ONYCHOMYCOSIS:EPIDEMIOLOGY:

Onychomycosis is a common problem and affects approximately 5% of the population worldwide⁽¹⁾ and represents up to 50% of all nail diseases.⁽²⁾

Other reports concerning the prevalence of onychomycosis are conflicting with estimates ranging from 2-3% to 13% in the western population.^(3,4) Unlike in western countries where it is the frequent cause of nail disorders, in Southeast Asia the prevalence of onychomycosis is relatively low. This was partially confirmed by a large scale-survey in Asia in the late 1990s in which the prevalence of onychomycosis was lower in tropical countries (3.8%) than in subtropical countries and the countries in the temperate zone (18%).⁽⁵⁾

One study conducted in Lahore, Pakistan found that onychomycosis is more common in women of 20 – 40 years of age.⁽⁶⁾

The prevalence rate of onychomycosis is determined by age, predisposing factor, social class, occupation, climate, living environment and frequency of travel.⁽⁷⁾ Several studies have shown that prevalence of onychomycosis increases with age, reasons for which may include poor peripheral circulation, diabetes, repeated nail trauma, longer exposure to pathogenic fungi, sub optimal immune function, inactivity or the inability to cut the toe nails or maintain good foot care.⁽⁴⁾

PATHOPHYSIOLOGY:

The pathogenesis of onychomycosis depends on the clinical subtype. In distal lateral subungual onychomycosis, the most common form of onychomycosis, the fungus spreads from plantar skin and invades the nail bed via the hyponychium. Inflammation occurring in these areas of the nail apparatus causes the typical physical signs of distal lateral subungual onychomycosis. In contrast, white superficial onychomycosis is a rarer presentation caused by direct invasion of the surface of the nail plate. In proximal subungual onychomycosis, the least common subtype, fungi penetrate the nail matrix via the proximal nail fold and colonize the deep portion of proximal nail plate. Endonyx onychomycosis is a variant of distal lateral subungual onychomycosis in which the fungi infect the nail via the skin and directly invade the nail plate. Total dystrophic onychomycosis involves the entire nail unit.

Nail invasion by Candida is not common because the yeast needs an altered immune response as a predisposing factor to be able to penetrate the nails. Despite the frequent isolation of Candida from the proximal nail fold or the subungual space of patients with chronic paronychia or onycholysis, in these patients Candida is only a secondary colonizer. In chronic mucocutaneous candidiasis, the yeast infects the nail plate and eventually the proximal and lateral nail folds.

TRANSMISSION:

Onychomycosis is contagious. It is transmitted by direct contact or contact with contaminated materials such as shoes, socks, or walking barefoot over surfaces with a high density of fungal or yeast spores.

Although it is not a hereditary condition, not everyone is equally susceptible. There are families with genes that make them more prone to fungal nail infections. They are the ones who usually get onychomycosis at a younger age and those with repeated infections. Likewise, there are genes that have been shown to protect against acquiring the infection.

NATURAL HISTORY:

Onychomycosis refers to a fungal infection that affects the toenails or the fingernails. Onychomycosis may involve any component of the nail unit, including the nail matrix, nail bed, or nail plate. Onychomycosis is not life threatening, but it can cause pain, discomfort, and disfigurement and may produce serious physical and occupational limitations. Psychosocial and emotional effects resulting from onychomycosis are widespread and may have a significant impact on quality of life.⁽⁸⁾

The main subtypes of onychomycosis are distal lateral subungual onychomycosis (DLSO), white superficial onychomycosis (WSO), proximal subungual onychomycosis (PSO), endonyx onychomycosis (EO), and candidal onychomycosis. Patients may have a combination of these subtypes. Total dystrophic onychomycosis refers to the most advanced form of any subtype.

SIGN AND SYMPTOMS:

Onychomycosis usually does not cause any symptoms (painless) unless the nail becomes so thick it causes pain when wearing shoes. People with onychomycosis usually go to the doctor for cosmetic reasons, not because of physical pain or problems related to fungal nail infection.

• As the nail thickens, however, onychomycosis may interfere with standing,walking, and
• Paresthesia (a sensation of pricking, tingling, or creeping on the skin having no objective cause and usually associated with injury or irritation of a nerve), pain, discomfort, and loss of agility (dexterity) may occur as the disease progresses. Loss of self-esteem, embarrassment, and social problems can also develop.
• Severe cases ofCandida infections can disfigure the fingertips and nails.

