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Deep dermatophytosis caused by Trichophyton rubrum with concomitant disseminated nocardiosis in a renal transplant recipient
Deep dermatophytosis caused by Trichophyton rubrum with concomitant disseminated nocardiosis in a renal transplant recipient Deniz Sec¸kin, MD,a Sevtap Arıkan, MD,c and Mehmet Haberal, MD, FACSb Ankara, Turkey Deep dermatophytosis and nocardiosis are uncommon infections. This article describes a patient who was immunosuppressed with deep dermatophytosis caused by Trichophyton rubrum and concurrent disseminated nocardiosis. The infections occurred 16 years after the patient underwent renal transplantation, and may have been related to tacrolimus therapy. ( J Am Acad Dermatol 2004;51:S173-6.)
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rgan transplant recipients receive long-term immunosuppressive therapy to help prevent graft rejection and are, therefore, at increased risk for opportunistic infection.1,2 Dermatophytes are keratinophilic organisms, and most dermatophytic infections are confined to the stratum corneum, hair, and nails. These organisms are not generally regarded as opportunistic pathogens; however, they do occasionally invade the dermis, subcutaneous tissue, and internal visceral organs and cause atypical aggressive infections, particularly in individuals who are immunocompromised.3-5 The current literature documents fewer than 100 cases of deep dermatophytosis. Nocardia species are ubiquitous environmental saprophytes that live in soil, organic matter, and water.6 Nocardiosis is usually an opportunistic infection, and is an uncommon but important cause of morbidity and mortality in organ transplant re-
The pagination of this article was incorrect as originally published (2004:51;S101-S104). Please use the corrected page numbers listed online at www.eblue.org, in the corrected table of contents, or in the December 2004 index in future citations. This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. Departments of Dermatologya and General Surgery,b Basxkent University Faculty of Medicine; and Department of Microbiology, Hacettepe University Faculty of Medicine.c Funding sources: None. Conflicts of interest: None identified. Presented at the American Academy of Dermatology 60th Annual Meeting, New Orleans, Louisiana, February 22-27, 2002. Reprint requests: Deniz Sec¸kin, MD, Basxkent University Faculty of Medicine, Department of Dermatology, 5. Sokak, No. 48, Bahc¸elievler, 06490, Ankara, Turkey. E-mail: denizs@baskent-ank. edu.tr. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.05.008
cipients.7,8 Most such infections arise from direct inoculation of skin or soft tissues, or by inhalation.6-8 We describe a renal transplant recipient who had deep dermatophytosis caused by Trichophyton rubrum and concurrent disseminated nocardiosis. To our knowledge, no such association in a patient with renal transplant has been reported in the literature to date.
CASE REPORT In December 2000, a 45-year-old man was referred for evaluation of a mass on his left thigh that had been present for 2 weeks. The patient had undergone kidney transplantation 16 years earlier. He had no history of penetrating trauma or insect bite at the affected site. His immunosuppressive treatment had consisted of prednisolone, azathioprine, and cyclosporine until October 2000, when he had experienced an episode of allograft rejection. This was treated with pulse-corticosteroid therapy, and the cyclosporine in his regimen was switched to tacrolimus. Dermatologic examination revealed a 2.5-cm diameter, well-demarcated, solitary, firm, nontender, dusky-red to purple tumor on the medial aspect of the patient’s left thigh (Fig 1). Interdigital toe-web maceration, onychodystrophy, and discoloration of the fingernails (first, second, and fourth fingers of the right hand) and both big toenails were also noted. Complete blood count, erythrocyte sedimentation rate, urinalysis, and serum levels of C-reactive protein, fasting glucose, liver enzymes, blood urea nitrogen, and creatinine were within normal limits. Serology was negative for antihuman immunodeficiency virus antibodies, and positive for antihepatitis C virus and antihepatitis B surface antigen antibodies. Potassium hydroxide preparations of scrapings of the toe webs and dystrophic nails showed septate hyphae. Samples from an excisional biopsy specimen S173
S174 Sec¸kin, Arıkan, and Haberal
Fig 1. Firm, nontender, dusky-red to purple tumor caused by Trichophyton rubrum.
