DOI: 10.1111/jdv.70115 #### **SYSTEMATIC REVIEW** ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_0_Picture_4.jpeg) # **Deep and disseminated dermatophytosis in immunocompromised populations—A systematic review** **Aditya K. Gupt[a1,2](#page-0-0)** | **Tong Wang[2](#page-0-1)** | **Susmita[2](#page-0-1)** | **Ditte Marie L. Saunte[3,4](#page-0-2)** | **Roderick Hay[5](#page-0-3)** | **Vincent Pigue[t1,6](#page-0-0)** 1 Division of Dermatology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Mediprobe Research Inc., London, Ontario, Canada 3 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 4 Department of Allergy and Dermatology, Copenhagen University Hospital – Herlev and Gentofte, Gentofte, Denmark 5 St. John's Institute of Dermatology, King's College London, London, UK 6 Division of Dermatology, Women's College Hospital, Toronto, Ontario, Canada #### **Correspondence** Aditya K. Gupta, 645 Windermere Road, London, ON N5X 2P1, Canada. Email: [agupta@mediproberesearch.com](mailto:agupta@mediproberesearch.com) #### **Abstract** **Background:** Dermatophytes—a group of obligate keratinophilic fungi that infect the skin, hair and nails—represent the most common cause of fungal infections worldwide. In immunocompromised individuals, a growing body of literature has documented rare instances of dermatophyte infections of the dermis and subcutaneous tissue, which can lead to deep dermatophytosis with systemic dissemination and pseudomycetoma as secondary complications. **Objectives:** To assess patient characteristics, risk factors, diagnostic evidence and treatment options for deep dermatophytosis. **Methods:** A systematic review was conducted in June 2025 to identify patients presenting with deep dermatophytosis of the glabrous skin; all cases were validated by confirmatory testing per histopathologic examination and fungal culture. Majocchi's granuloma diagnoses were excluded. **Results:** The search yielded 96 studies (1954–2025) documenting 134 patients. The number of reports has notably increased since the 21st century; however, diagnosis remains challenging due to possible dermatophyte adaptation in the dermal/subcutaneous environment. *Trichophyton rubrum* is the most frequently isolated pathogen. Acquired immunodeficiencies (e.g. renal transplant recipients) and primary immunodeficiencies (e.g. CARD9, STAT3 mutations) elevate the risk of deep dermatophytosis. Systemic dissemination, often accompanied by lymphadenopathy, was reported in 24 patients, with the most common being infection of the axillary and inguinal lymph nodes. Infections of the bones, lungs, and brain were also reported. Terbinafine (125–1000mg/day) and itraconazole (100–400mg/day), with adjunctive topical antifungals and surgical interventions, have been tried for deep dermatophytosis. The use of newer triazoles (voriconazole, posaconazole) should follow the principles of antifungal stewardship and therapeutic drug monitoring recommendations. Multidrug resistance is a potential concern in immunocompromised patients who will often require extended or lifelong treatment. **Conclusions:** Healthcare providers should be cognizant that dermatophytosis may become invasive and disseminated in immunocompromised populations. Testing and early treatment should not be overlooked in these patients. ### **KEYWORDS** deep dermatophytosis, dermatophyte, disseminated fungal infection, invasive fungal infection, ringworm, tinea This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs](http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2025 The Author(s). *Journal of the European Academy of Dermatology and Venereology* published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. # **INTRODUCTION** Cutaneous fungal infections—commonly caused by dermatophytes—affected 1.7 billion persons globally in 2021 and are projected to worsen by approximately 30%, in terms of incidence, prevalence and morbidity burden, between years 2022 and 2046[.1](#page-10-0) This concerning trend is partially due to the rise in antifungal resistance across Global North and Global South regions associated with *Trichophyton* species, in particular *T.rubrum* and the *T. mentagrophytes* complex.[2–4](#page-10-1) Furthermore, there is an emerging phenomenon of fungal elements being detected in the deeper aspect of the stratum corneum which is associated with the use of immunosuppressive agents.[5](#page-10-2) A recent meta-analysis examining the risk of dermatophytosis in psoriasis patients found an almost twofold increase in risk after the use of biologics targeting the IL-17 response.[6](#page-10-3) Deep dermatophytosis (tinea profunda)—characterized by dermatophyte invasion of the dermis and subcutaneous tissues with granulomatous formation—is a rarely reported condition whose pathogenesis is not yet clear[.7,8](#page-10-4) In some cases, excluded as outside the scope of this review, dermal penetration is associated with follicular hair/shaft invasion as in nodular folliculitis or Majocchi's granuloma.