AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Onychomycosis (OM) refers to a fungal infection that affects the toenails or the fingernails. It may involve any component of the nail unit, including the nail matrix, the nail bed, or the nail plate. OM 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 OM are widespread and may have a significant impact on quality of life.

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

Pathophysiology

The pathogenesis of OM depends on the clinical subtype. In DLSO, the most common form of OM, the fungus spreads from plantar skin and invades the underside of the nail via the hyponychium or the distal lateral nail bed. Inflammation occurring in these areas of the nail apparatus causes the typical physical signs of DLSO. In contrast, WSO is a rarer presentation caused by direct invasion of the surface of the nail plate and by secondary infection of the nail bed and the hyponychium. In PSO, the least common subtype, fungi invade the cuticle and the proximal nail fold and then penetrate the dorsum of the nail plate. EO is a variant of DLSO whereby the fungi infect the nail via the skin and directly invade the nail plate.

Candidal nail infection may manifest in 3 ways: onycholysis, paronychia, or chronic mucocutaneous disease. Onycholysis may be caused primarily by yeast, or the organism may secondarily colonize onycholytic nails. Candidal paronychia is usually secondary to trauma of the nail fold. Chronic mucocutaneous candidiasis affects the nail plate and eventually infects the proximal and lateral nail folds. Total dystrophic OM involves the entire nail unit and may include permanent scarring of the nail matrix (see Media file 1).

Frequency

United States

The recent proliferation of fungal infections in the United States can be traced to the large immigration of dermatophytes, especially Trichophyton rubrum, from West Africa and Southeast Asia to North America and Europe.

International

The incidence of OM has been reported to be 2-13% in North America. A multicenter survey in Canada showed the prevalence of OM at 6.5%. OM accounts for half of all nail disorders, and it is the most common nail disease in adults. Toenails are much more likely to be infected than fingernails. Thirty percent of patients with a cutaneous fungal infection also have OM. The incidence of OM has been increasing, owing to such factors as diabetes, immunosuppression, and increasing age.

Studies in the United Kingdom, Spain, and Finland found prevalence rates of OM to be 3-8%.

Race

OM affects persons of all races.

Sex

OM affects males more commonly than females. However, candidal infections are more common in women than in men.

Age

Studies indicate that adults are 30 times more likely to have OM than children. OM has been reported to occur in 2.6% of children younger than 18 years but as many as 90% of elderly people.

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
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History

• OM is usually asymptomatic; therefore, patients usually first present for cosmetic reasons without any physical complaints.
• As the disease progresses, OM may interfere with standing, walking, and exercising.
• Patients may report paresthesia, pain, discomfort, and loss of dexterity. They also may report loss of self-esteem and lack of social interaction.
• A careful history may reveal many environmental and occupational risk factors.

Physical

The subtypes of OM may be distinguished on the basis of their usual presenting clinical features.

• DLSO presents as a thickened and opacified nail plate, subungual hyperkeratosis, and onycholysis. Discoloration ranges from white to brown. The edge of the involved area is often dystrophic, while the edge of the nail itself becomes severely eroded.
• EO presents as a milky white discoloration of the nail plate, but, in contrast to DLSO, no evidence of subungual hyperkeratosis or onycholysis is present.
• WSO is usually confined to the toenails and manifests as small, white speckled or powdery patches on the surface of the nail plate. The nail becomes roughened and crumbles easily.
• PSO presents as an area of leukonychia in the proximal nail fold, and it may extend to deeper layers of the nail. The nail plate becomes white proximally and remains normal distally.
• Candidal nail infection may involve both the toenails and the fingernails. It can manifest as an erythematous swelling of the nail fold (paronychia) or as a separation of the nail plate from its bed (onycholysis). Gross subungual hyperkeratosis and inflammation of the nail fold is observed in patients with chronic mucocutaneous disease. The digits may take on a bulbous or drumstick appearance, and the entire thickness of nail may be affected.
• Total dystrophic OM presents as a thickened, opaque, and yellow-brown nail and involves the entire nail plate and matrix.