of the tumoral lesion were sent for histopathologic study, and bacterial and fungal cultures. The histopathologic examination revealed pseudoepitheliomatous hyperplasia of the epidermis, and dense inflammatory infiltrate, focal microabscess formation, and extensive hemorrhage throughout the reticular dermis. The infiltration was not associated with hair follicles. The microabscesses featured polymorphonuclear leukocytes and nuclear debris at their center, and histiocytes and multinuclear giant cells at the periphery. Some of the giant cells had engulfed clear globular material, which periodic acid-Schiff staining confirmed was a fungal structure. Multiple swollen, thick-walled, periodic acidSchiff—positive, septate hyphae were also observed in the extracellular component of the dermis (Fig 2). Deep fungal infection, including dermatophytosis, was suggested. The patient was started on oral terbinafine (250 mg/d); however, 2 weeks later he was readmitted because of pain and diminished vision in his left eye. Fundoscopic examination revealed a plaque lesion suggestive of fungal endophthalmitis. Terbinafine was discontinued, and empirical treatment with intravenous liposomal amphotericin B (3 mg/kg/d) and an intravitreal injection of amphotericin B were administered for probable invasive fungal infection of the eye. The patient became febrile on the third day in hospital. A chest radiograph showed diffuse patchy infiltration of both lungs. Thoracic computed tomography demonstrated a 3-cm diameter solid mass in the basal segment of the left lung. Neurologic examination revealed weakness of the left lower limb and diminished consciousness. Magnetic resonance imaging showed multiple brain abscesses (Fig 3). The patient’s clinical condition worsened; he developed generalized seizures and was placed on antiepileptic therapy. A vitreous sample was obtained by fine-needle aspiration, and modified acid-fast staining of this material showed delicate, long, thin, branching, and
J AM ACAD DERMATOL NOVEMBER 2004
Fig 2. Thick-walled, short, swollen septate hyphae and sporelike organisms in reticular dermis. (Periodic acidSchiff stain; original magnification: 340.)
weakly acid-fast filaments characteristic of Nocardia species (Fig 4). A sample of vitreous and a blood culture both grew N asteroides. The patient was given the diagnosis of disseminated nocardiosis featuring multiorgan involvement, namely, ophthalmic, pulmonary, and central nervous system lesions. Tacrolimus, azathioprine, and amphotericin B were discontinued. The immunosuppressive therapy was continued with prednisolone and combination antimicrobial therapy with trimethoprim-sulfamethoxazole, amikacin, and cefotaxime was initiated. The patient’s clinical status improved dramatically in the first week, and 2 weeks later he was discharged from hospital. One month after initial presentation, fungal cultures of the skin tumor and the nail and toe-web scrapings grew T rubrum (Fig 5). This confirmed the diagnoses of deep dermatophytosis for the skin tumor, and tinea unguium and tinea pedis. After discharge, the patient continued to receive long-term treatment for nocardiosis with trimethoprim-sulfamethoxazole, amikacin, and imipenem. Amikacin was stopped after 3 months, as a result of ototoxicity. Trimethoprim-sulfamethoxazole was discontinued in the fifth month because of elevated liver enzymes, and imipenem was switched to meropenem at this stage as well. After 7 months of therapy, the lesions in the lungs and central nervous system were almost completely resolved. The nocardiosis therapy was stopped after 12 months. In July 2002, cyclosporine and mycophenolate mofetil were added to the immunosuppressive treatment with prednisolone. Three years after his first admission, the patient remains free of disease but is totally blind in his left eye.
DISCUSSION Dermatophyte infections can present in various atypical ways. These presentations include different types of subcutaneous and deep dermal lesions
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Sec¸kin, Arıkan, and Haberal S175
Fig 4. Modified acid-fast staining of vitreous specimen. Note long, thin, branching, weakly acid-fast filaments characteristic of Nocardia species. (Original magnification: 3600.) Fig 3. Magnetic resonance imaging shows brain abscess in patient’s left parietal lobe.
