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Onychomycosis
Lauren M. Simon, MD, MPH, FAAFP, FACSM
image BASICS
DESCRIPTION
  • Fungal infection of fingernails/toenails
  • Caused mostly by dermatophytes but also yeasts and nondermatophyte molds
  • Toenails are more commonly affected than fingernails.
  • System(s) affected: skin, exocrine
  • Synonym(s): tinea unguium; ringworm of the nail
EPIDEMIOLOGY
Prevalence
  • Occurs in 2-10% of general population
  • Predominant age: 20% in adults >60 years of age
  • Rare before puberty
  • Prevalence 15-40% in persons with human immunodeficiency infection (1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Dermatophytes: Trichophyton (Trichophyton rubrum most common), Epidermophyton, Microsporum
  • Yeasts: Candida albicans (most common), Candida parapsilosis, Candida tropicalis, Candida krusei
  • Molds: Scopulariopsis brevicaulis, Hendersonula toruloidea, Aspergillus sp., Alternaria tenuis, Cephalosporium, Scytalidium hyalinum
  • Dermatophytes cause 90% of toenail and most of fingernail onychomycoses.
  • Fingernail onychomycosis is more often caused by yeasts, especially Candida.
  • Dermatophytes can invade normal keratin, whereas nondermatophyte molds invade altered keratin (dystrophic/injured nails).
RISK FACTORS
  • Older age
  • Tinea pedis
  • Occlusive footwear
  • Cancer/diabetes/psoriasis
  • Peripheral vascular disease
  • Cohabitation with others with onychomycosis
  • Immunodeficiency
  • Communal swimming pools
  • Smoking
  • Peripheral vascular disease
  • History of nail trauma
  • Autosomal dominant genetic predisposition
COMMONLY ASSOCIATED CONDITIONS
  • Immunodeficiency/chronic metabolic disease (e.g., diabetes)
  • Tinea pedis/manuum
image DIAGNOSIS
PHYSICAL EXAM
  • Dermatophytes: commonly preceded by dermatophyte infection at another site; 80% involve toenails, especially hallux; simultaneous infection of fingernails and toenails is rare. Five clinical forms occur.
    • Distal/lateral subungual onychomycosis (most common): mainly due to T. rubrum. Spreads from distal/lateral margins to nail bed to nail plate; subungual hyperkeratosis; onycholysis; nail dystrophy; discoloration—yellow-white or brownblack, yellow streaking laterally; can progress proximally, bois vermoulu (“worm-eaten wood”); onychomadesis
    • Proximal subungual onychomycosis (rare <1% of cases): hands/feet; leukonychia—begins at proximal part of nail plate, appearing to occur from the proximal underside of the nail (or direct invasion of the nail plate from above); spreads to nail plate and lunula; seen with immunosuppressive conditions
    • Superficial (formerly known as superficial white onychomycosis) about 10% of cases: hallux is preferentially affected; infection of outer surface of nail plate; opaque white spots on nail plate eventually merge to involve entire surface of the nail. Most commonly due to Trichophyton mentagrophytes
    • Endonyx onychomycosis involves interior of nail plate, sparing nail bed. Nail develops milky white appearance with indentations. Subungual hyperkeratosis is absent.
    • Totally dystrophic onychomycosis causes complete destruction of nail plate by fungus, resulting in thickened and ridged nail bed covered with keratotic debris.
  • Candidal
    • Hands, 70%, especially for the dominant hand
    • Middle finger is most common.
    • Pain is mild, unless secondarily infected.
    • Increases on prolonged contact with water
    • Primarily affects tissue surrounding nail
    • Begins with cuticle detachment
    • White or white-yellow nail discoloration
    • Secondary ungual changes: convex, irregular, striated nail plate with dull, rough surface
    • Onycholysis, especially on hands
    • Distal subungual onychomycosis may occur.
    • Primary involvement of the nail plate is uncommon (thin, crumbly, opaque, brownish nail plate deformed by transverse grooves).
    • Periungual edema/erythema may occur (clubshaped, bulbous fingertips).
  • Molds (nondermatophyte)
    • More common in those >60 years of age
    • More common in nails of hallux
    • Resembles distal and lateral onychomycosis
Pediatric Considerations
  • Candidal infection presents more commonly as superficial onychomycosis.
  • The U.S. Food and Drug Administration (FDA) has not approved any systemic antifungal agents for treatment of onychomycosis in children. Efficacy and safety profiles in children for some systemic antifungals are similar to those previously reported in adults (2).
DIFFERENTIAL DIAGNOSIS
  • Psoriasis (most common alternate diagnosis)
  • Traumatic dystrophy
  • Lichen planus
  • Onychogryphosis (“ram's horn nails”)
  • Eczematous conditions
  • Hypothyroidism
  • Drugs and chemicals
  • Yellow nail syndrome
  • Neoplasms (0.7-3.5%) of all melanoma cases are subungual. In a brownish yellow nail, if dark pigment extends into periungual skin fold, consider subungual melanoma.
DIAGNOSTIC TESTS & INTERPRETATION
  • Accurate diagnosis requires both laboratory and clinical evidence.
