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Onychomycosis


Synonyms

When the infection is due to a dermatophyte, both "Ringworm of the nail" and "Tinea unguium" are sometimes used as synonyms. For an extended discussion of the nomenclature of the fungal infections of skin and nails, please see our overview of this area.
Definition

Onychomycosis refers to the invasion of the nail plate by a fungus. The infection may be due to a dermatophyte, yeast, or nondermatophyte mould. The term "tinea unguium" is used specifically to describe invasive dermatophytic onychomycosis [656].

Onychomycosis, particularly fingernail infections have an important impact on the life of affected individuals. Shame may preclude patients from acting in social and occupational circumstances where they feel unwilling to show their hands or feet. Equally, work recruitment may be important if the job requires interaction with the public [2043]. Therefore, even if considered a cosmetic problem, this is an infection that is often worth treating.
Epidemiology

Rates of onychomycosis vary with the population considered. A recent study in a general U.S. population revealed a prevalence of 2 to 3%, while a study performed in Finland report a rate of 13% [658, 1017]. The disease is twice as frequent among men than women, and it seems to increase with age [656]. Both of the above-mentioned North American and Finnish studies reported rates of ~25% among elderly patients. Several factors have been implicated in the age-related increase in disease, including reduced peripheral circulation, diabetes, inactivity, increased nail trauma, and difficulty (or inability) to maintain proper nail hygiene [658, 2043].

Children have infection rates 30 times lower than adults. In addition to the lack of the previously discussed factors, children have smaller nail surfaces and faster nail growth [951].

The prevalence of onychomycosis in patients with diabetes has been reported to be 26%. Indeed, diabetics appear almost three times as likely to have onychomycosis as non-diabetic individuals [949]. Although there are no studies addressing the relationship between onychomycosis and diabetic foot ulcers, it is possible that one could predispose to the other. Fungal nail infections cause, as we will discuss, thickening and dystrophy of the nails, which should favor pressure erosions of the nail bed and hyponychium [1920].

Immunosuppressed individuals, both HIV and non-HIV, have also a particular tendency to suffer this type of fungal infection [1038, 2140].

Risk Factors
The general risk factors for any type of onychomychosis are [457]:
  1. Increasing age
  2. Male gender
  3. Diabetes
  4. Nail trauma (onychogryphosis)
  5. Hyperhydrosis
  6. Peripheral vascular diseases
  7. Poor hygiene
  8. Tinea pedis, especially the "moccasin type"
  9. Immunodeficiencies
  10. In the case of candidal onychomycosis in particular, chronic exposure of the nails to water can be a significant risk factor
Mycology
The dermatophytes are indeed the most common causes of onychomycosis. Trichophyton rubrum is the principal agent causing both onychomycosis and tinea pedis in USA, followed by Trichophyton mentagrophytes. The third most common fungi on this list is Epidermophyton floccosum, but its frequency is notably less than that of the two Trichophyton spp. [2193]. The complete list of implicated dermatophytes includes:
But, a variety of other fungi also cause onychomycosis:
Natural habitat

Dermatophytes: Animals
Other fungi: Generally soil and rotting vegetation
Clinical Manifestations

General Features

We discuss here the forms of onychomycosis due to the dermatophytes and/or moulds. The closely related entity of onychomycosis due to Candida spp. is discussed elsewhere.

To better understand the clinical varieties of onychomycosis, it is important to review the anatomy of the fingernail and surrounding tissues (the "nail unit"). The matrix is where the cells multiply and keratinize before being incorporated into the nail plate. This tissue starts about 5mm proximal to the nail fold and covers all the area called "lunula" or "half moon". The matrix is protected from infection by the cuticle, a fold of modified stratum corneum proximal to the nail plate [656].





