INTRODUCTION
Dermatophytes, a keratinophilic fungus, causes the most common superficial fungal skin infection worldwide, affecting up to 20% to 25% of the world population.1 Although not associated with severe outcomes, it is known to have a significant psychosocial impact and decrease in quality of life in affected individuals.2,3 In the past, dermatophytosis was considered an easily treatable disease with short durations of conventional antifungal treatment. However, a changing scenario of extensive disease with chronic, recurrent, and recalcitrant dermatophytosis has been observed in different parts of India during the past 5 to 6 years.4–7 This alarming epidemic of recalcitrant dermatophytosis has led to extensive research, dedicated conferences on the topic, and consensus guidelines that have helped practicing clinicians tackle it more effectively.8,9
In keeping with the trend seen in India, dermatologists in Sri Lanka have also observed a lack of therapeutic response to conventionally used drugs and dosages of antifungals during the past 2 to 3 years. This development in Sri Lanka is quite disturbing because it signals that recalcitrant dermatophytosis could soon become a significant public health problem in the country. Moreover, considering the commonness of dermatophytosis and migration and travel between countries, this scenario of recalcitrant dermatophytosis could be the norm and not a rarity in Southeast Asia in the foreseeable future.
Many factors could be contributing to this lack of therapeutic response in dermatophytosis. Host immunity, virulent pathogenic species, drug resistance, and environmental factors are a few possible contributory causes.10–12 To overcome this problem, a thorough understanding of these contributory factors in the local community is mandatory. Unfortunately, there is a dearth of scientific research on this subject from Sri Lanka. Therefore, our multicenter study with representations from all nine provinces was undertaken to assess the magnitude and possible causative factors for this emerging problem of recalcitrant dermatophytosis.
METHODS
A descriptive, observational, cross-sectional study was carried out in nine hospitals, representing each province in Sri Lanka. Participants were recruited over 6 months, from June 2019 to December 2019. All ethical policies were adhered to in the conduct of this study, and ethical clearance was obtained from the Ethical Review Committee of the Medical Research Institute, Sri Lanka. Informed consent was acquired from all participants.
Study participants.
All patients with dermatophyte infection in glabrous skin, diagnosed clinically by a consultant dermatologist, were included. Children younger than 18 years, pregnant and lactating women, patients with tinea infections that did not warrant systemic antifungal medication, and patients with contraindications for systemic antifungal medications were excluded from the study.
Study procedure.
Study instrument.
Sociodemographic characteristics, symptoms, and prior treatment patterns were gathered using a questionnaire. After that, the treatment options used, microscopic findings, culture findings, treatment outcomes, and relapse information were recorded prospectively on data sheets.
Mycology studies.
All subjects underwent mycological studies. Skin scrapings were obtained with a blunt scalpel from the active edge of the lesions and were sent to the Mycology Reference Laboratory at the Medical Research Institute, Sri Lanka.
Skin scrapings were subjected to direct microscopy with 10% potassium hydroxide. Using direct microscopy, specimens with fungal filaments, fungal spores, or arthrospores, or any combination thereof were considered positive for dermatophytosis.
Fungal culture was performed using Sabouraud dextrose agar with chloramphenicol, and Sabouraud dextrose agar with chloramphenicol and cycloheximide. All cultures were incubated at 26°C for 2 weeks. Any growth of fungi belonging to dermatophytes was considered positive.
Treatment protocol.
All patients were given a standard treatment regimen. Itraconazole 100 mg twice daily and topical miconazole twice daily were offered with other necessary instructions on preventing the spread of the disease. The group of patients who had not used topical steroids previously were treated with a 2-week course of itraconazole, whereas the steroid-treated group was given the drug for 4 weeks. Clinical response was assessed at weeks 2 and 4 for the two groups, respectively. If the clinical response was partial, an additional 2 weeks of itraconazole was prescribed, for a maximum of 6 weeks. Partial responders for itraconazole at week 6 were given a course of terbinafine 250 mg daily for 4 weeks.
Outcome assessment.
The observation points were at weeks 2, 6, and 10 for patients who had not used topical steroids, and at weeks 4, 6, and 10 for the group of patients that did use topical steroids. The patients were assessed clinically by a dermatologist at each point and were categorized as complete clearance or partial clearance, based on examination findings. Clinical cure was defined as the complete resolution of symptoms and signs with or without post-inflammatory changes.9 Those who achieved complete clearance were observed for an additional 3 months to identify recurrences.
Outcome.
The study’s primary outcome was to assess the therapeutic response of dermatophytosis to standard antifungal treatment in Sri Lanka. The secondary outcome was to identify possible contributory factors in cases showing inadequate therapeutic response.
