Is your patient immunodeficient to fungal skin infection?

In a recent blog I asked the question why antifungal nail treatments fail - creating a checklist of reasons emphasizing it’s not just due to fungal resistance. In this blog, I look at a fascinating paper which takes a deep dive into immune status of a cohort of patients who despite antifungal therapy just can’t shift their dermatomycosis or suffer persistent rapid relapse known as “Chronic Relapsing Dermatophyte Infection” (CRDI). This builds on a previous blog which asked if fungal susceptibility was genetic – click here

Patient Factors in Fungal Recurrence and Persistence

If you have been following my blogs and publications you will note I have been discussing the emergence of a new strain of dermatophyte named Tinea Indotineae, showing drug resistance to terbinafine. The idea of an emerging super strain becomes foremost on one’s mind when dealing with tinea pedis or nail infection that just doesn’t seem to go away. However, there is another potential dimension. It may not be the fungus; it may be the individual.

Professor Rod Hay recalls cases of patients in the early days of griseofulvin, who just didn’t respond to drug. On testing the fungus there was little evidence of any drug resistance [1]. The inference was that perhaps the patient’s immunity to the infection is not effective. Vinh has termed this “inborn errors of immunity” [2].  The concept was easy to theorise but hard to prove until recent advances in genetic sequencing has allowed researchers to begin to uncover evidence.

In a forthcoming paper published in the British Journal of Dermatology, a team of researchers have assembled a group of patients who have had a minimum of five-year history of dermatophyte infections which have failed at least three different antifungal agents [3]. These had to be recognised drug regimens such as oral terbinafine, fluconazole or itraconazole for greater than three months.

Each underwent genomic analysis (using whole exome sequencing -  a precise method to identify potential causative genes in disease), lymphocyte analysis and IL-17 quantification. IL-17 is a critical cytokine for antifungal defence in the skin [4].

Eleven patients (0.2%) were identified fitting the inclusion criteria (10 male) from a pool of 5910 with dermatophyte skin infection. and had an average disease duration of 26.4 years and all presented with extensive dermatophytosis on the skin. None had any evidence of other chronic infections or dermatological disease.

Results

Just over half of patients had an identifiable immune alteration (54.5%) including 3 with CARD9 mutations and FOXN1, one with acquired immunodeficiency (Good's syndrome), and two with isolated IL-17 deficiencies. The majority had skin infection plus onychomycosis (72.7%) and 90% had concomitant groin infection. Response to treatment following diagnosis in the majority of patients was limited with only 1 patient out of the eleven showing complete cure.

What does this mean?

This research suggests in a very small subset of patients with chronic dermatophyte infection there maybe underlying deficiencies within the immune system which can predispose to chronic infection. Most of these conditions are rare.

CARD9 immunodeficiency is a genetic condition that leaves an individual suspectable dermatophyte and candida infections. Responses to other types of microbial infections are normal. Variation in the CARD9 gene means that neutrophils and macrophages are unable to respond normally to dermatophyte infection. The condition is normally inherited in an autosomal recessive pattern.

FOXN1 deficiency (also known as severe combined immunodeficiency [SCID]) is a rare condition characterised by a lack of thymus tissue resulting in T cell immunodeficiency. Clinically the patient may present with alopecia and nail dystrophy (which may lead to secondary fungal infection) [5]. Life threatening infections often mean patients have a poor prognosis [6].

IL17 deficiencies have been recognised as causing susceptibility to a number of infectious and autoimmune conditions including viral and fungal infections [7]. As a group of 6 cytokines, their effects can be varied in individuals but chronic dermatophytosis can be observed.

Goods Syndrome is a rare genetic condition characterised by low immunoglobulin levels and a thymus tumour. Normally manifesting in adulthood, it may result in reduced T and B cell functions leading to increased susceptibility to a range of infections.

Ultimately, when assessing patients with chronic dermatophyte infection or rapid recurrence, the patient’s immune status is another factor to be considered. Based on these results however, it suggests that such conditions are relatively rare but should always be in the back of ones mind when faced with  stubborn dermatophytosis.

References

1.            Hay RJ: Persistent and recalcitrant dermatophyte infections, not caused by Trichophyton indotineae – a new perspective. Br J Dermatol 2025: early view

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2.            Vinh DC: Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases. Pathogens 2023, 12.

3.            Galili E, Barzilai A, Lev A, Amit S, Barel O, Lubitz I, Gazit Z, Lyakhovitsky A, Somech R, Shemer A: Genetic, immunological and clinical assessment of isolated chronic recalcitrant dermatophytosis: A prospective study. Br J Dermatol 2025: early view.

4.            Sparber F, LeibundGut-Landmann S: IL-17 Takes Center Stage in Dermatophytosis. J Invest Dermatol 2018, 138:1691–1693.

5.            Pignata C, Fusco A, Amorosi S: Human clinical phenotype associated with FOXN1 mutations. Adv Exp Med Biol 2009, 665:195–206.

6.            Rota IA, Dhalla F: FOXN1 deficient nude severe combined immunodeficiency. In Book FOXN1 deficient nude severe combined immunodeficiency (Editor ed.^eds.), vol. 12. pp. 6. City; 2017:6.

7.            Welch EZ, Anderson KL, Feldman SR: Interleukin 17 deficiency and implications in cutaneous and systemic diseases. Journal of Dermatology & Dermatologic Surgery 2015, 19:73–79.