In all forms of onychomycosis, the nail becomes variously disfigured and distorted. Based on the form of infection and the associated clinical appearance, onychomycosis is classified in this way:


Type Distal subungual onychomycosis (DSO) Proximal subungual onychomycosis (PSO) White superficial onychomycosis (WSO)
Frequency It is the most common clinical form [656] Uncommon in the general population but very frequent in AIDS patients [55] Represents about 10% of cases of onychomycosis [2485]
Evolution Infection begins with invasion of the hyponychium (the place where the nail separates from the nail bed) Infection by invasion of the proximal nail fold, with subsequent penetration into the newly forming nail plate that is underneath. The distal nail remains normal until late in the disease. Infection begins at the superficial layer of the nail plate invading progressively deeper layers
Clinical appearance Onycholysis (separation of the nail plate from the nail bed) and thickening of subungueal area; when superinfection with bacteria and/or molds occurs, the nail plate turns yellowish brown Subungual hyperkeratosis, leukonychia, proximal onycholysis, and destruction of the nail unit. Initially "white islands" are seen on the external nail plates. These gradually coalesce until the entire nail plate is involved
Most common etiologic agent Trichophyton rubrum Trichophyton rubrum Trichophyton mentagrophytes
Aspergillus terreus
Acremonium roseogriseum
Fusarium oxysporum
Affected nails Toenails are most commonly affected but may affect fingernails as well Much more common on the toenails

Rarely affects fingernails
Mainly affect toenails


Atypical presentations can occur, particularly among immunosuppressed individuals. Nodular and papular lesions that extend from the foot to the leg (calf) and that are suggestive of blastomycosis have been described [1038, 2140].

Finally, the term "Total dystrophic onychomycosis" is not a subtype, but is instead the final stage of any of the previously described forms of onychomycosis and/or Candida onychomycosis
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Specific Diagnostic Strategies

Fungal infections only explain about 50% of nail dystrophies [656]. Several entities have to be considered in the differential diagnosis (table at right). As therapy for onychomycosis is prolonged and not completely without risk of complications, the clinician should always confirm the diagnosis of onychomycosis. The value of obtaining a good specimen for microscopic examination and culture cannot be overemphasized. The following steps will increase the yield of these studies:

  1. Nails ideally should be clipped rather than just scraped
  2. In cases of DSO, the sample should be taken from the nail bed as proximally as possible to the cuticle
  3. In cases of PSO, the sample should be taken from the infected proximal nail as close as possible to the lunula
  4. In cases of WSO, the sample should be taken from the plate surface by scraping the white area
  5. The microscopic examination shold be preceded by treating the nail fragments in 10-20% KOH
  6. The nail should be sent to a reputable laboratory for culture processing
Differential Diagnosis of Onychomycosis
Psoriasis
Lichen planus
Contact dermatitis
Traumatic onychodystrophies
Congenital pachyonychia
Bacterial infections
Yellow-nail syndrome
Idiopathic onycholysis
Onychogryphosis
 
Therapeutic Strategies

Systemic antifungal agents
Onychomycosis has long been one of the most difficult fungal infections to treat. The lengthy period the nail takes to grow, the hardness of the nail plate, and location of the infectious process between the nail bed and plate are major factors interfering with the eradication of fungal agents affecting these tissues [656]. For about 40 years, griseofulvin was the only oral antifungal agent available. However, its effectivity was always limited because it has a limited antifungal spectrum and a poor pharmacokinetic profile. Clinical and mycological cure rates with this agent were low and recurrence was frequent [656]. The appearance of new antifungal agents has revolutionized the treatment of this condition. These new drugs provide adequate therapy for a prolonged period of time with minimal systemic toxicity. Two agents, terbinafine and itraconazole, have emerged as good therapies for onychomycosis. The key to both of these agents is that once given, they are absorbed into the nail matrix where they remain active for months. Indeed, one can detect itraconazole in nail clippings for up to a year after administration and terbinafine for up to 3 months [1934].

The standard therapies are:
  • Terbinafine, given at 250 mg daily for three months [114, 617]. This medication has been proven to be effective also in HIV patients and no drug interactions or significant adverse effects related to the drug have been reported [1038].
  • Itraconazole 200 mg twice daily for 1 week/month, followed by nothing for the remainder of the month. This cycle is repeated twice for fingernails or 3-4 times for toenails [525, 1000, 1676]. An important consideration at the time of treating HIV/AIDS patients are the interactions of itraconazole with protease inhibitors. Itraconazole inhibits enzymes of the cytochrome P450, therefore it is not recommended to use it simultaneously with protease inhibitors.
  • Fluconazole has proven to be less effective than these two options, particularly because effective courses of therapy are very long [656, 1001]. Recommended regimen is 150 to 450 mg weekly for 6 to 9 months [1352, 2044].
These therapies yield cure rates in most clinical studies of ~80%. The cause(s) of failures of therapy are not well understood. Microbiological resistance does not appear to be common [315].