(papules,5,9,10 nodules,3,5,10 plaques,3,5 cellulitis,11 abscesses,4,12 draining sinuses,13 verrucous lesions,14 blastomycosis-like lesions15) and, rarely, lymphogenous or hematogenous extension.16 Such atypical features are mostly encountered in individuals who are immunocompromised.3-5 T rubrum is the causal agent in most cases of deep dermatophytosis.3 Patients with deep dermatophytosis usually have concurrent chronic superficial dermatophyte infection, such as tinea unguium, which suggests autoinoculation in the pathogenesis.3,4,15 Clinical, pathologic, and microbiologic diagnosis of deep dermatophytosis in individuals who are immunocompromised can be difficult.3,4,9,15,17,18 Our patient initially presented with a red-purple tumoral lesion, so we initially suspected a neoplastic condition (cutaneous lymphoma or Kaposi’s sarcoma) or a deep fungal infection like cutaneous aspergillosis. When histopathologic examination revealed multiple septate hyphae in the dermis, our focus was a deep fungal infection, such as dermatophytosis. However, as has been noted previously in the literature on deep dermatophytosis,9-12,15 instead of the typical slender hyphae found in the stratum corneum in superficial dermatophytosis, the hyphae in our patient’s dermis were thicker, shorter, and thick-walled. The isolated T rubrum also had unusual microbiologic properties, and was difficult to identify. Early on, the growth on fungal culture featured hyphae with occasional septae and rare microconia. To induce sporulation, we subcultured the strain to several different types of complex media. However, sporulation took a full 2 weeks, and relatively few teardrop-shaped microconidia were produced. The isolated strain also produced pigment late. Such unusual morphologic features might reflect adaptations that allow der-
Fig 5. Microscopic examination of Trichophyton rubrum colonies from skin tumor: Note teardrop-shaped microconidia borne laterally along sides of hyphae. (Lactophenol cotton blue mounting; original magnification: 3400.)
matophytes to survive in deep dermal and subcutaneous locations.11 Nocardiosis is a rare suppurative infection that is most often caused by N asteroides, a delicate, branching, gram-positive, acid-fast micro-organism.6 The majority of nocardiosis cases are septicemic infections, usually of pulmonary origin, in patients who are immunocompromised. Dissemination from the lung to the brain, skin and soft tissue, and other organs occurs in up to 50% of cases.7,8 Ocular involvement is uncommon but remains a valuable clue to diagnosis of endogenous infection,8 as was the case with our patient. Of renal transplant recipients, 10% develop dual infections.19 Nocardiosis has been reported to occur simultaneously with other opportunistic infections.19,20 Therefore, attempts to establish a single diagnosis that explains multisystemic findings in a patient who is immunocompromised can sometimes be misleading. One should keep a high index of suspicion for simultaneous infections in this patient group, and to identify the causal pathogens completely. With improved immunosuppression and early allograft survival, chronic allograft nephropathy
S176 Sec¸kin, Arıkan, and Haberal
has become the dominant cause of kidney transplant failure. Currently, the 5- and 10-year graft survival for cadaver donor transplants are 61.3% and 35.8%, respectively.21 The biopsy specimen—proven chronic allograft nephropathy in our patient was attributed to the impact of possible subclinical acute rejections, atherosclerosis, or both. Our patient developed deep dermatophytosis and disseminated nocardiosis 16 years posttransplantation. Both infections arose soon after he had undergone rescue therapy for chronic allograft rejection. It is likely that development of these infections was somehow related to pulse-corticosteroid therapy, the switch from cyclosporine to tacrolimus immunosuppression, or both. Tacrolimus is a more potent immunosuppressive than cyclosporine.22,23 Although the data are controversial,24 some studies have indicated a trend toward higher frequency of infection in kidney25 and heart26 transplant recipients receiving tacrolimus than in the ones using cyclosporine. Currently, whether or not tacrolimus represents a greater risk for deep dermatophytosis and nocardiosis than other immunosuppressive regimens is not known. However, isolated case reports of both deep dermatophytosis27 and Nocardia28 infections under tacrolimus therapy have recently been published. For this reason, it is important to bear in mind that newer and more potent immunosuppressive regimens may increase the risk of opportunistic infection in transplant recipients. We thank Dr Beyhan Demirhan and Dr Muhtesxem Agˇıldere for providing histopathologic and radiologic figures of the patient. REFERENCES 1. Abel AA. Cutaneous manifestations of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989;21: 167-79. 2. Sec¸kin D, Ogˇuz Gu¨lec¸ T, Demiragˇ A, Bilgin N. Renal transplantation and skin diseases. Transplant Proc 1998;30:802-4. 3. Chastain MA, Reed RJ, Pankey GA. Deep dermatophytosis: report of two cases and review of the literature. Cutis 2001;67: 457-62. 4. Novick NL, Tapia L, Bottone EJ. Invasive Trichophyton rubrum infection in an immunocompromised host: case report and review of the literature. Am J Med 1987;82:321-5. 5. Elewski BE, Sullivan J. Dermatophytes as opportunistic pathogens. J Am Acad Dermatol 1994;30:1021-2. 6. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol Rev 1994;7:357-417. 7. Arduino RC, Johnson PC, Miranda AG. Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine. Clin Infect Dis 1993;16:505-12. 8. Tan SY, Tan LH, Teo SM, Thiruventhiran T, Kamarulzaman A, Hoh HB. Disseminated nocardiosis with bilateral intraocular involvement in a renal allograft patient. Transplant Proc 2000; 32:1965-6.