[8](#page-10-5) In many cases of true deep dermatophyte infection, there is a proven association with primary immunodeficiencies (e.g. CARD9 [caspase-associated recruitment domain-containing protein 9] deficiency also known as Hadida's disease) and acquired immunodeficiencies (e.g. HIV/AIDS, transplant recipients).[9,10](#page-10-6) This is especially concerning for those with pre-existing chronic dermatophytoses, where superficial infections may become invasive in the setting of immunosuppression; hematogenous or lymphatic spread can also occur[.11](#page-10-7) We have systematically reviewed histopathology-proven, mycology-confirmed cases of deep dermatophytosis in the literature. Secondary complications of deep dermatophytosis include disseminated dermatophytosis and pseudomycetoma[.12](#page-10-8) The term 'mycetoma' is reserved for infections caused by exogenous fungi and should not be used for describing dermatophyte infections to avoid confusion[.13](#page-10-9) ## **METHODS** An electronic literature search was conducted on June 06, 2025 without date restrictions. The search terms, including Medical Subject Headings (MeSH) and Emtree terms, were queried using PubMed, Embase (Ovid) and Web of Science (Core Collection). These terms included 'dermatophytosis', 'tinea', 'ringworm', '*Trichophyton*', '*Epidermophyton*', '*Microsporum*', 'tinea profunda', 'pseudomycetoma', 'deep', 'invasi\*', 'systemic spread', 'dissminat\*', 'immunodeficient\*' and 'immunosuppress\*'. Search results were then ported into Covidence for de-duplication and screening of titles and abstracts (Appendix [S1\)](#page-13-0)[.14](#page-10-10) #### **Why was the study undertaken?** • Dermatophyte invasion of the dermis and subcutaneous tissue (i.e. deep dermatophytosis) is an emerging concern. Current global trends, such as the expansion of vulnerable aging and immunocompromised populations, climate change altering the epidemiology of fungal pathogens, and emergence of antifungal resistance that threatens our already limited number of treatment options, warrant re-examination of this rarely reported condition. ### **What does this study add?** • Through a systematic literature search, we collated 134 cases of deep dermatophytosis (1954–2025). Diagnostic methods and evidence for deep dermatophytosis, as well as for secondary complications (e.g. systemic dissemination and pseudomycetoma), are summarized. In these patients, primary and acquired immunodeficiencies are significant risk factors. Conventional treatment options include terbinafine and itraconazole. The use of newer triazoles (voriconazole, posaconazole) and amphotericin B has also been reported. ## **What are the implications of this study for disease understanding and/or clinical care?** • While not easily overlooked, deep dermatophytosis can occur in immunocompromised populations and requires testing, especially for those exhibiting signs of superficial dermatophytoses. Healthcare providers should remain vigilant about testing for deep dermatophytosis in the era of targeted immunotherapies, where invasive infectious adverse events are on the rise. Advances in genomics have elucidated inborn errors of immunity associated with this rare condition, which helps to identify vulnerable populations. A consensus on treatment and antifungal stewardship should be established for deep dermatophytosis. The following parameters were recorded in Microsoft Excel: author name, year, number of patients, age, sex, patient population (e.g. solid organ transplant recipient, cancer patients, diabetics, HIV/AIDS), concomitant tinea, chronic tinea (defined as infection lasting for more than 6month[s15](#page-10-11)), primary immunodeficiencies, clinical diagnosis (i.e. deep dermatophytosis, systemic dermatophytosis, pseudomycetoma), body site affected, symptoms (e.g. papules/nodules, ulcers, abscess), disseminated/systemic infection, dermatophyte identification methods and results, treatment regimen and outcome, and cause of death (if applicable). Numerical 14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.70115, Wiley Online Library on [29/10/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_2_Figure_2.jpeg) **FIGURE 1** PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flow chart. variables were summarized using median (interquartile range [IQR]) and analysed using the Kruskal–Wallis *H* test (IBM SPSS Statistics 20; *α*=0.05); categorical variables were summarized using percentage (counts) and analysed using the chi-squared test (*α*=0.05). # **RESULTS AND DISCUSSION** Ninety-six studies, totalling 134 deep dermatophytosis patients, are included (Figure [1](#page-2-0))[.16–111](#page-10-12) The earliest study identified described a female patient seen in 1954, who presented with tumefactive lesions of the lower limbs with concomitant fingernail and toenail onychomycosis.