Detailed onychomycosis diagnosis is a prerequisite for any system therapy. Dermatophytes are among the most common fungal pathogens. Systemic therapy should always be combined with topical treatment. If nail infestation is less than 50% without matrix infestation, local therapy is sufficient.
Nail fungal infection (onychomycosis) is a common dermatological condition affecting up to 20% of adults. The toenails are much more commonly affected than the fingernails, and affected individuals most commonly present with interdigital foot mycosis. Single, several or rarely all nails may be affected. Pathogens include dermatophytes (filamentous fungi) and molds and yeasts. Onychomycoses of the toes are mainly caused by dermatophytes (most frequent representative Trichophyton rubrum), whereas onychomycoses of the fingers are more often caused by yeasts [1–3].
How does onychomycosis occur?
As a rule, predisposing factors must be present for nail fungal disease to occur. These include genetic predisposition, age, and angio- and polyneuropathy. Tinea pedis is almost always present at the same time. Furthermore, a warm and humid environment, recurrent trauma, diabetes mellitus, immunodeficiency, nail psoriasis as well as eczema of the foot may favor a nail fungal disease [4,5].
Clinic: Fungal nail disease usually begins with subungual hyperkeratosis, where the main mass of fungi is located. Later, a whitish-yellowish-brownish discoloration of the nail plate occurs. In the later course, crumbly decay of the nail may occur. This indicates a complete infestation of the nail bed and matrix, from where the fungi invade the nail plate. Depending on the infection route, different types are distinguished:
- distal subungual type (90% of cases, most frequent pathogen Trichophyton rubrum) (Fig. 1)
- proximal subungual type (Fig. 2)
- white superficial type (in Central Europe mainly caused by Trichophyton mentagrophytes) (Fig. 3)
- Endonyx type (infestation of the inside of the nail plate, leaving the nail surface and bed intact; preferably caused by T. soudanense or T. violaceum)
- total dystrophic onychomycosis (end stage)
Differential diagnosis should include nail psoriasis, lichen ruber, eczema and post-traumatic nail changes.
Diagnostics: Laboratory diagnostics are optional before topical therapy, but mandatory before any systemic therapy. Two examination methods have become established in the meantime, histology on the one hand and direct microscopy with culture on the other. Histology allows differentiation between colonization and infection (Fig. 4) . The culture allows the exact determination of the pathogen. The main advantages and disadvantages of both methods are listed in Table 1. Because of the frequently false-negative results of culture, we recommend histology as a diagnostic procedure. In complex cases, both diagnostic measures can be performed.
How to obtain the nail material?
In the distal subungual type, material is obtained from the nail bed under the affected nail for culture, and the nail with the nail bed keratosis is obtained for histology. For the remaining types of onychomycosis, the nail material can be obtained by punch biopsy. This does not require local anesthesia, but the necessary sensitivity to avoid nail bed injuries. The nail plate should be softened beforehand with a lukewarm hand or foot bath for at least 10 minutes.
Does onychomycosis need to be treated?
It may or may not always be treated. For the patient, onychomycosis is often a cosmetic problem. However, it may also cause pain and limit the patient’s sports activity [6]. It should not be forgotten that onychomycosis is an infectious disease. The fungus can spread to the surrounding skin as well as to the other nails and in individual cases lead to total onychodystrophy of all nails. Furthermore, there is a risk of infecting contact persons. In the presence of concomitant diabetes mellitus or immunosuppression, onychomycosis may promote bacterial infection such as erysipelas [7].
Treatment is quite reasonable and desirable in young patients to prevent nail dystrophy and/or recurrent cutaneous mycoses. In older patients, it is perfectly reasonable to refrain from treatment. The decision of systemic therapy should be made individually depending on the level of suffering (pain? cosmetically disturbing?), age, co-morbidities (known liver disease? ipsilateral recurrent erysipelas?) after clarification of the side effect profile and the high recurrence rate.