SYMPTOMS OR SIGNS OF ONYCHOMYCOSIS BASED ON SUBTYPE:

Onychomycosis is divided into subtypes that can be identified based on where the infection appears to be located relative to the structure of the nail.

• In distal lateral subungual onychomycosis (DLSO), the nail plate is thick with a cloudy appearance (opaque), the nail bed underneath the nail thickens (becomes raised) and hardens (nail bed hyperkeratosis), and the nail separates from the bed underneath (onycholysis). The nail can be discolored and appear in a range from white to brown. The edge of the nail becomes severely eroded (ragged and brittle) and may become flaky (peeling).
• In endonyx onychomycosis (EO), the nail plate has a milky white discoloration, but unlike DLSO, the nail does not separate from the bed (no onycholysis). The area under the nail (subungual area) does not thicken or harden (no hyperkeratosis).
• White superficial onychomycosis (WSO) is usually confined to the toenails. Small white speckled or powdery-looking patches appear on the surface of the nail plate. The nail becomes rough and crumbles easily (crumbly nails).
• In proximal subungual onychomycosis (PSO), an area of white spotting, streaking, or discoloration (leukonychia) develops near the nail fold and may extend to deeper layers of the nail. The nail plate becomes white near the cuticle and remains normal at the end.
• In total dystrophic onychomycosis, the nail is thickened, opaque, and yellow-brown and / or greenish-brown to black. The entire nail plate and matrix are affected.
• Yeast infection(Candida albicans), while affecting the nail, can appear with additional signs. Candidal infection can occur in the toenails and the fingernails but may also infect the tissue that surrounds the nail. The nail fold becomes inflamed (erythematous), or the nail plate separates from its bed (onycholysis). The nail bed thickens and hardens (nail bed hyperkeratosis), and inflammation of the nail fold is observed in chronic mucocutaneous disease (disease of mucous membrane and regular skin). The affected fingers or toes start to look rounded on the ends, like drumsticks, and, sometimes, the entire thickness of the nail becomes infected.
• Some fungal infections may be associated with an odor described as a slightly foul odor or a "cheesy" odor. This odor may be due to chemicals (S-methyl thioesters) produced by bacteria that can colonize fungal-infected and other warm, damp areas.

DIAGNOSTIC TESTS:

DIRECT MICROSCOPY: A 20% potassium hydroxide (KOH) preparation in dimethyl sulfoxide (DMSO) is a useful screening test to rule out the presence of fungi.

Specimens suspected of candidal onychomycosis should be taken from the affected nail bed closest to the proximal and lateral edges.

CULTURE: Direct microscopy cannot identify the specific pathogen involved in onychomycosis. A fungal culture must be used to identify the species of organism. Cultures should be obtained from pulverized nail scrapings or clippings while the patient has abstained from antifungal medication for at least 2 weeks.

OTHER TESTS: Polymerase chain reaction (PCR) assays have been developed to detect fungal DNA from infected nails. A highly sensitive nested PCR assay using species-specific primer pairs based on the 28S ribosomal RNA gene has been developed. This methodology permits detection of both dermatophytes and nondermatophytes.

HISTOLOGIC FINDINGS: Histologic examination of the nail is a very useful alternative to culture or KOH testing. Nail clippings may be sent to the laboratory for diagnosis in a formalin-filled container, or, as a last resort, an incisional nail biopsy (by punch or scalpel) may be performed to help confirm the diagnosis. A comparison of diagnostic methods revealed that a nail biopsy and staining with PAS is the most sensitive technique available to diagnose onychomycosis. Examining formalin-fixed, PAS-stained specimens has a higher probability (a higher negative predictive value) than KOH examination in determining that a patient is disease free if the test results are negative.

STAGING: The onychomycosis severity index (OSI) has recently been proposed to grade the severity of distal subungual onychomycosis. The OSI score is obtained by multiplying the score for the area of involvement (range, 0-5) by the score for the proximity of disease to the matrix (range, 1-5). Ten points are added for the presence of a longitudinal streaking or a patch (dermatophytoma) or for greater than 2 mm of subungual hyperkeratosis. Mild onychomycosis corresponds to a score of 1-5; moderate, 6-15; and severe, 16-35. ⁽⁹⁾

PATIENT SELECTION FOR TREATMENT:

Treatment of onychomycosis is not mandatory in all patients. It is suggested to treat onychomycosis in:

• Patients with a history of cellulitis of the lower extremity, especially if repeated, who have ipsilateral toenail onychomycosis
• Patients with diabetes and toenail onychomycosis who have additional risk factors for cellulitis (i.e. prior cellulitis, venous insufficiency, edema)⁽¹⁰⁾
• Patients who are experiencing discomfort or pain associated with infected nails^(11-13)
• Immunosuppressed patients
• Patients who desire treatment for cosmetic reasons

TREATMENT OPTIONS:

Treatment options for onychomycosis include topical and systemic antifungal drugs, laser treatment, photodynamic therapy (PDT), and surgery. In addition, patients with symptomatic onychomycosis may benefit from measures to reduce discomfort regardless of whether they proceed with curative treatments.

