Onychomycosis: predisposed populations and some predictors of suboptimal response to oral antifungal agents

ARTICLE

With the availability of the newer antifungal agents, terbinafine, itraconazole and fluconazole for the treatment of onychomycosis, it is now possible to achieve markedly higher cure rates compared to griseofulvin [1-11]. However, in many cases mycological cure is not observed at follow-up 6 or 9 months after completing a standard course of therapy for fingernail and toenail onychomycosis, respectively. With increasing fiscal restraints on the delivery of healthcare, it is more important than ever to provide cost-effective therapy. Therefore, physicians must be aware of populations predisposed to onychomycosis, factors that may be associated with a suboptimal response to the new oral antifungal agents, and possible solutions. Five main groups need to be considered: genetic, environmental, systemic, local and others. In some of the patient groups the onychomycosis may be more likely to relapse. The importance of this topic is highlighted by other publications on this subject [12-15].

Genetic factors

Onychomycosis may have a genetic predisposition [16]. In practice it is often difficult to separate a genetic component from environmental exposure [17]. Distal subungual disease (the most common type of onychomycosis) caused by Trichophyton rubrum may be familial and possibly an autosomal dominant disorder [16]. In many instances tinea pedis precedes onychomycosis. Where possible genetic transmission has been identified, it is particularly important to treat tinea pedis early and effectively before onychomycosis develops. As a rule, tinea pedis should be treated and the patient counseled about ways to reduce the development of onychomycosis [13, 18].

Environmental factors

It is important to be aware of clinical situations where there may be a high prevalence of tinea pedis [19-23]. Fungal foot infections are uncommon in populations that are habitually bare-footed [23]. The incidence of tinea pedis may be higher in individuals living in a community setting, those frequenting communal washing facilities or swimming baths. Furthermore, sharing of socks should be discouraged since laundering may fail to eliminate fungal organisms from worn socks [21]. When an individual walks barefoot over surfaces or wears shoes that have a high density of spores, there may be direct contact of healthy feet with fungal inoculum from skin scales and fragments shed by infected individuals [22]. Subsequent incubation of the organisms in the warm humid environment created by wearing shoes for prolonged periods of time predisposes to tinea pedis and onychomycosis [24]. This is facilitated in situations where there is microtrauma to the feet, peripheral vascular disease, etc.

Systemic conditions

Immune dysfunction, chronic mucocutaneous candidiasis:

Some patients with immune dysfunction, particularly of cell-mediated immunity, may be more likely to have onychomycosis. For example, chronic mucocutaneous candidiasis (CMCC) is a complex group of disorders [25-27]. Primarily there is deficiency of the cellular immune system with or without disorder of the humoral immune system. The most commonly identified immunological defect is a specific inability to respond to antigens of Candida albicans. Cutaneous responses to other antigens may be intact [25].

Immune dysfunction, chronic dermatophytosis syndromes:

Certain dermatophyte infections may fail to respond to therapy, relapse or exhibit a chronic course [28-36]. Subjects with the chronic dermatophytosis syndrome due to Trichophyton rubrum may exhibit tinea infection at various anatomical sites including distal subungual onychomycosis [36]. Chronic infections with T. rubrum may be associated with atopy [31], diabetes mellitus [37], Cushing's syndrome [38] and lymphoma [39]. However, the exact relationship between the underlying disease, the causative organism, the clinical pattern and duration of infection and poorly sustained response to therapy are not clear [29]. Hay and Brostoff [28] showed that 47% of patients chronically infected with T. rubrum had immediate type hypersensitivity responses to intradermal Trichophyton, with a much lower proportion (5%) showing delayed type responses, and 11% having both types.

Chronic dermatophytosis or clinically similar dermatomycoses may also be caused by other fungal organisms, for example, Trichophyton mentagrophytes, Epidermophyton floccosum, Scytalidium dimidiatum or S. hyalinum [36]. T. mentagrophytes is more likely to cause white superficial onychomycosis and may also be associated with tinea pedis of the interdigital type or the variety that is vesicular and affects the arch of the foot [36]. Infection caused by
E. floccosum is relatively uncommon and may manifest itself as distal subungual onychomycosis, tinea pedis, tinea cruris and tinea corporis [36]. Scytalidium species may infect the nails or relatively heavy keratinized areas of the sole and palm, but interdigital infection is unusual.

In a proportion of patients there may be a natural resistance to the disease, although the nature of the resistance and the proportion of the population protected are unknown [40-42]. Strauss and Kligman [41] demonstrated that it was not easy to establish a tinea infection in subjects with completely normal feet. In their series the conditions for infection were a heavy inoculum and a persistently wet environment. The positive infectivity rate was at best about 50%, and the infections tended to be transient and self-limiting [41].

