Onychomycosis is a fungal infection of the nail unit. When onychomycosis is caused by dermatophytes, it is called tinea unguium. The term onychomycosis encompasses not only the dermatophytes but the yeasts and saprophytic molds infections as well. An abnormal nail that is not caused by a fungal infection is a type of dystrophic nail. Onychomycosis can infect both fingernails and toenails, but onychomycosis of the toenail is much more prevalent. The disease burden, clinical types, staging, diagnosis, and management of toenail onychomycosis will be discussed.
The most frequent cause of onychomycosis is Trichophyton rubrum, but other dermatophytes, including Trichophyton mentagrophytes and Epidermophyton floccosum, can be caused as well. The dermatophytes are identified in 90% of the toenail and 50% of fingernail onychomycosis. Candida albicans accounts for 2% of onychomycosis, occurring especially in fingernails. Nondermatophytic mold onychomycosis is primarily cultured from toenails. Examples of these saprophytic molds include Fusarium, Aspergillus, Acremonium, Scytalidium, and Scopulariopsis brevicaulis. They account for about 8% of nail infections.
Onychomycosis is a common infection that is increasing in incidence. In the United States, Trichophyton rubrum was initially thought to be a culture contaminant, but since the advent of international travel to Asia, T. rubrum has become the dominant causative organism in the United States. At least half of abnormal toenails are mycotic. Prevalence estimates range from 1% to 8%, and the incidence is increasing. It has been reported that patients are genetically susceptible to dermatophyte infections in an autosomal dominant pattern. Risk factors include aging, diabetes, tinea pedis, psoriasis, immunodeficiency, and living with family members who have onychomycosis. 
Causative organisms can be cultured from hotel carpets, public showers, and pool decks. In most cases, onychomycosis is preceded by an asymptomatic, dry hyperkeratotic tinea pedis. Over time, the dark, warm, moist environment of shoes and micro traumatic pressure on the nail unit compromise and break the hyponychial seal, allowing penetration of the dermatophyte into the nail bed. Repeated exposure to water in wet work compromises fingernails. Dermatophytes only live on the keratin of dead corneocytes in skin, nails, and hair. In the foot, the dermatophytes produce keratinases that begin the infection between the lesser toes, spread to the hyperkeratotic sole, and gradually extend to the distal hyponychial space of micro-traumatized nail units. Once the distal nail hyponychium is breached, the dermatophytes infect the nail bed, spreading proximally as onycholysis and subungual hyperkeratosis. 
The primary site of the infection is the nail bed, where the acute infection occurs with a low-grade inflammatory response and progresses to a chronic phase of the nail bed infection as total dystrophic onychomycosis. Histologically, the acute lesion of onychomycosis manifests as spongiosis, acanthosis, papillomatosis with edema, and hyperkeratosis. These signs resemble the pathology of psoriasis. As in most infections, a dense inflammatory infiltrate develops. Onychomycosis does infect viable nail matrix. Onychomycosis secondarily damages the nail matrix as the nail bed becomes hyperkeratotic and thickened in an effort to shed the fungal infection. The dermatophyte also invades the overlying nail plate, detaching and distorting it over time. The nail plate becomes elevated and misaligned as the infection enters the chronic total dystrophic clinical stage of onychomycosis (TDO). At this chronic stage of the infection, there are large amounts of compact hyperkeratosis, hypergranulosis, acanthosis, and papillomatosis with sparse perivascular infiltrate. Dermatophytosis and subungual seromas can occur. Zaikovska et al. found high levels of cytokines interleukin-6- and interleukin-10-positive cells in the nail bed as well as the bloodstream in onychomycosis. A significant amount of fibers containing human beta defensin-2 were found in the bed and plate of the mycotic nails.
The duration, progression, and success of previous treatments are all important aspects of the evaluation of a patient with nail disease. In addition, in suspected onychomycosis, medication history is important to assess the potential impact of systemic antifungals with current medications. A history of hepatitis or travel to areas where hepatitis is endemic is an important aspect in considering appropriate tests to order in the laboratory workup. Alcohol usage should be chronicled. Recreational activities can predispose patients to recurrence or reinfection. Tinea manuum, cruris, or psoriasis often accompany onychomycosis. The focused cutaneous examination should include special attention to the hands and feet and scalp.