Topical and systemic antifungal drugs are the mainstays of therapy. Factors that may influence the selection of topical versus systemic therapy include the clinical subtype, causative organism, disease severity, treatment side effects, feasibility of monitoring for side effects, treatment availability, and cost. Despite the availability of multiple therapies, onychomycosis can be challenging to treat. Treatment failure and disease recurrence are common.

MILD TO MODERATE DERMATOPHYTE ONYCHOMYCOSIS:

First-line treatment options for mild to moderate onychomycosis (e.g. distal lateral subungual onychomycosis involving ≤50 percent involvement of the nail and sparing the matrix / lunula) include oral terbinafine and several topical agents including efinaconazole, amorolfine, tavaborole, and ciclopirox.

Although oral antifungal therapy is considered the gold standard treatment for onychomycosis because of higher complete cure rates and shorter courses of treatment when compared to topical therapy, the clinical scenario determines whether oral therapy is the most appropriate first-line treatment for mild to moderate onychomycosis. Examples of scenarios in which topical therapy may be preferred include:

• Patients with contraindications to systemic antifungal therapy
• Patients at risk for drug-drug interactions with systemic antifungal drugs
• Patients who prefer to avoid systemic treatment (especially with three or fewer nails involved)

Children may be more favorable candidates for topical therapy than adults because of a thinner nail plate and potentially faster nail growth rate. A small randomized trial suggested that the likelihood of response to topical ciclopirox is higher in children.⁽¹⁴⁾

ORAL TERBINAFINE: Terbinafine is the first-line oral agent for mild to moderate dermatophyte onychomycosis. Treatment is given in the same manner as terbinafine therapy for more severe disease. Itraconazole is an alternative systemic treatment for patients who cannot tolerate terbinafine or fail to respond to terbinafine.

TOPICAL THERAPY: First-line topical therapies include efinaconazole, amorolfine, tavaborole, and ciclopirox. High quality head-to-head trials are lacking, leaving insufficient data for definitive conclusions on the comparative efficacy of these therapies.

Topical treatment is limited to agents specifically indicated for nail disease. Topical antifungal agents developed for cutaneous fungal infections generally are poorly effective for onychomycosis because of poor penetration of the nail plate.^(15-17)

MODERATE TO SEVERE DERMATOPHYTE ONYCHOMYCOSIS:

Oral terbinafine is the first-line treatment for moderate to severe dermatophyte onychomycosis (e.g. dermatophyte onychomycosis involving >50 percent of the nail or involving the matrix or lunula, proximal subungual onychomycosis, or total dystrophic onychomycosis). Itraconazole is an alternative systemic treatment for patients who cannot tolerate terbinafine or fail to respond to terbinafine.

ORAL TERBINAFINE: Terbinafine is an allylamine antifungal drug with fungicidal activity.

• Efficacy: Terbinafine may have advantages over A randomized, double-blind trial found terbinafine more effective than itraconazole pulse therapy on measures of long-term clinical outcomes.⁽¹⁸⁾ In addition, long-term cure rates appear to be better with terbinafine than with a continuous itraconazole regimen.^(19,20)
• Administration: Terbinafineis administered daily.⁽²¹⁾ The following regimen is used for adults:
• Fingernail onychomycosis:  250 mg per day for 6 weeks
• Toenail onychomycosis: 250 mg per day for 12 weeks

Weight-based pediatric dose regimens include:⁽²²⁾

• Terbinafine(6 weeks for fingernails; 12 weeks for toenails):

10 to 20 kg: 62.5 mg daily
20 to 40 kg: 125 mg daily
Above 40 kg: 250 mg daily

Monitoring of transaminase levels is performed at baseline and repeated at six weeks if therapy will continue beyond six weeks.

ITRACONAZOLE: Itraconazole, a triazole antifungal drug that is primarily fungistatic, is a second-line systemic antifungal therapy for dermatophyte onychomycosis primarily used for patients who cannot tolerate oral terbinafine or fail to respond to oral terbinafine. The potential for drug-drug interactions is higher for itraconazole than terbinafine.

