Are You Confident of the Diagnosis?
What you should be looking for in the history
The diagnosis of onychomycosis is made based on history, physical examination, and diagnostic studies.
Patients with onychomycosis often complain of nail discoloration, brittleness, or thickening, that often becomes worse with time. Nails affected by onychomycosis can cause local pain, social embarrassment, and affect quality of life. Predisposing factors such as diabetes mellitus, older age, peripheral vascular disease, and immunosuppression should increase the clinical suspicion.
Characteristic findings on physical examination
White/yellow or orange/brown longitudinal streaks in the nail plate (dermatophytoma) are quite specific for onychomycosis. Nonspecific, but common clinical findings include: onycholysis, subungual hyperkeratosis, nail thickening, and crumbling (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). There may be scale present in the web spaces and plantar feet.
The main subtypes of onychomycosis are distal lateral subungual, proximal subungual, superficial, endonyx, mixed pattern, totally dystrophic and secondary onychomycosis. They are classified based on the route of the fungal invasion into the nail unit.
Distal lateral subungual onychomycosis (DLSO) is the most common pattern of onychomycosis and manifests as distal onycholysis, subungual hyperkeratosis, nail plate thickening, and yellow to brown discoloration. In fingernails, minimal hyperkeratosis with prominent onycholysis may occur.
Superficial onychomycosis (SO) is characterized by superficial white patches that are easily scraped off the nail plate.
Proximal subungual onychomycosis (PSO) is characterized by white discoloration of the proximal nail plate, and spreads distally.
Endonyx onychomycosis (EO) is characterized by lamellar nail splitting and milky patches of the nail plate.
Mixed pattern onychomycosis (MPO) describe more than one pattern of nail plate infection in the same nail. The most common patterns are PSO with SO or DLSO with SO.
Total dystrophic onychomycosis (TDO), which manifests as a crumbled nail plate, is the end-stage of onychomycosis, typically DLSO.
Secondary onychomycosis occurs when fungi invade the nail plate secondary to other non-fungal nail diseases, such as psoriasis or prior trauma.
Expected results of diagnostic studies
History and physical examination are necessary, but not sufficient for making a diagnosis of onychomycosis and confirmation is necessary before initiating treatment. The nail is cleaned carefully with soap and water, as well as 70% alcohol and the specimen is collected from the most proximal part of the affected nail plate along with subungual debris.
The most commonly employed diagnostic studies are potassium hydroxide (KOH) smear, mycological culture, and histopathologic examination with periodic acid-Schiff (PAS) staining. Calcofluor white is a sensitive dye that may be used to stain the culture or a paraffin-embedded specimen, but a fluorescent microscope is required. Polymerase chain reaction is a new, rapid, and sensitive technique, but is not widely used.
Diagnostic laboratory criteria include: microscopic evidence of septate hyphae and/or arthroconidia on KOH preparation, PAS-stained septate hyphae embedded in nail (hyphae on nail represent colonization), or fungal culture positive for dermatophytes (Trichophyton, Epidermophyton, and Microsporum species).
KOH staining can be used to rapidly determine the presence or absence of fungi, however, the viability of the identity of the organism cannot be determined. Mycological culture is a highly specific technique, but has low sensitivity. It may also take several weeks for the organism to grow and allow for identification. Histopathology results take just a few days, but the identification and viability of the organism cannot be determined with this technique.
The growth of nondermatophytes in culture does not prove the pathogen, since the same fungi can be contaminants. Therefore, all cultured nondermatophytes should be considered contaminants unless KOH or microscopy indicates that they have the atypical frond-like hyphae associated with nondermatophyte molds, or if the same organism is cultured repeatedly at different times. Candida albicans may be a contaminant and clinical correlation is critical.
Histopathology and KOH smear have sensitivities of 80.8% and 76.5%, respectively, and 97.8% when combined. Culture has a lower sensitivity, at 53.2%, but is the most specific. However, positive cultures may represent nail invasion or colonization. Clinical and laboratory correlation is required.