J AM ACAD DERMATOL NOVEMBER 2004
9. Radentz WH, Yanase DJ. Papular lesions in an immunocompromised patient: Trichophyton rubrum granulomas (Majocchi’s granuloma). Arch Dermatol 1993;129:1189-93. 10. Tsang P, Hopkins T, Jimenez-Lucho V. Deep dermatophytosis caused by Trichophyton rubrum in a patient with AIDS. J Am Acad Dermatol 1996;34:1090-1. 11. Smith KJ, Neafie RC, Skelton HG III, Barrett TL, Graham JH, Lupton GP. Majocchi’s granuloma. J Cutan Pathol 1991;18: 28-35. 12. Faergemann J, Gissle´n H, Dahlberg E, Westin J, Roupe G. Trichophyton rubrum abscesses in immunocompromised patients. Acta Derm Venereol 1989;69:244-7. 13. Franco RC. Deep dermatophytosis in a post-transplant recipient. Int J Dermatol 2001;40:363-4. 14. Grossman ME, Pappert AS, Garzon MC, Silvers DN. Invasive Trichophyton rubrum infection in the immunocompromised host: report of three cases. J Am Acad Dermatol 1995;33:315-8. 15. Squeo RF, Beer R, Silvers D, Weitzman I, Grossman M. Invasive Trichophyton rubrum resembling blastomycosis infection in the immunocompromised host. J Am Acad Dermatol 1998;39: 379-80. 16. Hironaga M, Okazaki N, Saito K, Watanabe S. Trichophyton mentagrophytes granulomas: unique systemic dissemination to lymph nodes, testes, vertebrae, and brain. Arch Dermatol 1983;119:482-90. 17. Sommer S, Barton RC, Wilkinson SM, Merchant WJ, Evans EGV, Moore MK. Microbiological and molecular diagnosis of deep localized cutaneous infection with Trichophyton mentagrophytes. Br J Dermatol 1999;141:323-5. 18. King D, Cheever LW, Hood A, Horn TD, Rinaldi MG, Merz WG. Primary invasive cutaneous Microsporum canis infections in immunocompromised patients. J Clin Microbiol 1996;34:460-2. 19. Scully RE, Mark EJ, McNeely WF, Ebeling SH, Ellender SM, Peters CC. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises, case 29-2000. N Engl J Med 2000;343:870-7. 20. McCown HF, Sahn EE. Subcutaneous phaeohyphomycosis and nocardiosis in a kidney transplant patient. J Am Acad Dermatol 1997;36:863-6. 21. Djamali A, Premasathian N, Pirsch JD. Outcomes in kidney transplantation. Semin Nephrol 2003;23:306-16. 22. Trompeter R, Filler G, Webb NJA, Watson AR, Milford DV, Tyden G, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002;17:141-9. 23. Yagˇmurdur MC, Sevmis S, Emirogˇlu R, Moray G, Bilgin N, Haberal M. Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients. Transplant Proc 2003;36:144-7. 24. Kusne S, Martin M, Shapiro R, Jordan M, Fung J, Alessiani A, et al. Early infections in kidney transplant recipients under FK 506. Transplant Proc 1991;23:956-7. 25. Abbott KC, Hypolite I, Poropatich RK, Hshieh P, Cruess D, Hawkes CA, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001;3:203-11. 26. Peraira JR, Segovia J, Arroyo R, Ortiz P, Fuertes B, Mo~ nivas V, et al. High incidence of severe infections in heart transplant recipients receiving tacrolimus. Transplant Proc 2003;35:1999-2000. 27. Sequeira M, Burdick AE, Elgart GW, Berman B. New-onset Majocchi’s granuloma in two kidney transplant recipients under tacrolimus treatment. J Am Acad Dermatol 1998;38:486-8. 28. Wong KM, Chak WL, Chan YH, Choi KS, Chau KF, Lee KC, et al. Subcutaneous nodules attributed to nocardiosis in a renal transplant recipient on tacrolimus therapy. Am J Nephrol 2000;20:138-41.