• Efficacy: Use ofitraconazole for onychomycosis stems from efficacy demonstrated in randomized trials.^(23,24) A systematic review of randomized trials evaluating systemic antifungal drugs for toenail dermatophyte onychomycosis found mycologic cure rates of 63±7 percent for pulsed itraconazole and 59±5 percent for continuous itraconazole therapy.⁽²³⁾ Pooled rates of clinical response (clinical cure or marked improvement) were 70±11 percent and 70±5 percent, respectively.
• Administration: Both continuous and pulse therapy are accepted oral regimens for onychomycosis. Standard regimens for adults are:
• PULSE THERAPY:

Fingernail onychomycosis: 200 mg twice daily for one week per month for two months
Toenail onychomycosis: 200 mg twice daily for one week per month for three months

• CONTINUOUS THERAPY:

Fingernail onychomycosis: 200 mg per day for 6 weeks
Toenail onychomycosis: 200 mg per day for 12 weeks

CHILDREN CAN BE TREATED WITH THE FOLLOWING REGIMEN:

• Itraconazoledaily for one week per month (two months of therapy for fingernails; three months of therapy for toenails):

Less than 20 kg: 5 mg/kg per day
20 to 40 kg: 100 mg per day
40 to 50 kg: 200 mg per day

More than 50 kg: 200 mg twice daily

Liver function tests should be monitored in patients with preexisting liver disease and in all patients receiving treatment for more than one month.

WHITE SUPERFICIAL ONYCHOMYCOSIS: White superficial onychomycosis usually can be treated by mechanical removal of the involved area (i.e. scraping the superficial nail plate) followed by use of a topical antifungal agent for onychomycosis.^(25,26) The duration of topical antifungal treatment is dependent on the clinical response. Up to several months of topical treatment may be required.⁽²⁶⁾

Clinical experience suggests that systemic therapy (with or without concomitant topical antifungal therapy) may be the treatment of choice for WSO that occurs in association with other clinical subtypes of onychomycosis or that appears to originate from the proximal nail fold.⁽²⁵⁾ The approach to systemic therapy is similar to that used for other forms of onychomycosis and is dependent on the causative organism. Dermatophytes are responsible for most cases of WSO. Occasionally, WSO is caused by yeast or nondermatophyte molds.

OTHER THERAPIES: Less common therapeutic interventions for onychomycosis include oral antifungal agents other than terbinafine and itraconazole, laser therapy, photodynamic therapy, and surgical nail removal.

ALTERNATIVE ORAL ANTIFUNGAL DRUGS: Fluconazole, 150 to 300 mg once weekly for adults has been effective for onychomycosis and may be useful in patients with complicated medication regimens.⁽²⁷⁾ However, head-to-head comparisons have not found once weekly fluconazole to be as effective or as cost-effective as itraconazole and terbinafine.^(28-30)

GRISEOFULVIN: has been used for the treatment of onychomycosis. However, terbinafine and itraconazole appear to have higher rates of cure in head-to-head randomized trials than griseofulvin.^(31-34) Griseofulvin also requires prolonged courses of treatment (four to six months or longer).

POSACONAZOLE: a newer oral broad spectrum antifungal agent, may be effective for onychomycosis. In a phase II randomized trial. The best results with posaconazole were obtained when patients were given 200 mg or 400 mg daily for 24 weeks (54 and 46 percent complete cured, respectively); the cure rates in these groups did not differ significantly from the terbinafine group (37 percent cured). Adverse event rates were similar among the groups. The high cost of posaconazole favors the preferred use of other systemic therapies.

ALBACONAZOLE: is a broad spectrum oral antifungal agent that is not commercially available. A phase II randomized trial suggests that this drug may be a future treatment option for onychomycosis.⁽³⁵⁾

Oral ketoconazole should not be used for the treatment of onychomycosis. The drug is an unfavorable choice because of risk for life-threatening hepatotoxicity, adrenal insufficiency, and multiple drug-drug interactions.⁽³⁶⁾

LASERS: Although neodymium-doped:yttrium aluminum garnet (Nd:YAG) and diode lasers have emerged as treatment options for onychomycosis, data on the efficacy of these interventions are limited and the mechanisms of action and optimal regimens for these treatments remain unclear.^(35,36)

PHOTODYNAMIC THERAPY: Photodynamic therapy has been studied for the treatment of onychomycosis.⁽³⁷⁾ The procedure involves the application of a topical photosensitizer followed by irradiation of the treatment site with an appropriate light source. Successful treatment with this modality was reported in case reports and a small, open-label study.^(38-41)

SURGERY: Surgical removal of the nail (nail avulsion) is typically reserved for patients who cannot be successfully treated with pharmacologic therapy alone.⁽⁴²⁾ Topical or systemic antifungal therapy is usually initiated after surgery. Recurrences are common in the absence of subsequent systemic or topical treatment.