While onychomycosis makes up for 50% of nail diseases, it is necessary to differentiate onychomycosis from other disorders that interfere with the proper development of the nail unit. The differential diagnosis includes inflammatory disorders such as psoriasis and lichen planus; genetic disorders such as pachyonychia congenita; as well as nail unit neoplasms, repeated trauma, drugs, bacterial infections, and systemic diseases. Onychomycosis can also coexist with other nail diseases. A nail unit biopsy may be needed to confirm diagnosis.
Differential diagnoses are summarized in Table I.
|Nail infection||Bacterial (Pseudomonas aeruginosa)|
|Viral (herpes simplex virus, human papillomavirus)|
|Dermatological/systemic disease||Bullous diseases (congenital or acquired)|
|Langerhans cell histiocytosis|
|Pityriasis rubra pilaris|
|Chronic contact dermatitis|
|Neurological disorders (reflex sympathetic dystrophy/spinal cord injury)|
|Yellow nail syndrome|
|Peripheral vascular disease|
|Twenty nail dystrophy|
|Connective tissue disease|
|Uremia (half-and-half nails, Muehrcke’s lines)|
|Liver cirrhosis (Terry’s nails)|
|Subungual tumors||Benign tumors|
|Malignant tumors (melanoma, squamous cell carcinoma)|
|Trauma (physical or chemical)||Repeated microtrauma (shoes, overiding toes, sports, manicure/pedicure)|
|Nail polish/ base coat|
|Drugs||Cytotoxic (bleomycin, 5-fluorouracil, placitaxel)|
|Arsenic (Mees’ lines)|
Who is at Risk for Developing this Disease?
The incidence of onychomycosis has been rising in developed countries and accounts for approximately half of all nail abnormalities seen in dermatological practice. Its prevalence varies with geographic location from 2% to 13%. It affects toenails ten times more than fingernails, and males three times more than females. Predisposing factors include: diabetes mellitus, peripheral vascular disease, immunosuppression, genetic predisposition, occlusive footwear, repeated nail microtrauma, use of communal showers, and older age.
What is the Cause of the Disease?
Dermatophytes are the most common cause of onychomycosis, followed by yeasts, nondermatophyte molds, and mixed infections. Among dermatophytes, Trichophyton rubrum (60%), T. mentagrophytes var interdigitale (20%), and Epidermophyton Floccosum (10%) are the most common pathogens. Yeasts are cultured from 5%-17% of the cases, with 70% of these being Candida albicans. Nondermatophyte molds such as Scopulariopsis, Scytalidium, Aspergillus, and Fusarium are the infecting organisms in less than 5% of cases.
Onychomycosis occurs when fungi invade any component of the nail unit via a compromised barrier and/or host defense. The route of fungal invasion determines the clinical pattern of onychomycosis.
In DLSO, the fungus invades the cornified layer of the hyponychium and distal or lateral nail bed. Subsequently, there is proximal invasion of the nail bed and ventral invasion of the nail plate.
In SO, the fungus infects the nail plate and then invades the nail bed and hyponychium.
In PSO, the organism first invades the stratum corneum of the proximal nail fold and then penetrates the emerging nail plate.
In EO, the fungus directly invades the nail plate, but there is no penetration of the nail bed.
Systemic Implications and Complications
Onychomycosis may cause local pain, difficulty with ambulation, social embarrassment, and thus impacts the quality of life in otherwise healthy individuals.
PSO is more common in the immunocompromised host, and may be an early manifestation of human immunodeficiency virus infection. Candida onychomycosis is seen in patients with chronic mucocutaneous candidiasis who are prone to direct invasion of Candida into their nail plate.
Infected nails may be the source of disseminated mycosis in immunosuppressed patients, especially those with hematologic malignancies or neutropenia. In a prospective study, onychomycosis was a significant risk factor for foot ulcers in diabetics, ranking fourth after prior amputation, prior foot ulcer, and monofilament insensitivity (a measure of peripheral sensory neuropathy).
Treatment options are summarized in Table II.
Optimal Therapeutic Approach for this Disease
Antifungal lacquers are water-soluble polymers that create a colorless film on the nail surface. They are well tolerated, with a low risk of side effects, which include: transient local irritation, chromonychia, and contact dermatitis.
