Relapse of Cutaneous Fungal Infection in Healthy Individuals - A Rising Concern

Background: Superficial fungal infections are among the most common skin diseases, affecting millions of people with history of relapse. Tinea cruris (34.38%) was the most common site to come with history of relapse followed by onychomycosis (15.6%). Relapse occurred in 38.75% of the cases treated with terbinafine as this was the most common drug used. Conclusion: Regardless of the drug taken there were cases of relapse in cases of cutaneous fungal infection even in healthy individuals.


INTRODUCTION
Fungi can cause both cutaneous and systemic infections. They are ubiquitous organisms and hence the human skin can get exposed to fungi from the soil (geophilic fungi), animals (zoophilic fungi) and even from contact with humans (anthrophillic fungi) [1,2]. Cutaneous fungal infections are caused either by the group of fungi known as dermatophytes -viz; trichophyton, epidermatophyton and microsporon or by candida species or by non dermatophyte moulds [1]. They are a common phenomenon, affecting millions of people worldwide. While cutaneous fungal infection is not normally life threatening, it can be very uncomfortable and associated with a significant decrease in quality of life [3,4].
Relapse after cure of fungal infections is common. Some patients are more susceptible to develop recurrence even after the complete cure with medications like in elderly, diabetics, immunocompromised patients, and patients on systemic steroids or other immunsuppresants [5][6][7][8]. Even otherwise immunocompetant persons can also experience a recurrence of fungal infections which may be due to genetic susceptibility [9], presence of resistant fungal spores, improper hygiene, reinfection from infected partners, ubiquitious nature of fungal organisms and inability to eradicate the reservoir of fungal infections.
In the present scenario, relapse of the cutaneous fungal infections has acquired serious dimensions. Much has been studied about the recurrences in the immunocompromised patients but there are a very few studies on the recurrences in normal people even after complete cure.

Aims and Objectives
To study the relapse of cutaneous fungal infection in healthy individuals.

MATERIALS AND METHODS
During a period of six months, all healthy individuals who came to the out-patient department of dermatology with the history of first episode of relapse of cutaneous fungal infection were enrolled in the study. A total of 160 such patients were entered into the study and for each patient a detailed clinical history and examination was carried out. Number of lesions -single or multiple, anatomical site of the fungal infection were noted for each case. Occupation, residence -urban or rural and other pertinent demographic details were noted. Important personal history and family history of any fungal infection were recorded for each case. Nature and the duration of the drug taken for the previous episode of fungal infection was noted either from history of patient or documents available with the patient to exclude the patients who had taken inadequate therapy.
The skin scrapings were taken from the affected site and subjected to microscopic examination using 10% potassium hydroxide for confirming the fungal infection, however fungal culture was not done. Routine investigations including blood tests, fasting blood sugars, hepatitis and retroviral serology was carried out.

Exclusion Criteria
Patients with generalized immunosuppression like diabetics, HIV patients, extremes of age (<1 year and > 70 years) and patients on systemic steroids or immunosuppressants were excluded from the study.

RESULTS
During the period reviewed in this study, the total number of otherwise healthy patients who came with the relapse of fungal infection was 160. Relapse was more common in the adults in the age groups of 40-50 years (25.62%) and 30-40 years (21.88%) ( Table 1).
In this study, relapse of cutaneous fungal infections occurred more commonly in males 67.5 % (Fig. 1).
To determine the correlation between socioeconomic conditions and prevalence of relapse in patients, residential distribution of the patients were investigated. Patients living in urban area (56%) were more likely to have relapse than those living in rural areas (Fig. 2). 142 patients had lesions involving a single site while 18 had lesions involving the multiple sites. 15.6% of the relapse cases had family history of fungal infection in one or more members.
Regarding the occupation, farmers (38 cases, 23.75%) and housewives (35 cases, 21.88%) formed the bulk of the patients. Table 2 shows the occupation of the study cohort.