[60](#page-11-0) Histopathologic examination revealed fungal elements in the dermis and subcutaneous tissue, with pustular aspirates yielding *T.rubrum*. [60](#page-11-0) The number of patients reported per year has increased (1954–1999: 18 patients; 2001–2025: 116 patients) (Figure [2a](#page-3-0)), coinciding with the global increase in dermatophytosis incidences by the late 20th century attributed to the spread of *T.rubrum* as the dominant pathogen[.112](#page-13-1) Temporal analysis of the pathogen spectrum indicated *T.rubrum* as the most frequently isolated species (45.5%–75.9%), which is followed by the *T.mentagrophytes* complex (7.3%–10.5%) and *T. violaceum* (0%–27.3%) (Figure [2b](#page-3-0)). # **Patient characteristics and special populations** The median age of all deep dermatophytosis patients identified in this review is 51 years (IQR: 22), with 70.1% (94/134) males, 28.4% (38/134) females, and 1.5% (2/134) for whom sex was not reported. Symptoms include nodules/papules (78.4% [105/134]), ulcers (25.4% [34/134]), and abscesses (8.2% [11/134]). Secondary complications were reported in 24.6% (33/134) of patients including disseminated dermatophytosis and pseudomycetoma (Table [S1](#page-13-0)). Deep infections of the lower extremities (57.4% [58/101]), coupled with pre-existing onychomycosis (45.5% [46/101]) and/or tinea pedis (27.7% [28/101]), were frequently reported reflective of autoinoculation as the main causative factor. However, 33 deep dermatophytosis cases were identified without reporting signs or known ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_3_Figure_2.jpeg) **FIGURE 2** (a) Number of deep dermatophytosis patients reported in the literature stratified per the publication year (*N*=134). (b) Pathogen spectrum reported in deep dermatophytosis patients stratified per the publication year from a total of 144 isolates (mixed infections included). histories of superficial tinea infections and/or trauma, making it difficult to ascertain the point of entry for fungal invasion. ## Disseminated dermatophytosis Hay and Baran hypothesized the potential for systemic dermatophyte infections, and raised the idea of 'occult' or undetected systemic dissemination in the presence of proximal subungual onychomycosis—where infection occurs without originating from the nail fold, the distal free edge (hyponychium), or preexisting onycholysis—that may signal the reactivation of an underlying systemic infection that has been dormant.[7,113](#page-10-4) In a case study, Vu et al. reported pulmonary symptoms (chest pain, hemoptysis) in a patient presenting with nodular lesions of the scalp and elbow[.107](#page-13-2) Subsequent PET/ CT scan revealed a nodular lesion in the left lung, with sputum culture yielding *Trichophyton* spp., suggesting a case of fungal pneumonia caused by dermatophytes; fluconazole treatment (150 mg twice daily) led to the resolution of both subcutaneous and pulmonary lesions after 2 months[.107](#page-13-2) In a similar case, Trottier et al. reported nodular lesions of the face and the chest wall—with skin and tissue cultures yielding *T. rubrum*—in a patient who recently received a renal transplant; a subsequent CT scan also revealed clusters of nodules in the left lung that decreased in size following posaconazole (4 mg/kg/day) and terbinafine (500 mg twice daily) treatments[.100](#page-12-0) Notably, the peculiarity of these two cases is that authors did not report pre-existing superficial tinea infections, which leaves the possibility of fungal sequestration in lymph nodes that may have disseminated, leading to the development of subcutaneous and pulmonary nodules,[7,113](#page-10-4) warranting further investigations. A disseminated dermatophyte infection was reported in 24 cases; lymphadenopathy including generalized lymphadenopathy was more commonly observed in these patients (Table [S1](#page-13-0)). A CARD9 deficiency was identified in half of the patients (54.2% [13/24]). Disseminated lymph node infections were confirmed in 15 cases by visualizing fungal elements per direct microscopy or histopathologic ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_4_Figure_1.jpeg) **FIGURE 3** Summary of extracutaneous complications observed in deep dermatophytosis patients involving dissemination into lymph nodes, bones, viscera (lungs), testis, or the central nervous system. ^{19,25,26,39,42,44,50,57,68,86,92,96,100,107} examination, and/or tissue culture yielding dermatophytes.^{26,39,42,57,68,76,96} A summary of disseminated dermatophytosis cases by anatomical site is shown in Figure 3. Bone involvement including osteomyelitis was identified in five cases, three of which were CARD9-deficient patients with infected foot or toes by T. rubrum. 42,50,57,68,92 In two patients there was pre-existing tinea pedis, one of whom also presented with onychomycosis, lesions on the left foot gradually disseminated to other parts of the lower extremity, accompanied by lymphadenopathy.57,68 Radiological examination revealed infiltration of the toes, which led to toe amputations in both cases.