Deep dermatophytosis caused by Trichophytonrubrum with concomitant disseminated nocardiosis

in a renal transplant recipient

Deniz Seckin, 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 wasimmunosuppressed with deep dermatophytosis caused by Trichophyton rubrum and concurrentdisseminated nocardiosis. The infections occurred 16 years after the patient underwent renaltransplantation, and may have been related to tacrolimus therapy. ( J Am Acad Dermatol 2004;51:S173-6.)

Organ transplant recipients receive long-termimmunosuppressive therapy to help pre-vent graft rejection and are, therefore,

at increased risk for opportunistic infection.1,2

Dermatophytes are keratinophilic organisms, andmost dermatophytic infections are confined to thestratum corneum, hair, and nails. These organismsare not generally regarded as opportunisticpathogens; however, they do occasionally invadethe dermis, subcutaneous tissue, and internal visceralorgans and cause atypical aggressive infections,particularly in individuals who are immunocompro-mised.3-5 The current literature documents fewerthan 100 cases of deep dermatophytosis.

Nocardia species are ubiquitous environmentalsaprophytes that live in soil, organic matter, andwater.6 Nocardiosis is usually an opportunistic in-fection, and is an uncommon but important causeof 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 BasxkentUniversity Faculty of Medicine; and Department of Microbiol-

ogy, 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 Seckin, MD, Basxkent University Faculty

of Medicine, Department of Dermatology, 5. Sokak, No. 48,

Bahcelievler, 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 directinoculation of skin or soft tissues, or by inhalation.6-8

We describe a renal transplant recipient who haddeep dermatophytosis caused by Trichophytonrubrum and concurrent disseminated nocardiosis.To our knowledge, no such association in a patientwith renal transplant has been reported in theliterature to date.

CASE REPORTIn December 2000, a 45-year-old man was re-

ferred for evaluation of a mass on his left thigh thathad been present for 2 weeks. The patient hadundergone kidney transplantation 16 years earlier.He had no history of penetrating trauma or insectbite at the affected site. His immunosuppressivetreatment had consisted of prednisolone, azathio-prine, and cyclosporine until October 2000, when hehad experienced an episode of allograft rejection.This was treated with pulse-corticosteroid therapy,and the cyclosporine in his regimen was switched totacrolimus.

Dermatologic examination revealed a 2.5-cm di-ameter, well-demarcated, solitary, firm, nontender,dusky-red to purple tumor on the medial aspect ofthe patient’s left thigh (Fig 1). Interdigital toe-webmaceration, onychodystrophy, and discoloration ofthe fingernails (first, second, and fourth fingers of theright hand) and both big toenails were also noted.Complete blood count, erythrocyte sedimentationrate, urinalysis, and serum levels of C-reactive pro-tein, fasting glucose, liver enzymes, blood ureanitrogen, and creatinine were within normal limits.Serology was negative for antihuman immunodefi-ciency virus antibodies, and positive for antihepatitisC virus and antihepatitis B surface antigen antibodies.

Potassium hydroxide preparations of scrapings ofthe toe webs and dystrophic nails showed septatehyphae. Samples fromanexcisional biopsy specimen

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of the tumoral lesion were sent for histopathologicstudy, and bacterial and fungal cultures. The histo-pathologic examination revealed pseudoepithelio-matous hyperplasia of the epidermis, and denseinflammatory infiltrate, focal microabscess forma-tion, and extensive hemorrhage throughout thereticular dermis. The infiltration was not associatedwith hair follicles. Themicroabscesses featured poly-morphonuclear leukocytes and nuclear debris attheir center, and histiocytes and multinuclear giantcells at the periphery. Some of the giant cells hadengulfed clear globular material, which periodicacid-Schiff staining confirmed was a fungal structure.Multiple swollen, thick-walled, periodic acid-Schiff—positive, septate hyphae were also observedin the extracellular component of the dermis (Fig 2).Deep fungal infection, including dermatophytosis,was suggested.