DISCUSSION
Dermatophyte infections are common disorders worldwide that cause infection of the skin and nails [10][11][12]. They were reported as the fourth most common disease in 2010 affecting 984 million people [13]. Although no living tissue is invaded, however a variety of pathological changes occur in the host because of the presence of the infectious agent and/or its metabolic products.
Fungal infections respond favourably to the antifungal agents presently available in the market, but are more prone to develop recurrences. Numerous environmental and physiological conditions can contribute to the development of relapsing fungal diseases. Predisposing host factors play an important role for the development of dermatophytosis of the skin and nails. Chronic venous insufficiency, diabetes mellitus, disorders of cellular immunity, and genetic predisposition should be considered as risk factors [14]. Very young and very old people, also, are groups at risk [5].
All the patients who came with a relapse of cutaneous fungal infection were entered in this study however the patients belonging to the susceptible subgroup were excluded from the study.
In this study, relapse was most common in adults. Adults greater than 30 years comprised more than 75% of the total cases. Relapse rates are lower in children and adolescents because of the faster clearance of the fungal infection from the reservoir sources like nails as nail growth is faster in young as compared to the adults [15]. Also, environmental exposure to the fungus increases with age and immunity decreases with age.
There were more cases of relapse in the males (67.5%) as compared to the females (32.5%) which may be due to the more of exposure in males associated with the outdoor work.
Environmental exposure to fungi is more common in rural areas, however in our study relatively more of the relapse cases came from urban areas (56 %). Numerous factors may contribute to the relapsing fungal infections in the urban areas which include poor housing conditions due to overcrowding causing person to person spread and reinfection despite adequate initial control.
Family history of fungal infection was seen in 25 cases (15.6%). Two factors may contribute to the relapse seen in the families. First and foremost is the genetic predisposition to fungal infections and such persons are likely to experience repetition of the disease [9]. Second factor that contributes to the relapse in the family members is the reinfection after the initial cure that occurs in the family due to sharing of infected footware, towels, clothing, and bedding. The scales shed from the skin contain fungal spores which survive for much longer period of time in the immediate environment of the patients. [16] In this study, farmers (23.75%) and housewives (21.88%) constituted the bulk of the cases that came with relapse. More cases in the farmers occur due to more contact with fungi associated with soil (geophilic) and cattle (zoophilic). Again in house wives, wet work and frequent immersion in water makes them more predisposed to develop relapsing fungal infections. Pertinent to mention here, 10 cases of relapse were from military or police personal. This subgroup is more prone to develop relapsing fungal infection of nails and groins due to wearing of occlusive footwear and tight clothing. Medical/veterinary personal also came with a relapse of fungal infections (4 cases). This subgroup is important to identify because they may serve as a quiescent focus of infection to the other persons for whom they provide care. Few outbreaks have been reported to occur due to this nosocomial spread from the caregivers [17,18].
Regarding the anatomical site, most of the patients came with a relapse of tinea cruris (34.38%). High rates of relapse are seen with tinea cruris which may be explained because high humidity and moisture cause maceration of the groins which makes this area particularly susceptible to develop the recurring fungal infection even after initial adequate control with anti-fungal agents. Also, reinfection from untreated infected partners contributes to the high rates of relapse for groin infections. Tinea pedis and onychomycosis are risk factors for tinea cruris, and failure to treat concomitant tinea pedis usually results in prompt recurrence. A common mistake that many clinicians make is to prescribe combination antifungal corticosteroid products for the treatment of this common fungal skin infection without confirming the diagnosis. This course of action is not recommended for several reasons. First, topical corticosteroids can exacerbate tinea infections and may contribute to treatment failure, especially when infections are due to Microsporum species [19][20][21] Tinea cruris requires antifungal treatment for several weeks; using a combination product puts the patient at risk unnecessarily for side effects, such as skin atrophy, from topical corticosteroids. Combination products are far more expensive than simple antifungal agents, or even generically available corticosteroid preparations. In one study, nondermatologists were more likely than dermatologists to prescribe combination products (34 versus 4 percent), leading to excess medical costs of $10 to 25 million [22].
Among the other sites, tinea unguam (15.62%) and associated tinea pedis (10%) also accounted for large number of cases. Although the overall rate of recurrence for onychomycosis is not known, recurrence rates between 6.5% and 53% have been reported, despite successful treatment with oral antifungal drugs [23][24][25]. It is important to identify the onychomycosis and associated tinea pedis cases because nails may serve as a reservoir of fungal infections and whenever the conditions are condusive the spread occurs to the other parts of body. Also scales shed from the tinea pedis patients may reside in the carpets, floor of the house and bathroom slippers and serve as a source of reinfection to the other people.