Amorolfine 5% nail lacquer is approved for use in Europe but not in the United States. Complete cure rates in randomized trials with 6 months of active treatment followed by 3 months of follow-up were 38% to 54% in patients without matrix involvement.
Ciclopirox 8% nail lacquer is FDA approved for immunocompetent patients with mild-to-moderate onychomycosis without lunula involvement due to T. rubrum. Complete cure rates of 5.5% to 8.5% are reported compared to placebo, which are 0% to 0.9%.
Efinaconazole 10% solution is FDA approved for mild to moderate toenail onychomycosis. Complete cure rates were 17.8% and 15.2% in the each of the treated groups, and 3.3% and 5.5% in each of the control groups.
Tavaborole is a benzoxaborole, which inhibits protein synthesis by blocking aminoacyl transfer RNA synthetase. Tavaborole 5% solution is FDA approved for mild to moderate toenail onychomycosis with complete cure rates of 6.5% and 27.5% for tavaborole and 0.5% and 14.6% for vehicle.
In addition to efficacy, there are some significant differences between the older ciclopirox and the newer topicals, efinaconazole and tavaborole. Firstly, nail debridement is necessary for ciclopirox, but not for the newer topicals. Secondly, ciclopirox nail lacquer must be removed weekly, but with efinaconazole and tavaborole no removal is necessary.
Monotherapy with topicals is appropriate for the treatment of superficial onychomycosis, mild-to-moderate DLSO with less than 2/3 involvement of the distal nail plate is infected, and children who have rapidly growing nails. Topical therapy is not curative for severe onychomycosis affecting the nail matrix (lunula). In conjunction with oral antifungals, topical antifungals increase the clinical cure rate of nondermatophyte onychomycosis. The combination of amorolfine topical with oral terbinafine was more cost-effective and efficacious than terbinafine alone in a multicenter open-label randomized parallel group study of 249 patients with dermatophyte toenail onychomycosis involving the matrix.
Oral antifungal agents are generally more effective than topicals in the treatment of onychomycosis and treatment courses are shorter. There is no evidence that fungal drug resistance is important in treatment of dermatophyte onychomycosis. Therefore, a systemic antifungal agent is chosen based on its potential adverse effects, drug-drug interactions, cost, and pathogen, as well as the patient’s comorbidities and preferred dosing regimen. Appropriate monitoring tests must be employed.
Terbinafine is an allylamine oral antifungal and is FDA-approved for the treatment of dermatophyte onychomycosis. In vitro, terbinafine is fungicidal against dermatophytes, molds, and some Candida species such as C. parapsilosis. It is fungistatic against most other Candida species. FDA complete cure rates are 59% for fingernails and 38% for toenails when taken daily for 6 or 12 weeks, respectively.
Several pulse regimens have similar efficacy to continuous dosing, but have theoretical advantages of increased compliance and reduced cost and drug exposure. Terbinafine inhibits cytochrome P450 2D6 and has fewer drug-drug interactions compared to azoles. It should be used with caution in patients taking CYP 2D6 substrates including tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and beta-blockers.
Most adverse effects are mild and transient. These include gastrointestinal disturbances (diarrhea, taste changes, dyspepsia), liver function abnormalities, and dermatological effects (rashes, urticaria, pruritus). More seriously, hepatotoxicity, precipitation or exacerbation of systemic lupus erythematosus, and Stevens-Johnson syndrome have been reported. Terbinafine can exacerbate psoriasis. Laboratory testing is controversial. The risk of hepatotoxicity and leukopenia is low; however, hematopoietic and hepatic function tests may be reasonable at baseline and during therapy.
Itraconazole is a triazole antifungal that is FDA-approved for the treatment of dermatophyte onychomycosis. Itraconazole is fungistatic against dermatophytes, nondermatophytes, and yeasts, but has a better profile against Candida species than terbinafine. The FDA-approved dosing regimen is 200 mg daily for 6 or 12 weeks for fingernail and toenail onychomycosis, respectively, for continuous dosing. A pulse regimen for fingernails is 200mg twice daily one week per month for 2 months. A 3-month pulse regimen has been advocated for toenail onychomycosis, but is not FDA-approved.