OTHER: Iontophoretic drug delivery, in which a low electrical current is used to enhance the absorption of topical medications, may have promise for improving the efficacy of topical antifungal treatment.^(43-45) In a small, unblinded randomized trial that compared treatment of toenail onychomycosis with topical terbinafine plus iontophoresis to topical terbinafine alone, combination therapy appeared to increase the likelihood for new healthy nail growth.⁽⁴³⁾ Additional studies are necessary to determine the role of iontophoresis in the treatment of onychomycosis.

There are few data on the efficacy of a medicated chest rub containing eucalyptus oil, camphor, menthol, thymol, oil of turpentine, oil of nutmeg, and oil of cedar leaf (e.g. Vicks VapoRub) in the treatment of onychomycosis. In a series of 18 patients who were instructed to apply this type of medicated chest rub to affected nails daily for 48 weeks, four patients (22 percent) achieved both clinical and mycological cure.⁽⁴⁶⁾

GOALS OF THERAPY:

The goals for antifungal therapy are mycological cure, a normal looking nail and to prevent complications.

GUIDELINES:

To review “British Association of Dermatologists’ guidelines for the management of onychomycosis 2014”, please click on below link:

http://onlinelibrary.wiley.com/doi/10.1111/bjd.13358/pdf

To review “American Family Physician - Onychomycosis: Current Trends in Diagnosis and Treatment”, please click on below link:

http://www.aafp.org/afp/2013/1201/p762.html

To review “British Journal of Dermatology - Guidelines for treatment of onychomycosis”, please click on below link:

http://www.mycology.adelaide.edu.au/docs/onychomycosis.pdf

LONG TERM MONITORING

Although hepatotoxic reactions are unlikely, periodic monitoring of patients undergoing oral antifungal therapy should include a Complete blood count (CBC) and measurements of liver enzyme levels approximately every 4-6 weeks.

Treatment may be discontinued after standard dosing with terbinafine or itraconazole when no evidence of fungal infection (by microscopy or culture) is present. Nails may continue to look dystrophic after a cure is achieved in the laboratory.

After antifungal therapy, disease-free nail growth should be measured at every visit. Nails should grow at a rate of 1.5-2 mm per month and may take up to 1 year to look normal. A clinician may consider an additional dose of antifungal medication if the outgrowth distance slows or stops after discontinuing therapy.

CONSULTATION AND COUNSELING:

This is not always necessary to treat and patients should be given the information to make an informed decision based on:

• Even after successful treatment of the fungal infection, the nail may not look completely normal.
• Cure is not achieved in 20-40% of patients.
• Even in those in whom it is successful, nails may appear abnormal for over 12 months due to their slow growth.
• Relapse occurs in about 20-25% of people.
• Oral medication is taken for several weeks
• Topical treatments may need to be applied for up to several months.
• All medication has potential side-effects.

PRECAUTIONS:

Offer following preventions to patients:

Thick, dystrophic nails can make it difficult for patients to trim nails and may lead to pain during ambulation. The removal of hyperkeratotic nail debris may help to ameliorate these symptoms.

Topical urea is a keratolytic agent that have found useful for this purpose in patients who forgo antifungal treatment and as an adjunctive measure in those who proceed with treatment.^(47,48) For patients with very thick, dystrophic nails, following night time regimen should be followed:

• Apply a generous, protective layer of petrolatum to the periungual skin
• Apply a thick layer of topical urea 40% cream or ointment to the nail
• Occlude the nail with a bandage or tape and leave on overnight
• Wash the topical urea off with soap and water in the morning
• Repeat this procedure nightly until the nail softens and can be easily clipped or debrided
• Reapplication of topical urea without occlusion on an as-needed basis can be used to maintain improvement. Treatment without occlusion also is often sufficient for reducing nail hyperkeratosis in patients with less severe nail thickening.

Other preventions include:⁽⁴⁹⁾

• Wear comfortable shoes and hosiery that allow your feet some breathing space.
• Wear clean socks or stockings every day.
• Disinfect pedicure tools before you use them.

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• patienteducationcenter.org/articles/toenail-fungus-onychomycosis