Immune dysfunction, human immunodeficiency virus infection (HIV): Individuals infected with HIV may be more likely to develop onychomycosis when their helper T-lymphocyte (CD4) count is approximately 400/mm³ (normal range: 1,200-1,400) [43]. The clinical presentation and organisms causing onychomycosis are often similar to patients without HIV disease; however, there may be some important differences [43-48]. In HIV positive individuals onychomycosis is more likely to spread faster to involve all the fingernails and toenails compared to normal individuals [44]. In HIV positive individuals the periungual region may demonstrate dermatophyte infection. Also, "one hand two feet tinea" which is relatively uncommon in the general population is more likely to be present in HIV positive individuals [44]. Proximal white subungual onychomycosis is generally an indication of HIV disease although other immunocompromised individuals such as transplant patients may uncommonly exhibit the same pattern of infection. In both immunocompromised and immunocompetent individuals the most common organism is T. rubrum. In immunocompetent individuals white superficial onychomycosis (WSO) is generally due to T. mentagrophytes; in HIV individuals the causative organism in WSO is more likely to be T. rubrum [44].

Special patient populations, Down's syndrome: Compared to the normal population, subjects with Down's syndrome may have a higher prevalence of onychomycosis and tinea pedis/manuum. In this condition there may be diminished cellular immunity which could predispose to onychomycosis and tinea pedis/manuum [49-52]. Some patients with Down's syndrome live in communal housing and this could further increase the probability of developing onychomycosis.

Special patient populations, leprosy patients: Patients with leprosy may have a higher prevalence of onychomycosis (Personal communication: AKG with Dr. Douglas W. Johnson, Honolulu, Hawaii, USA). This could in part be related to cellular immune dysfunction. Communal housing may contribute to the development of onychomycosis.

Special patient populations, diabetics: In the study by Buxton et al. [53] the prevalence rate of onychomycosis in 100 diabetics and 100 non-diabetics was 12% and 11%, respectively. In contrast, another study [54] suggested that onychomycosis may be found more frequently in diabetics compared to the non-diabetic population. In the survey by Gupta et al. [54] onychomycosis was present in 26.2% of diabetics (N = 550) and was projected to affect approximately one-third of diabetics in the general population of Ontario, Canada or Boston, Mass., USA, the two centers where the survey was conducted. After controlling for age and sex, the risk odds ratio for diabetic subjects to have onychomycosis of the toes was 2.77 times compared to normal individuals [54]. After controlling for age and sex, a stepwise logistic regression demonstrated that significant predictors for onychomycosis included a family history of onychomycosis, concurrent intake of immunosuppressive therapy and peripheral vascular disease [54].

Special patient populations, psoriasis patients: Psoriatic patients are more likely to have onychomycosis compared to a control population [55]. In a sample of 561 psoriatics the prevalence of pedal onychomycosis was 13%. The odds of patients with psoriasis having onychomycosis was 56% greater than for non-psoriatics of the same age and sex (P = 0.02) [55-57].

Special patient populations, peripheral vascular disease: It has been our impression that patients with peripheral vascular disease are more likely to have onychomycosis. In fact, in diabetics, after controlling for age and sex, a stepwise logistic regression indicated that peripheral vascular disease was a significant predictor for onychomycosis [54].

Normal population, age and gender: Children are less likely to have onychomycosis compared to adults [58]. The prevalence of onychomycosis in North American children, 18 years old or younger (n = 2,500) visiting dermatologists' offices, and whose primary or referring diagnosis was not onychomycosis or tinea pedis, was 0.16% [58]. Furthermore, the prevalence of onychomycosis in children in different studies (n = 27,930) is 0.3% (95% confidence interval: 0.24 to 0.38%) [58]. In contrast, adults over age 40 years are more likely to have onychomycosis [56, 57]. Possible reasons are slower rates of outgrowth and larger surface area of the nail plate in adults compared to children, adults have more cumulative trauma and microtrauma to the nail, greater likelihood of peripheral vascular disease in adults, and reduced prevalence of tinea pedis in the younger age group [56, 58]. In susceptible children from families where T. rubrum occurs chronically, tinea pedis may predispose to onychomycosis [16, 58].

Males may be more likely to have onychomycosis because of hormonal differences between the sexes [59]. Progesterone and related steroids bind with high specificity to a cytoplasmic protein, and binding appears to be a general property of T. mentagrophytes and other taxonomically related fungi [59]. In addition, progesterone and other steroids that are capable of binding are able to inhibit growth of dermatophytes.