The complete cure rate in FDA studies was 14% for toenails, with continuous dosing, and 47% for fingernails, when pulsed. Itraconazole inhibits cytochrome P450 3A4 and has adverse drug-drug interactions with many commonly used medications such as statins and sildenafil. It is inactivated via liver metabolism.
Itraconazole is contraindicated in patients with heart failure, since it decreases cardiac contractility. It should be taken with food, and is better absorbed in acidic pH. Itraconazole oral solution has lower bioavailability than the capsules. Hepatic injury has been reported during and after treatment completion in patients without a history of liver disease. Liver function tests are advised at baseline, especially in patients with history of liver disease, and after each month of therapy, or sooner, if symptomatic.
Fluconazole is a triazole with fungistatic against dermatophytes, Candida, and some nondermatophytes. Fluconazole is approved in Europe for the treatment of onychomycosis, but used off-label in the US. In countries where it is approved, the most common dosing schedule is 150 mg to 300 mg weekly until the infected nail plate grows out completely.
In one large study, toenail onychomycosis was treated with 150 mg, 300 mg, or 450 mg of fluconazole for up to 9 months; the complete cure rate was 37%, 46% and 48%, respectively. Other studies have shown comparable success rates with similar dosing schedules for the treatment of fingernail onychomycosis. Fluconazole inhibits cytochrome P450 3A4 and 2C9. At once-weekly dosing, the risk of drug-drug interaction is minimal. Fluconazole is well tolerated. Laboratory testing is controversial, but when used long term, a baseline and periodic testing of hematopoietic and hepatic function may be reasonable.
Historically, onychomycosis had been treated by surgical nail avulsion, however, it is rarely used today, due to significant morbidity. One potential side is an ingrown nail, due to lack of counterpressure on the nail bed. It is ineffective alone, but efficacy can be increased by combining with antifungals. Chemical avulsion may achieved with keratolytics such as 40% urea gel. Avulsion with matricectomy is reserved for patients who have failed conservative treatment and have severely deformed or painful nails.
Nail debridement may used to debulk dystrophic nails. Debulking decreases the fungal load and the risk of pressure-induced ulcer and pain. It allows topical antifungals to access the nail bed. It helps concomitant oral therapy by reducing the burden of disease. Therefore, debridement increases the cure rate of topical and oral antifungals. A hand-held nail nipper is used for manual debridement. Podiatrists often employ an electric drill with a rotary burr to smooth the rough edges and further decrease the nail plate thickness.
Laser and device based treatments are emerging areas for onychomycosis therapy. Several Nd:Yag lasers are approved for the temporary cosmetic improvement of onychomycosis, rather than complete cure. Photodynamic therapy (PDT) and plasma therapy have also been employed with some success.
Combination therapy for onychomycosis can increase the cure rate. Safety of combination therapy with two oral antifungals has not been studied on a large scale. Topical agents and debridement can be safely combined with oral antifungals to increase the rate of cure, especially in patients with severe onychomycosis and poor prognosis. Topical antifungals and surgical techniques are employed for palliative care in patients who are intolerant of oral therapy or as curative care for mild disease that spares the lunula.
Currently, moderate to severe onychomycosis is best treated with oral antifungals. Systemic therapy for onychomycosis should be customized, based on the causative agent, clinical pattern, drug interactions, adverse effects, cost, the patient’s comorbidities, and dosing preference. These medications have potential for adverse effects and monitoring tests must be employed as appropriate. Relapse has been reported as high as 53%, either due to reinfection or treatment failure. Therefore, it is important to monitor and evaluate for cure after treatment completion.
Patients should be reminded that the infected nail plate will continue to grow out after the completion of oral therapy. It may take 6 to 9 months for fingernails and 12 to 18 months for toenails to completely grow out. Patients and physicians must have realistic expectations, since the nails may not appear normal even after the eradication of fungi. Chronic onychomycosis, trauma, or nail diseases may result in nail deformities, which persist even after mycological cure. In severe onychomycosis, up to 10% of the nail plate may remain abnormal after mycological cure.