O
rgan transplant recipients receive long-term immunosuppressive therapy to help prevent graft rejection and are, therefore, at increased risk for opportunistic infection.1,2 Dermatophytes are keratinophilic organisms, and most dermatophytic infections are confined to the stratum corneum, hair, and nails. These organisms are not generally regarded as opportunistic pathogens; however, they do occasionally invade the dermis, subcutaneous tissue, and internal visceral organs and cause atypical aggressive infections, particularly in individuals who are immunocompromised.3-5 The current literature documents fewer than 100 cases of deep dermatophytosis. Nocardia species are ubiquitous environmental saprophytes that live in soil, organic matter, and water.6 Nocardiosis is usually an opportunistic infection, and is an uncommon but important cause of morbidity and mortality in organ transplant re-
The pagination of this article was incorrect as originally published (2004:51;S101-S104). Please use the corrected page numbers listed online at www.eblue.org, in the corrected table of contents, or in the December 2004 index in future citations. This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. Departments of Dermatologya and General Surgery,b Basxkent University Faculty of Medicine; and Department of Microbiology, Hacettepe University Faculty of Medicine.c Funding sources: None. Conflicts of interest: None identified. Presented at the American Academy of Dermatology 60th Annual Meeting, New Orleans, Louisiana, February 22-27, 2002. Reprint requests: Deniz Sec¸kin, MD, Basxkent University Faculty of Medicine, Department of Dermatology, 5. Sokak, No. 48, Bahc¸elievler, 06490, Ankara, Turkey. E-mail: denizs@baskent-ank. edu.tr. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.05.008
cipients.7,8 Most such infections arise from direct inoculation of skin or soft tissues, or by inhalation.6-8 We describe a renal transplant recipient who had deep dermatophytosis caused by Trichophyton rubrum and concurrent disseminated nocardiosis. To our knowledge, no such association in a patient with renal transplant has been reported in the literature to date.
CASE REPORT In December 2000, a 45-year-old man was referred for evaluation of a mass on his left thigh that had been present for 2 weeks. The patient had undergone kidney transplantation 16 years earlier. He had no history of penetrating trauma or insect bite at the affected site. His immunosuppressive treatment had consisted of prednisolone, azathioprine, and cyclosporine until October 2000, when he had experienced an episode of allograft rejection. This was treated with pulse-corticosteroid therapy, and the cyclosporine in his regimen was switched to tacrolimus. Dermatologic examination revealed a 2.5-cm diameter, well-demarcated, solitary, firm, nontender, dusky-red to purple tumor on the medial aspect of the patient’s left thigh (Fig 1). Interdigital toe-web maceration, onychodystrophy, and discoloration of the fingernails (first, second, and fourth fingers of the right hand) and both big toenails were also noted. Complete blood count, erythrocyte sedimentation rate, urinalysis, and serum levels of C-reactive protein, fasting glucose, liver enzymes, blood urea nitrogen, and creatinine were within normal limits. Serology was negative for antihuman immunodeficiency virus antibodies, and positive for antihepatitis C virus and antihepatitis B surface antigen antibodies. Potassium hydroxide preparations of scrapings of the toe webs and dystrophic nails showed septate hyphae. Samples from an excisional biopsy specimen S173
S174 Sec¸kin, Arıkan, and Haberal
Fig 1. Firm, nontender, dusky-red to purple tumor caused by Trichophyton rubrum.