Relapse of tinea mannum (8.75%) occurs particularly in those who frequently immerse their hands in water or indulge in wet work like in house wives.
Eight cases showed the relapse of fungal infection from the bearded area in males -tinea barbrae. In T. rubrum infection in some patients, the organism may persist within villous hair shafts and follicles leading to chronic recurrences of the infection [26].
Although fungi respond very well to all the agents and clear completely irrespective of whatever drug is used, there are cases of relapse. Treatment of dermatophyte infections is based on the clinical picture and mycological detection of the causative pathogen [27]. Griseofulvin has long been used for treatment of cutaneous fungal infections, although cure rates of 60% only have been noted [28]. Griseofulvin-resistant isolates have been obtained from clinical sources and from laboratory mutagenesis experiments [28]. Hence this drug is not used frequently now and for the same purpose none of relapse patients had used griseofulvin. Ketoconazole has been used and has a lower relapse rate, [29,30] but a greater chance of inducing side effects, such as hepatotoxicity and depressed adrenal activity [30]. In July, 2013, the US Food and Drug Administration (FDA) withdrew the indication of oral ketoconazole for use in dermatophyte infections due to its high toxicity profile. In the present study only two cases of relapse came with history of ketoconazole intake. In recent times, itraconazole and terbinafine have become widely available for the treatment of cutaneous fungal infections. In our study, 38.75% of relapse cases had used terbinafine and 20% of the patients had taken itraconazole to clear their fungal infection in the previous episode. Various studies have shown greater efficacy of itraconazole than griseofulvin in tinea corporis, tinea cruris, tinea manuum, and tinea pedis [31]. Mycological cure rates of tinea corporis and tinea cruris 1 month after 15 days of therapy with itraconazole at 100 mg/day were approximately 80% [32]. Rates of success for terbinafine have been 75 to 90% in tinea corporis and chronic tinea pedis [33]. 26.88% of relapse cases had used fluconazole in their previous episodes. Fluconazole has to be taken weekly and is cheaper as compared to other drugs and a large number of the patients (26.88%) had used it in their previous episode of fungal infection.
To sum up, irrespective of drug used relapse was seen even after effective clearing at first. This is supported by the study conducted by Tosti et al. which shows that 22.2% of patients with onychomycosis successfully treated with systemic antifungals experienced a relapse [34].
Patient education is just as important as pharmacologic therapy for controlling the recurrence of cutaneous fungal infections. Need of the hour is to stress on the various measures that have to be taken to control the relapse of cutaneous fungal infections. Since tinea corporis and tinea cruris caused by anthropophilic fungi can be transmitted by infected clothing, towels, and bedding, these items should be disinfected after use and infected individuals should not permit others to share them. Individuals with tinea corporis should not engage in contact sports such as wrestling [35]. It is important to locate the animal reservoir in infections caused by the zoophilic dermatophytes. The infected hair and scales have been shown to survive for years on fomites such as wooden fences [36]. Good hygiene and sanitation and fungicidal sprays and washes have been effective in controlling theseinfection [26]. When economically feasible, systemic griseofulvin could be used to treat infected cattle. Human infections are common in personnel handling of animals (dogs, cats, and rodents) infected with a dermatophyte. Many of these infections are subclinical; therefore, routine wearing of protective clothing, especially gloves, is recommended.
Measures for prevention should be based on maintenance of local resistance to infection by individual care and hygiene of the feet and groin. For prevention of relapse in tinea cruris, patients should also be advised to avoid hot baths and tight-fitting clothing; men should be advised to wear boxer shorts rather than briefs, and women to wear cotton underwear and avoid tight-fitting pants [37,38].
Prevention of tinea pedis may be enhanced by using good foot hygiene (includes regular washing of the feet, thorough drying, and application of foot powder); avoiding excessive moisture and occlusion by wearing sandals or other well-ventilated shoes; avoiding trauma to the feet, especially blistering by ill-fitting footgear; and not sharing towels, socks, or shoes. The individuals carry pathogenic fungi in quiescent foci on their nails, feet, and groin and the infection exacerbates when trigger factors lower resistance. It is important to recognize that the toe web spaces are the major reservoir on the human body for these fungi and therefore it is not practical to treat infections at other sites without concomitant treatment of the toe web spaces. This is essential if a "cure" is to be achieved.

CONCLUSION
As dematophyte infection is worldwide, the present study provides an insight into the alarming trend of relapse even after successful treatment with antifungal agents at first. A lot of research has been done regarding this in the immunocompromised population groups and the present study fills the void existing in the research of the relapse in normal healthy individuals. In addition, the study presents a relation between this relapse and many other demographic and therapeutic factors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.