Tinea gone wild: The emergence of Trichophyton indotineae as a global phenomenon
By Warren R. Heymann, MD, FAAD
May 24, 2023
Vol. 5, No. 21
“Well, Jane, it just goes to show you, it’s always something — if it’s not one thing, it’s another.” – Gilda Radner (as Roseanne Roseannadanna) to Jane Curtin, Saturday Night Live
Just as I quietly celebrated the retreat of COVID-19 this week by not wearing a mask when examining patients comes the Dermatology Daily headline “May 12: CDC reports two cases of highly contagious, drug-resistant ringworm infections in US.” Yes, Yogi, “It’s déjà vu all over again!”
This commentary is presented in a question and answer format.
What is Trichophyton indotineae (Ti)?
Ti is a newly identified dermatophyte species causing a near epidemic in the Indian subcontinent. Since 2016, Indian dermatologists have detailed this chronic and recalcitrant tinea infection that is frequently resistant to terbinafine. (1,2) In 2020, Kano et al isolated two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with tinea corporis in Japan. These strains exhibited a TRF minimal inhibitory concentration (MIC) of > 32 mg/L and contained a missense mutation (Phe397Leu) in the squalene epoxidase (SQLE) gene. The authors stated, “To avoid confusion in the taxonomy of the T. mentagrophytes/T. interdigitale complex, we suggest that the highly TRF-resistant Indian strains be considered a new species independent of T. interdigitale, according to clinical and mycological features,” now known as Ti. (3)
How does Ti infection present clinically?
Gupta et al (4) thoroughly describe the clinical features of Ti infection:
“T. indotineae lesions are generally highly inflammatory, strongly associated with tinea cruris, corporis, and faciei, and less commonly with fingernail onychomycosis and tinea pedis. Patients present with scaly concentric plaques and erythematosquamous morphology with active red borders, mainly affecting the lower body and groin...Additionally, the morphology of lesions observed in some patients includes papulosquamous, pustular, pseudo-imbricata (tinea faciei), lichenoid, and pityriasis rosea (tinea corporis of the neck) types. Dermatophytosis due to T. indotineae spreads rapidly to multiple sites and causes painful lesions with an itching or burning sensation. Over half of these patients had used topical corticosteroids alone or in combination with antibacterial and/or antifungal agents, and some of them exhibited adverse reactions such as striae, hypopigmentation, and local atrophy.”
(WRH editorial comment — in reviewing the literature on this topic the term pseudoimbricata is utilized, because it resembles tinea imbricata caused by Trichophyton concentricum. As the lesions may be clinically identical, my preference is to call the lesions tinea imbricata, expanding the concept that tinea imbricata may be due to organisms other than Trichophyton concentricum, such as Ti.)
What is the epidemiology of Ti infection?
Using internal transcribed spacer (ITS) sequence-based screening, Jabet et al determined that “T. indotineae was present in India, Australia, Iran, and Oman during 2004–2013. After 2014, a substantial increase in reported cases was observed, related to the outbreak in India. Since 2019, the number of reported T. indotineae cases has increased in Europe, confirming its spread. Currently, 76% of the known sequences have been identified in India, 12.8% in the Middle East, 9.6% in Europe, and 1.1% in other countries. Cases reported in Europe are supposed to have been introduced by migrants or travelers from India, Bangladesh, Pakistan, Bahrain, Libya, Saudi Arabia, or Thailand, suggesting the presence of T. indotineae in those countries. The cases imported from Bangladesh that were reported in France, together with those reported in Germany, suggest that T. indotineae transmission could be endemic in Bangladesh.” Human-to-human transmission was observed in 526/537 sequences with 6 sequences indicating an animal origin. (1)
Caplan et al have reported the first documented Ti dermatophytosis cases in the United States — a 28-year-old woman without a history of international travel and no known exposure to Ti, and a 47-year-old woman who first noted the eruption in Bangladesh. Neither patient improved with terbinafine — the former responded to itraconazole and the latter demonstrated approximately 80% improvement with griseofulvin. (5)
Why has Ti dermatophytosis emerged worldwide?
The answer to this question is speculative. Current theories consider the inappropriate use of ultrapotent topical steroids combined with antimycotics and antibiotics, changes in the skin microbiome, and other immunological findings in patients with chronic dermatophytosis (a reduced Th1 response). (6)
When should dermatologists suspect Ti dermatophytosis?
Clinicians should be suspicious of the diagnosis when confronting patients with extensive tinea infections that are recalcitrant to standard topical antifungal agents and oral terbinafine.
How should practitioners confirm the diagnosis of Ti dermatophytosis?
According to Caplan et al, “Culture-based identification techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentographytes or T. interdigitale; correct identification requires genomic sequencing. Health care providers who suspect T. indotineae infection should contact their state or local public health department for assistance with testing,** which is available at certain public health laboratories and specialized academic and commercial laboratories.” (5)
** Public health officials who are concerned about potential cases of drug-resistant tinea infections can email email@example.com for assistance with recommendations and testing.
How should Ti dermatophytosis be treated?
The drug of choice is itraconazole (100 mg twice daily for 4 to 8 weeks; some patients may require 12 weeks of therapy). Second-line agents include fluconazole and griseofulvin. Topically, luliconazole may be valuable. (6) Topical voriconazole cream (1%) resulted in a complete remission in a 28-year-old man from Bangladesh who was unresponsive to terbinafine and topical azoles. (7) Miltefosine, used to treat leishmaniasis, has shown in vitro efficacy compared to other antifungal agents, and could have potential use in treating Ti infection. (8) As in all cases of dermatophytosis, hygienic measures are essential in preventing reinfection or transmission. Sharing of personal belongings, close body contact, and skin maceration should be avoided. (2)
In conclusion, extensive, recalcitrant Trichophyton indotineae dermatophytosis is a global phenomenon that is now in the United States. Clinicians must be familiar with its presentation, confirmation, and therapy. I began this commentary with a quote from Gilda Radner — she always made me smile. Unfortunately, extensive tinea infection and antifungal resistance is no laughing matter. Ti infection is a clarion call for the proper use of antimicrobial agents and topical steroids.