  • About 50% of nail dystrophy seen on visual inspection is not fungal in origin, so laboratory assessment improves diagnostic accuracy.
  • If onychomycosis is suspected clinically and initial diagnostic laboratory tests are negative, the tests should be repeated.
  • A nail plate biopsy or partial/full removal of nail with culture is needed to diagnose proximal subungual onychomycosis.
Initial Tests (lab, imaging)
  • Direct microscopy with potassium hydroxide (KOH) preparation (1)[C]
    • Clean nail with 70% isopropyl alcohol.
    • Using sterile clippers, remove diseased, discolored nail plate.
    • Collect debris from stratum corneum of most proximal area (beneath nail or crumbling nail itself) with 1-mm curette/scalpel.
    • Place sample on microscope slide with drop of 5-10% KOH. View after 5 minutes.
    • Gentle heat applied to slide can enhance keratin breakdown.
    • High sensitivity if >2 preparations were examined
    • Look for hyphae, pseudohyphae, or spores.
  • Cultures: False-negative finding in 30% (secondary to loss of dermatophyte viability; improved by immediate culture on Sabouraud cell culture medium); results may take 3 to 6 weeks.
  • In office dermatophyte test, medium culture indicates dermatophyte growth with yellow-to-red color change of the medium; results in 3 to 7 days; limited studies.
  • Histologic examination of nail clippings/nail plate punch biopsy: proximal lesions; stain both with periodic acid-Schiff (PAS) stain (1)[C].
  • KOH-treated nail clipping stained with PAS: significantly higher rates of detection of onychomycosis as compared with standard methods of KOH preparation and fungal culture (3)[C]
  • Polymerase chain reaction (PCR) increases sensitivity of detection of dermatophytes in nail specimen, results available within 3 days can be used as complementary to direct microscope exam and fungal culture; not widely available.
  • Fluorescence microscopy can be used as a rapid screening tool for identification of fungi in nail specimens.
  • Commercial laboratories may use KOH with calcofluor white stain to improve view of fungal elements in fluorescent microscopy.
  • Discontinue all topical medication for at least 1 week before obtaining a sample.
Test Interpretation
Pathogens within the nail keratin
image TREATMENT
GENERAL MEASURES
  • Avoid factors that promote fungal growth (i.e., heat, moisture, occlusion, tight-fitting shoes).
  • Treat underlying disease risk factors.
  • Treat secondary infections.
MEDICATION
Pregnancy Considerations
Oral antifungals and ciclopirox are pregnancy Category B (terbinafine, ciclopirox) or C (itraconazole, fluconazole, and griseofulvin). Griseofulvin is not advised in pregnancy due to risks of teratogenicity and conjoined twins. Ideally postpone treatment of onychomycosis until after pregnancy.
P.729

First Line
  • Oral antifungals are preferred due to higher rates of cure but have systemic adverse effects and many drug-drug interactions.
  • Terbinafine: 250 mg/day PO for 6 weeks for fingernails and 12 weeks for toenails; most effective in cure and prevention of relapse compared with other antifungals and with itraconazole pulse in metaanalysis for toenail onychomycosis I (4)[A]
  • Itraconazole pulse: 200 mg PO BID for 1 week, then 3 weeks off, repeat for two cycles for fingernails and three to four cycles for toenails; does not need to monitor liver function tests (LFTs) with pulse dosing
  • Itraconazole continuous: 200 mg/day PO for 6 weeks for fingernails and 12 weeks for toenails (less effective than itraconazole pulse for dermatophytes, more effective than terbinafine for Candida and molds)
Second Line
  • Fluconazole pulse: 150 to 300 mg PO weekly for 6 months (lower cure rate); not FDA-approved for onychomycosis
  • Griseofulvin: 500 to 1,000 mg/day PO for up to 18 months (lower cure rate, continue until the diseased nail is replaced)
  • Posaconazole: 100, 200, or 400 mg once daily for 24 weeks; 400 mg once daily for 12 weeks; higher cost
  • Topical agents: Use limited to disease not involving the lunula (proximal nail plate). Topical therapy does not cause systemic toxicity but is less effective than oral therapy. Head-to-head comparison of efficacy of available agents is generally not available.
