, Friedrich M. Epidemiological trends in skin mycoses worldwide. Mycoses. 2008;51: Weitzman I, Summerbell RC. The dermatophytes. Clin Microbiol Rev. 1995;8: Hay RJ, Moore M. Mycology. In: Champion RH, Burton JL, Burns DA, Breathnach SM, editors. 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