Pedal onychomycosis often presents as one or more thickened, discolored toenails. Usually, one or both great toenails are affected. Most cases have concurrent mild, dry, hyperkeratotic tinea pedis that patients often mistake for simple xerosis. Baseline images of the target nail and measuring the extent of the infection are important to predict the duration of treatment and evaluate therapeutic progress in an infection that can take 12 months to clear. Estimate toenail growth at approximately one millimeter per month and measure the infected area of the nail unit to estimate the duration of the treatment. Keep in mind that fingernails grow faster than toenails, and aging and peripheral vascular insufficiency slow growth rates.
Determining the severity and clinical stage of the infection helps guide therapy and improves outcomes. The most common clinical subtype of onychomycosis is distal lateral subungual onychomycosis(DSLO). It presents as partial distal onycholysis with subungual hyperkeratosis or crumbling. Much less common is white superficial onychomycosis (WSO), which appears as white chalky deposits on the surface of the affected nail plate. It can be easily scraped away with a curette or rotary burr. The rarest subtype is proximal subungual onychomycosis (PSO), which develops overlying the nail matrix. It has been associated with acquired immunodeficiency syndrome (AIDS) and may be hematogenously spread. In the endonyx subtype, the interior of the nail plate is infected first, and the key feature of subungual hyperkeratosis of the nail bed is not evident. Total dystrophic onychomycosis (TDO) refers to the most advanced form of all sub-types. TDO is a later severe stage of the chronic subungual dermatophyte infection that may take 10 to 15 years to develop. There is significant subungual hyperkeratosis and destruction of abnormal nail plate and ridging of the nail bed. It is not only the most difficult stage to clear but also the type with the highest risk of developing subungual ulcerations, secondary bacterial infection and precipitating gangrene in patients with impaired peripheral circulation.
It is important to know that almost half of abnormal appearing toenails are not actually mycotic, so mycological testing is important to establish an accurate diagnosis. This is especially important if systemic therapy is planned. The traditional potassium hydroxide (KOH) wet mount preparation of subungual debris is only 60% sensitive but cannot identify the species. However, if the KOH is positive, it can separate dermatophytes from saprophytes. Currently, the most sensitive test (95%) is a pathologist interpreted nail clip biopsy that has been stained with periodic acid-Schiff (PAS) plus Grocott methenamine silver. Today, a mycologist is required to interpret fungal culture testing. Fungal cultures are very specific but not very sensitive (60%). Fungal cultures grow slowly, adding weeks and cost to the workup.
Fungal culture or PCR is required to speciate on the cause of the infection. They are useful to help determine the source of the infection in atypical cases or when one suspects a primary saprophytic infection. To confirm this suspicion, two subsequent cultures of the same saprophytic mold should be obtained before concluding that the saprophyte is the primary pathogen and not a contaminant. PCR improves the species-specific detection of dermatophytes 20% over fungal cultures alone.
Dermoscopy can clinically diagnose onychomycosis. It also can readily differentiate between onychomycosis and nail dystrophy. The presence of subungual short spikes and longitudinal striae indicates onychomycosis, while transverse onycholysis is consistent with micro traumatic nail dystrophy.
The most effective treatments for onychomycosis are systemic antifungals. Due to an increased risk of subungual ulceration, one also should consider oral antifungal therapy in moderate to severe disease, especially in patients with diabetes mellitus. Combination therapy with topical agents, periodic debridement, or chemical nail avulsion, may produce better results than systemic medication alone. For mild to moderate cases and in patients who prefer to avoid systemic antifungals, the newer topical antifungal therapies have improved cure rates. Meta-analyses have shown the mycological cure rate for terbinafine is 76%, itraconazole pulse dosing is 63%, and fluconazole is 48% effective while topical therapy mycological cure rates are 55% for efinaconazole and 36% for tavaborole or ciclopirox.