of the tumoral lesion were sent for histopathologic study, and bacterial and fungal cultures. The histopathologic examination revealed pseudoepitheliomatous hyperplasia of the epidermis, and dense inflammatory infiltrate, focal microabscess formation, and extensive hemorrhage throughout the reticular dermis. The infiltration was not associated with hair follicles. The microabscesses featured polymorphonuclear leukocytes and nuclear debris at their center, and histiocytes and multinuclear giant cells at the periphery. Some of the giant cells had engulfed clear globular material, which periodic acid-Schiff staining confirmed was a fungal structure. Multiple swollen, thick-walled, periodic acidSchiff—positive, septate hyphae were also observed in the extracellular component of the dermis (Fig 2). Deep fungal infection, including dermatophytosis, was suggested. The patient was started on oral terbinafine (250 mg/d); however, 2 weeks later he was readmitted because of pain and diminished vision in his left eye. Fundoscopic examination revealed a plaque lesion suggestive of fungal endophthalmitis. Terbinafine was discontinued, and empirical treatment with intravenous liposomal amphotericin B (3 mg/kg/d) and an intravitreal injection of amphotericin B were administered for probable invasive fungal infection of the eye. The patient became febrile on the third day in hospital. A chest radiograph showed diffuse patchy infiltration of both lungs. Thoracic computed tomography demonstrated a 3-cm diameter solid mass in the basal segment of the left lung. Neurologic examination revealed weakness of the left lower limb and diminished consciousness. Magnetic resonance imaging showed multiple brain abscesses (Fig 3). The patient’s clinical condition worsened; he developed generalized seizures and was placed on antiepileptic therapy. A vitreous sample was obtained by fine-needle aspiration, and modified acid-fast staining of this material showed delicate, long, thin, branching, and
J AM ACAD DERMATOL NOVEMBER 2004
Fig 2. Thick-walled, short, swollen septate hyphae and sporelike organisms in reticular dermis. (Periodic acidSchiff stain; original magnification: 340.)
weakly acid-fast filaments characteristic of Nocardia species (Fig 4). A sample of vitreous and a blood culture both grew N asteroides. The patient was given the diagnosis of disseminated nocardiosis featuring multiorgan involvement, namely, ophthalmic, pulmonary, and central nervous system lesions. Tacrolimus, azathioprine, and amphotericin B were discontinued. The immunosuppressive therapy was continued with prednisolone and combination antimicrobial therapy with trimethoprim-sulfamethoxazole, amikacin, and cefotaxime was initiated. The patient’s clinical status improved dramatically in the first week, and 2 weeks later he was discharged from hospital. One month after initial presentation, fungal cultures of the skin tumor and the nail and toe-web scrapings grew T rubrum (Fig 5). This confirmed the diagnoses of deep dermatophytosis for the skin tumor, and tinea unguium and tinea pedis. After discharge, the patient continued to receive long-term treatment for nocardiosis with trimethoprim-sulfamethoxazole, amikacin, and imipenem. Amikacin was stopped after 3 months, as a result of ototoxicity. Trimethoprim-sulfamethoxazole was discontinued in the fifth month because of elevated liver enzymes, and imipenem was switched to meropenem at this stage as well. After 7 months of therapy, the lesions in the lungs and central nervous system were almost completely resolved. The nocardiosis therapy was stopped after 12 months. In July 2002, cyclosporine and mycophenolate mofetil were added to the immunosuppressive treatment with prednisolone. Three years after his first admission, the patient remains free of disease but is totally blind in his left eye.
DISCUSSION Dermatophyte infections can present in various atypical ways. These presentations include different types of subcutaneous and deep dermal lesions
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Sec¸kin, Arıkan, and Haberal S175
Fig 4. Modified acid-fast staining of vitreous specimen. Note long, thin, branching, weakly acid-fast filaments characteristic of Nocardia species. (Original magnification: 3600.) Fig 3. Magnetic resonance imaging shows brain abscess in patient’s left parietal lobe.