In some patients, booster therapy (one additional month of treatment) within 6 to 9 months of starting terbinafine or itraconazole may increase the cure rate. Booster therapy is indicated for patients with immunosuppression, history of relapse, or severe onychomycosis involving matrix. Booster therapy is also recommended if the cultures are positive 6 months after starting the treatment, if less than 50% of the diseased nail has grown out, or if the nail plate is thicker than 2mm.
Criteria have been proposed for assessing cure in clinical trials. These criteria can also help clinicians assess patients who have completed a course of antifungal therapy. It has been suggested that the complete resolution of clinical signs of onychomycosis warrants no further testing; however, if nail thickening has not improved or distal onycholysis/hyperkeratosis affects more than 10% of the nail plate, then mycology should be performed.
Cure is not obtained if the culture is positive. With negative mycology, infection is considered persistent in the presence of dermatophytoma, lateral onycholysis with debris, lateral hyperkeratoses, or when clinical signs of onychomycosis affect more than 10% of the nail.
The Onychomycosis Severity Index (OSI) is a new scoring system that takes into account the area of involvement, the proximity of disease to the matrix, the presence of a dermatophytoma, and subungual hyperkeratosis. It may be helpful in selecting an appropriate therapy and assessing response to treatment.
Unusual Clinical Scenarios to Consider in Patient Management
Diagnosis and treatment of onychomycosis is often difficult and cumbersome. Accurate diagnosis is based on the presence of both clinical and laboratory evidence. When clinical signs of onychomycosis exist, laboratory test(s) confirm the diagnosis. Negative mycology should be repeated if the clinical suspicion for fungal infection is high. The diagnosis of other diseases that mimic onychomycosis may require a nail unit biopsy.
Predictors of poor response to therapy include: greater than 50% total nail plate involvement, lateral nail plate involvement, subungual hyperkeratosis greater than 2mm, dermatophytoma (white/yellow or orange/brown streaks in the nail), matrix involvement, total dystrophic pattern (TDO), nail infection by nondermatophytes, immunosuppressed status, and peripheral vascular disease.
Prophylaxis against recurrence using amorolfine lacquer was evaluated in a randomized open-label pilot study. Amorolfine lacquer was applied once every two weeks in twenty-six patients after successful treatment of toenail dermatophytic infection. The treated group had a longer disease-free interval (median time to recurrence was 200 days longer) and decreased global recurrence rate compared to the untreated group at the end of 36 months of follow-up.
Although fungal drug resistance is not a problem in the treatment of dermatophyte onychomycosis, Candida species such as C. albicans, C. tropicalis, and C. krusei can generate resistance to azoles. This resistance may be a problem in the immunosuppressed.
Diabetic patients have high risk of onychomycosis. They show high rate of recurrence post-treatment, and are at high risk of foot ulcer secondary to onychomycosis. These patients should be treated vigorously and monitored closely.
What is the Evidence?
Scher, RK, Tavakkol, A, Bact, D, Sigurgeirsson, B, Hay, RJ, Joseph, WS. “Onychomycosis: diagnosis and definition of cure”. J Am Acad Dermatol. vol. 56. 2007. pp. 939-44. (Authors suggest primary and secondary criteria for diagnosis of onychomycosis as well as clinical and laboratory parameters to assess the treatment response.)
Karimzadegan-Nia, M, Mir-Amin-Mohammadi, A, Bouzari, N, Firooz, A. “Comparison of direct smear, culture and histology for the diagnosis of onychomycosis”. Australasian Journal of Dermatology. vol. 48. 2007. pp. 18-21. (Nail specimens of ninety-six patients with clinically suspected onychomycosis were evaluated with KOH smear, culture, and histology. One positive test was considered confirmatory. The sensitivity of each test and their various combinations were calculated.)
Boyko, EJ, Ahroni, JH, Cohen, V. “Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle diabetic foot study”. Diabetes Care. vol. 6. 2006. pp. 1202-7. (Diabetic veterans [1,285] without foot ulcer were followed over a mean duration of 3.38 years. Clinical data were gathered, with annual clinical evaluations and quarterly questionnaires. Two hundred sixteen foot ulcers occurred. The predictive values of various clinical data for development of the diabetic foot ulcer were calculated.)
