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Fungal Nail Disease

David de Berker, M.R.C.P.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors clinical recommendations.

A 68-year-old man reports changes in his left big toenail. It has been discolored distally for the past 2 years. It has become thickened and difficult to cut and is painful when the man is walking in certain shoes. He is otherwise well. On physical examination, the nail appears thickened, has crumbling yellow material beneath, and is more discolored distally than proximally. The nearby skin is normal, although the interdigital space of the little toe is macerated. How should his case be managed?

The Cl inic a l Probl em

From the Bristol Dermatology Centre, Bristol Royal Infirmary, University Hospitals Bristol, Bristol, United Kingdom. Address reprint requests to Dr. de Berker at the Bristol Dermatology Centre, Bristol Royal Infirmary, University Hospitals Bristol, Bristol BS2 8HW, United Kingdom, or at david.deberker@uhbristol.nhs.uk. N Engl J Med 2009;360:2108-16.
Copyright 2009 Massachusetts Medical Society.

An audio version of this article is available at NEJM.org

The reported prevalence of toenail onychomycosis in Western adult populations is 2 to 14%1,2 and increases with age.2 The higher estimate includes patients who visit medical clinics for other diseases. Fungal nail disease is most common in people with other nail problems (e.g., a history of nail trauma), in immunocompromised persons (e.g., those with diabetes mellitus or human immunodeficiency virus infection or those taking immunosuppressive medications), in persons with peripheral vascular insufficiency, and in children with Downs syndrome.3 Onychomycosis is associated with tinea pedis in one third of cases4; cracking of the skin of the sole and interdigital clefts increases the risk of soft-tissue infection and, in particular, cellulitis of the leg.5 Onychomycosis may result in pain and a negative self-image.6,7 The most common pathogens are the dermatophytes Trichophyton rubrum and T. mentagrophytes.1 Nondermatophytes account for 10 to 20% of toenail onychomycosis in temperate climates,1,8 with the higher prevalence in areas of greater humidity. Of the nondermatophytes, candida species is the most common, and saprophytes (molds, such as acremonium species, scopulariopsis species, scytalidium species, aspergillus species, and fusarium species) account for most of the rest. Many of these are found in soil or plant material (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Most commonly, fungus invades the nail and nail bed by penetrating the distal or lateral margins (distolateral subungual onychomycosis). In other cases, it invades the nail plate directly from above, resulting in a powdery, white, patchy discoloration of the nail surface (superficial white onychomycosis); this presentation is most common in children. Invasion through the proximal margin, which is embedded within the proximal nail fold, is more prevalent in those with immunodeficiency and results in the appearance of infection emerging from beneath the nail as it grows (proximal subungual onychomycosis)9 (Fig. 1). Progression of disease can lead to variants and overlap of these presentations.