Statistical analysis.
Data entry and analysis were carried out using SPSS 21 statistical software (SPSS Corporation, Chicago, IL). Descriptive statistics are presented using numbers and percentages for categorical variables, and mean and range for continuous variables. Clinical outcome and recurrences were analyzed in the two groups—used topical steroids and did not use topical steroids—separately and according to the fungal culture. Recurrences are presented for those who obtained complete clearance. The associations in groups were compared using χ2 statistics at P < 0.05.
RESULTS
Sociodemographic data.
A total of 796 patients with a clinical diagnosis of dermatophytosis in glabrous skin were included in the study. A female preponderance of 57.5% (458) was seen, and 408 subjects (51.3%) were younger than 40 years of age (age range, 18–92 years).
Symptom analysis and previous treatment.
In 219 patients (27.5%), symptoms were present for 3 to 6 months before presentation; in 191 patients (24%), for more than 6 months before they presented to a dermatology clinic. In addition, multiple sites, as defined by the involvement of three or more body sites, were affected in 159 patients (65.2%). Facial involvement was noted in 165 patients (20.7%).
Diabetes mellitus was the most common comorbidity, accounting for 105 cases (13.2%), and 25 patients (3.2%) were noted to be taking immunosuppressants.
When analyzing the previous treatment patterns of the patients, the following observations were made: of the patients who had details of previous topical antifungal treatment (n = 651), it was noted that 493 (75.7%) had used topical antifungals. Furthermore, treatment details about oral medication were available in 444 patients (55.7%), and of these patients, oral antifungals were used by 128 (28.8%).
Details of topical steroid use were obtainable from 626 patients, 368 (58.8%) of whom had a history of topical steroid use before presenting to a dermatology clinic. Out of the steroids used, 0.1% betamethasone valerate was the most commonly used preparation (n = 200, 54.3%), whereas hydrocortisone and clobetasol were used by 89 patients (24.2%) and 76 patients (20.7%), respectively. When the duration of topical steroid use was considered, it was noted that 105 patients using a topical steroid (28.53%) had used it for more than 6 weeks.
The source of the topical steroid prescription was investigated, and we discovered that the most common source was from outpatient departments of government hospitals, which accounted for 175 patients (47.6%), with general practitioners contributing an almost equal proportion (n = 157, 42.7%). Pharmacists were responsible for prescriptions to 55 patients (14.9%), and only 6% of patients self-administered. The clinical features of prior steroid use observed among the patients are described in Table 1. Based on history and clinical observations, 503 patients (63.2%) had used topical steroids for their dermatophyte infection before presenting to a dermatology clinic.
Description of clinical features of previous steroid use
| Feature* | No. of patients (N = 796) | % |
|---|---|---|
| Broken rings | 272 | 34. 2 |
| Flattened margins | 316 | 39.7 |
| Prominent pustules | 78 | 9.8 |
| Hypopigmentation | 95 | 11.9 |
| Skin atrophy | 91 | 11.4 |
| Ring-within-ring appearance | 60 | 7.5 |
*Multiple responses.
Mycological studies.
Details of the mycological studies are presented in Table 2. Skin scrapings were positive for fungal elements in the direct smears of 659 patients (82.8%). Of the cultures positive for dermatophytes (n = 500), 328 (65.6%) were Trichophyton mentagrophytes and 168 (33.6%) were Trichophyton rubrum.
Details of mycological investigations
| Mycological investigation (N = 796) | Test result | n | % |
|---|---|---|---|
| Direct microscopy | Negative | 124 | 15.6 |
| Fungal hyphae | 446 | 56.0 | |
| Fungal arthrospores | 145 | 18.2 | |
| Fungal hyphae plus arthrospores | 68 | 8.5 | |
| Yeast cells | 13 | 1.6 | |
| Culture | Specimen not sufficient for culture | 69 | 8.7 |
| Negative | 220 | 27.6 | |
| Trichophyton mentagrophytes | 328 | 41.2 | |
| Trichophyton rubrum | 168 | 21.1 | |
| Epidermophyton floccosum | 2 | 0.25 | |
| Microsporum canis | 2 | 0.25 | |
| Candida species | 7 | 0.9 |
Clinical outcome.
In 139 patients (47.4%), symptoms were cleared only partially after 2 weeks of itraconazole treatment in the group that had not used topical steroids earlier (n = 293). This number decreased to 27 patients (9.2%) with prolonged use of itraconazole for up to 6 weeks. At this point, the oral antifungal drug was changed to terbinafine, and only five patients (1.7%) had partial clearance at the end of 4 weeks of taking terbinafine. However, the group that used topical steroids earlier showed a greater number of patients with partial clearance at each review point of the follow-up. The response in the two groups was statistically significant at week 6 (χ2 = 91.9, df = 2, P < 0.001) and week 10 (χ2 = 86.37, df = 2, P < 0.001) (Table 3).