Tosti, A, Piraccini, BM, Lorenzi, S, Iorizzo, M. “Treatment of nondermatophyte mold and Candida onychomycosis”. Dermatol Clin. vol. 21. 2003. pp. 491-7. (The article claims that the incidence of mold onychomycosis is increasing worldwide and that the treatment must be based on the type of mold and the pattern of onychomycosis. The article provides treatment suggestions based on authors’ observations and the literature.)
Baran, R, Sigurgeirsson, B, de Berker, D. “A multicenter, randomized, controlled study of the efficacy, safety and cost effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement”. Br J Dermatol. vol. 157. 2007. pp. 149-57. (Two hundred forty-nine patients randomly received either a combination of amorolfine 5% nail lacquer once weekly for 12 months plus oral terbinafine 250 mg qd x 3 months [AT group, n=120] or terbinafine alone [T group, n=129]. The primary efficacy criterion was overall response. At 18 months, a higher success rate was observed in AT group: 59.2% vs 45.0%; P=0.03. Treatment cost per cured patient was lower for the AT group in all countries.)
Scher, RK. “Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail”. J Am Acad Dermatol. vol. 38. 1998. pp. S77-86. (A multicenter double-blind study of 362 patients with distal subungual dermatophyte toenail onychomycosis. Subjects received 150 mg, 300 mg, or 450 mg fluconazole; or a placebo; weekly for 12 months. At the end of the study and 6 months after, fluconazole was superior to placebo in efficacy at all doses. Fluconazole groups did not differ significantly in efficacy measures, adverse events, and mean time to clinical success.)
Sigurgeirsson, B, Olafsson, JH, Steinsson, JT, Kerrouche, N, Sidou, F. “Efficacy of amorolfine nail lacquer for the prophylaxis of onychomycosis over 3 years”. J Eur Acad Dermatol Venereol. vol. 24. 2010. pp. 910-5. (The prophylactic efficacy and the safety of amorolfine nail lacquer [ANL] were studied over a period of 3 years. Fifty-two subjects were required to be cured of confirmed toenail onychomycosis with matrix involvement after treatment with oral terbinafine with or without ANL in a previous study. 26 subjects were treated with ANL once every two weeks (that is half the frequency of the standard regimen). Twenty-six subjects were not treated. At 12 months, statistically significant differences were observed between the groups. ANL was well tolerated, decreased the recurrence rate significantly, and delayed recurrence by nearly 200 days.)
Gupta, AK. “How to improve the cure rates for the management of onychomycosis”. Dermatol Clin. vol. 21. 2003. pp. 499-505, vii. (Strategies that may decrease treatment failure and recurrence rates for onychomycosis are reviewed. These include suggestions for decreasing misdiagnosis, choosing the appropriate therapy, as well as combination and booster or supplemental oral therapy.)
Scher, RK, Baran, R. “Onychomycosis in clinical practice: factors contributing to recurrence”. Br J Dermatol. vol. 149. 2003. pp. 5-9. (Authors point out that misdiagnosis and undertreatment jeopardizes the perception of therapeutic efficacy. They discuss factors that contribute to poor treatment response and increase the recurrence rate.)
Hay, RJ, Baran, R. “Onychomycosis: a proposed revision of the clinical classification”. J Am Acad Dermatol. vol. 65. 2011. pp. 1219-27. (This manuscript reviews the currently accepted classification of onychomycosis and describes both common and rare subtypes.)
Lipner, SR, Scher, RK. “Onychomycosis – a small step for quality of care”. Curr Med Res Opin. vol. 32. 2016 May. pp. 865-7. (This paper discusses diagnosis of onychomycosis and problems with treating onychomycosis empirically.)
Hay, J, Baran, R. “Onychomycosis: a proposed revision of the clinical classification”. J Am Acad Dermatol. vol. 65. 2011 Dec. pp. 1219-27. (Authors describe a new classification system for onychomycosis.)
Carney, C, Tosti, A, Daniel, R, Scher, R, Rich, P, DeCoster, J, Eleski, B. “A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index”. Arch Dermatol. vol. 147. 2011 Nov. pp. 1277-82. (Authors explain a new scoring system for onychomycosis. This may be useful for choosing appropriate therapy and assessing response to treatment.)
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