Special patient populations, fungal infection coexisting at other anatomic sites: When tinea infection is present at sites other than the nails it may be possible to excoriate the palms/soles or pick toe-/fingernails and autoinoculate the fungal organism into these sites. In a proportion of this group the "two feet-one hand" syndrome can be present [60]. In general, onychomycosis affects the toenails to a greater extent than fingernails [56, 57]. However, it is interesting to note that historically in the 1800's onychomycosis of the fingernails was more common in children with tinea capitis and their care givers [58]. This was consistent with transmission of fungal infection from the infected scalp to the nails.

Local factors involving the nail

Slow outgrowth of the nail plate: Toenails and fingernails grow out at approximately 3 mm/month and 1 mm/month, respectively [61, 62]. Patients with onychomycotic nails that exhibit faster outgrowth are likely to demonstrate a better response compared to nails with slow outgrowth. Also, the success of itraconazole (pulse) [63], terbinafine (AKG: preliminary observations) and fluconazole [64] therapies is in part due to the faster outgrowth of nails when treated with these antimycotic agents.

Lateral nail fungal disease: Poor penetration of the oral antifungal agent to the lateral nail plate from the underlying nail bed may be present because of reduced adhesion [65]. Therefore, supplemental therapies might need to be considered: partial surgical or chemical nail avulsion, use of a transungual drug delivery system using a topical antifungal agent, or additional oral antifungal therapy [65].

Extensive onycholysis: This may result in reduced delivery of the oral antifungal agent from the nail bed to the adjacent ventral nail plate [13, 14]. Possible treatment strategies include extensive trimming back of the diseased nail plate, or supplemental therapy as described in the section on lateral onychomycosis. Patients appear to respond better to oral antifungal therapy when there is minimal onycholysis and absence of lateral onychomycosis.

Central spike or subungual dermatophytoma: In some nails there is a longitudinal yellow or white-colored area that is in the shape of a spike, oval or round mass [13, 14, 66, 67]. The overlying nail plate is onycholytic and when the nail is cut back a thick hyperkeratotic mass, not particularly adherent to the underlying nailbed, may be observed [67]. Histological evaluation may reveal a dense mass of dermatophyte hyphae which are thick walled and somewhat abnormal-appearing [67]. Such lesions can be poorly responsive to oral antifungal agents [13, 14, 67]. A possible explanation could be that inadequate drug levels are reached within the fungal mass. A therapeutic option is to surgically remove such a lesion. In a substantial number of patients we are able to cut the nail back and curet out the diseased nail plate, without using local anesthesia.

Thickened nail plate (> 2 mm thickness): Additional antifungal therapy may be required in order to achieve an adequate concentration of drug within the entire thickness of the nail plate [13, 14]. Another option may be to debride the nail.

Extensive nail plate/nail bed disease: When there is onychomycosis involving the nail matrix, or if there is onychomycosis affecting a substantial portion of the nail plate/nail bed (e.g. > 75% nail plate involvement), then the treatment required for mycological cure may exceed the standard recommended dosage regimen for the oral antifungal agent [4, 68].

Pre-existing trauma to nail or pre-existing nail abnormality/disease: Trauma to the nail unit may produce a nailplate that is irreversibly damaged. In a proportion of cases this may predispose to onychomycosis associated with a dermatophyte or a non-dermatophyte. In fact, in a series of 15,000 patients who were assessed both clinically and mycologically for the presence of onychomycosis, when an abnormally-appearing nail had mycological evidence of onychomycosis, the risk-odds ratio of a history of significant trauma being associated with the nail was 5.3 (95% confidence interval: 3.9 to 7.1) [69]. When the nailplate is irreversibly damaged, or if there is a coexisting pathology e.g. psoriasis ("onychomycosis-psoriasis complex"), then the nail may continue to appear clinically abnormal despite persistently negative mycology indicating mycological cure following antifungal therapy. In such instances clinical failure following a course of antifungal therapy may be wrongly attributed to the antifungal agent.

Presence of arthroconidia: In general, a fungal organism may exist as arthroconidia or filamentous hyphae. Antifungal agents may have more activity against the growing phase of the fungal organism, that is, filamentous hyphae [15, 70]. Arthroconidia may have thicker cell walls and this may reduce drug penetration [15]. If the fungal organism is present in the non-growing phase (existing as arthroconidia), then it may be more resistant to antifungal therapy [15, 70]. In such instances an approach may be to enhance conversion of the arthroconidial phase to the mycelial phase, which is more sensitive to antifungal therapy.