^57,68 Ansai et al. reported infection of the calcaneus, evidenced by the visualization of fungal elements by histopathologic examination and tissue culture.⁵⁰ The patient—with a history chronic tinea corporis and a more recent trauma to the toes-developed nodular lesions of the sole and a subsequent bone infection, signalled by the observation of inguinal lymphadenopathy, ultimately leading to leg amputation.⁵⁰ Brain abscess and neurological symptoms were reported in four patients,^19,42,57,86 two of which were identified with CARD9 deficiency. Hironaga et al. cultured the *T. mentagrophytes* complex from the skin, inguinal lymph node, and brain abscess of a patient presenting nodular, ulcerative lesions of the right thigh, with histopathologic examination demonstrating fungal invasion of the dermis, lymph nodes, testis, the vertebrae, and brain.⁴² The patient had a history of tinea pedis and toenail onychomycosis since childhood and was unable to mount a lymphocyte response against *Trichophyton* antigens in vitro.⁴² Following the advent of genomic sequencing, Lanternier et al. reported a case series of deep dermatophytosis patients (previously called Hadida's disease)—detected with autosomal recessive CARD9 deficiency impairing the IL-6 and IL-17 responses—born to consanguineous families from Algeria, Morocco and Tunisia.⁵⁷ One Algerian patient—with a family member detected with a deleterious variant of CARD9 (Q289X)—had a history of chronic onychomycosis, tinea capitis and tinea corporis.⁵⁷ He subsequently developed ulcerative, nodular lesions and disseminated lymph node infection positive for *T. violaceum*, then developed seizures, brain abscesses, and septicemia ultimately leading to patient death.⁵⁷ Although a history of immunosuppression is commonly suspected to be the cause of deep dermatophytosis, early studies have reported seemingly idiosyncratic cases without a remarkable medical history[.42,58,93](#page-11-2) Some cases were also accompanied by unexplained serological (i.e. elevated IgE, low serum transferrin) and immunological (i.e. reduced neutrophil fungicidal activity, negative skin delayed hypersensitivity reaction, no lymphocyte response to *Trichophyton* antigens) findings[.42,58](#page-11-2) In recent years, several inborn errors of immunity have been shown to increase the risk of fungal infections[.114](#page-13-3) In particular, IL-17—produced by innate lymphoid cells, T helper 17 (Th17) cells, and CD8 T cells—upregulate the neutrophil response against dermatophyte infections as well as produce antimicrobial peptides[.114,115](#page-13-3) In CARD9-deficient patients, the ability to express pro-inflammatory cytokines and chemokines in antigenpresenting cells may be impaired—due to disruption of CARD9/BCL10/MALT1 signalling—which inhibits T-cell polarization and IL-17 production[.114,115](#page-13-3) A summary of CARD9 mutations detected in deep dermatophytosis patients is shown in Figure [4](#page-5-0). In addition to a decreased production of IL-17 (IL-17A), other Th17 cytokines (IL-22), IL-1β, IL-6, granulocyte/macrophage colony-stimulating factor production and natural killer cell proliferation, have been observed to be impaired in these patients.[38,39,57,98](#page-11-5) Signal transducer and activator of transcript 3 (STAT3) mutations leading to a gain-of-function deficiency is associated with the hyper-IgE syndrome that increases susceptibility to fungal infections[.114](#page-13-3) These mutations also impair the Th17 response (decreased IL-17 and IL-22 production), cytotoxic CD8 T-cell differentiation, and memory B cells[.114](#page-13-3) Simpson et al. reported a deleterious, loss-of-function STAT3 variant (F561del)—located in the linker domain inhibiting STAT3 transcriptional activation of downstream targets—in an Indian patient presenting with subcutaneous nodular infections of the groin by *T. mentagrophytes* var. *interdigitale*. [80](#page-12-1) The patient had an elevated IgE level and was eosinophilic as well as prurigoassociated pseudoperforation that may have created points of entry for deep dermatophyte infections.[80](#page-12-1) # Acquired immunodeficiencies A history of solid organ transplantation was reported in 46 cases, with the most common being renal transplants (69.6% [32/46]), followed by heart (15.2% [7/46]), liver (8.7% [4/46]), lung (4.3% [2/46]), and pancreas (2.2% [1/46]). Among renal transplant recipients, the median duration from transplantation to the onset of deep dermatophytosis symptoms was 8 months (IQR: 21.8), indicating that most cases were late-transplant infections, some of which possibly attributable to rescue treatments for graft rejection and up-dosing immunosuppressive treatments; however, infections appearing as early as 1–3 months post-transplant were also reported.