S t r ategie s a nd E v idence
The standard for the diagnosis of fungal nail disease is a positive result on microscopical examination and culture of nail clippings with subungual debris or from sur2108
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Figure 1. Patterns of Fungal Nail Infection. The three main patterns of fungal nail infection are infection gaining access from the distal or lateral margin (distolateral onychomycosis) (Panel A), infection on the surface of the nail plate (superficial white onychomycosis) (Panel B), RETAKE 1st AUTHOR de Berker ICM and fungal invasion appearing to occur from the proximal underside of the nail (proximal white onychomycosis) 2nd REG F FIGURE 1a-c (Panel C). 3rd
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face debris in superficial white onychomycosis includes a large sample of nail (a clipping of 2 to AUTHOR, 3 mm NOTE: (Fig. 2). However, a European survey of primary PLEASEtype in thickness) and subungual debris from Figure has been redrawn and has been reset. Please check carefully. care physicians and dermatologists indicated that the most discolored and friable area of the nail treatment was commonly prescribed in the ab- and nail bed. ISSUE: 5-14-09 10 Positive Certain clinical criteria are sensitive for the disence of confirmatory sampling.JOB: 36020 microscopical examination after preparation with potas- agnosis of fungal nail disease. Evidence of tinea sium hydroxide and staining with chlorazol black pedis including redness with peripheral scalE to increase sensitivity was reported to have a pos- ing and central clearing (which may be multiitive predictive value of 94% for confirmed fun- centric on the sole), maceration and a margin of gal infection, as compared with 99%11 for histo- advancing scaling between the toes, or both pathological assessment of the nail plate, which or a history of tinea pedis in the preceding year was a more costly procedure. Some clinicians use and discoloration of the nail are highly predictive microscopy alone to make a diagnosis.12 An ad- of the diagnosis.15 However, confirmatory testing vantage of this strategy is that a diagnosis may is recommended, to avoid the unnecessary use of be made at the initial visit; however, fungal hy- antifungal treatment and to highlight the possiphae identified in abnormal nails may be dead or bility of an alternative cause of the nail changes. may represent bystanders that are not contributThe most common alternative diagnoses are ing to the nail pathology. chronic trauma and psoriasis (Table 1). Both conDocumentation of a positive culture shows that ditions respond well to podiatric management if the fungus is viable and also identifies it and in- they are limited to the toes; more widespread psodicates whether it is likely to be pathogenic. When riatic nail disease warrants assessment by a dermaculture reveals nondermatophyte fungi, it may be tologist. About a quarter of dystrophic psoriatic big unclear whether they represent a contaminant or toenails may harbor fungal infection.16 Inflammaare the cause of the clinical findings. Repeated tory and neoplastic diseases of the periunguium heavy growth on culture media, positive direct can result in misdiagnosis. Although they may be microscopical examination, and characteristic clin- distinguishable from onychomycosis by the findical features13 indicate likely relevance. Culture has ing of soft-tissue changes with secondary alterapoor sensitivity, with false negative rates of 30 to tion of nail shape or inadequate nail production, 50%.14 This rate is minimized when the specimen biopsy may be needed for diagnosis (Fig. 3).
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Figure 2. Superficial White Onychomycosis. Samples of superficial white onychomycosis (Panel A) are obtained by scraping from the nail surface (Panel B). The superficial variant of onychomycosis (Panel C) is easy to treat with topical agents (Panel D), although less accessible RETAKE 1st AUTHOR ICM areas may need extra care and dbridement (arrow). de Berker
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There are several considerations in the decision PLEASE NOTE: It is reasonable not to treat persons who have AUTHOR, whether to treat onychomycosis.Figure has been redrawnminimal toenail involvement and no associated These include and type has been reset. Please check carefully. complications of the condition, the certainty of di- symptoms. Onychomycosis often affects more
JOB: 36020 ISSUE: 5-14-09

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Table 1. Differential Diagnosis of Fungal Nail Disease. Diagnosis Psoriasis Features Suggesting the Diagnosis Nail pitting, rash on elbows and knees, and family history of psoriasis Management Keep nails short, protect periungual skin with emollient and wear gloves during wet work, apply medium-potency topical corticosteroid to affected periungual skin at night, and manage more severe disease with systemic psoriatic treatments Wear appropriate footwear, which may involve orthotic devices, and seek podiatric consultation Biopsy may be needed for diagnosis; may require systemic immunosuppressive therapy

Trauma Lichen planus

Single nail affected, homogeneous alteration of nail color, and altered shape of nail May have nail atrophy and appearance of scarring at the proximal aspect of the nail; on the fingernails, it can reduce dexterity and hinder social interaction (see Fig. 1 in the Supplementary Appendix) Single nail affected, pain, warty nail-fold change, or ooze from edge of nail; often mistaken for paronychia, fungal nail, or wart Multiple nails become yellow, grow slowly, have increased longitudinal and transverse curvature, and are intermittently painful and shed; associated with chronic sinusitis, bronchiectasis, and lymphedema; candida can be grown in some instances but has little or no pathologic relevance