Practical tips for therapeutic measures
The therapy requires perseverance and good compliance of the patient. Hygiene measures such as regular washing of socks and towels at at least 60°C (better 95°C) and keeping feet dry are recommended. The affected nail should be removed as far as possible by cutting or filing. In case of a very thick nail plate, urea 20-40% in ointment base can be applied occlusively for at least 3-5 days to soften the nail and then remove the affected area with scissors or scalpel as atraumatically as possible.
Topical therapy: If less than 50% of the nail plate is affected and the nail matrix is not affected, topical therapy is often sufficient. Two nail polish preparations have proven effective: Ciclopirox 8% and Amorolfine 5%. Ciclopirox 8% is applied 1× daily or 1× weekly depending on the nail polish (Ex: Ciclopoli® nail polish application 1× daily; Ciclocutan® nail polish application 1st month every 2nd day, 2nd month 2×/week, from 3rd month 1×/week). Amorolfine 5% should be applied 1-2×/week. The duration of therapy for both active substances is at least 9-12 months for toenails and at least 6 months for fingernails. Efinaconazole 10% solution and tavaborole 5% solution are new therapeutic options that are not yet available in Switzerland [8].
Systemic therapy: If more than 50% of the nail plate or the nail matrix is affected, systemic therapy (Tab. 2) can be applied after positive fungal detection by histology and/or culture.
First-line agent for systemic therapy is terbinafine (>40 kg 250 mg/day, 20-40 kg 125 mg/day). The duration of therapy is 3 months for toenails and 1.5 months for fingernails. Terbinafine has a broad spectrum of activity and, above all, has the best effect against Trichophyton rubrum, the most common nail fungus in Europe. The drug is basically well tolerated and has the lowest recurrence rate. The most common side effects include headache and nausea. However, it can also cause reversible taste disturbances and skin lesions (exanthema, psoriasis, subacute lupus) as well as hepatitis (1/1000-10,000). Liver enzyme monitoring (ASAT/ALAT) is recommended before therapy initiation and every 4-6 weeks during therapy. If liver enzymes are elevated, the drug should not be given or should be discontinued. In renal insufficiency with a glomerular filtration rate below 50%, terbinafine therapy is not recommended because insufficient data are available.
As therapy Itraconazole is the 2nd choice for dermatophyte infections, but the 1st choice for Candida infections. Pulse therapy is preferable to continuous therapy because it is considered more effective, has fewer side effects, and is less expensive.
- Pulse therapy: 1 pulse = 200 mg 2×/day for 1 week, then 3 weeks treatment-free interval.
- Therapy duration of toenails: 3 pulses, fingernails: 2 pulses.
- Continuous therapy: 100 mg 2×/day. Therapy duration of toenails: 3 months, fingernails 1.5 months.
As an alternative to itraconazole, fluconazole 150-450 mg/week can be used until the onychomycosis heals. Liver enzyme monitoring is recommended during continuous itraconazole therapy as well as fluconazole therapy. Due to frequent interactions with other drugs, the patient’s drug list should be clarified regarding interactions with itraconazole and fluconazole (= CYP3A4 inhibitors) before starting therapy.
Success/Recurrence Rate: The success rate of terbinafine therapy (primarily fungicidal) is approximately 1/2 to 2/3 of cases, and itraconazole (primarily fungistatic) is approximately 1/3 to 1/2 of cases. Systemic therapy should always be combined with topical therapy. This can cut the failure rate in half. Onychomycosis recurrence after successful therapy will be observed after 2 years in approximately 1/3 to 1/2 of cases [9–11]. Interval therapy with topical antifungal agents may be attempted to decrease the recurrence rate [10].
Update Fusarium
10% of nail fungal infections are caused by non-dermatophytes. Fusarium (mold) is responsible for at least 1-6% of nail fungal infections. Women are more frequently affected. Most Fusarium species are plant parasites and can produce mycotoxins. Fusarium has been observed in warm climates with significant damage potential to crops or cereals. Predominantly in tropical rural areas, Fusarium keratitis and occasionally Fusarium onychomycosis have been described. Fusarium can cause life-threatening skin infections in immunocompromised individuals.
