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Clinical Updates

Onychomycosis

Julie Jefferson, Phoebe Rich

Monday, September 19, 2011

Onychomycosis is a fungal infection of the nail unit resulting in nail discoloration, thickening, and deformity.1 Millions of people suffer from this condition annually, and the incidence and prevalence of onychomycosis continue to increase worldwide.1,2 In Western countries, 10% of the general population, 20% of the population over 60 years of age, and possibly even 50% of individuals over age 70 years have been reported to have onychomycosis.3 The prevalence of onychomycosis increases with age, seemingly as a result of peripheral vascular insufficiency, repeated nail trauma, longer exposure to pathogenic fungi, suboptimal immune function, and/or the inability to maintain good foot care.2,4,5

The condition is also prevalent among individuals suffering from immunodeficiency.1,2 It is estimated that one-third of all diabetics and 25% of those with human immunodeficiency virus (HIV) have onychomycosis.2,3 Other risk factors for onychomycosis include tinea pedis, Down's syndrome, genetic predisposition, living with family members who have onychomycosis, use of communal bathing facilities, frequent environmental contact with pathogens, popularity of fitness, occlusive clothing and shoes, and residing in a warm, humid climate.1,2,6

Although onychomycosis is not life-threatening, it may create sequelae that markedly impact the physical, functional, and psychosocial aspects of life.1,2 Complications such as pain, cellulitis, and extensive dermatophytic infections can occur.1 Patients frequently suffer from feelings of embarrassment, self-consciousness, anxiety, and/or depression because visible mycotic infections are often viewed as a sign of poor hygiene and elicit withdrawal by the general public out of fear of contagion.1 The implications of fungal nail infections are magnified in those with certain comorbidities. Persistent untreated onychomycosis in the diabetic patient can be complicated by osteomyelitis and tissue necrosis, ultimately requiring lower limb amputation.1 Additionally, because onychomycosis is a hallmark sign of immunodeficiency, it often has a profound emotional impact on those suffering from HIV and subsequent immune system deterioration.1,2

The dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes are the most commonly cited pathogens involved in onychomycosis, but other dermatophytes including epidermophyton species and microsporum species are also frequently reported.2,7 Non-dermatophytes, including Candida albicans, Scytalidium dimidiatum, Scytalidium hyalinum, and certain species of acremonium, alternaria, aspergillus, fusarium, onychocola, and scopulariopsis, are implicated in 10-20% of cases, with a higher prevalence in humid climates.7,8

Onychomycosis is currently divided into three subtypes: distolateral subungual onychomycosis, white superficial onychomycosis, and proximal subungual onychomycosis (Figure 1).9 The most common subtype - distal subungual onychomycosis - occurs when the fungus invades the nail plate and nail bed by way of penetration of the distal or lateral margins.2,8

White superficial onychomycosis is the most common presentation observed in children and occurs when the fungus invades the nail plate directly from above yielding a nail surface characterized by powdery, white patchy discoloration.2,8

Proximal subungual onychomycosis, which occurs when the fungus invades the proximal margin embedded within the nail fold, is most prevalent in the immunodeficient population and is characterized by the appearance of infection from beneath the nail as it grows.2,8 Disease progression often produces overlap variants of these presentations, and additional subtypes of onychomycosis have been proposed.8,9

 

Figure 1. The three established subtypes of fungal nail infection: (A) distolateral subungual onychomycosis (pictured here in the presence of tinea pedis); (B) white superficial onychomycosis; and (C) proximal subungual onychomycosis.

Diagnosis

Mycologic confirmation is critical for the proper diagnosis and management of onychomycosis, as only about 50% of all dystrophic nails are caused by fungal infection.1 Other nail dystrophies, including those attributed to psoriasis, eczematous conditions, senile ischemia (onychogryphosis), trauma, lichen planus, periungual squamous cell carcinoma, and iron deficiency, are often clinically indistinguishable from onychomycosis.7-9

The following are considered definitive laboratory criteria for the diagnosis of onychomycosis:

  1. microscopic evidence of septate hyphae and/or arthroconidia using either potassium hydroxide (KOH) or Calcofluor white stains;
  2. positive fungal culture of nail clippings with subungual debris (or from surface debris in superficial white onychomycosis);
  3. positive histopathologic examination of nail clippings with periodic acid-Schiff (PAS) stain.7,9