In addition to the use of an effective drug, it is also important to understand what to expect in terms of a clinical response. Nails grow very slowly--it can take well more than a year to completely regrow a toenail. Thus, complete clinical resolution of the infection will require at least this long. However, due to the binding of terbinafine and itraconazole to the nail, the course of therapy need not be this long. Instead, 3-4 months of therapy suffices to "load" the growing nail with the drug. Then, as the nail continues to grow, the disfigured nail is gradually replaced with normal nail [1014].

Topical antifungals
Until recently, topical therapy alone was in general not useful for the treatment of onychomycosis. However, ciclopirox solution 8%, an innovative topical nail lacquer, has been recently approved for the treatment of mild to moderate onychomycosis [85]. Recent studies have shown successful cure rates when using this agent alone [941, 942, 946]. The solution is applied daily covering the entire nail plate and approximately 5 mm of surrounding skin for 12 months. Overall, however, this approach is not nearly as effective as systemic therapy with the above-mentioned agents.

Other topical agents, particularly those effective for the treatment of tinea pedis are recommended to avoid the relapse of this skin infection and thereby reduce the likelihood of recurrent nail infection.

Surgical procedures
Nail surgery is not recommended as a routine procedure for the treatment of onychomycosis. This is a painful and disfiguring procedure that should be reserved for isolated cases when there are either contraindications to use of systemic antifungals, or a drug-resistant fungal agent is present [656].

Home Remedies
Everyone does seem to have a story about how Aunt Jane once soaked her nails in vinegar (or baking soda or even more exotic concoctions) and was cured. All of the home remedies seem to have one thing in common: lots of attention to local nail hygiene. Maybe this helps! Anyway, People's Pharmacy In-Depth Guide to Skin and Nail Disease is a good place to start if you are interested in alternative strategies.
Other Resources






References

55. Aly, R., and T. Berger. 1996. Common superficial fungal infections in patients with AIDS. Clin Infect Dis. 22 Suppl 2:S128-32.

85. Anonymous. 2000. Cicloprox (Penlac) nail lacquer for onychomycosis. The Medical Letter. 42:51.

114. Arenas, R., J. Dominguez-Cherit, and L. M. Fernandez. 1995. Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int. J. Dermatol. 34:138-43.

315. Bradley, M. C., S. Leidich, N. Isham, B. E. Elewski, and M. A. Ghannoum. 1999. Antifungal susceptibilities and genetic relatedness of serial Trichophyton rubrum isolates from patients with onychomycosis of the toenail. Mycoses. 42:105-110.

457. Cohen, J. L., R. K. Scher, and A. S. Pappert. 1992. The nail and fungus infections, p. 106-122. In B. Elewski (ed.), Cutaneous fungal infections. Igaku-Shoin, Inc, New York.

525. de Doncker, P., A. K. Gupta, G. Marynissen, P. Stoffels, and A. Heremans. 1997. Itraconazole pulse therapy for onychomycosis and dermatomycoses: An overview. J. Am. Acad. Dermatol. 37:969-974.

617. Drake, L. A., N. H. Shear, J. P. Arlette, R. Cloutier, F. W. Danby, B. E. Elewski, S. Garnis-Jones, J. M. Giroux, D. Gratton, W. Gulliver, P. Hull, H. E. Jones, M. Journet, A. L. Krol, J. J. Leyden, S. C. Maddin, J. B. Ross, R. C. Savin, R. K. Scher, G. R. Sibbald, N. H. Tawfik, N. Zaias, M. Tolpin, S. Evans, J. E. Birnbaum, and et al. 1997. Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J. Amer. Acad. Dermatol. 37:740-745.

656. Elewski, B. E. 1998. Onychomycosis: Pathogenesis, diagnosis, and management. Clin. Microbiol. Rev. 11:415-429.

658. Elewski, B. E., and M. A. Charif. 1997. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol. 133:1172-3.

941. Gupta, A. K. 2000. Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the United States. J Amer Acad Dermatol. 43:S81-S95.

942. Gupta, A. K., and R. Baran. 2000. Ciclopirox nail lacquer solution 8% in the 21st century. J Amer Acad Dermatol. 43:S96-S102.

946. Gupta, A. K., P. Fleckman, and R. Baran. 2000. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Amer Acad Dermatol. 43:S70-S80.

