Photo Quiz: Treatment-resistant rash in cardiac transplant patient

PHOTO QUIZ 

A 48-year-old man of southeastern Indian descent was admitted to the hospital for treatment of non-ischemic cardiomyopathy and cardiogenic shock. While admitted, the dermatology service was consulted for a pruritic rash present for about 1 year. The rash had previously been managed by an outpatient dermatology clinic; although the patient was unsure of the working diagnosis or medications he was prescribed. The symptoms reportedly improved until he received systemic corticosteroids for suspected cardiac sarcoidosis, which was later ruled out. Upon clinical examination, several brown, scaly plaques, some atrophic and annular, were noted to the face, chest, and bilateral upper and lower extremities (Fig. 1A).

Fig 1.

(A) Representative skin lesion from the left forearm, area from which a biopsy was taken. (B) Potato flake agar subculture from right leg fungal culture showing white to tan fluffy and granular colonies at day 13. (C) DTM/RSM biplate subculture from right leg fungal culture showing white, fluffy colonies with red media color change on DMT, and white, fluffy colonies with blue-green media color change on RSM. (D) PAS-stained histopathology from left forearm biopsy showing septate fungal hyphae within the stratum corneum. Magnification, ×400. (E–F) LPCB tape prep from potato flake agar subculture showing aleurioconidia, spindle-shaped, multi-cell macroconidia that narrow at the end, and septate and spiraled hyphae. Magnification, ×400. (G) LPCB slide culture from potato flake agar subculture showing round aleurioconidia, spindle-shaped macroconidia, and septate and spiraled hyphae. Magnification, ×400.

A biopsy from the left forearm revealed a scale containing aggregates of neutrophils and fungal hyphae, which were well-visualized on periodic acid-Schiff (PAS) stain (Fig. 1D). A subsequent fungal culture grew a few white colonies with tan reverse on inhibitory mold agar (Remel) and mycobiotic agar (Remel) at day 7 and was subcultured to potato flake (Remel), dermatophyte test media (DTM) (Remel), and a DermDuet II biplate consisting of DTM and rapid sporulating media (RSM) agars (Hardy Diagnostics) (Fig. 1B and C). A lactophenol cotton blue (LPCB) tape prep and slide culture prepared from potato flake agar subcultures showed round aleurioconidia in clusters, spindle-shaped, multi-cell macroconidia that narrow at the ends, and long septate hyphae with occasional spiral hyphae (Fig. 1E through G). The patient has since undergone a heart transplant and remains immunocompromised.

ANSWER TO PHOTO QUIZ

The skin biopsy and fungal culture results were characteristic of Trichophyton species. These findings include pruritic parakeratotic scale with fungal hyphae within the stratum corneum on biopsy; white, fluffy colonies on fungal culture agar and red color change on DTM; and round aleurioconidia, spindle-shaped, multi-cell macroconidia, and long septate and spiral hyphae on LPCB tape prep and slide culture from potato flake agar subcultures. A urease test performed on the isolate returned a negative result. Prior to identification and susceptibility testing, our patient was treated with topical and oral terbinafine, oral fluconazole, and topical ketoconazole for 4 weeks each with no response.

The severe and extensive rash refractory to terbinafine raised clinical suspicion for Trichophyton indotineae, a rare fungal pathogen requiring molecular sequencing to definitively diagnose. Sequencing of the ITS, LSU (D1/D2 domains), beta tubulin protein coding (TUB2) genes was performed as previously described (Fungus Testing Laboratory, UT Health San Antonio) (1). T. indotineae showed as top matches from BLASTn searches with ITS and TUB2 in GenBank. This was confirmed by phylogenetic analysis (maximum likelihood analysis) of ITS, showing the isolate grouping with T. indotineae strains with high statistical support (1.00 PP from a Bayes test and 99% bootstrap proportions) (2). Although there are no official breakpoints, susceptibility testing was performed by broth microdilution according to the methods published in the CLSI M38 document 3rd edition (Fungus Testing Laboratory, UT Health San Antonio). Minimum inhibitory concentration (MIC) values of ≤0.03 μg/mL for itraconazole, 0.06 μg/mL for voriconazole, ≤0.03 μg/mL for posaconazole, 0.25 μg/mL for isavuconazole, 2.0 μg/mL for griseofulvin, and >2.0 μg/mL for terbinafine were consistent with other terbinafine-resistant and azole-susceptible T. indotineae strains (3). Finally, the patient was started on oral voriconazole, leading to symptomatic control and clearance. The patient remains on voriconazole for transplant precautions.

T. indotineae is an emerging pathogen of worldwide concern that is endemic to the Indian subcontinent, initially reported in 2014 with increasing cases worldwide attributed to immigration, travel, and local transmission (4). The first cases within the USA were recorded in 2021 (5). T. indotineae causes a severe tinea corporis infection that is frequently resistant to the first-line treatment, terbinafine. T. indotineae is challenging to differentiate from Trichophyton mentagrophytes or Trichophyton interdigitale based on morphology and requires genomic sequencing for correct identification. Initially, these terbinafine-resistant cases were considered T. mentagrophytes ITS genotype VIII. However, T. indotineae was determined sufficiently different based on sequencing and classified as a separate species in 2020 (6). Current treatment practices include oral itraconazole, a triazole antifungal, for 12 weeks or more, although there is documented molecular triazole resistance, complicating treatment of this organism even further.