Onychomycosis

Onychomycosis is fungal infection of the nail unit by any fungus: dermatophytes, yeasts or non dermatophyte moulds. Tinea unguium is dermatophyte onychomycosis specifically. Both terms are used in practice, and the distinction matters because the choice of drug and the expected response depend on the organism.

Onychomycosis accounts for roughly half of all nail disease. Prevalence is about 5 to 10 percent in the general population and over 20 percent in older adults. Toenails are affected far more often than fingernails. It is rare in children.

Risk factors: age, tinea pedis, diabetes mellitus, peripheral arterial disease, immunosuppression including HIV, psoriasis, nail trauma, smoking, family history, occlusive footwear, and communal bathing.

Mixed infection with a dermatophyte and a mould or yeast occurs, and the clinically important organism is not always the one that grows first.

The usual route is spread from tinea pedis to the hyponychium and nail bed. Hyphae then invade the ventral nail plate and the nail bed, digest keratin with secreted keratinases, and spread proximally. Hyphae in the nail plate are protected from the immune system and from topical drug penetration. Infected nails are dystrophic, thickened and detached, which gives a reservoir for reinfection.

Nail growth rates determine treatment duration. Fingernails grow about 3 mm per month and are replaced in 4 to 6 months. Toenails grow about 1 mm per month and take 12 to 18 months to be replaced, and slower in older adults and in those with poor circulation.

A dermatophytoma is a dense mass of fungal hyphae within or beneath the nail plate, seen as a longitudinal yellow or white streak or a spike. It resists oral therapy because drug penetration is poor, and it is a recognised cause of treatment failure.

Mixed patterns are common. A dermatophyte nail infection in an adult with HIV and recent onset proximal disease should prompt HIV testing.

Roughly half of dystrophic nails are not fungal, so treatment is started only after laboratory confirmation.

Sampling determines the result.

• Distal and lateral subungual disease: clip the distal nail, and scrape debris from the nail bed with a curette, as far proximally as possible, because the viable fungus lies at the leading edge.
• Proximal subungual disease: sample after cleaning the surface with alcohol, by drilling or paring down to the affected proximal plate.
• White superficial disease: scrape the surface of the plate.
• Candidal disease: scrape beneath the proximal fold and from the nail.

Investigations:

• Potassium hydroxide preparation: 20 to 40 percent potassium hydroxide with dimethyl sulphoxide, or calcofluor white. Uniform, septate, branching hyphae and arthroconidia indicate a dermatophyte or mould. Pseudohyphae and yeasts indicate Candida.
• Periodic acid Schiff stain of nail clippings: the most sensitive test and the one that demonstrates fungal elements in the nail plate itself. It cannot name the organism.
• Culture: Sabouraud dextrose agar with chloramphenicol, with and without cycloheximide, incubated at 25 to 30 degrees Celsius for 4 weeks. Culture identifies the organism and has a sensitivity of only about 50 to 60 percent, so a negative culture with positive microscopy still supports the diagnosis.
• Polymerase chain reaction: more sensitive and faster than culture, but unable to separate viable from non viable organisms.
• Dermoscopy: longitudinal striae with a jagged proximal edge (the spike sign) support dermatophyte onychomycosis.

Interpretation of isolates:

• A dermatophyte is accepted as the cause.
• A non dermatophyte mould is accepted as the cause when microscopy shows fungal elements, the same mould grows from repeated samples, and no dermatophyte grows. Growth of Scopulariopsis, Fusarium, Aspergillus or Neoscytalidium from a single sample is often contamination.
• Candida isolated from a nail more often indicates colonisation or paronychia than primary nail infection, unless pseudohyphae are seen on microscopy and the pattern is compatible.

Principles

• Confirm the diagnosis before treatment.
• The goals are mycological cure (negative microscopy and culture), clinical cure (a normal nail), and prevention of spread.
• Even with correct treatment, a complete cure is achieved in about 35 to 40 percent with oral terbinafine, and lower with topical therapy, and relapse or reinfection is common, so counselling about duration and outcome is essential.
• The clinical outcome is judged by new, clear proximal nail growth at 3 months, and not by the appearance of the old nail. Toenails need 12 to 18 months for full clearance.
• Treat tinea pedis and any other affected sites at the same time.