[32,47,56,100](#page-11-6) The majority of patients had pre-existing superficial tinea infections (69.6% [32/46]), which should warrant early, aggressive treatments to reduce the risk of developing deep dermatophytosis. Immunotherapies (biologics, small molecules) have revolutionized medicine in the 21st century, shifting away from broad-acting agents and expanding care for patients with cancers and certain chronic diseases. However, infectious adverse events are also being increasingly reported with the use of these newer agents, often requiring early preventative approaches.[116](#page-13-4) Forster et al. reported a case of deep *T.rubrum* infection in the setting of PD-1 checkpoint inhibition by pembrolizumab.[30](#page-11-7) The patient initially presented with tinea manuum and tinea corporis characterized by papulopustular lesions, as well as signs of fingernail onychomycosis, which persisted due to mistreatment using glucocorticoid.[30](#page-11-7) Due to the appearance of dimorphic fungi by histopathologic examination, PCR testing was required to rule out blastomycosis.[30](#page-11-7) In another patient with a history of ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_5_Figure_10.jpeg) **FIGURE 4** Schematic representation of the human CARD9 protein. CARD9 mutations (shown with amino acid abbreviations) identified in deep dermatophytosis patients with corresponding countries of origin (if available) are indicated. Dashed box summarizes noncoding (intron or exon–intron junction) CARD9 variants. Amino acid positions are not drawn to scale for illustrative purposes. Q289X denotes the substitution of glutamine to a premature stop codon at the 289th amino acid position. CC1/2, coiled-coil 1/2 domain. prednisone use for asthma for over a decade, the addition of infliximab (TNF- $\alpha$ inhibitor) for rheumatoid arthritis was followed by the development of nodular, pustular lesions on her legs and hand with concomitant toenail onychomycosis.⁵⁴ The authors speculated that the additional, cumulative immunosuppressive effect by infliximab triggered deep dermatophytosis in this case.⁵⁴ #### Pseudomycetoma The term 'pseudomycetoma' is used for dermatophyte-positive cases where there are clusters of fungal hyphae resembling grains under histopathologic examination.^17,31,69 Moreover, draining sinuses have been reported in four cases identified in the present review, which have followed subcutaneous abscess formation, associated with dermatophytes.^18,66,92,104 In a patient with chronic tinea cruris, plantar tinea pedis, and toenail onychomycosis caused by T. rubrum-along with a history of oral corticosteroids treatment for >15 years due to asthma-Burgoon et al. reported the development of tumefactive lesions with draining sinuses on the foot dorsum.¹⁸ By histopathologic examination, pseudomycetoma can also be characterized by 'pseudogranules', which contain microcolonies of dermatophytes that form granules in a sequential manner (i.e. individual hyphae compacting into small then large clusters).^22,117,118 Pseudomycetoma was diagnosed in 11 cases (Table S1); of which two cases were also found with systemic dissemination associated with primary immunodeficiencies. In a patient with suspected primary immunodeficiency, evidenced by a consanguineous family history and chronic dermatophytosis (>20 years) of the skin and nails, pseudomycetomas of the scalp gradually disseminated to the thorax characterized by clusters of vegetative, tumefactive lesions positive for *T. violaceum*.²⁶ This worsened prognosis was accompanied with generalized lymphadenopathy (cervical, axillary, mammary) that fistulized, and a retropharyngeal abscess collection causing respiratory stress and ultimately patient death.²⁶ In another immunocompromised patient with CD4 lymphocytopenia, tinea faciei caused by zoophilic M. canis developed initially after being in contact with a cat.⁹² Possibly due to the tinea infection being left untreated for 10 years, a disseminated infection involving the mandible developed, which progressed into a pseudomycetoma with a draining sinus connecting the cheek and ear, ultimately leading to patient death from cachexia.92 In the event of trauma compromising the skin barrier and facilitating dermal invasion, the availability of growth substrates in the dermis (e.g. keratin) and lowering of the dermis pH may contribute to the proliferation of dermatophytes and the development of pseudomycetoma.^12,66,104 Ulcerative deep dermatophytosis may also occur without developing into pseudomycetoma.^50,64,98 In a CARD9-deficient patient with a history of chronic tinea corporis, an abdomen injury led to the development of an ulcerative lesion in the same region—positive for *T. tonsurans*—that spread to the thorax.⁹⁸ #### **Diagnostics challenges** Diagnostic clues reported for deep dermatophytosis is shown in Table 1. Although autoinoculation is suspected to be the main reason deep dermatophytosis develops in immunocompromised individuals—evidenced by the frequent observation of patients with concomitant superficial infection—the possibility of lymphatic or haematogenous spread has been raised in patients where no such linkage can be made.