Dematiaceous Fungal Infections in Kidney Transplant Recipients – Case Series

Abstract

This retrospective, single-center study analyzed the clinical profile and outcomes of dematiaceous fungal infections in kidney transplant recipients over a 12-year period (2010–2022). Out of 1,041 transplant recipients, 69 developed major fungal infections, with dematiaceous fungi accounting for 8.6% of cases (n=6). These infections affected predominantly middle-aged adults (mean age 47 ± 13.1 years), with a slight male predominance. Most patients received kidneys from live-related donors and were maintained on standard immunosuppressive regimens. Dematiaceous fungal infections manifested on average 3.43 ± 1.8 years post-transplant, presenting as skin lesions, arthritis, or sinusitis. Diagnosis was confirmed through culture and histopathology, revealing phaeohyphomycosis in most cases. Management included long-term oral itraconazole therapy with regular monitoring; only one patient experienced a recurrence after five years. The findings underscore the need for heightened clinical suspicion in transplant recipients presenting with atypical skin or joint lesions, and highlight the importance of early microbiological and histopathological assessment. Prompt antifungal therapy, often alongside surgical intervention, is essential to prevent disease progression.

Introduction

Dematiaceous fungi are rare, pigmented fungi with primarily two clinicopathological groups, chromoblastomycosis and phaeohyphomycosis that represent extremes of a continuum of infections.^[1] Pigmented fungi may also produce mycetomas, which are tumefactive lesions with draining sinuses and the presence of grains in the tissue. They are prevalent in tropical and subtropical areas and are found in soil and decaying vegetable matter.^[2] The clinical presentation ranges from mild superficial cutaneous lesions to deep-seated organ involvement and invasive disease, including pulmonary, sinus, and bloodstream infections, more so in immuno-compromised individuals. In this retrospective study, we describe six cases of kidney transplant recipients with dematiaceous fungal infections over a period of 12 years at our center.

Case Series

Case 1

A 57-year-old male patient underwent live-related ABO-compatible kidney transplantation in 2006. His native kidney disease was primary focal segmental glomerulo sclerosis. He received basiliximab induction followed by maintenance immunosuppression with prednisolone/Cyclosporine (CsA) and azathioprine (AZA). He had developed posttransplant diabetes within 1 year of transplant and had no rejections. He had stable graft function with mean serum creatinine 1.8 ± 0.9 mg/dl. At 7 years of posttransplant, he developed recurrent left great toe infection with pus discharge which showed no response to antibiotics. The CsA trough level (C0) was 180.2 ng/ml at the time of infection. He underwent debridement. The pus grew dematiaceous fungi, and the skin biopsy showed phaeohypomycosis. He has received oral antifungal, itraconazole for 3 years as there was a recurrence of symptoms. The drug level was monitored during Itraconazole therapy. He showed clinical improvement for fungal infection with no other recurrences. However, he developed end-stage kidney disease in 2024 due to graft failure caused by diabetic nephropathy and required initiation of hemodialysis.

Case 2

A 43-year-old women, underwent live-related ABO compatible kidney transplantation in 2008. The native kidney disease was unknown. She received basiliximab induction followed by maintenance immunosuppression with Prednisolone/CsA and Mycophenolate (MPA) Mofetil. He had no history of rejections and other posttransplant complications. She had stable graft function with mean serum creatinine 0.9 ± 0.43 mg/dl. She presented one year after transplantation, with 1-month history of nasal discharge and headache, which was not responded to anti-histaminics and anti-pyretics. On further evaluation, she was diagnosed with left maxillary sinusitis and underwent functional endoscopic sinus surgery. The aspirated from sinus and nasal swab grew dematiaceous fungus (EXSEROHILUM ROSTRATUM). The CsA trough (C0) level at the time of infection was 210.5 ng/ml, and the MPA area under the curve (AUC) was 58.82 mg.h/L, which was slightly on the higher side. She was treated with itraconazole, along with a reduction of MPA dose and close monitoring of CsA C0 level. She required 6 months of oral antifungal therapy and showed complete clinical improvement. She had stable graft function throughout the curse of illness with mean serum creatinine 1.2 ± 0.5 mg/dl.