Causes

OM is caused by 3 main classes of fungi: dermatophytes, yeasts, and nondermatophyte molds. The clinical appearance of OM is indistinguishable based on the species of fungus causing the infection. Dermatophytes (including the genera Epidermophyton, Microsporum, and Trichophyton) are by far the most common cause of OM worldwide. Two major pathogens are responsible for approximately 90% of all OM cases. T rubrum accounts for 70% and Trichophyton mentagrophytes accounts for 20% of all cases. Yeasts and nondermatophyte molds account for 8% and 2% of OM cases, respectively.

• T rubrum is the most common pathogen in DLSO and PSO.
• Most often, T mentagrophytes and, more rarely, species of nondermatophyte molds cause WSO.
• Candida albicans primarily causes chronic mucocutaneous candidiasis of the nail.
• Risk factors for OM include family history, increasing age, poor health, prior trauma, warm climate, participation in fitness activities, immunosuppression (eg, HIV, drug induced), communal bathing, and occlusive footwear.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Bacterial paronychia (including pseudomonal infection)
Darier disease
Drug reaction (eg, tetracyclines, quinolones, psoralens)
Pachyonychia congenita
Periodic nail shedding
Thyroid disease
Yellow nail syndrome
Melanonychia (caused by malignant melanoma)

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• The clinical features of OM are often diagnostic. However, the differential diagnosis reveals that many dystrophic nails represent different pathologic causes. Therefore, laboratory diagnosis of OM must be confirmed before beginning a treatment regimen.
• Direct microscopy
• • A 20% potassium hydroxide (KOH) preparation in dimethyl sulfoxide (DMSO) is a useful screening test to rule out the presence of fungi. Before obtaining a specimen, the nails must be clipped and cleansed with an alcohol swab to remove bacteria and debris. The preparation does not require heating or prolonged incubation if DMSO is a component of the KOH solution.
  • In DLSO, a specimen should be obtained from the nail bed by curettage. It should be obtained at a site most proximal to the cuticle, where the concentration of hyphae is greatest.
  • In PSO, the overlying nail plate must initially be pared with a number-15 blade. Then, a sample of the proximal nail bed may be taken. A number-15 blade may also be used to remove a specimen from the nail surface in WSO.
  • Specimens suspected of candidal OM should be taken from the affected nail bed closest to the proximal and lateral edges.
  • Nail fragments must be small enough for examination under low power. Large pieces of nail plate may be pulverized prior to microscopy by using a hammer or a nail micronizer. Counterstains, such as Chlorazol black E or Parker blue-black ink, may be used to accentuate the hyphae.
• Culture
• • Direct microscopy cannot identify the specific pathogen involved in OM. A fungal culture must be used to identify the species of organism. Nondermatophyte molds may be resistant to the conventional therapy used for the more common dermatophytes. Therefore, 2 types of growth medium should be used, one with cycloheximide (dermatophyte test medium [DTM], Mycosel, or Mycobiotic) to select for dermatophytes and one without cycloheximide (Sabouraud glucose agar, Littman oxgall medium, or inhibitory mold agar) to isolate yeasts and nondermatophyte molds.
  • Cultures should be obtained from pulverized nail scrapings or clippings while the patient has abstained from antifungal medication for at least 2 weeks. The specimen should be kept at room temperature with the cap placed loosely over the inoculated medium.

Other Tests

• Immunohistochemistry and dual flow cytometry are 2 other potential diagnostic techniques.

Histologic Findings

Histologic examination of the nail is a very useful alternative to culture or KOH. 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. Staining in the laboratory should be performed with periodic acid-Schiff stain (PAS) or methenamine silver stain to reveal fungal elements. A recent comparison of diagnostic methods revealed that a nail biopsy and staining with PAS is the most sensitive technique available to diagnose OM. 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.

In addition to excluding other conditions (eg, psoriasis, lichen planus), the topographic distribution, the density, and the nature of the fungal elements may help guide treatment. Biopsy specimens of OM may show features of psoriasiform hyperplasia, including parakeratosis, thinned rete ridges, narrow suprapapillary plates, and dilated tortuous capillaries. As in direct microscopy, histopathologic diagnosis does not identify the species of causative pathogen.