^40,41,46,88 Indeed, deep dermatophytosis can occur in areas without an overlying superficial infection, which undermines the utility of the commonly used direct KOH microscopic examination by skin scraping.^47,56,69 In patients with nodular lesions, Xia et al. proposed a point-of-care diagnosis by sampling the pustular exudate guided by high-frequency ultrasonography, followed by direct KOH microscopic examination revealing septate hyphae.¹⁰⁹ In patients with a clinical suspicion of deep dermatophytosis, histopathologic examination demonstrating invasion of the dermis or subcutaneous tissue, and culture yielding dermatophytes, are required for a definitive diagnosis (Appendix S2).¹⁰⁹ #### Treatment options and pitfalls A proposed management algorithm is shown in Figure 5. *Terbinafine* and *itraconazole* are commonly tried as first-line treatment accounting for 22.4% and 35.2% of cases, respectively (Table 2). The most commonly prescribed dose of *terbinafine* is 250 mg/day resulting in an improved outcome in 64.8% (35/54) of patients; among the responders, treatment duration varied from 2 weeks to 8 months. In patients with disseminated dermatophytosis, an increased terbinafine dosage—up to 1000 mg/day—has been reported.^68,92,100 In two CARD-9-deficient patients, terbinafine treatment was extended to 4 years^38,68; however, its efficacy gradually waned even with a higher dose of 500 mg/day.⁶⁸ The inability to mount an effective immune response, combined with a constant drug selection pressure, could predispose vulnerable patients to developing treatment resistance overtime. *Itraconazole*—most commonly prescribed at 200 mg/day has generally shown effectiveness that improved outcomes in 46.5% (33/71) of patients, with a treatment course varying from 2 weeks to 1 year in responders. Doubling the dosage to 400 mg/ day was also shown to be effective, including for transplant recipients.^27,32 There were no reports of itraconazole being prescribed at 600 or 800 mg/day. In 5 patients, itraconazole 400 mg/day was prescribed as an initial loading dose, which was tapered down to 200 mg/day after a period of 2 weeks to 2 months when treatment response is observed.^31,32,36,74 In a paediatric patient, itraconazole was prescribed at 50 mg/day #### TABLE 1 Features of deep dermatophytosis. | Parameter | Diagnostic clues | References | |-----------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------| | Patient history |

Use of immunosuppressive therapies (e.g. topical/oral corticosteroids, tacrolimus)
Chronic dermatophytosis (most common are tinea pedis and onychomycosis)
Poorly controlled diabetes
Atopic disease (e.g. atopic dermatitis)
Consanguineous family history (CARD9, STAT3 deficiency)
Injuries or trauma (pseudomycetoma)

| 31,40,97 | | Physical examination |

Fluctuant or firm papules near sites of dermatophytoses
Dusky or haemorrhagic nodules near sites of dermatophytoses
Cold abscess
Ulcerative lesion
Lymphadenopathy
Pseudomycetoma: tumour-like swelling or large, indolent inflammatory nodules, with or without draining sinuses, absence of macroscopically visible grains/granules

| 31,40,42,69 | | Histopathologic examination |

Involvement of the deep dermis and/or subcutaneous tissues beyond perifollicular regions or without evidence of follicular invasion
Epidermal acanthosis
Pseudoepitheliomatous hyperplasia
Papillomatosis
Hyperkeratosis
Spongiosis
Granulomatous formation with central suppuration, necrosis and polymorphonuclear leukocytes (neutrophils, eosinophils)
Infiltrative lymphocytes, histocytes, plasma cells and multinucleated giant cells containing septate fungal hyphae
Splendore-Hoeppli phenomenon
Microabscesses with fungal elements
Fungal hyphae detectable in lymph nodes and deep organs
Atypical fungal elements: large, thick-walled, pleomorphic hyphae with mucinous coating, yeast cells, pseudobudding, budding arthrospores that are few and scattered

| 31,42,47,53,56,57,64,67,69,83,86,94,99 | | Fungal culture |

Lymph node specimen yield dermatophytes
Pustular or granular specimens yield dermatophytes
Delayed sporulation/non-sporulating
T. rubrum: delayed pigmentation, few pyriform microconidia

| 43,57,86,104 | for 1 week, followed by 100 mg/day for 1 year until clinical and mycological cure was achieved.⁵⁸ Treatment cessation due to adverse event was reported in 4 patients receiving itraconazole 100–200 mg/day attributed to renal injury (N=1),⁸³ abdominal distention (N=1),⁴⁹ and drug–drug interaction with tacrolimus $(N=2)^{81}$ ; in all cases, clinical resolution was achieved by switching to terbinafine 125–250 mg/day. As with terbinafine treatment, a prolonged course of itraconazole treatment has been tried in CARD9-deficient patients.^23,38,50,57 In patients with concomitant superficial tinea infections who are at risk of relapse due to autoinoculation—it may be advisable to treat until all extracutaneous and cutaneous lesions are clinically and mycologically cured, especially concerning toenail onychomycosis that typically requires longer treatment periods.