Periungual squamous-cell carcinoma Yellow-nail syndrome

Diagnosis may require nail biopsy followed by surgical treatment Provide intensive therapy for systemic elements, combined with local management of periungual inflammation; oral itraconazole and vitamin E might be helpful

than one family member.17 However, it is unclear whether familial cases reflect transmission within a shared living space or similar susceptibility due to shared genetic, environmental, or behavioral characteristics. Thus, although simple measures that might minimize the risk of transmission such as not sharing nail clippers or footwear are reasonable, pharmacologic treatment cannot be justified for the purpose of reducing transmission. Data are lacking on the risk of progression of untreated disease. Even in persons whose onychomycosis is not treated, associated tinea pedis should be treated5 (to reduce the risk of associated cellulitis) and relapse should be prevented by maintaining appropriate foot care. This includes the use of footwear that minimizes humidity, careful drying of the feet and interdigital spaces after washing, and the use of emollient on cracked skin that might otherwise allow entry of fungus. Aggressive dbridement may serve to curb minimal nail disease, although its efficacy has not been well studied. Dbridement may be accomplished with nail clippers on nails softened by bathing or with a file. A podiatrist may use a nail burr.

in the United States), and ciclopirox olamine 8% (Penlac), formulated as lacquers, are the topical agents that have been most studied for onychomycosis (Table 2). All are best suited to use for distal dermatophyte infection. Open-label studies and limited randomized trials of these drugs have suggested a benefit, with reported mycologic cure rates for distal fungal nail disease (caused by infection with dermatophytes) of 38 to 54% with amorolfine 5% lacquer used twice a week for 6 months,18,19 20 to 70% with tioconazole 28% solution used twice a day for 6 to 12 months,20 and 28 to 36% for ciclopirox olamine 8% lacquer used daily for 48 weeks.21 However, the lack of control groups is a serious limitation of many of these studies, and several are published in non peer-reviewed supplements. Furthermore, mycologic cure does not equal clinical cure; in the study of ciclopirox olamine 8% lacquer, a normal nail was achieved in only 7% of cases.22 Clinical experience suggests that when topical therapy is used, combining it with vigorous dbridement (filing the upper surface of the nail, which diminishes the amount of infected nail to treat) may increase the likelihood that therapy is successful. Topical therapy should be considered for those in whom systemic treatment is contraindicated or Topical therapy declined. Filing the upper surface of the nail may Amorolfine 5% (Loceryl, not available in the Unit- almost normalize appearance and improves access ed States), tioconazole 28% (Trosyl, not available for topical medication (Fig. 2).
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Figure 3. Conditions Misdiagnosed as Fungal Nail Infection. Conditions that may be misdiagnosed as fungal nail infection include psoriasis (Panel A), although fungus and nail psoriasis may coexist; chronic trauma, particularly in the elderly (Panel B); squamous-cell carcinoma of the nail bed RETAKE ICM (Panel C) and proximal nail fold (Panel D)AUTHOR of a clear diagnosis mandates 1st (absence de Berker biopsy); and the yellow-nail syn2nd REG F association with chronic sinusitis or bronchiectasis and lymphedema. 3a-e FIGURE drome (Panel E), which is often seen in
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FILL There is no good rationale for treating onychoappears superior, although the mycosis with antifungal creams applied toAUTHOR, PLEASE NOTE: and the differences between the drugs the in- efficacies Figure has been redrawn and type has been reset. tact nail, except possibly in cases of superficial vary substantially in different reports. A multiPlease check carefully. white onychomycosis, in which fungus occupies center, randomized trial, involving 508 subjects, ISSUE: 5-14-09 the upper surface of the nail. JOB: 36020 of no that compared terbinafine and itraconazole showed I am aware studies that have specifically examined this issue. clinical cure (i.e., negative mycologic analysis and clearance of more than 87.5% of the nail) at Systemic therapy 72 weeks in 54% of the patients taking terbinafine Oral agents that randomized trials have shown for 12 weeks and 60% of the patients taking terare effective for onychomycosis and that are ap- binafine for 16 weeks, as compared with 32% of proved by the Food and Drug Administration (FDA) the patients receiving 7-day pulses of itraconazole for the treatment of onychomycosis include terbi- each month for 3 or 4 months. Complete cure nafine (Lamisil) and itraconazole (Sporanox) (Ta- rates (i.e., negative mycologic analysis and a norble 2).23,24 In head-to-head trials comparing these mal nail) were 46% and 23% for terbinafine and