Oral therapy

Children: terbinafine by weight (under 20 kg: 62.5 mg daily; 20 to 40 kg: 125 mg daily; over 40 kg: 250 mg daily) for 6 weeks for fingernails and 12 weeks for toenails. Topical therapy is preferred for mild disease in children.

Choice of agent by organism:

• Dermatophytes: terbinafine first line, itraconazole second.
• Candida: itraconazole or fluconazole, because terbinafine is less active against Candida albicans. Chronic paronychia is treated by keeping the hands dry, avoiding irritants, and applying a topical azole or a topical corticosteroid to the proximal fold.
• Non dermatophyte moulds: response is poorer. Scopulariopsis brevicaulis and Neoscytalidium are difficult to cure with oral drugs alone. Nail avulsion or debridement plus a topical antifungal is combined with an oral agent such as itraconazole or terbinafine, guided by culture and, where available, susceptibility testing. Fusarium is resistant to most agents.

Topical therapy

Topical therapy is for mild to moderate distal subungual disease with less than about half of the nail plate affected and no matrix involvement, white superficial disease, patients who cannot take oral drugs, and as an adjunct to oral therapy. Cure rates are low (complete cure in roughly 5 to 20 percent), because penetration through the nail plate is limited.

Adjunctive and procedural measures

• Mechanical or chemical debridement of thickened nail improves drug penetration and reduces pain from pressure.
• A dermatophytoma is removed by debridement or avulsion in combination with oral therapy.
• Surgical or chemical avulsion with topical treatment is considered when the nail is very thick, painful, or the matrix is spared, and when oral drugs are contraindicated.
• Combined oral and topical therapy gives higher cure rates than oral therapy alone.
• Laser and photodynamic therapy are not established treatments, because evidence is limited.

Drug safety and monitoring

• Terbinafine: taste or smell disturbance, gastrointestinal upset, rash, and rare idiosyncratic hepatotoxicity (including liver failure), neutropenia, severe skin reactions and exacerbation of lupus. Baseline liver tests are checked in patients with a history of liver disease, alcohol excess or other hepatotoxic drugs, with a repeat at 4 to 6 weeks. Terbinafine is stopped for jaundice, dark urine, pale stools or persistent nausea. It is avoided in chronic or active liver disease and when creatinine clearance is below 50 mL per minute. It inhibits CYP2D6, which raises levels of tricyclic antidepressants, selective serotonin reuptake inhibitors, beta blockers and codeine, and rifampicin lowers terbinafine levels.
• Itraconazole: negative inotropy (contraindicated in heart failure and in those with ventricular dysfunction), hepatotoxicity, and strong CYP3A4 inhibition. It is contraindicated with simvastatin, lovastatin, oral midazolam, triazolam, dofetilide and quinidine, and avoided in pregnancy. Liver tests are checked in prolonged courses.
• Fluconazole: hepatotoxicity, QT prolongation, and inhibition of CYP2C9, CYP2C19 and CYP3A4, which raises warfarin and phenytoin levels. The dose is halved when creatinine clearance is below 50 mL per minute.
• Pregnancy and breastfeeding: oral therapy is deferred. Topical treatment is preferred.
• Diabetes and peripheral arterial disease: treatment is worthwhile because nail dystrophy and tinea pedis cause ulceration and cellulitis, and drug interactions need attention.
• Immunosuppressed hosts: longer or combination therapy, and attention to drug interactions with calcineurin inhibitors.

Treatment failure

Causes: wrong diagnosis (nail dystrophy that is not fungal), non dermatophyte mould or Candida infection, dermatophytoma, thick or lateral nail disease, poor adherence, poor absorption of itraconazole, immunosuppression, persistent tinea pedis and reinfection from footwear, and resistance. Terbinafine resistant Trichophyton rubrum and Trichophyton indotineae carry squalene epoxidase mutations, and itraconazole is the usual alternative. Repeat sampling is advised if no new clear growth appears after 6 months of correct treatment.

Prevention of recurrence

• Treat tinea pedis in the patient and in household members.
• Keep nails short, and avoid trauma and nail salon instruments that are not disinfected.
• Dry the feet, wear absorbent socks, and rotate shoes.
• Treat shoes with an antifungal powder or spray, or discard long worn shoes.
• A topical antifungal lacquer or cream to the nail or foot after clearance reduces relapse. Intermittent oral prophylaxis has limited evidence.
• Wear sandals in communal bathing areas.