¹¹⁹ In five deep dermatophytosis patients with concomitant toenail onychomycosis, authors noted persistent/relapsing nail lesions despite the resolution of dermal/subcutaneous infections.^{18,31,49,58,73} The appearance of deep dermatophytosis on the lower extremities (foot, shin) suggests toenail onychomycosis as the likely source of infection.^18,49,58,73 Furthermore, of the three deep dermatophytosis cases identified in this review that required amputation,^50,57,68 all cases involved amputation of the lower extremity (i.e. bilateral below the knee, left leg, toes), and two cases were linked to tinea pedis, which is often associated with onychomycosis that disseminated to adjacent skin surfaces. Continuous and pulsed terbinafine or itraconazole treatments, or topical treatments such as efina-conazole 10%, ciclopirox 8%, or amorolfine 5%, should be considered to treat toenail onychomycosis.^119,120 Adjuvant treatment options include surgical intervention (abscess drainage, excision), as well as topical agents such as allylamines (tolnaftate, terbinafine), azoles (bifonazole, clotrimazole, econazole, ketoconazole, miconazole) and ciclopirox. However, surgical intervention should not be performed without confirmatory testing and initiating antifungal treatments. In a patient presenting with nodular lesions, incision and drainage procedures were carried out without histopathologic examination to rule out infectious aetiologies, which led to the enlargement of nodules and new satellite nodules.⁷¹ In a renal transplant recipient, drainage of subcutaneous abscesses led to organ dissemination of *T. rubrum* ultimately resulting in patient death despite itraconazole treatment.⁸⁷ ![](https://assets.reachrx.ai/images/10.1111%E2%98%8Djdv.70115/_page_8_Figure_1.jpeg) **FIGURE 5** Proposed diagnosis and treatment decision guide for deep dermatophytosis patients. Disclaimer: Due to the limited reporting on deep dermatophytosis, these recommendations may only serve general informational purposes; continued research is needed to develop a standardized management algorithm. New generation triazoles and amphotericin B Despite a paucity of studies that have performed antifungal susceptibility testing, multidrug resistance development is evident in patients with primary immunodeficiencies, who often will require extended, sometimes life-long, treatm ents.[38,39,48,57,65,68,98](#page-11-5) Newer triazoles should be used in line with antifungal stewardship recommendations; therapeutic drug monitoring—measuring circulating drug levels and tailoring treatment regimens based on pharmacokinetic parameters—is recommended when using voriconazole and posaconazole due to concerns of unpredictable pharmacokinetics, different formulations and drug–drug interactions[.121,122](#page-13-7) *Posaconazole* was tried successfully in 58.8% (10/17) of patients, of which the trough level was reported as >1μg/ | TABLE 2 | | Summary of common treatment options tried for deep dermatophytosis (N=128a | | ). | |---------|--|----------------------------------------------------------------------------|--|----| |---------|--|----------------------------------------------------------------------------|--|----| | Drug (route of administration) | First-line treatment % (N) | Most common dosage (range) | Duration | |-------------------------------------------|----------------------------|--------------------------------------------------------------------------------------------------------------|----------------| | Itraconazole
(Oral) | 35.2 (45) | 200mg/day
(100–400mg/day) | 1week–3 years | | Terbinafine
(Oral) | 23.4 (30) | 250mg/day
(125–1000mg/day) | 1month–4 years | | Griseofulvin
(Oral) | 12.5 (16) | 1000mg/day
(500–2000mg/day) | 2weeks–9months | | Fluconazole
(Oral, Intravenous) | 8.6 (11) | 200mg/day
(150mg/week–400mg/day) | 1week–1 year | | Amphotericin B
(Intravenous) | 4.7 (6) | N/A
(40–450mg/day)
Weight adjusted: 0.25–0.4mg/kg | 1week–10weeks | | Liposomal Amphotericin B
(Intravenous) | 0.8 (1) | 250mg 3 times/week
(N/A)
Weight adjusted: 3–5mg/kg/day | 1week–90days | | Voriconazole
(Oral, Intravenous) | 3.1 (4) | 400mg/day
(200–400mg/day)
(Loading) 6mg/kg twice then
(Maintenance) 4mg/kg twice daily | 8days–1 year | | Posaconazole
(Oral) | 3.1 (4) | N/A
(300–800mg/day)
(Loading) 800mg/day then
(Maintenance) 600mg/day