Description of the therapeutic response to antifungals
| Group | Response | Follow up, n (%) | |||
|---|---|---|---|---|---|
| Week 2 | Week 4 | Week 6 | Week 10 | ||
| Did not use topical steroids (n = 293) | Partial clearance | 139 (47.4) | – | 27 (9.2) | 5 (1.7) |
| Complete clearance | 104 (35.5) | – | 190 (64.8) | 204 (69.6) | |
| Lost to follow-up | 50 (17.1) | – | 76 (25.9) | 84 (28.7) | |
| Used steroids (n = 503) | Partial clearance | – | 367 (72.9) | 201 (40) | 125 (24.9) |
| Complete clearance | – | 108 (21.5) | 242 (48.1) | 290 (57.7) | |
| Lost to follow-up | – | 28 (5.6) | 60 (11.9) | 88 (17.5) | |
The therapeutic response at week 10 was less in subjects with T. mentagrophytes compared with T. rubrum (Table 4). The response in the two groups was statistically significant at week 10 (χ2 = 9.16, df = 2, P = 0.01).
Therapeutic response at 10 weeks according to fungal species
| Fungal culture | Clinical response at 10 weeks, n (%) | ||
|---|---|---|---|
| Partial clearance | Total clearance | Lost to follow-up | |
| Trichophyton mentagrophytes (n = 328) | 66 (20.1) | 207 (63.1) | 55 (16.8) |
| Trichophyton rubrum (n = 168) | 16 (9.5) | 118 (70.2) | 34 (20.2) |
Recurrences.
Of those who achieved complete clearance (n = 494), a recurrence of dermatophytosis was observed in 174 (35.2%) during the 3-month follow-up. Of the 174 recurrences, 59 (33.9%) were observed at week 4. However, in 47 patients (27%), symptoms reappeared 3 months after complete clearance, indicating a late recurrence. It was noted that 128 of 290 patients (44.1%) experienced a recurrence of dermatophytosis in the group that used topical steroids before presentation compared with 46 of 204 patients (22.5%) in the group that did not use steroids earlier. This association is statistically significant (χ2 = 26.09, df = 2, P < 0.001) (Table 5).
Details of recurrences during the 3-month follow-up period
| Group | Outcome, n (%) | ||
|---|---|---|---|
| Recurrence | No skin rash | Lost to follow-up | |
| Complete responders in the group that received no prior steroid (n = 204) | 46 (22.5) | 66 (32.4) | 92 (45.1) |
| Complete responders in the group that received prior steroid (n = 290) | 128 (44.1) | 79 (27.2) | 83 (28.6) |
It was also noted that recurrences were seen more in patients with T. mentagrophytes than T. rubrum (Table 6). This association is statistically significant (χ2 = 15.76, df = 2, P < 0.001).
The recurrence of dermatophytosis after complete clearance according to fungal species
| Fungal culture | Clinical response, n (%) | ||
|---|---|---|---|
| No skin rash | Recurrence | Lost to follow-up | |
| Trichophyton mentagrophytes (n = 328) | 49 (23.6) | 95 (45.9) | 63 (30.4) |
| Trichophyton rubrum (n = 168) | 41 (34.7) | 28 (23.7) | 49 (41.5) |
DISCUSSION
Our study signals that Sri Lanka is heading for an island-wide epidemic of extensive, recurrent, and challenging-to-treat dermatophytosis. To our knowledge, this is the first study to report a similar trend outside India.
Upon presentation to dermatology clinics, 191 patients (24%) had symptoms for more than 6 months, which falls into the definition of chronic dermatophytosis.9 In addition, 519 patients (65.2%) had symptoms at more than three sites, pointing toward extensive disease. Similar to the few other studies done recently.5,13 greater facial involvement was seen, with 165 patients (20.7%) affected. All this evidence suggests the current wave of dermatophyte infections tends to be chronic, extensive, and atypical.
The mycological studies showed a predominance of T. mentagrophytes as the causative fungal species of dermatophytosis in glabrous skin. In the past, T. rubrum was the predominant fungal species causing dermatophytosis in Sri Lanka.14 Nenoff et al.15 reported a country-wide shift of T. mentagrophytes predominance in dermatophytosis in India. For the first time, we report a similar trend in the predominant mycological species of dermatophytosis in Sri Lanka. Trichophyton mentagrophytes is a more virulent fungal species. Thus, this shift may have several therapeutic implications.16
Our study tried to adopt a standard regimen at all treatment centers, and the patients’ therapeutic response was observed prospectively. Itraconazole was preferred as a first-line treatment over terbinafine because of drug availability in government hospitals where the study was conducted.