The complete cure rate is defined as both negative mycology and 100% clear nail is the gold standard for comparing efficacies. However, it is a very stringent criterion as residual nail dystrophy from chronic infection may scar the nail plate and not allow some results to be considered completely clear even though there may be a significant clinical improvement. On the other hand, the nail unit may be 100% clear, but the post-treatment fungal culture may detect fungal colonization. The complete cure rate for systemic terbinafine is 38%.
Oral therapy is the most effective therapy for severe onychomycosis, but for some patients, it is medically inappropriate. Additionally, many patients have a strong personal preference for a non-systemic approach. Topical therapy would seem to be a good solution to the problem if the efficacy rates were better. Many over the counter and prescription products are available, hinting that there is no clearly effective topical choice. The evidence concludes that complete cure rates for FDA-approved topical therapies have recently improved from 8.5% for ciclopirox lacquer to 18% for an efinaconazole solution. The tavaborole solution has a complete cure rate of 9.1% in mild to moderate distal subungual onychomycosis.
It is important to carefully review the patient history for alcohol use disorder and hepatitis. Ordering alanine aminotransferase and aspartate aminotransferase hepatic function tests before the beginning of continuous therapy establishes a baseline. If there is a history of living overseas where hepatitis is endemic, one can add a hepatitis antigen screening panel to the workup. Follow-up hepatic function tests at five weeks serve to detect the less than 2% of idiosyncratic reactions. If the follow-up tests are significantly elevated, one can stop the drug and retest.
Additionally, concurrent medications may preclude the use of oral antifungals. Terbinafine may alter the metabolism of a number of drugs, so monitoring is appropriate. Concerns regarding drug-to-drug interactions with statin therapy and systemic antifungal therapy are actually with the azole class of antifungals and not terbinafine. It might be best to avoid systemic therapy in patients on psychotropic medications. Terbinafine carries a contraindication for concurrent use with the phenothiazines and pimozide for increased risk of QT prolongation. Gupta reports one can use terbinafine safely in children as well as the elderly. However, clinicians should always exercise caution in patients with polypharmacy major. It may be best to use an alternative therapy or periodic debridement alone to control symptoms in these cases to avoid adverse drug reactions in patients with essentially benign disease.
Risk of infections are usually higher in patients with diabetes and include the following:
To control symptoms and reduce the risks of subungual ulceration and secondary bacterial infection, clinicians can use periodic debridement to successfully manage severe onychomycosis in patients who elect to avoid systemic therapy or are unable to apply topical antifungals. In addition, many patients are reluctant to accept the potential risk of idiosyncratic hepatic reactions that may occur during 90 days of continuous systemic antifungal therapy. Some patients will, however, accept and do well with pulsed systemic therapy. In moderate onychomycosis, 250mg of terbinafine daily for one week every nine weeks for three pulses is acceptable.
Although periodic thorough debridement is unlikely to clear onychomycosis, it appears to improve the immediate patient satisfaction and aid the efficacy of medications. Concurrent treatment of the tinea pedis should be undertaken and along with the long-term daily use of an antifungal powder to reduce reinfection and recurrence.
The management of onychomycosis is interprofessional. While the fungal infection is not life-threatening, it has enormous morbidity. The key is patient education. The public should be educated about appropriate footwear when visiting community swimming pools, saunas, and health clubs. If the patient works in a wet environment like washing dishes, then they should be encouraged to wear gloves. The pharmacist should inform the patient that treatment is often required for a minimum of 12 months, and some patients may require prophylactic treatment to prevent recurrence. They should also monitor compliance, and educate patients about use and side effects. Dermatology and foot and nail care nurses are involved in screening, arranging follow up, and documenting progress and compliance for the team. For those who want a faster option, the patient should be referred to a dermatologist or a surgeon for complete nail removal.  [Level 5]
For patients who delay seeking care, nail deformity usually progresses and may lead to disfigurement and pain. Even though antifungal drugs are available, the treatment is often for months or years before one sees an obvious improvement. Several studies have shown that terbinafine is more effective than other antifungals. However, individuals who have yellow streaks along the lateral nail border tend to have poor responses to treatment. Overall, fungal infections of the toenails have a much poorer outcome compared to fingernail infections. Finally, despite treatment, there is a high rate of recurrence ranging from 5%-50%. [Level 5]
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