Weight adjusted: 4mg/kg/day | 1month–3 years | a Six patients were excluded due to the lack of reporting on treatment. mL in two studies in accordance with current recommendations.[48,104,122](#page-11-16) In a CARD-9-deficient patient unresponsive to itraconazole, ketoconazole and terbinafine, Jachiet et al. administered an initial loading dose of posaconazole at 800mg/day for the first month followed by 600mg/day for another 2months—with a trough concentration of 1.27μg/ mL—leading to clinical improvement of both deep dermatophytosis and onychomycosis[48;](#page-11-16) clinical resolution was achieved following an additional 8months of posaconazole treatment. *Voriconazole*, by contrast, was tried successfully in 38.5% (5/13) of patients, with treatment cessation reported in 3 cases due to hepatotoxicity, vision disturbances, or drug–drug interaction with tacrolimus.[90,100,101](#page-12-9) In a STAT3-defiicient patient unresponsive to itraconazole, significant improvements was observed after prescribing voriconazole 200 mg/day for 12 month albeit without therapeutic drug monitoring results.[80](#page-12-1) In a patient unresponsive to voriconazole that was later successfully treated using posaconazole, despite demonstrating in vitro susceptibility to both antifungals, Tan et al. speculated that the neutrophil suppression by voriconazole was a potential factor for treatment failure.[98](#page-12-3) With regards to *amphotericin B*, Smith et al. reported inadequate treatment response to intravenous amphotericin B treatment in three deep dermatophytosis patients positive for *T.rubrum*, possibly due to the limited biodistribution in the stratum corneum, sweat and sebum.[79](#page-12-10) Topical amphotericin B was also tried without success in a CARD-9-deficient patient positive for *T. tonsurans*. [98](#page-12-3) Recently, the emergence of antifungal resistance in dermatophytes has prompted discussions about the use of novel antifungals including the lipid-based amphotericin B formulation; however, there is inadequate clinical data to support its use at present[.123](#page-13-8) ## **CONCLUSIONS** Although typically treated as a limited, superficial infection, the pathogenesis of dermatophytosis appears to be evolving—particularly in vulnerable populations—where it can manifest as a severe, invasive disease. In immunocompromised individuals presenting with atypical infections, healthcare providers should recognize the risk of possible deep dermatophytosis. In these patients, pre-existing superficial dermatophyte infections present a significant risk and should be promptly treated before immunotherapy is initiated. In deep dermatophytosis patients without a history of immunosuppression, genomic sequencing should be considered to identify underlying risk factors, in particular an impaired IL-17 response attributed to CARD9 or STAT3 mutations. This review is limited by potential publication bias due to most of the eligible studies being case reports or small case series. Further studies are warranted to better understand the prevalence and pathogenesis of deep dermatophytosis, as well as develop standardized treatments concerning the emergence of antifungal resistance, in view of an increasing burden of dermatophytosis globally[.1](#page-10-0) #### **AUTHOR CONTRIBUTIONS** Conceptualization: AKG, TW; data curation: TW, S; formal analysis: TW; investigation: TW; methodology: TW, S; project administration: TW; resources: AKG; supervision: AKG; Visualization: TW; writing—original draft preparation: TW; writing—review and editing: AKG, DMLS, RH, VP. #### **FUNDING INFORMATION** No funding was received for this work. #### **CONFLICT OF INTEREST STATEMENT** AKG, TW and S have no competing interests to declare that are relevant to the content of this article. DMLS has received personal honoraria for speaker and/or advisory board member roles from UCB, Leopharma, Galderma, Novartis and received travel grants from Pfizer, Leopharma, UCB, Novartis during the past 36 months. RH serves as an unpaid trustee for LEPRA, an NGO dedicated to leprosy. VP has received grants from AbbVie, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Incyte, Janssen, LEO Pharma, L'Oréal, Novartis, Organon, Pfizer, Sandoz and Sanofi; received payment or honoraria for speaking engagement from Sanofi; participated on an advisory board for LEO Pharma, Novartis, Sanofi, Union Therapeutics, Abbvie and UCB and received equipment donation from L'Oréal. #### **DATA AVA I L A BI L I T Y STAT E M E N T** The data that support the findings of this study are available from the corresponding author upon reasonable request. #### **ET H IC A L A PPROVA L** Not applicable. ## **ETHICS STATEMENT** Not applicable. ## **ORCID** *Aditya K. Gupt[a](https://orcid.org/0000-0002-8664-7723)* *Tong W[ang](https://orcid.org/0009-0004-6114-569X)* *Susmita* *Ditte Marie L. Saunte* [https://orcid.](https://orcid.org/0000-0001-7953-1047) [org/0000-0001-7953-1047](https://orcid.org/0000-0001-7953-1047) *Vincent Piguet* ### **REFERENCES** - 1. Li D, Fan S, Zhao H, Song J, Guo L, Li W, et al. Worldwide trends and future projections of fungal skin disease burden: a comprehensive analysis from the Global Burden of Diseases Study 2021. Front Public Health. 2025;13:1580221. - 2. Gupta AK, Susmita, Nguyen HC, Liddy A, Talukder M, Wang T, et al. *Trichophyton indotineae*: epidemiology, antifungal resistance and antifungal stewardship strategies. J Eur Acad Dermatol Venereol. 2025. - 3. Khan SS, Hay R, Saunte DML. An international survey of recalcitrant and recurrent tinea of the glabrous skin—a potential indicator of antifungal resistance. J Eur Acad Dermatol Venereol. 2025;39(6):1185–91. - 4. 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