(papules,5,9,10 nodules,3,5,10 plaques,3,5 cellulitis,11 abscesses,4,12 draining sinuses,13 verrucous lesions,14 blastomycosis-like lesions15) and, rarely, lymphogenous or hematogenous extension.16 Such atypical features are mostly encountered in individuals who are immunocompromised.3-5 T rubrum is the causal agent in most cases of deep dermatophytosis.3 Patients with deep dermatophytosis usually have concurrent chronic superficial dermatophyte infection, such as tinea unguium, which suggests autoinoculation in the pathogenesis.3,4,15 Clinical, pathologic, and microbiologic diagnosis of deep dermatophytosis in individuals who are immunocompromised can be difficult.3,4,9,15,17,18 Our patient initially presented with a red-purple tumoral lesion, so we initially suspected a neoplastic condition (cutaneous lymphoma or Kaposi’s sarcoma) or a deep fungal infection like cutaneous aspergillosis. When histopathologic examination revealed multiple septate hyphae in the dermis, our focus was a deep fungal infection, such as dermatophytosis. However, as has been noted previously in the literature on deep dermatophytosis,9-12,15 instead of the typical slender hyphae found in the stratum corneum in superficial dermatophytosis, the hyphae in our patient’s dermis were thicker, shorter, and thick-walled. The isolated T rubrum also had unusual microbiologic properties, and was difficult to identify. Early on, the growth on fungal culture featured hyphae with occasional septae and rare microconia. To induce sporulation, we subcultured the strain to several different types of complex media. However, sporulation took a full 2 weeks, and relatively few teardrop-shaped microconidia were produced. The isolated strain also produced pigment late. Such unusual morphologic features might reflect adaptations that allow der-
Fig 5. Microscopic examination of Trichophyton rubrum colonies from skin tumor: Note teardrop-shaped microconidia borne laterally along sides of hyphae. (Lactophenol cotton blue mounting; original magnification: 3400.)
matophytes to survive in deep dermal and subcutaneous locations.11 Nocardiosis is a rare suppurative infection that is most often caused by N asteroides, a delicate, branching, gram-positive, acid-fast micro-organism.6 The majority of nocardiosis cases are septicemic infections, usually of pulmonary origin, in patients who are immunocompromised. Dissemination from the lung to the brain, skin and soft tissue, and other organs occurs in up to 50% of cases.7,8 Ocular involvement is uncommon but remains a valuable clue to diagnosis of endogenous infection,8 as was the case with our patient. Of renal transplant recipients, 10% develop dual infections.19 Nocardiosis has been reported to occur simultaneously with other opportunistic infections.19,20 Therefore, attempts to establish a single diagnosis that explains multisystemic findings in a patient who is immunocompromised can sometimes be misleading. One should keep a high index of suspicion for simultaneous infections in this patient group, and to identify the causal pathogens completely. With improved immunosuppression and early allograft survival, chronic allograft nephropathy
S176 Sec¸kin, Arıkan, and Haberal
has become the dominant cause of kidney transplant failure. Currently, the 5- and 10-year graft survival for cadaver donor transplants are 61.3% and 35.8%, respectively.21 The biopsy specimen—proven chronic allograft nephropathy in our patient was attributed to the impact of possible subclinical acute rejections, atherosclerosis, or both. Our patient developed deep dermatophytosis and disseminated nocardiosis 16 years posttransplantation. Both infections arose soon after he had undergone rescue therapy for chronic allograft rejection. It is likely that development of these infections was somehow related to pulse-corticosteroid therapy, the switch from cyclosporine to tacrolimus immunosuppression, or both. Tacrolimus is a more potent immunosuppressive than cyclosporine.22,23 Although the data are controversial,24 some studies have indicated a trend toward higher frequency of infection in kidney25 and heart26 transplant recipients receiving tacrolimus than in the ones using cyclosporine. Currently, whether or not tacrolimus represents a greater risk for deep dermatophytosis and nocardiosis than other immunosuppressive regimens is not known. However, isolated case reports of both deep dermatophytosis27 and Nocardia28 infections under tacrolimus therapy have recently been published. For this reason, it is important to bear in mind that newer and more potent immunosuppressive regimens may increase the risk of opportunistic infection in transplant recipients. We thank Dr Beyhan Demirhan and Dr Muhtesxem Agˇıldere for providing histopathologic and radiologic figures of the patient. REFERENCES 1. Abel AA. Cutaneous manifestations of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989;21: 167-79. 2. Sec¸kin D, Ogˇuz Gu¨lec¸ T, Demiragˇ A, Bilgin N. Renal transplantation and skin diseases. Transplant Proc 1998;30:802-4. 3. Chastain MA, Reed RJ, Pankey GA. Deep dermatophytosis: report of two cases and review of the literature. Cutis 2001;67: 457-62. 4. Novick NL, Tapia L, Bottone EJ. Invasive Trichophyton rubrum infection in an immunocompromised host: case report and review of the literature. Am J Med 1987;82:321-5. 5. Elewski BE, Sullivan J. Dermatophytes as opportunistic pathogens. J Am Acad Dermatol 1994;30:1021-2. 6. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol Rev 1994;7:357-417. 7. Arduino RC, Johnson PC, Miranda AG. Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine. Clin Infect Dis 1993;16:505-12. 8. Tan SY, Tan LH, Teo SM, Thiruventhiran T, Kamarulzaman A, Hoh HB. Disseminated nocardiosis with bilateral intraocular involvement in a renal allograft patient. Transplant Proc 2000; 32:1965-6.