Case 3

A 59-year-old woman underwent a deceased donor kidney transplant in 2010. She received antithymocyte globulin (ATG) as induction, followed by maintenance immunosuppression with prednisolone, tacrolimus (Tac), and MPA. Her native kidney disease was unknown. She had stable graft function and no posttransplant complications. She presented after 9 years of posttransplant with complaints of erythematous macular lesions over her left elbow. The tissue cultures grew dematiaceous fungi. She received itraconazole therapy for 12 months with close monitoring of Tac Co. The Tac trough level (Co) was 7.8 ng/ml, and MPA AUC was 50.2 mg.h/L. She had stable graft function throughout the curse of illness with mean serum creatinine 1.42 ± 0.6 mg/dl.

Case 4

A 44-year-old male patient underwent live-related ABO compatible kidney transplantation in 2015 with pretransplant positive B-cell flow cross-match with class II donor-specific antibodies positive with mean fluorescence intensity (MFI) 1382. He did not receive any desensitization in view of low MFI. He received ATG as induction, followed by maintenance immunosuppression with prednisolone, Tac, and MPA. The native kidney disease was probable chronic pyelonephritis. At 2 years’ posttransplant, he presented with complaints of right knee joint swelling associated with pain and purulent. The pus swab grew dematacious fungi and was treated with itraconazole for 12 months along with a reduction of MPA and close monitoring of Tac Co. At the time of infection, the Tac tough level (Co) was 6.8 ng/ml and MPA AUC was 54.2 mg.h/L. After 5 years, he presented with swelling of the left ankle with purulent discharge. He was required antifungal therapy with itraconazole for 24 months. He had stable graft function throughout the curse of illness with mean serum creatinine 1.3 ± 0.6 mg/dl. He had no other posttransplant complications.

Case 5

A 55-year-old man underwent ABO incompatible kidney transplantation in 2015 and received rituximab and 3 sessions of plasmapheresis as a part of the desensitization protocol. His native kidney disease was unknown. He received basiliximab induction followed by maintenance immunosuppression with prednisolone/CsA and MPA mofetil. However, the MPA was stopped within 4 months due to persistent leucopenia. At 5 months of posttransplant, he developed nonpruritic maculopapular rash over both legs and underwent skin biopsy, which was suggestive of phaeohypomyosis. The Tac Co at the time of infection was 6.9 ng/ml. He required 6 months of Itraconazole therapy. He had stable graft function throughout the curse of illness with mean serum creatinine 1.48 ± 0.3 mg/dl. He had no other posttransplant complications.

Case 6

A 24-year-old male patient underwent ABO incompatible kidney transplantation in 2022 and received rituximab and 3 sessions of plasmapheresis as a part of the desensitization protocol. His native kidney disease was refractory primary membranous nephropathy. He received basiliximab induction followed by maintenance immunosuppression with prednisolone, Tac, and MPA Mofetil. At 1-year, posttransplant, he developed painful soft swelling over his left foot and underwent an excision biopsy which showed phaeohypomycosis. The Tac trough level (Co) was 8.8 ng/ml, and MPA AUC was 48.5 mg.h/L. He received 6 months of itraconazole therapy along with monitoring of Tac Co. He had stable graft function throughout the course of illness with mean serum creatinine 1.32 ± 0.6 mg/dl. He had no other posttransplant complications.

Skin biopsies [Figure 1a-c] showed granulomatous inflammation, associated with suppuration, containing both yeast and hyphae forms of fungi, highlighted by periodic acid-schiff (PAS) and grocott-gomori methenamine sliver (GMS). The fungi were noted within areas of suppuration and also in the multinucleate giant cells. The patient described in case 5 showed histiocytic aggregates and epithelioid granulomas were not appreciable, as shown in Figure 1d-f. In the patient who had fungal sinusitis, the dematiaceous fungi were seen lying separately without any granulomas.

Figure 1.

