Trichophyton rubrum-induced Majocchi’s Granuloma in a heart transplant recipient. A therapeutic challenge.

Abstract

Background

Solid organ transplant recipients are at an increased risk for infections because of long-term immunosuppression to prevent graft rejection. Fungal infections with dermatophytes are a common cause of cutaneous infections seen in organ transplant recipients and cutaneous dermatophyte infections may progress to Majocchi’s granuloma. Itraconazole is an anti-fungal compound used for the treatment of infections of the skin, nails and mucous membranes.

Main observation

We report on a heart transplant recipient who developed widespread Trichophyton rubrum infection presenting as Majocchi’s granuloma. Itraconazole treatment was complicated by drug interactions. Tricho­phyton rubrum infection progressed, while itraconazole treatment was varied in dose and delivery form.

Conclusions

In patients with Trichophyton rubrum infections, refractory to itraconazole treatment, altered drug absorption or drug interactions has to be considered. Careful monitoring and adjustment of itraconazole is of vital importance.

Introduction

Solid organ transplant recipients (OTRs) are exposed to severe infections because of immuno­suppressive drug regimens to prevent graft rejection. Fungal infections with dermatophytes are common seen in OTRs.[1]

Due to impaired cell-mediated immunity, cutaneous fungal infection may penetrate deep into the skin and induce a pronounced inflam­matory reaction resulting in granulomatous skin disease, or in systemic spread.

Case Report

A 49-year-old male underwent heart trans­plantation two years ago because of cardio­myopathy. Immuno­suppression consisted of Prednisone, Azathio­prine and Tacro­limus. The patient was referred to the depart­ment of dermatology with newly diagno­sed papulo­nodular lesions of the dorsal aspects of both feet [Fig. 1].

Figure 1.

The back of both feet with brownish-red plaques with an infiltrated peripheral rim and peripheral scaling. In the central parts of these plaques, atrophic wrinkling of the epidermis becomes apparent. On the dorsal aspects of certain toes, dark red to brown nodules with or without erosions are seen. Nails are dystrophic and onycholytic.

Clinical examination, histology and mycology of the lesional biopsy revealed a Tricho­phytum rubrum induced Majocchi’s granuloma [Fig. 2].

Figure 2.

Pseudoepitheliomatous hyperplasia of the epidermis and extensive, poorly formed granulomas (A). Lympho­histiocytic cells with focal collections of neutrophils (B). The PAS stain reveals an abun­dance of strikingly pleomorphic segmented hyphae and arthro­spores (C).

Treatment with itraco­nazole capsules 100 mg bid was started. After 8 weeks new sporotrichoid skin lesions developed. As serum levels of itraco­nazole were found below 100 ng/ml, the dose was increased to 300 mg daily. The formulation was switched from capsules to an intra­venous preparation and then to the peroral solution with higher bio­availability. Within 10 days, a clinical improve­ment was seen, but Tacrolimus plasma levels rose from 5.9 ug/l to 21.8 ug/l, enhancing immuno­sup­pression. Dose reduction reestablished the therapeutic range (8.7 ug/l).

At the same time the patient became septic due to Staphylo­coccus aureus. Treat­ment with Floxacillin and Rifampicin was initiated affecting anti­fungal and immu­no­sup­pres­sive therapy, keeping itraco­nazole plasma levels below 100 ng/ml and reducing plasma levels of Tacrolimus < 2.5 ug/l.

Discussion

The common clinical presentation of cutaneous fungal infection is tinea corporis with super­ficial dermal inflam­mation. Deep skin- penetration of fungal agents may induce an inflam­matory granulo­matous skin reaction first described by Majocchi.[2] From two forms distinguished, the deep subcuta­neous form is seen in immunosuppressed individuals. Tricho­phyton rubrum is commonly associated with Majocchi’s granuloma.[3] Diagnosis is confirmed by skin histology with PAS staining and tissue culture. Systemical treatment is mandatory. The preferred drug is itraconazole because it accu­mulates in skin appendages.[4]

In the described patient clinical symptoms were refractory to itraco­nazole for several reasons: Initially the dose of itraco­nazole was too low and absorption was diminished as itraco­nazole needs a low gastric pH and a high-fat meal for optimal absorption.[5] Our patient was intermittently on proton- pump inhibitors and was unable to follow dietary recommen­da­tions.

As itraconazole inhibits CYP3A4, plasma levels of Tacro­limus rose, enhancing immuno­suppression and susceptibility for infections.

In sepsis, treatment with Rifampicin, a strong inducer of CYP3A4, kept itraconazole plasma concentrations below 100 ng/ml in spite of rising the dose and induced a decrease of Tacrolimus plasma levels.

Conclusion

In severely ill patients on multiple drug regimens, careful monitoring and adjustment of prescribed drugs is of vital importance because of drug interactions and different absorption and bioavaiability depending on the application form.

No definitive correlation exists between itraconazole serum levels and efficacy or toxicity.[5] Determination of itraconazole serum levels may provide more information of the threshold level for successful therapy.