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Table 2. Therapeutic Interventions for Fungal Nail Disease.* Variable Topical therapy Nail For superficial white onychomycosis or fungal infection limited to the distal third; should be continued until there is no evidence of residual viable fungus Amorolfine 5% lacquer (Loceryl and Curanail, not available in the United States) once or twice a week for 6 to 12 months Ciclopirox olamine 8% lacquer (Penlac) daily for 48 weeks Tioconazole 28% paint (not available in the United States) twice daily for 6 to 12 months Terbinafine cream (Lamisil) Ketoconazole (Nizoral) or other azole cream Foot care, including washing, careful drying, and wearing footwear that minimizes trauma, warmth, and humidity Terbinafine (Lamisil): 250 mg daily for 6 weeks (fingernails) or 12 weeks (toenails) Itraconazole (Sporanox): 200 mg daily for 12 weeks for a toenail (U.S. guidelines) or 200 mg twice daily for 1 week a month for 2 months (fingernails) or 3 months (toenails) (European guidelines) Considerations Treatment

Skin

For associated tinea pedis; should be repeated if relapse occurs

Oral therapy

Has a success rate of approximately 50% in extensive or proximal subungual onychomycosis; less successful in the elderly

Topical and systemic therapy combined

Inconsistent evidence that combined therapy leads to a better cure rate than does oral therapy alone Has a general role in reducing the main part of the infected nail; may reduce discomfort; may have a particular role in treating more resistant nondermatophytes and for managing deformed nails Dbridement can require the care of a podiatrist, especially as the nail becomes thicker, harder, and more difficult to cut; in patients with diabetes mellitus or peripheral vascular disease, particular care is needed during dbridement to avoid damage to adjacent soft tissues

Dbridement or avulsion combined with topical or systemic therapy

* In cases of minimal distal involvement, with no discomfort or progression, some people may choose treatment with podiatric dbridement alone. This can also be a preferred option when the pathogen is a nondermatophyte that has only a small chance of responding to standard therapies.

itraconazole, respectively, after 12 weeks of treatment and 55% and 26%, respectively, after 16 weeks.23 Consistent with these data, clinical cure rates for terbinafine have been approximately 50% in several other studies.24-26 Reported success rates appear lower in patients over 65 years of age, with one report noting rates of clinical cure and complete cure of 26% and 15%, respectively.27 Most studies focus on disease of the big toenail because it is commonly involved and provides a sufficiently large surface to quantitatively assess results. Follow-up between 48 and 72 weeks is required for meaningful interpretation of outcome, since a big toenail can take 18 months to grow and, except for superficial white onychomycosis, the effect of treatment is to allow new uninfected

nail growth, rather than to change the appearance of the existing nail. The slow growth of the large toenail can mean that even these ranges of time are inadequate to assess the final outcome. The longer the follow-up period, however, the more likely it is that there will be a relapse or reinfection of a nail that is incompletely cured or inherently abnormal and prone to further infection. Among 151 subjects followed for 42 months after completion of the trial comparing terbinafine and itraconazole,23 clinical cure rates had fallen to 42% and 18%, respectively, and complete cure rates to 35% and 14%, respectively. These outcomes are consistent with a 25 to 30% relapse rate,28 with marginally lower relapse rates when patients were treated with terbinafine for 16 weeks rather than 12 weeks.29