Co-existing bacterial infection with onychomycosis: The term "onychomycosis-bacterial complex" has been used to identify the situation where onychomycosis is present concurrently with a bacterial infection [14]. The bacterial infection e.g. Pseudomonas needs to be treated first followed by appropriate antifungal therapy for the onychomycosis [14, 71].

Co-existing viral infection with onychomycosis: This has been termed "onychomycosis-herpes complex" [13, 14] and signifies herpetic infection of the nail unit co-existing with the onychomycosis. Herpes simplex of the nail is very uncommon and is limited to the fingernail. Even if the patient experiences recurrences these usually resolve within a few weeks. Therefore, the above is likely to play a minimal role in the response of onychomycosis to treatment.

Other factors

Incorrect diagnosis: Whenever possible, it is important to obtain mycological confirmation of onychomycosis, rather than relying on the clinical appearance of the nail plate alone. In surveys, onychomycosis with mycological confirmation was present in only 40 to 50% of toenails that appeared clinically abnormal [56, 69]. Mycological confirmation could consist of light microscopy and culture or nail biopsy with examination of the diseased nail plate following staining with periodic acid schiff (PAS) or silver [72, 73].

Unresponsive organism: Antifungal agents have a spectrum of activity with some having a narrower spectrum of activity than others. For example, griseofulvin is active only against dermatophytes [1]. Organisms such as Scytalidium dimidiatum [74, 75], Trichophyton rubrum nigricans, possibly Onychocola canadensis [76, 77], Scopulariopsis brevicaulis and Fusarium species may be poorly responsive or unresponsive to oral antifungal agents.

Poor compliance: There are different regimens available for the treatment of onychomycosis: continuous, one week a month (pulse) and once weekly (intermittent). To ensure high compliance the regimen needs to be carefully explained to the patient, using a calendar, if necessary.

Inadequate gastric acidity with reduced bioavailability: The absorption of terbinafine and fluconazole is not significantly affected by the presence of food or the fasting state. With itraconazole capsules, the oral absorption is best when the drug is taken following a full meal [78]. Absorption of itraconazole capsules under fasted conditions in individuals with relative or absolute achlorhydric such as patients with AIDS or those taking gastric acid secretion suppressors (e.g. H₂ inhibitors) is increased when itraconazole capsules are administered with a classic cola beverage (8 oz.) [79-81]. In contrast, itraconazole oral solution is best taken in the fasting state [82].

Drug interactions: A careful drug history should include enquiry about prescription and non-prescription medications. Drug interactions are predictable and in some instances may be associated with a lower concentration of the oral antifungal agent, for example rifampin may decrease the plasma level of each of the three antimycotics, terbinafine, itraconazole and fluconazole [83-86].

Resistance to dermatophytes: There is no convincing evidence of resistance to dermatophytes with terbinafine, itraconazole and fluconazole [15, 17]. The possibility of resistance of dermatophytes to griseofulvin has been raised [87, 88]. In one report the mean inhibitory concentration (MIC) value for Trichophyton rubrum isolates obtained from patients unresponsive to griseofulvin was substantially higher than the MIC for responsive control isolates. Artis et al. [87] observed that therapeutic failure with griseofulvin appeared to correlate with the relative in vitro resistance.

Discussion

Some population groups predisposed to onychomycosis and the factors that may be associated with a poor response to oral antifungal agents have been discussed. When mycologically confirmed onychomycosis appears to be poorly responsive to therapy with terbinafine or itraconazole, the patient may benefit from extra therapy administered either immediately following the standard duration of therapy (that is, an extra four week course of terbinafine in addition to twelve weeks of continuous therapy, or a fourth pulse of itraconazole), or at six to nine months following initiation of treatment [4, 13]. In the latter instance this may consist of four weeks of continuous therapy with terbinafine (250 mg/day) or a pulse of itraconazole (200 mg twice daily for one week). In some instances combination therapy with two oral antifungal agents [88], or sequential therapy [89] may be an option when monotherapy is unsuccessful. In countries where an effective nail lacquer or topical therapy is available this may function as an effective transungual drug delivery system for onychomycosis of minimal to moderate severity [90, 91]. Topical antifungal agents of proven efficacy may also have a role in the management of the early stages of reinfection/relapse. When moderate to severe onychomycosis is present then an oral antifungal agent should be considered. Sometimes oral antifungal therapy for onychomycosis may need to be supplemented with chemical or partial surgical avulsion (e.g. with severe onycholysis, lateral nail fungal disease, hyperkeratotic thickened nail and longitudinal spike).

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