Although microscopy allows for diagnosis upon the initial visit, the fungus identified in the abnormal nails may be dead or a mere bystander not responsible for the actual nail pathology.8 A positive culture can confirm fungal viability and also allow for its identification and the determination of pathogenicity, but has poor sensitivity.8,10,11 While histopathologic examination of nail clippings with PAS stain is more sensitive than either KOH examination or fungal culture, the procedure is more expensive.9,12 Like PAS, Calcofluor white stain possesses a higher sensitivity than KOH examination or fungal culture, but its use is limited because fluorescent microscopy is required for the interpretation of results.11

When non-dermatophyte species are identified, it is often unclear whether they contribute to the clinical findings.7,8 In order to diagnose non-dermatophyte infection, the same organism must be isolated from sequential specimens, and correlation with direct microscopy and clinical changes is required.7,8 Clinical criteria reported to be highly predictive of the diagnosis of onychomycosis include evidence of tinea pedis or tinea manuum, ie advancing scale between digits and/or redness with peripheral scaling and central clearing, or a history of tinea pedis or tinea manuum during the preceding year with noted nail discoloration.8 If onychomycosis is suggested clinically, but routine laboratory testing produced only negative results, testing should be repeated.7 If repeated testing continues to be negative, a nail-unit biopsy may be indicated to rule out other causes of nail dystrophy.7

Treatment

The decision on whether to treat onychomycosis involves several considerations, including the certainty of diagnosis, complications of the condition, and the efficacy, costs, and potential side effects of treatment.8 Unfortunately, all current therapeutic options are associated with a high rate of initial treatment failure or recurrence.8,9 Moreover, mycologic cure is not synonymous with clinical cure.7 Even when treatment is effective, nails may continue to have an abnormal appearance. In 2007, Scher et al. defined cure for onychomycosis as:

  1. the total absence of clinical signs; or
  2. the presence of negative microscopy and/or nail culture results with one or more of the following minor clinical criteria: (i) nail plate thickening secondary to a comorbid condition; and (ii) minimal distal subungual hyperkeratosis or onycholysis leaving less than 10% of the nail affected.7

Food and Drug Administration (FDA)-approved oral agents shown to be effective in the treatment of onychomycosis through randomized control trials include terbinafine and itraconazole.9 A randomized, double-blind trial published in 2002 reported that terbinafine was more effective than itraconazole pulse therapy on measures of long-term clinical outcomes.9,13 Furthermore, terbinafine was also associated with fewer interactions than itraconazole.9 Although not currently FDA approved, once-weekly fluconazole has been found to be effective in patients with onychomycosis and could be particularly useful in patients with complicated medication regimens.9,14 However, head-to-head trials have found once-weekly fluconazole to be neither as effective nor as cost-effective as terbinafine or itraconazole.9,15-17

Studies using FDA-approved topical ciclopirox olamine 8% lacquer found that only 7% of patients attained disease-free, normal-appearing nails after 48 weeks of therapy, and only 4% of patients were able to maintain both clinical and mycological cure 3 months after the completion of therapy.18 In contrast, 40-60% of patients treated with oral terbinafine achieved complete cure at the end of the course of therapy.18 Thus, topical therapy is typically reserved to treat those patients in whom systemic treatment is contraindicated or declined, or in those suffering from the white superficial subtype.8 Topical therapy appears to be more effective when combined with vigorous filing of the upper surface of the nail.8,19 Randomized trials have found no greater clinical efficacy of ciclopirox in combination with oral terbinafine when compared with oral terbinafine alone.9,20,21

Preliminary data have been collected on several potential therapeutic modalities, including infrared and near-infrared laser therapy,22,23 photodynamic therapy,24-26 iontophoretic delivery of topical medications,27-29 and the use of medicated chest rubs containing eucalyptus oil, camphor, menthol, thymol, oil of turpentine, oil of nutmeg, and oil of cedar leaf.30,31 Additional studies that support their efficacy are necessary before treatment with these agents can be recommended.9 Surgery is generally used only in the treatment of an isolated nail infection or dermatophytoma (a collection of dermatophytes in solid form beneath the nail).9

Conclusions

The clinical impact of onychomycosis may reach far beyond mere cosmetic concern to affect the functional and psychosocial aspects of life. Quality of life is especially reduced in those diabetic and immunodeficient patients who suffer from severe complications. An accurate diagnosis is essential for proper management and, although current treatment options are associated with high rates of initial failure and recurrence, more successful treatments could be on the horizon.