TREATMENT

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Medical Care

Several years ago, the medical management of OM was limited to topical therapy and 2 unreliable systemic drugs: griseofulvin and ketoconazole. Topical therapy is beneficial only for mild cases involving the very distal nail plate. The use of griseofulvin and ketoconazole is plagued by high relapse rates (70-85%), prolonged treatment regimens (10-18 mo for toenails), constant laboratory monitoring, and numerous adverse effects. The introduction of newer oral agents has revolutionized the medical treatment of OM and reduced potential adverse effects and drug interactions. As the rate of recurrence remains high, even with newer agents, the decision to treat should be made with a clear understanding of the cost and risks involved as well as the risk of recurrence.

• Topical antifungals
• • The use of topical agents should be limited to cases involving less than half of the distal nail plate or for patients unable to tolerate systemic treatment. Agents include amorolfine (approved in other countries), ciclopirox olamine 8% nail lacquer solution, sodium pyrithione, bifonazole/urea (available outside the United States), propylene glycol-urea-lactic acid, the imidazoles, and the allylamines.
  • Topical treatments alone are generally unable to cure OM because of insufficient nail plate penetration. Ciclopirox solution has been reported to penetrate through all nail layers but has low efficacy when used as monotherapy. It may be useful as adjunctive therapy in combination with oral therapy or as prophylaxis to prevent recurrence in patients cured with systemic agents.
• Oral therapy
• • The newer generation of oral antifungal agents (itraconazole and terbinafine) has replaced older therapies in the treatment of OM. They offer shorter treatment regimens, higher cure rates, and fewer adverse effects. Fluconazole (not approved by the Food and Drug Administration [FDA] for treatment of OM) offers an alternative to itraconazole and terbinafine. Derivatives of fluconazole may also be available soon. The efficacy of the newer antifungal agents lies in their ability to penetrate the nail plate within days of starting therapy. Recent evidence shows better efficacy with terbinafine than other oral agents (see Prognosis).
  • To decrease the adverse effects and duration of oral therapy, topical and surgical treatments may be combined with oral antifungal management.

Surgical Care

Surgical approaches to OM treatment include surgical nail avulsion and matrixectomy by chemical or mechanical means.

• Chemical removal by using a 40-50% urea compound should be reserved for patients with very thick nails or for those who may not tolerate mechanical avulsion.
• Removal of the nail plate should be considered an adjunctive treatment in patients undergoing oral therapy.
• A combination of oral, topical, and surgical therapy can increase efficacy and reduce cost.

Activity

Activity does not need to be limited during treatment, but patients should be educated about avoiding direct contact with high-risk areas in public places.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antifungals

Mechanism of action may involve alteration of RNA and DNA metabolism or intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug Name	Itraconazole (Sporanox)
Description	Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Adult Dose	Toenails: 200 mg PO qd for 12 wk or 200 mg PO bid for 1 wk, then 3 wk without treatment; repeat for 3 pulses Fingernails: 200 mg PO bid for 1 wk, then 3 wk without treatment, then 200 mg PO bid for 1 additional wk for 2 pulses
Pediatric Dose	Not established; suggested dose of 100 mg/d for systemic fungal infections
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hepatic disease; achlorhydria (may impair absorption); not recommended in breastfeeding; heart failure has been reported

Drug Name	Fluconazole (Diflucan)
Description	Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Treatment should continue until infection resolves.
Adult Dose	Toenails: 150-300 mg PO qwk Fingernails: 150-300 mg PO qwk
Pediatric Dose	3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg PO qd, depending on severity of infection
Contraindications	Documented hypersensitivity; concomitant warfarin, theophylline, oral hypoglycemics, phenytoin, cyclosporine, rifampin, hydrochlorothiazide, cimetidine, or cisapride
Interactions	Levels may increase with thiazides; levels may decrease with chronic coadministration of rifampin; coadministration may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with coadministration; increases in cyclosporine concentrations may occur when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death), with underlying medical conditions (eg, AIDS, malignancy) and while taking multiple concomitant medications; not recommended in breastfeeding

Drug Name	Ciclopirox (Penlac)
Description	Interferes with synthesis of DNA, RNA, and protein by inhibiting transport of essential elements in fungal cells.
Adult Dose	Apply evenly over entire nail plate and 5 mm of surrounding skin qhs or 8h before washing; if possible, apply to nail bed, hyponychium, and undersurface of nail plate when free of nail bed; do not remove product on daily basis; apply daily over previous coat and remove with alcohol q7d; repeat cycle throughout duration of therapy
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Avoid contact with eyes and other internal routes

FOLLOW-UP

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Further Outpatient Care

• Although hepatotoxic reactions are unlikely, periodic monitoring of patients undergoing oral antifungal therapy should include a complete blood count 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.