At the end of standard oral antifungal treatment at week 2, 139 of 293 patients (47.4%) patients with no prior history of steroid use showed partial clearance. The therapeutic response improved with a longer duration of itraconazole treatment, with 27 patients (9.2%) having partial clearance at week 6 in the same group. The current recommended first-line treatment of naive tinea is 2 to 4 weeks of either itraconazole or terbinafine.9 Our findings suggest that longer durations of therapy are needed to obtain a better therapeutic response in the current setting.
There was a significant difference in the therapeutic response in the group that received topical steroids previously, with a partial clearance rate of 40% at week 6 compared with 9.2% in the group with no steroid use. This lower therapeutic response in the steroid-treated group tends to remain the same for terbinafine, with a partial response rate of 24.9% compared with 1.7% in the group that did not use steroids (Table 3). Topical steroids are known to reduce the host’s immune response.10 In India, steroid abuse is a major contributory factor in treatment-resistant dermatophytosis.5–7 Our data confirm this finding, with a significant lower therapeutic response in patients in the steroid-treated group who were treated subsequently with both itraconazole and terbinafine. In our study, a significant proportion of patients received topical steroids from hospital outpatient departments (47.6%) and general practitioners (42.7%). This finding emphasizes the importance of maintaining continuous medical education among medical practitioners. Primary care physicians should be educated about the emerging problem of recalcitrant dermatophytosis, the role of steroids in reducing the therapeutic response, and proper dosing and duration of antifungal treatment in dermatophytosis.
Of the complete responders (n = 494), 174 (35.2%) showed a recurrence of dermatophytosis during the 3-month follow-up. Fifty-nine recurrences (33.9%) were observed as early as week 4. This early recurrence may be a result of a reactivation of fungi when the persistent antifungal drug concentrations in the epidermis gradually decrease. However, it is worth noting that a striking number of recurrences (27%) occurred 3 months after complete clearance, emphasizing the need for continuous follow-up. In addition, recurrences were significantly greater in the steroid-treated group, further highlighting the harm done by the inadvertent use of steroids in the management of dermatophytosis.
Trichophyton mentagrophytes is known to be a virulent species that causes more inflammatory tinea infections.16 In our study, partial responders and recurrences were greater in the T. mentagrophytes group compared with T. rubrum, indicating that the change of predominant fungal species could also be primarily responsible for the recent epidemic proportions of dermatophytosis.
In addition to the findings of the study, there are other contributory factors for the low therapeutic response of dermatophytosis in Sri Lanka. Overcrowding and spread within the household, new fashion trends in the younger generation with tight-fitting clothes, and an increasing number of patients with immunosuppression are few host-related factors. Prescriptions of inadequate doses of antifungals, poor-quality drugs, and poor compliance are some other factors. The high cost of antifungal drugs and the unavailability of a continuous drug supply at government hospitals add to the problem of low compliance.
Although our study was a prospective multicenter one with representations from all provinces in Sri Lanka, there are several limitations. First, there is a significant number of participants who failed to complete the follow-up. Because the study participants were offered free access to dermatology consultations during the study period, it was expected the patients would return if an inadequate therapeutic response was achieved. Therefore, we feel the reason for not returning could be the clearance of their skin lesions.
Molecular identification of the fungal species was not done because of resource constraints. Although the therapeutic response to commonly used antifungal drugs was assessed, in vitro drug sensitivities were not done at this stage. Irrational drug regimens and suboptimal doses of antifungal medication are other causative factors for recalcitrant dermatophytosis. This information was not assessed because of the difficulty in extracting such information before presentation to dermatology clinics. As dermatologists, we may be seeing just the tip of the iceberg of the current epidemic of dermatophytosis. Larger-scale epidemiological data are needed to assess the true incidence and prevalence of the disease.
In conclusion, this study highlights the magnitude of the emerging problem of an inadequate therapeutic response in dermatophytosis in Sri Lanka. It also sheds light on possible causative factors—namely, the change of the predominant causative species and topical steroid misuse. Furthermore, our finding of inadvertent use of topical steroids in dermatophytosis at the primary care level highlights the need for continuous education of primary care physicians. Last, this study signifies that the relevant authorities should take necessary steps to control the current problem of recalcitrant dermatophytosis and steroid abuse in the Indian subcontinent before it becomes a regional public health problem.
ACKNOWLEDGMENTS
We thank the Sri Lanka College of Dermatologists for funding our study.
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