J AM ACAD DERMATOL NOVEMBER 2004
9. Radentz WH, Yanase DJ. Papular lesions in an immunocompromised patient: Trichophyton rubrum granulomas (Majocchi’s granuloma). Arch Dermatol 1993;129:1189-93. 10. Tsang P, Hopkins T, Jimenez-Lucho V. Deep dermatophytosis caused by Trichophyton rubrum in a patient with AIDS. J Am Acad Dermatol 1996;34:1090-1. 11. Smith KJ, Neafie RC, Skelton HG III, Barrett TL, Graham JH, Lupton GP. Majocchi’s granuloma. J Cutan Pathol 1991;18: 28-35. 12. Faergemann J, Gissle´n H, Dahlberg E, Westin J, Roupe G. Trichophyton rubrum abscesses in immunocompromised patients. Acta Derm Venereol 1989;69:244-7. 13. Franco RC. Deep dermatophytosis in a post-transplant recipient. Int J Dermatol 2001;40:363-4. 14. Grossman ME, Pappert AS, Garzon MC, Silvers DN. Invasive Trichophyton rubrum infection in the immunocompromised host: report of three cases. J Am Acad Dermatol 1995;33:315-8. 15. Squeo RF, Beer R, Silvers D, Weitzman I, Grossman M. Invasive Trichophyton rubrum resembling blastomycosis infection in the immunocompromised host. J Am Acad Dermatol 1998;39: 379-80. 16. Hironaga M, Okazaki N, Saito K, Watanabe S. Trichophyton mentagrophytes granulomas: unique systemic dissemination to lymph nodes, testes, vertebrae, and brain. Arch Dermatol 1983;119:482-90. 17. Sommer S, Barton RC, Wilkinson SM, Merchant WJ, Evans EGV, Moore MK. Microbiological and molecular diagnosis of deep localized cutaneous infection with Trichophyton mentagrophytes. Br J Dermatol 1999;141:323-5. 18. King D, Cheever LW, Hood A, Horn TD, Rinaldi MG, Merz WG. Primary invasive cutaneous Microsporum canis infections in immunocompromised patients. J Clin Microbiol 1996;34:460-2. 19. Scully RE, Mark EJ, McNeely WF, Ebeling SH, Ellender SM, Peters CC. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises, case 29-2000. N Engl J Med 2000;343:870-7. 20. McCown HF, Sahn EE. Subcutaneous phaeohyphomycosis and nocardiosis in a kidney transplant patient. J Am Acad Dermatol 1997;36:863-6. 21. Djamali A, Premasathian N, Pirsch JD. Outcomes in kidney transplantation. Semin Nephrol 2003;23:306-16. 22. Trompeter R, Filler G, Webb NJA, Watson AR, Milford DV, Tyden G, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002;17:141-9. 23. Yagˇmurdur MC, Sevmis S, Emirogˇlu R, Moray G, Bilgin N, Haberal M. Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients. Transplant Proc 2003;36:144-7. 24. Kusne S, Martin M, Shapiro R, Jordan M, Fung J, Alessiani A, et al. Early infections in kidney transplant recipients under FK 506. Transplant Proc 1991;23:956-7. 25. Abbott KC, Hypolite I, Poropatich RK, Hshieh P, Cruess D, Hawkes CA, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001;3:203-11. 26. Peraira JR, Segovia J, Arroyo R, Ortiz P, Fuertes B, Mo~ nivas V, et al. High incidence of severe infections in heart transplant recipients receiving tacrolimus. Transplant Proc 2003;35:1999-2000. 27. Sequeira M, Burdick AE, Elgart GW, Berman B. New-onset Majocchi’s granuloma in two kidney transplant recipients under tacrolimus treatment. J Am Acad Dermatol 1998;38:486-8. 28. Wong KM, Chak WL, Chan YH, Choi KS, Chau KF, Lee KC, et al. Subcutaneous nodules attributed to nocardiosis in a renal transplant recipient on tacrolimus therapy. Am J Nephrol 2000;20:138-41.