949. Gupta, A. K., N. Konnikov, P. MacDonald, P. Rich, N. W. Rodger, M. W. Edmonds, R. McManus, and R. C. Summerbell. 1998. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol. 139:665-71.

951. Gupta, A. K., R. G. Sibbald, C. W. Lynde, P. R. Hull, R. Prussick, N. H. Shear, P. De Doncker, C. R. Daniel, 3rd, and B. E. Elewski. 1997. Onychomycosis in children: prevalence and treatment strategies. J Am Acad Dermatol. 36:395-402.

1000. Havu, V., H. Brandt, H. Heikkila, A. Hollmen, R. Oksman, T. Rantanen, S. Saari, S. Stubb, K. Turjanmaa, and T. Piepponen. 1997. A double-blind, randomized study comparing itraconazole pulse therapy with continuous dosing for the treatment of toe-nail onychomycosis. Br. J. Dermatol. 136:230-4.

1001. Havu, V., H. Heikkila, K. Kuokkanen, M. Nuutinen, T. Rantanen, S. Saari, S. Stubb, R. Suhonen, and K. Turjanmaa. 2000. A double-blind, randomized study to compare the efficacy and safety of terbinafine (Lamisil (R)) with fluconazole (Diflucan (R)) in the treatment of onychomycosis. Brit J Dermatol. 142:97-102.

1014. Hecker, D. 1997. Current trends in onychomycosis therapy: a literature review. Mount Sinai Journal of Medicine. 64:399-405.

1017. Heikkila, H., and S. Stubb. 1995. The prevalence of onychomycosis in Finland. Br J Dermatol. 133:699-703.

1038. Herranz, P., J. Garcia, R. De Lucas, J. Gonzalez, J. M. Pena, R. Diaz, and M. Casado. 1997. Toenail onychomycosis in patients with acquired immune deficiency syndrome: treatment with terbinafine. Br J Dermatol. 137:577-80.

1352. Ling, M. R., L. J. Swinyer, M. T. Jarratt, L. Falo, E. W. Monroe, M. Tharp, J. Kalivas, G. D. Weinstein, R. G. Asarch, L. Drake, A. G. Martin, J. J. Leyden, J. Cook, D. M. Pariser, R. Pariser, B. H. Thiers, M. G. Lebwohl, D. Babel, D. M. Stewart, W. H. Eaglstein, V. Falanga, H. I. Katz, W. F. Bergfeld, J. M. Hanifin, S. W. Kang, C. J. McDonald, J. Muglia, B. S. Goffe, and M. R. Young. 1998. Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail. J Amer Acad Dermatol. 38:S95-S102.

1676. Odom, R. B., and C. R. Daniel, III. 1995. Itraconazole 200 mg daily for the treatment of toenail onychomycosis: A double-blind, placebo-controlled study. American Academy of Dermatology 1995 Annual Meeting, Abstract No. P-226.

1920. Rich, P. 2000. Onychomycosis and tinea pedis in patients with diabetes. J Am Acad Dermatol. 43:S130-S134.

1934. Roberts, D. T. 1994. Oral therapeutic agents in fungal nail disease. J. Amer. Acad. Dermatol. 31:S78-81.

2043. Scher, R. K. 1996. Onychomycosis: a significant medical disorder. J Am Acad Dermatol. 35:S2-5.

2044. Scher, R. K., D. Breneman, P. Rich, R. C. Savin, D. S. Feingold, N. Konnikov, J. L. Shupack, S. Pinnell, N. Levine, N. J. Lowe, R. Aly, R. B. Odom, D. L. Greer, M. R. Morman, A. D. Bucko, E. H. Tschen, B. E. Elewski, and E. B. Smith. 1998. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Amer Acad Dermatol. 38:S77-S86.

2140. Squeo, R. F., R. Beer, D. Silvers, I. Weitzman, and M. Grossman. 1998. Invasive Trichophyton rubrum resembling blastomycosis infection in the immunocompromised host. J Am Acad Dermatol. 39:379-80.

2193. Summerbell, R. C. 1997. Epidemiology and ecology of onychomycosis. Dermatology. 194:32-6.

2485. Zaias, N., B. Glick, and G. Rebell. 1996. Diagnosing and treating onychomycosis [see comments]. J Fam Pract. 42:513-8.



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