Fusarium onychomycosis is rarely diagnosed in Central Europe. Clinically, it cannot be distinguished from the usual dermatophyte onychomycosis. Histologically, however, there are slender to relatively thick septal hyphae with often characteristic ampullary dilatations in the course (Fig. 5). In culture, whitish cotton-like colonies form with brownish discoloration on one side. Lactophenol cotton blue staining shows characteristic banana-shaped macroconidia in addition to microconidia and hyphae.
Fusarium nail fungal infection can thus be suspected by an experienced histopathologist if the hyphal morphology is unusual. The experienced microbiologist can distinguish a Fusarium growth from another mold infection in culture. Confirmation can be done by PCR, but is expensive. Identification of Fusarium onychomycosis is important because it is more difficult to treat and special hygienic measures are required (e.g., in the food industry, direct contact with premature infants and immunocompromised persons should be avoided). Fluconazole is usually not effective. Terbinafine helps moderately. Agents of choice as systemic therapy are currently itraconazole, voriconazole and high-dose amphotericin combined with local therapy and standard hygiene measures [13].
Take-Home Messages
- Onychomycosis diagnosis by histology and/or culture is mandatory before any systemic therapy. Dermatophytes are among the most common fungal pathogens. If there is mold growth in culture, atypical hyphae in histology, and resistance to therapy, Fusarium onychomycosis should be considered.
- Topical therapy is sufficient if nail infestation is less than 50% without matrix infestation. New topical therapies are efinaconazole 10% solution and tavaborole 5% solution. Both preparations are not yet available in Switzerland.
- Systemic therapy should always be combined with topical therapy. The first choice of systemic therapy is terbinafine.
- Informing the patient about hygiene measures is always necessary.
Literature:
- Gupta AK, et al: 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.
- Romano C, Gianni C, Difonzo EM: Retrospective study of onychomycosis in Italy: 1985-2000. Mycoses 2005; 48: 42.
- Foster KW, Ghannoum MA, Elewski BE: Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to 2002. J Am Acad Dermatol 2004; 50: 748.
- Sigurgeirsson B, Steingrímsson O: Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol 2004; 18: 48.
- Faergemann J, Correia O, Nowicki R, Ro BI: Genetic predisposition–understanding underlying mechanisms of onychomycosis. J Eur Acad Dermatol Venereol 2005; 19 Suppl 1: 17.
- Elewski BE: The effect of toenail onychomycosis on patient quality of life. Int J Dermatol 1997; 36: 754.
- Roujeau JC, et al: Chronic dermatomycoses of the foot as risk factors for acute bacterial cellulitis of the leg: a case-control study. Dermatology 2004; 209: 301.
- Lipner SR: Pharmacotherapy for onychomycosis: new and emerging treatments. Expert Opin Pharmacother. 2019; 20(6): 725-735.
- Wilsmann-Theis D, et al: New reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis. J Eur Acad Dermatol Venereol 2011; 25: 235.
- Piraccini BM, Sisti A, Tosti A: Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol 2010; 62: 411.
- Gupta AK, Ryder JE, Johnson AM: Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol 2004; 150:537.
- Warshaw EM, St Clair KR: Prevention of onychomycosis reinfection for patients with complete cure of all 10 toenails: results of a double-blind, placebo-controlled, pilot study of prophylactic miconazole powder 2%. J Am Acad Dermatol 2005; 53: 717.
- Rammlmair A, Mühlethaler K, Haneke E: Fusarium onychomycoses in Switzerland-A mycological and histopathological study. Mycoses. 2019 Oct;62(10): 928-931.
Further reading:
- De Cuyper C, Hindryckx PH: Long-term outcomes in the treatment of toenail onychomycosis. Br J Dermatol 1999; 141 Suppl 56: 15.
DERMATOLOGY PRACTICE 2020; 30(1): 16-19