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Terbinafine is given for 12 to 16 weeks for a big toenail and 6 weeks for a fingernail. In the United States, it is recommended that oral itraconazole be given for the treatment of fingernail onychomycosis, in doses of 200 mg twice daily on weeks 1 and 5 (pulsed itraconazole), whereas toenails should be treated with 200 mg once daily for 12 weeks (continuous itraconazole). The efficacy of systemic treatment must be balanced against the risk of side effects. In a metaanalysis of treatment trials, side effects led to discontinuation of therapy in 3.4% of patients who received terbinafine, 2.6% of those who received pulsed itraconazole, and 4.2% of those who received continuous itraconazole.30 Common side effects of terbinafine include gastrointestinal upset, headache, and minor rashes. Serious side effects are reported in less than 1% of patients31 but include serious or even fatal liver toxicity. Thus, systemic therapy is not recommended in patients with chronic or active liver disease, and liverfunction testing is recommended by the FDA before treatment. Monitoring liver function at 4 to 6 weeks is recommended by several experts.32 The side effects of itraconazole are similar to those of terbinafine but also include congestive heart failure, which represents a contraindication. Side effects of itraconazole can be diminished when the drug is taken as pulsed doses rather than continuously. Drug interactions are more common with itraconazole than terbinafine. Fluconazole (Diflucan) is rarely used, given the superiority of alternatives.33
Combined topical and systemic therapy

benefit to removing all infected nail. The latter may require the involvement of a podiatrist using a nail burr, or surgical or chemical avulsion using concentrated preparations of urea or salicylic acid. In a randomized trial in which vigorous dbridement was compared with routine clipping among two groups of patients treated with terbinafine, there was a nonsignificant benefit to dbridement.27 In a report of eight patients with dermatophyte onychomycosis,36 surgical avulsion of the affected toenail (three patients) or fingernail (five) followed by ketoconazole 2% or ciclopirox 8% cream under occlusion with a polyethylene wrap at night until there was nail regrowth was reported to result in clearance in all cases at the 18-month follow-up. Chemical or surgical avulsion in combination with pharmacologic therapy may have a role in cases of infection with fungi that are less responsive to monotherapy with terbinafine or itraconazole (e.g., fusarium species or scopulariopsis species), although this has not been well studied. Decision making must take into account the risks of avulsion, including pain and the potential for wound infection and scarring.

A r e a s of Uncer ta in t y
There is controversy regarding the costbenefit ratio of treatment of onychomycosis. In one costeffectiveness analysis, the estimated cost per cure with the use of terbinafine (based on cure rates from clinical trials) ranged from $2,439 to $7,944, depending on disease severity.37 These costs are at the upper end of published calculations but appear more realistic than the lower costs derived from analyses that are based on topical therapies, for which the cure rate is poorly documented. However, people who receive treatment without meeting the diagnostic criteria specified in therapeutic trials, which is common in practice, are not accounted for in this analysis or in other costbenefit analyses10; inappropriate treatment greatly increases the costs per case cured. Also relevant to decisions regarding therapy are the potential risks of treatment and the effects of treatment on quality of life, which can be improved by cure.38 In one study translating these considerations into a sum of money a patient would deem reasonable to spend on treatment, the amount that the majority of patients reported being prepared to spend30 was considerably less than the current charges for a course of systemic therapy.37
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It remains unclear whether combined topical and systemic therapy is more effective than systemic therapy alone.34 In one randomized trial, the combination of topical amorolfine weekly for 12 months and 250 mg of oral terbinafine daily for 3 months resulted in a 59% success rate (i.e., negative mycologic analysis with clearance of at least 90% of the nail) at 18 months, as compared with a 45% rate with terbinafine alone (P = 0.03).26 A similar but smaller trial comparing terbinafine alone with the combination of ciclopirox and terbinafine failed to show significant benefit from the addition of ciclopirox olamine.35
Dbridement