Point to Remember: Trichophyton indotineae dermatophytosis is an extensive, recalcitrant infection frequently resistant to terbinafine, spreading worldwide. Dermatologists should consider this diagnosis when tinea infections do not respond to standard therapy and use itraconazole as the current treatment of choice.
Our experts’ viewpoints
Avrom S. Caplan, MD, FAAD
Assistant Professor, Ronald O. Perelman Department of Dermatology
NYU Grossman School of Medicine
Our patient’s story was compelling. She had multiple family members with the same eruption, all acquired in Bangladesh. Her skin was inflamed and very pruritic; she clearly had tinea corporis on exam. Topical steroids and antifungal creams had been used to no avail. She failed to improve with oral terbinafine. By the time the culture came back as Trichophyton mentagrophytes, the alarm bells in my head were fully sounding. (9,10,11)
Sequencing of her specimen and another culture at the New York State Department of Health Wadsworth Center confirmed our suspicions — T indotineae has arrived in the U.S. (5) It’s probably been here before. We have now confirmed our third case and are actively investigating a possible fourth. Fortunately, we have been alerted to this infection by colleagues in India. What we know of this dermatophyte largely stems from their painstaking efforts.
How should we proceed knowing that we will likely see more cases? We should be suspicious when patients present with widespread dermatophytosis who have failed terbinafine. They may or may not report a travel history. T. indotineae can look identical to T. mentagrophytes or resemble T. interdigitale on culture. (10,6) Specialized testing is required to confirm the diagnosis. Indeed, this dermatophyte was previously called Trichophyton mentagrophytes ITS genotype VIII (9), and there remains debate as to the taxonomy and name “indotineae.” Currently, discussions among leading experts are underway in an effort to address these controversies.
Ultimately, if suspicion for T. indotineae dermatophytosis is high enough, it may be prudent to skip terbinafine in favor of itraconazole. Remember to monitor for drug-drug interactions (itraconazole is a strong inhibitor of CYP3A4)and for clinical relapse. Moving forward in an increasingly globalized world, we would also do well to pursue global collaborations in researching this emerging infection. (12) Keep abreast of developments as new information is rapidly unfolding.
Shyam Verma, MBBS, DV&D, FRCP, PhD
Adjunct Professor of Dermatology, University of Pennsylvania Perelman School of Medicine
Nirvan & ‘In Skin Clinic,’ Vadodara, India
Thank you Dr. Heymann, my insightful, scholarly friend who true to his nature, has chosen to talk about this new fungal beast, the so-called ‘Trichophyton indotineae.’ Having been a rather fastidious and obsessive observer of the beast in India since 2014 I can confidently say that it must have entered the United States a long time ago and there are reports, albeit infrequent, of that happening since 2014 in my personal series of thousands of patients. I had the opportunity of showing these images in a lecture on this topic in CDC, Atlanta in 2019. This illegal migrant may be of interest to border security authorities too as it often rides piggyback sans the required travel documents on unsuspecting hapless travelers and immigrants who possess all required travel documents but are not aware of the existence of the beast hiding on their skin. Many of them travel on individuals as tinea incognita and confuse clinicians who are tempted to diagnose and treat them as atopic eczema, contact dermatitis, and a myriad inflammatory disorders that are generally steroid responsive and hence become recurrent. It remains to be seen if these steroid creams, mostly ultrapotent steroid (clobetasol propionate) + antifungal creams are the eggs and tinea is the chicken or vice versa. Irrespective of the sequence (and pardon the pun on ‘sequence’ since diagnosis of T. indotineae needs gene sequencing...) it is clear as daylight that tinea and these combination cocktail creams, in pharmacological parlance termed ‘fixed dose combinations’ (FDCs), have an indubitably unholy nexus. A causal association has been proposed and is scientifically tenable since steroid-containing combination creams used on lesions of dermatophytes can cause local immunosuppression. The creams help alleviate the significant itch with the erythema and scaling but retard shedding of the fungus as they suppress inflammation! In addition to the deleterious role of superpotent/ultrapotent steroid clobetasol propionate-containing creams in perpetuating and failing to clear the dermatophytosis, other factors also need to be considered such as a heightened virulence of this new species and its ability to grow quickly and survive on the skin and inanimate objects belonging to the host. The role of clobetasol propionate and topical azoles with or without antibacterial creams is implicated the most in patients from the entire Indian subcontinent, several countries in the Middle Eastern countries of Asia, and also in parts of Africa.
While terbinafine is falling out of favor due to resistance issues it would serve us better to be aware of this species’ potential to have multidrug resistance, most ominously to itraconazole which exhibits the least resistance to other drugs including other azoles like fluconazole.
I have always believed that the voice of dermatology is barely audible in the corridors of power where other seemingly ‘important diseases from public health point of view’ are given high priority. The reason for this bias is partly due to the policy makers’ tendency to pay more attention to mortality rather than morbidity. Lack of awareness of what such a fungal disease does to the quality of life of the patient and the family is difficult to be quantified for most bureaucrats. Therefore, the onus is on us to champion the cause of irrational antifungal medication, mainly containing topical steroids, and insist on a ban on clobetasol propionate to be included in FDCs, especially in countries where these drugs are purchased over the counter.
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