(a) (×40, H and E) and (b) (×100, H and E): Granulomatous inflammation (arrow) and cyst with suppuration. (c) (×400, PAS): Fungal hyphae within suppuration and multinucleate giant cell (arrow). (d) (×40, H and E) and (e) (×100, H and E): Fibrotic cyst wall lined by histiocytic aggregates (arrow) and central suppuration. (f) (×400, GMS): Fungal hyphae within the cyst

Discussion

Dematiaceous fungi are rare infections, constituting around 2.5% of all invasive fungal infections in solid organ transplant recipients. They usually present as superficial localized cutaneous and subcutaneous diseases, though immunocompromised individuals are at an increased risk of developing subsequent dissemination.^[3,4] It is difficult to determine the incidence of phaeohyphomycosis in solid organ transplant patients because of the rarity of the disease, and previous studies are limited to case reports and retrospective studies.^[5] The increasing trend was observed in recent years due to increased transplantation rates, resulting in increasing numbers of immunosuppressed patients who are at risk for such opportunistic infections due to advancements in laboratory diagnostics.

In dematiaceous fungi, lesions typically appear as isolated cysts or papules on exposed areas of the body, such as the forearm and hands, following trauma, especially in farmers. However, none of our patients are farmers and had no history of trauma, but one patient had uncontrolled hyperglycemia at the time of infection. The net state of immunosuppression at the time of infection along with environmental exposure, might be the probable reason for the development of infection in our patients.

In this study, the mean duration of time of development of infection posttransplant was 3.43 ± 1.8 years. One patient had a recurrence of infection at 5 years. The mean age of patients was 47 ± 13.1 years. The female-to-male ratio was 1:2. One patient received a deceased donor, and the remaining patients received live-related donor transplantation, whereas two patients received ABO-incompatible transplantation. The induction agent was ATG in two patients and basiliximab in four patients. The maintenance immunosuppression was prednisolone + Tac + MPA in three patients, prednisolone + Tac in one patient, prednislone + CsA + MPA in one patient, and prednisolone + CsA + azathioprone in one patient. The MPA AUC was 52.9 ± 4.5 mg.h/L. The mean serum creatinine at the time of infection was 1.6 ± 0.56 mg/dl.

In this case series, three patients had cutaneous involvement, which is the common presentation consistent with published literature.^[6,7] Two patients had joint involvement, which is an uncommon form of arthritis and hitherto described in case reports.^[8] Another rare form of presentation encountered was the involvement of maxillary sinus reported as case series^[9] and case report.^[10] The nasal biopsies in these studies (2.21%) showed the growth of Dematacious fungi (Alternaria spp. and Curvularia species). In our patient with fungal sinusitis, the species isolated was exserohilum rostratum.

Phaeohyphomycosis and Chromoblastocmycosis refer to chronic subcutaneous lesions caused by Dematiaceous or phaeoid fungi. The most common causative agents of phaeohyphomycosis include Alternaria species, Bipolaris species, Curvularia species, Exophiala jeaselmei, and Cladophialophora bantaiana. The most common causative agents of chromoblastocmycosis include Fonsecaea pedrosoi and Fonsecaea compacta, Phialophora verrucosa, Clasdosporium Carrionni, and Rhinocladiella aquaspersa. Both can be differentiated by the presence or absence of sclerotic bodies.^[11]

Phaehyphomycosis characteristically presents as a single circumscribed cyst or chronic abscess in the subcutis or lower dermis.^[12] The cyst wall shows fibrous tissue with chronic granulomatous reaction and multinucleate giant cells, with central necrotic debris admixed with neutrophils. The fungal elements are usually identified within the necrotic debris and the giant cells. Masson Fontana stain could be used to highlight the melanin pigment produced by the fungus, which is responsible for its brown color.^[12,13]

Phaeohyphomycosis can be differentiated from chromoblastomycosis, which produces round, thick-walled golden-brown sclerotic bodies (5–12 μm), intermediate forms between yeast and hyphae, with a tendency to stain with Ziehl–Neelsen and Wade–Fite stains.^[14] Chromoblastomycosis typically shows pseudo-epitheliomatous hyperplasia, intraepidermal microabscesses, and tuberculoid granulomas with suppuration.^[14] Rarely, phaeohyphomycosis may mimic chromoblastomycosis, as seen in one of our cases.^[15] When fungal pigmentation is subtle, phaeohyphomycosis may be mistaken for hyalohyphomycosis, but the latter has thin-walled hyphae, and faint pigmentation can be detected using oil immersion or Masson-Fontana stain. Another differential is mycetoma, which shares pigmentation but lacks the grain formation seen in mycetoma.^[16]