Regardless of the type of treatment used, it is advisable to keep the nail short, and there may be
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Guidel ine s
Guidelines for the management of fungal nail infections are available from the American Academy of Dermatology39 (these were published in 1996 and thus antedate much current data); national guidelines have been published more recently in the United Kingdom40 and Germany.41 All emphasize the importance of obtaining a sample of a nail plate and subungual debris for mycologic diagnosis, although the U.S. guidelines recommend obtaining the samples for diagnostic accuracy, rather than as a prerequisite to treatment. The guidelines published in the United Kingdom advocate topical therapy only in the case of superficial white onychomycosis or very early distolateral onychomycosis, whereas the German recommendations extend the use of topical therapy to cases in which up to 50% of distal nail is infected. Only the guidelines in the United Kingdom recommend terbinafine over itraconazole for infection with dermatophytes. Useful online resources include government agencies (e.g., www.nlm.nih.gov/ medlineplus/medlineplus.html and www.library. nhs.uk/Default.aspx) and professional bodies (http:// dermnetnz.org/fungal/onychomycosis.html).

C onclusions a nd R ec om mendat ions

Patients with an isolated nail dystrophy, such as the patient in the vignette, should have an evaluation to confirm the diagnosis of onychomycosis
References
1. Ghannoum MA, Hajjeh RA, Scher R,

and to avoid incorrect therapy resulting from misdiagnosis. After confirmation of the diagnosis by means of culture of a sample of discolored nail and subungual debris and microscopical examination after preparation with potassium hydroxide, possible treatments should be discussed with attention to their costs, success rates, and risks. Positive microscopy with negative culture warrants resampling. Regardless of other treatment, the nail should be kept short. Dbridement (by a podiatrist) should be considered if the nail is too thick for the patient to cut. I would offer topical therapy with amorolfine (outside the United States), used until clearance or for 12 months, or ciclopirox lacquer, used until clearance or for 48 weeks, although I would point out that the likelihood of complete cure appears low. I would also discuss the possibility of systemic therapy, noting the superiority of terbinafine over itraconazole in a randomized trial. However, I would warn that liver failure, though rare, has been reported and that congestive heart failure may be exacerbated by itraconazole. Liver-function testing is recommended in some countries, including the United States. The patient should understand that it takes approximately 6 to 12 months for the full clinical effects to be apparent. There is a 25 to 30% relapse rate in the long term for those who have an initial cure. Associated tinea pedis should be treated with topical therapy and good foot hygiene.
No potential conflict of interest relevant to this article was reported.

et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000;43:641-8. 2. Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997; 133:1172-3. 3. Svejgaard EL, Nilsson J. Onychomycosis in Denmark: prevalence of fungal nail infection in general practice. Mycoses 2004; 47:131-5. 4. Szepietowski JC, Reich A, Garlowska E, Kulig M, Baran E. Factors influencing coexistence of toenail onychomycosis with tinea pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol 2006;142:1279-84. 5. Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg

(cellulitis): case-control study. BMJ 1999; 318:1591-4. 6. Drake LA, Patrick DL, Fleckman P, et al. The impact of onychomycosis on quality of life: development of an international onychomycosis-specific questionnaire to measure patient quality of life. J Am Acad Dermatol 1999;41:189-96. 7. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol 1997;36:754-6. 8. Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol 2000; 43:244-8. 9. Daniel CR III, Norton LA, Scher RK. The spectrum of nail disease in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1992;27:93-7. 10. Effendy I, Lecha M, Feuilhade de

Chauvin M, Di Chiacchio N, Baran R. Epidemiology and clinical classification of onychomycosis. J Eur Acad Dermatol Venereol 2005;19:Suppl 1:8-12. 11. Lilly KK, Koshnick RL, Grill JP, Khalil ZM, Nelson DB, Warshaw EM. Cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests. J Am Acad Dermatol 2006;55:620-6. 12. Koshnick RL, Lilly KK, St Clair K, Finnegan MT, Warshaw EM. Use of diagnostic tests by dermatologists, podiatrists and family practitioners in the United States: pilot data from a cross-sectional survey. Mycoses 2007;50:463-9. 13. Summerbell RC, Cooper E, Bunn U, Jamieson F, Gupta AK. Onychomycosis: a critical study of techniques and criteria for confirming the etiologic significance of nondermatophytes. Med Mycol 2005; 43:39-59.

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