The patient was started on oral terbinafine (250mg/d); however, 2 weeks later he was readmittedbecause of pain and diminished vision in his left eye.Fundoscopic examination revealed a plaque lesionsuggestive of fungal endophthalmitis. Terbinafinewas discontinued, and empirical treatment with in-travenous liposomal amphotericin B (3 mg/kg/d)and an intravitreal injection of amphotericin B wereadministered for probable invasive fungal infectionof the eye. The patient became febrile on the thirdday in hospital. A chest radiograph showed diffusepatchy infiltration of both lungs. Thoracic computedtomography demonstrated a 3-cm diameter solidmass in the basal segment of the left lung. Neurologicexamination revealed weakness of the left lowerlimb and diminished consciousness. Magnetic reso-nance imaging showed multiple brain abscesses (Fig3). The patient’s clinical condition worsened; hedeveloped generalized seizures and was placed onantiepileptic therapy.

A vitreous sample was obtained by fine-needleaspiration, and modified acid-fast staining of thismaterial showed delicate, long, thin, branching, and

Fig 1. Firm, nontender, dusky-red to purple tumor causedby Trichophyton rubrum.

weakly acid-fast filaments characteristic of Nocardiaspecies (Fig 4). A sample of vitreous and a bloodculture both grewNasteroides. The patient was giventhe diagnosis of disseminated nocardiosis featuringmultiorgan involvement, namely, ophthalmic, pul-monary, and central nervous system lesions.Tacrolimus, azathioprine, and amphotericin B werediscontinued. The immunosuppressive therapy wascontinued with prednisolone and combination anti-microbial therapy with trimethoprim-sulfametho-xazole, amikacin, and cefotaxime was initiated. Thepatient’s clinical status improved dramatically in thefirst week, and 2 weeks later he was discharged fromhospital.

One month after initial presentation, fungalcultures of the skin tumor and the nail and toe-webscrapings grew T rubrum (Fig 5). This confirmed thediagnoses of deep dermatophytosis for the skintumor, and tinea unguium and tinea pedis.

After discharge, the patient continued to receivelong-term treatment for nocardiosis with trimetho-prim-sulfamethoxazole, amikacin, and imipenem.Amikacin was stopped after 3 months, as a resultof ototoxicity. Trimethoprim-sulfamethoxazole wasdiscontinued in the fifth month because of elevatedliver enzymes, and imipenem was switched to mer-openem at this stage as well. After 7 months oftherapy, the lesions in the lungs and central nervoussystem were almost completely resolved. Thenocardiosis therapy was stopped after 12 months.In July 2002, cyclosporine and mycophenolatemofetil were added to the immunosuppressive treat-ment with prednisolone. Three years after his firstadmission, the patient remains free of disease but istotally blind in his left eye.

DISCUSSIONDermatophyte infections can present in various

atypical ways. These presentations include differenttypes of subcutaneous and deep dermal lesions

Fig 2. Thick-walled, short, swollen septate hyphae andsporelike organisms in reticular dermis. (Periodic acid-Schiff stain; original magnification: 340.)

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(papules,5,9,10 nodules,3,5,10 plaques,3,5 cellulitis,11

abscesses,4,12 draining sinuses,13 verrucous le-sions,14 blastomycosis-like lesions15) and, rarely,lymphogenous or hematogenous extension.16 Suchatypical features are mostly encountered in individ-uals who are immunocompromised.3-5 T rubrum isthe causal agent in most cases of deep derma-tophytosis.3 Patients with deep dermatophytosisusually have concurrent chronic superficial derma-tophyte infection, such as tinea unguium, whichsuggests autoinoculation in the pathogenesis.3,4,15

Clinical, pathologic, and microbiologic diagnosisof deep dermatophytosis in individuals who areimmunocompromised can be difficult.3,4,9,15,17,18

