Tinea unguium

Management Strategy

Different clinical patterns of nail infection result from the way in which fungi colonize the nail.

The type of nail invasion depends on both the causative fungus (dermatophyte, mold or yeast) and host susceptibility. In distal subungual onychomycosis (DSO), the most common type, fungi reach the nail from the hyponychium and colonize the nail bed, producing onycholysis and subungual hyperkeratosis. In proximal subungual onychomycosis (PSO), fungi penetrate the nail matrix via the proximal nailfold and colonize the deep portion of proximal nail plate, resulting in a subungual white patch located in the lunula area. In white superficial onychomycosis (WSO), fungi are localized on the nail plate surface and produce whitish opaque, friable areas on the nail plate. The nail plate can also be deeply invaded (deep WSO) in cases of infection due to molds, in children, and in immunocompromised patients. Host factors, including the thinner nail plate typically seen in children, may contribute to the severity of WSO.

Onychomycosis is an infection and should always be treated. The goals for antifungal therapy are mycological cure and a normal-looking nail. The latter can be impossible to achieve when onychomycosis is associated with traumatic nail dystrophies. Signs of a good response are no proximal progression and growth of a proximal area of normal-appearing nail.

Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails, the severity of involvement, presence of comorbidities, and concomitant drugs.

A systemic treatment is always required in PSO, in DSO involving >50% of the nail plate or the lunula region, and in deep WSO. Superficial WSO and DSO limited to the distal nail can be treated with a topical agent such as efinaconazole, tavaborole, amorolfine, or ciclopirox. Combined systemic and topical treatments are useful to increase the cure rate.

In recent years, the number of patients with AIDS-related or iatrogenic immunosuppression has substantially increased, leading to the appearance of new patterns of nail invasion by fungi. Migratory flows have also changed the pattern of pathogens with new emerging agents. These factors substantially changed treatment options.

Terbinafine is an allylamine with fungicidal properties. Interactions of terbinafine with other drugs are extremely rare. Adverse effects may involve gastrointestinal function and the skin. Patients with known lupus erythematosus or photosensitivity are predisposed to drug-induced or drug-exacerbated disease. Liver toxicity and taste disturbances can occasionally occur. Recent evaluations confirm that among pregnant women exposed to terbinafine, no increased risk of major malformations or spontaneous abortion is identified (pregnancy category B). It is, however, excreted into breast milk. Terbinafine is usually administered at a dose of 250 mg daily; treatment duration is 6 weeks for fingernails and 12 weeks for toenails. Clinical trials have repeatedly demonstrated a higher efficacy of terbinafine compared with other antifungal treatments. A meta-analysis of 18 studies on terbinafine for onychomycosis showed a mycological cure rate of 76%. Since terbinafine persists in the nail for at least 30 weeks after the completion of treatment, it is also effective if administered as a pulse regimen (not US Food and Drug Administration [FDA] approved) at a dose of 250 mg/day for 1 month, every other month (2 pulses), or 500 mg/day for 1 week a month for 2–4 months.

Itraconazole is a synthetic triazole with fungistatic activity and a broad spectrum of action. It is approved at a daily 200 mg dose. It can also be administered as pulse therapy at a dose of 400 mg daily for 1 week per month (3–4 pulses). Treatment duration is 6 weeks for fingernails and 12 weeks for toenails. The drug should be administered with a high-fat meal and/or an acidic beverage to improve its absorption. It is now not widely prescribed due to safety profile and drug interactions. Adverse effects may involve the gastrointestinal system, the liver, and the skin. Its use has also been associated with congestive heart failure. A meta-analysis of six studies on pulse itraconazole for onychomycosis showed a mycological cure rate of 63%.

Supplemental (booster) therapy has been suggested to improve cure rates in patients with poor prognostic factors. An additional 4 weeks of terbinafine or itraconazole is advisable in these patients, but it is not FDA approved.

Poor prognostic factors include nail involvement >50%, involvement of the lateral portion of the nail plate, subungual hyperkeratosis thicker than 2 mm, white/yellow or orange/brown streaks in the nail (including dermatophytoma), matrix involvement, and immunosuppression. Recurrence (relapse or reinfection) of onychomycosis is, however, not uncommon, with reported rates ranging from 10% to 53%.

Fluconazole is a bis-triazole broad-spectrum fungistatic drug with high oral bioavailability, widely utilized, but not approved for onychomycosis. It is administered as pulse treatment, with regimens ranging from 150 to 450 mg once a week for 6 (fingernails) to 9 (toenails) months. A meta-analysis of three studies on fluconazole for onychomycosis showed a mycological cure rate of 48%.

Posaconazole is a new azole that has been evaluated in onychomycosis at 200 mg daily and its use is likely to be limited to second-line treatment in terbinafine-refractory infections, those with non-dermatophyte mold infections, or those sensitive to or intolerant of terbinafine. It showed a mycological cure rate of 48%.

A new systemic antifungal, VT-1161 , a potent and selective inhibitor of fungal CYP51, showed promising results in phase IIb clinical trials on toenail onychomycosis (61%–72% mycological cure).

Efinaconazole 10% solution is a topical triazole antifungal solution with a broad spectrum of activity. It should be applied daily and results from clinical studies indicate that 25% of patients achieve complete or almost complete cure, defined as ≤5% affected target nail area and mycological cure after 48 weeks of treatment.

Tavaborole 5% solution is a novel, broad-spectrum, oxaborole antifungal agent with strong antifungal activity against T. rubrum and T. mentagrophytes . It should be applied daily and results from clinical studies show that 16.6% of patients achieve almost complete cure, defined as ≤5% affected target nail area and mycological cure after 48 weeks of therapy.

Other topical antifungals include amorolfine 5% nail lacquer (not FDA approved) and ciclopiroxolamine 8% nail lacquer. Amorolfine is applied once a week, whereas ciclopiroxolamine should be applied daily.

The clinical efficacy of monotherapy with nail lacquers is low, but topical antifungals might increase cure rate when combined with oral treatment. Surgical or chemical debridement of the thickened nail plate also increases cure rate. Several new topical formulations are, however, currently on trials.

At present there is no FDA-approved treatment for onychomycosis in children and available drugs should be used off label. In a review of 26 studies, oral treatment of onychomycosis resulted in an overall 70.8% complete cure rate with a favorable safety profile. The same is for topical therapy.

Photodynamic therapy has recently been reported to be effective in T. rubrum onychomycosis, but affected toenails need to be filed or treated with urea before application of ALA.

Laser devices have also been utilized to treat onychomycosis, including neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and diode laser. Penetration of the nail plate and targeting of fungi occurs at wavelengths of 750–1300 nm. Evidence-based data on efficacy of these different lasers are, however, still poor.

The diagnosis of onychomycosis always requires laboratory confirmation, as differential diagnosis from psoriasis or traumatic onychodystrophy is often impossible on a clinical basis.

Dermoscopy is extremely helpful because it identifies three recurring patterns, two of which were present only in DSO (jagged proximal edge with spikes of the onycholytic area and longitudinal striae) and one only in traumatic onycholysis (linear edge – without spikes – of the onycholytic area). Fungal elements in the affected nails can be detected using KOH preparations of the nail samples or histopathology of PAS-stained nail clippings. An immunochromatography test, the dermatophyte test strip, can also be used to detect dermatophytes by visualizing mycotic antigens. PCR has high sensitivity and provides fast results, but it might be too sensitive, producing false positive results. All these methods, however, do not detect fungal viability.

Culture is the gold standard to identify the responsible specie of fungi, mandatory not only from an epidemiological point of view, but also to introduce the correct treatment. However, cultures have high rates of false negative results.