There are no standardized therapies for phaeohyphomycosis. The European Society of Clinical Microbiology and Infectious Diseases guidelines^[3] suggest voriconazole, posaconazole, and itraconazole as empirical therapy. In the TRANSNET cohort,^[17] the most used antifungal agent was voriconazole (44%), while in Schieffelin et al.’s review, itraconazole was the most used agent for skin lesions,^[18] but a combination of voriconazole andamphotericin B was preferred for disseminated disease. A surgical resection was performed. In Schieffelin et al.’s cohort, most of the patients received surgery (81%), not followed by antifungal therapy in 14% of the cases. Phaeohyphomycosis mortality is related to the dissemination of the disease and was reported 47% in the TRANSNET cohort, probably due to the greater proportion of disseminated disease. In our study, there was no mortality, and all patients responded to oral itraconazole with stable graft function.

In our case series, all patients received systemic oral antifungal monotherapy with oral Itraconazole 200 mg twice daily. In addition, three patients required surgical debridement. Three patients required 6 months of therapy, two patients required 12 months, and one patient required 36 months of therapy in view of recurrence. The dose of MPA and AZA was reduced to 50% during infection. The therapeutic drug monitoring for calcineurin inhibitors was done in view of significant drug interactions with Itraconazole. The liver function tests were monitored during antifungal therapy. All patients showed clinical improvement to oral itraconazole therapy, and only one patient had a recurrence of skin lesions at 5 years and required 1 year treatment with itraconazole. The demographics, transplant details, and treatment outcomes of patients are mentioned in Table 1.

Table 1. Demographic, transplant details, treatment out comes of kidney transplant patinets with dematiaceous fungal infections.

	Case-1	Case-2	Case-3	Case-4	Case-5	Case-6
Age (years)	57	43	59	44	55	24
Gender	Male	Female	Female	Male	Male	Male
NKD	Primary FSGS	Unknown	Unknown	CPN	Unknown	Unknown
Year of transplant	2006	2008	2010	2015	2015	2022
Type of transplant	Live related	Live related	Deceased	Live related	Live related	Live related
And ABO compatibility	compatible	compatible	Compatible	Compatible	Incompatible	Incompatible
Induction agent	Basiliximab	Basilixilmab	ATG	ATG	Basilixilmab	Basilixilmab
Maintenance Immunosuppression	P/CsA/AZA	P/cSA/MPA	P/Tac/MPA	P/Tac/MPA	P/Tac	P/Tac/MPA
Posttransplant complications	PTDM	Nil	Nil	Nil	Nil	Nil
Timing of infection since transplant (years)	7	1	9	2	0.58 Recurrence at 5 years	1
Site of infection	Left great toe	Left maxillary sinus	Left elbow joint	Right knee and left ankle joints	Bilateral legs	Left foot
Biopsy findings	Suppurative granulomatous inflammation with pigmented septate hyphae-s/o phaeohyphomycosis except in patient with sinus involvement where fungal organisms were noted without accompanying granulomatous inflammation
Graft function At the time of infection	Stable	Stable	Stable	Stable	Stable	Stable
Antifungal used and duration of treatement	Itraconazole 36 months Surgical debridement	Itraconazole 6 months Surgical debridement	Itraconazole 12 months	Itraconazole 12 months Surgical debridement	Itraconazole 6 months	Itraconazole 6 months Surgical debridement
Long term graft function	Lost graft at 18 years of transplant due to diabetic nephropathy	Stable graft function	Stable graft function	Stable graft function	Stable graft function	Stable graft function

ATG: Anti thymocyte globulin, CPN: Chronic pyelonephritis, CsA: Cyclosporine, FSGS: Focal Segmental glomerulo sclerosis, MPA: Mycophenolate acid, P: Pred, PTDM: Posttransplant diabetes mellitus, Tac: Tacrolimus, NKD: Native kidney disease

Conclusion

In solid organ transplant recipients with atypical cutaneous lesions, a skin biopsy should always be performed. The diagnosis relies on a high index of clinical suspicion paired with accurate laboratory investigations, including microbiology with fungal cultures and histology, to establish an etiologic diagnosis of rare fungal infection. An early diagnosis and appropriate anti-fungal therapy are of paramount importance in preventing the dissemination of disease, given the immunosuppressed state of the patients.