References

  1. Elewski BE. Onychomycosis: treatment, quality of life, and economic issues. Am J Clin Dermatol 2000;1:19-26.
  2. Kaur R, Kashyap B, Bhalla P. Onychomycosis- epidemiology, diagnosis, and management. Indian J Med Microbiol 2008;26:108-116.
  3. Thomas J, Jacobson GA, Narkowics CK, Perterson GM, Burnet H, Sharpe C. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther 2010;35:497-519.
  4. Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997;133:1172-1173.
  5. Ghannoum MA, Hajjeh RA, Scher R, 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;43:641-648. 
  6. Svejgaard EL, Nilsson J. Onychomycosis in Denmark: prevalence of fungal nail infection in general practice. Mycoses 2004;47:131-135.
  7. Scher R, Tavakkol A, Bact D, et al. Onychomycosis: Diagnosis and definition of cure. J Am Acad Dermatol 2007;56:939-944.
  8. De Berker D. Fungal nail disease. N Engl J Med 2009;360:2108-2116.
  9. Goldstein, AO, Goldstein, BG. Onychomycosis. In: UpToDate, Basow, DS (Ed). Waltham, MA: UpTpDate, 2011.
  10. Denning DW, Evans EG, Kibbler CC, et al. Fungal nail disease: a guide to good practice (report of a Working Group of the British Society for Medical Mycology). BMJ 1995;311:1277-1288.
  11. Weinberg JM, Koestenblatt EK, Tutrone WD, et al. Comparison of diagnostic methods in the evaluation of onychomycosis. J Am Acad Dermatol 2003;49:193-197.
  12. Wilsmann-Theis D, Sareika F, Bieber T, et al. New reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis. J Eur Acad Dermatol Venereol 2011;25:235-237.
  13. Sigurgeirsson B, Olafsson JH, Steinsson JB, et al. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch Dermatol 2002;138:353-357.
  14. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol 1998;38:S77-S86.
  15. Gupta AK. Pharmacoeconomic analysis of oral antifungal therapies used to treat dermatophyte onychomycosis of the toenails. A US analysis. Pharmacoeconomics 1998;13: 243-256.
  16. Havu V, Heikkilä H, Kuokkanen K, et al. A double-blind, randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of onychomycosis. Br J Dermatol 2000;142:97-102.
  17. Salo H, Pekurinen M. Cost effectiveness of oral terbinafine (Lamisil) compared with oral fluconazole (Diflucan) in the treatment of patients with toenail onychomycosis. Pharmacoeconomics 2002;20:319-324.
  18. Epstein E. Fungus-free versus disease-free nails. J Am Acad Dermatol 2004;50:151-152.
  19. Tavakkol A, Fellman S, Kianifard F. Safety and efficacy of oral terbinafine in the treatment of onychomycosis: analysis of the elderly subgroup in Improving Results in ONychomycosis-Concomitant Lamisil and Debridement (IRON-CLAD), an open-label, randomized trial. Am J Geriatr Pharmacother 2006;4:1-13.
  20. Gupta AK, Onychomycosis Combination Therapy Study Group. Ciclopirox topical solution, 8% combined with oral terbinafine to treat onychomycosis: a randomized, evaluator-blinded study. J Drugs Dermatol 2005;4:481-485.
  21. Avner S, Nir N, Henri T. Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis. J Dermatolog Treat 2005;16:327-330.
  22. Manevitch Z, Lev D, Hochberg M, et al. Direct antifungal effect of femtosecond laser on Trichophyton rubrum onychomycosis. Photochem Photobiol 2010;86:476-479.
  23. Landsman AS, Robbins AH, Angelini PF, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc 2010;100:166-177.
  24. Watanabe D, Kawamura C, Masuda Y, et al. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol 2008;144:19-21.
  25. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol 2008;59:S75-S76.
  26. Sotiriou E, Koussidou-Eremonti T, Chaidemenos G, et al. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: Preliminary results of a single-centre open trial. Acta Derm Venereol 2010;90:216-217.
  27. Amichai B, Nitzan B, Mosckovitz R, Shemer A. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol 2010;162:46-50.
  28. Amichai B, Mosckovitz R, Trau H, et al. Iontophoretic terbinafine HCL 1.0% delivery across porcine and human nails. Mycopathologia 2010;169:343-349.
  29. Nair AB, Kim HD, Chakraborty B, et al. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J Pharm Sci 2009;98:4130-4140.
  30. Derby R, Rohal P, Jackson C, et al. Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med 2011;24:69-74.
  31. Ramsewak RS, Nair MG, Stommel M, Selanders L. In vitro antagonistic activity of monoterpenes and their mixtures against 'toe nail fungus' pathogens. Phytother Res 2003;17:376-379.
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