  • Ciclopirox: 8% nail lacquer (available generically): Apply once daily to affected nails (if without lunula involvement) for up to 48 weeks; remove lacquer with alcohol every 7 days, then file away loose nail material and trim nails (low-cure rate, avoids systemic adverse effects, less cost-effective). Application after PO treatment may reduce recurrences. Systematic review >60% failure rate after 48 weeks of use (5)[A],(6)
  • Tavaborole 5% solution, a topical oxaborole antifungal is indicated for onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. Complete or almost-complete cure 15-18% after 48 weeks (NNT compared to vehicle approx 7)
  • Efinaconazole solution 10% (7). Complete or almost-complete cure after 48 weeks in range of 15-18% (NNT compared to vehicle 7 to 10)
  • Contraindications for oral antifungals
    • Hepatic disease
    • Pregnancy (see “Pregnancy Considerations”)
    • Current/history of congestive heart failure (CHF) (itraconazole)
    • Ventricular dysfunction (itraconazole)
    • Porphyria (griseofulvin)
  • Precautions/adverse effects
    • Oral antifungals
      • Hepatotoxicity/neutropenia
      • Hypersensitivity
      • Photosensitivity, lupus-like symptoms, proteinuria (griseofulvin)
      • Chronic kidney disease (avoid terbinafine for patients with creatine clearance [CrCI] <50 mL/min, decrease fluconazole dose)
      • CHF, peripheral edema, pulmonary edema (itraconazole)
      • Rhinitis (itraconazole)
  • Ciclopirox: rash, nail disorders; avoid contact with skin except along nail edge; caution with broken skin or vascular compromise
  • Oral agents: numerous significant drug-drug interactions. Need to check each medication:
    • Terbinafine (inhibits cytochrome P450 2D6 isozyme [CYP2D6]): for example, &bgr;-blockers, monoamine oxidase inhibitors (MAOIs), SSRIs, tricyclic antidepressants (TCAs), warfarin, oxycodone
    • Itraconazole, fluconazole (inhibit CYP3A4): for example, antiarrhythmics, benzodiazepines, ergot alkaloids, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, calcium channel blockers, corticosteroids, hydrochlorothiazide, hypoglycemics, oral contraceptives (OCPs), warfarin, zolpidem
    • Griseofulvin: for example, OCPs, salicylates, warfarin
SURGERY/OTHER PROCEDURES
  • Nail débridement to remove infected keratin (efficacy not well studied): Use for few nails involved or if not, for candidate of systemic therapy.
    • Mechanical: Soften with occlusive dressing with 40% urea gel; detach from nail bed with tweezers, file with abrasive stone or curette.
    • Chemical: Protect peripheral tissue with adhesive strips; apply ointment of 30% salicylic acid, 40% urea, or 50% potassium iodide under occlusive dressing.
    • Débridement may be combined with topical antifungal therapy.
    • Surgical avulsion if few nails are involved; for pain control.
  • Laser treatment has shown some positive results but limited efficacy data (7).
  • Photodynamic therapy using topical photosensitizing agents and irradiation with appropriate light source some success for treatment of superficial nail infections; limited data.
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Melaleuca alternifolia (tea tree oil) Cochrane review found no evidence of benefit (5).
  • Vicks VapoRub application to nails daily for 48 weeks has been found safe, but efficacy is uncertain.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Formation of a new fingernail takes 4 to 6 months, and a new toenail takes 12 to 18 months.
  • Cure defined as:
    • Clinical cure, 100% absence of clinical signs, and/or
    • Mycotic cure, negative mycology with ≥1 of the following clinical signs:
      • Distal subungual hyperkeratosis/onycholysis leaving <10% of the nail plate affected
      • Nail plate thickening that does not improve with treatment because of comorbid condition
Patient Monitoring
  • Topical agents: Slow response is expected; visits every 6 to 12 weeks.
  • Terbinafine, griseofulvin: baseline, and as needed, LFTs and CBC
  • Itraconazole continuous: baseline, and as needed, LFTs
PATIENT EDUCATION
  • Advise patient to:
    • Keep affected area clean and dry.
    • Avoid rubber/other occlusive, tight-fitting footwear.
    • Wear absorbent cotton socks.
    • Launder clothing and towels frequently in hot water.
    • Avoid sharing nail implements or use on both normal and abnormal nails.
  • Cure of all toenails may not be attainable.
  • Nails may not appear normal after cure.
PROGNOSIS
  • Complete clinical cure in 25-50% (higher mycologic cure rates) with oral therapy
  • Recurrence is 10-50% (relapse/reinfection).
  • Poor prognostic factors
    • Areas of nail involvement >50%
    • Significant proximal/lateral disease
    • Subungual hyperkeratosis >2 mm
    • White/yellow or orange/brown streaks in the nail (includes dermatophytoma)
    • Total dystrophic onychomycosis (with matrix involvement)
    • Nonresponsive organisms (e.g., Scytalidium mold)
    • Patients with immunosuppression
    • Diminished peripheral circulation
REFERENCES
1. Westerberg DP, Voyack MJ. Onychomycosis: current trends in diagnosis and treatment. Am Fam Physician. 2013;88(11):762-770.
2. Gupta AK, Paquet M. Systemic antifungals to treat onychomycosis in children: a systematic review. Pediatr Dermatol. 2013;30(3):294-302.
3. Eisman S, Sinclair R. Fungal nail infection: diagnosis and management. BMJ. 2014;348:g1800.
4. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004;150(3):537-544.
5. Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev. 2007;(3):CD001434.
6. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013;31(5):544-554.
7. Ameen M, Lear J, Madan V, et al. British Association of Dermatologists' guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014; 171(5):937-958.
Codes
&NA;
ICD10
  • B35.1 Tinea unguium
  • B37.2 Candidiasis of skin and nail
Clinical Pearls
&NA;
  • Psoriasis and chronic nail trauma are commonly mistaken for fungal infection.
  • Diagnosis should be based on both clinical and mycologic laboratory evidence.