Complications

• Skin injury adjacent to the nail may allow organisms to colonize, thereby increasing the risk of infectious complications. Reports of complications in elderly persons and persons with diabetes include cellulitis, osteomyelitis, sepsis, and tissue necrosis.

Prognosis

• Published data indicate that for toenail OM, mycologic cure rates (ie, obtaining negative laboratory results) with standard terbinafine therapy are 35-50%. Success rates with itraconazole therapy are 25-40% regardless of dosing schedules. Clinical cure rates (ie, a normal-appearing nail) may be as high as 75% with either drug. Data are difficult to evaluate and compare because of differing clinical end points, but recent studies have confirmed that terbinafine provides superior long-term efficacy and lower rates of relapse than griseofulvin, ketoconazole, fluconazole, or itraconazole. One recent study suggests no statistically significant difference in the mycologic cure rate between terbinafine and itraconazole. However, stratifying the results by age in this study showed terbinafine to be more effective than itraconazole in patients older than 55 years. Subjectively, patients report greater satisfaction with terbinafine compared with itraconazole.
• Investigators have found that recurrent nail dystrophy may increase from 8% at 12 months to 22% at 36 months following a laboratory cure by standard therapy. Mycologic failure rates may be higher. One study found positive cultures in 45% of patients 2 years after achieving a normal-appearing nail; however, the positive cultures may represent a new pathogen rather than a relapse of an old infection. Factors that may be related to relapse include extremely thickened nails, age, lateral nail disease, trauma, and other associated disorders.
• Fungal infections of the fingernails have a much more favorable prognosis than toenail infections.

Patient Education

• Patients should be educated about the use of appropriate footwear, especially in high-exposure areas, such as communal bathing facilities and health clubs.
• Following treatment, patients must be advised that nails may not appear normal for up to 1 year, and prophylactic antifungal therapy may be required to prevent reinfection of the skin and the nails. Patients may use topical terbinafine cream twice daily for 1-2 weeks for early tinea pedis or a 1-week pulse of itraconazole (200 mg PO bid) at the first signs of OM.
• For excellent patient education resources, visit eMedicine's Psoriasis Center and Yeast and Fungal Infections Center. Also, see eMedicine's patient education articles Nail Psoriasis and Onychomycosis.

MISCELLANEOUS

Section 9 of 11  

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Special Concerns

• HIV: OM in patients who are immunocompromised is associated with increased severity and morbidity. Lesions may appear atypical and require more aggressive management compared with the healthy population. Proximal subungual (ie, PSO) involvement is much more prevalent in patients with HIV infection than in those without HIV infection. WSO is more commonly caused by T rubrum, rather than T mentagrophytes, in this population.
• Diabetes: The diabetic foot may lead to serious complications associated with OM. Peripheral neuropathy and sensory loss may lead to increased trauma without pain in patients with diabetes. Bacterial colonization and vascular insufficiency may exacerbate the problem and may lead to serious sequelae.
• Elderly age: OM in elderly people is complicated by diseases (eg, poor vision, arthritis) that prevent optimal foot care. Nail changes are much more common in elderly persons and often involve the fingernails and the toenails. The potential for drug-drug interactions is more evident and must be addressed before initiating oral therapy.

MULTIMEDIA

Section 10 of 11  

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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Total dystrophic onychomycosis with the nail plate partially removed.
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Media file 2:  Superficial onychomycosis.
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Media file 3:  Distal lateral onychomycosis with surrounding erythema.
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Media file 4:  Proximal onychomycosis.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Miscellaneous
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• References

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Article Last Updated: Apr 3, 2007