Our patient initially presented with a red-purpletumoral lesion, so we initially suspected a neoplasticcondition (cutaneous lymphoma or Kaposi’s sar-coma) or a deep fungal infection like cutaneousaspergillosis. When histopathologic examinationrevealed multiple septate hyphae in the dermis,our focus was a deep fungal infection, such asdermatophytosis. However, as has been notedpreviously in the literature on deep dermatophyto-sis,9-12,15 instead of the typical slender hyphae foundin the stratum corneum in superficial dermatophyto-sis, the hyphae in our patient’s dermis were thicker,shorter, and thick-walled. The isolated T rubrum alsohad unusual microbiologic properties, and wasdifficult to identify. Early on, the growth on fungalculture featured hyphae with occasional septae andrare microconia. To induce sporulation, we sub-cultured the strain to several different types ofcomplex media. However, sporulation took a full 2weeks, and relatively few teardrop-shaped micro-conidia were produced. The isolated strain alsoproduced pigment late. Such unusual morphologicfeatures might reflect adaptations that allow der-

Fig 3. Magnetic resonance imaging shows brain abscessin patient’s left parietal lobe.

matophytes to survive in deep dermal and subcuta-neous locations.11

Nocardiosis is a rare suppurative infection that ismost often caused by N asteroides, a delicate,branching, gram-positive, acid-fast micro-organism.6

The majority of nocardiosis cases are septicemicinfections, usually of pulmonary origin, in patientswho are immunocompromised. Dissemination fromthe lung to the brain, skin and soft tissue, and otherorgans occurs in up to 50% of cases.7,8 Ocularinvolvement is uncommon but remains a valuableclue to diagnosis of endogenous infection,8 as wasthe case with our patient.

Of renal transplant recipients, 10% develop dualinfections.19 Nocardiosis has been reported to oc-cur simultaneously with other opportunistic in-fections.19,20 Therefore, attempts to establish a singlediagnosis that explains multisystemic findings ina patient who is immunocompromised can some-times be misleading. One should keep a high indexof suspicion for simultaneous infections in thispatient group, and to identify the causal pathogenscompletely.

With improved immunosuppression and earlyallograft survival, chronic allograft nephropathy

Fig 4. Modified acid-fast staining of vitreous specimen.Note long, thin, branching, weakly acid-fast filamentscharacteristic of Nocardia species. (Original magnification:3600.)

Fig 5. Microscopic examination of Trichophyton rubrumcolonies from skin tumor: Note teardrop-shaped micro-conidia borne laterally along sides of hyphae. (Lactophe-nol cotton blue mounting; original magnification: 3400.)

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has become the dominant cause of kidney trans-plant failure. Currently, the 5- and 10-year graft survi-val for cadaver donor transplants are 61.3% and35.8%, respectively.21 The biopsy specimen—provenchronic allograft nephropathy in our patient wasattributed to the impact of possible subclinical acuterejections, atherosclerosis, or both. Our patient de-veloped deep dermatophytosis and disseminatednocardiosis 16 years posttransplantation. Both in-fections arose soon after he had undergone rescuetherapy for chronic allograft rejection. It is likely thatdevelopment of these infections was somehow re-lated to pulse-corticosteroid therapy, the switch fromcyclosporine to tacrolimus immunosuppression, orboth. Tacrolimus is a more potent immunosuppres-sive than cyclosporine.22,23 Although the data arecontroversial,24 some studies have indicated a trendtoward higher frequency of infection in kidney25 andheart26 transplant recipients receiving tacrolimusthan in the ones using cyclosporine. Currently,whether or not tacrolimus represents a greater riskfor deep dermatophytosis and nocardiosis than otherimmunosuppressive regimens is not known.However, isolated case reports of both deep der-matophytosis27 and Nocardia28 infections undertacrolimus therapy have recently been published.For this reason, it is important to bear in mind thatnewer and more potent immunosuppressive reg-imens may increase the risk of opportunistic infec-tion in transplant recipients.

We thank Dr Beyhan Demirhan and Dr MuhtesxemAgıldere for providing histopathologic and radiologicfigures of the patient.

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