Nail Unit Disorders

Amanda Zubek

The nail is an often-overlooked cutaneous appendage that can exhibit signs of a number of primary dermatoses, both inflammatory and infectious. Nail art, cosmeceuticals, and manicuring comprise a large proportion of the cosmetic industry, and nail disease causes a great deal of distress to patients suffering from primary and secondary nail disorders. This chapter will focus on the most common forms of nail disease, diagnostic approaches, and recommendations for management.

ONYCHOMYCOSIS

BACKGROUND

Onychomycosis is the most prevalent nail disorder worldwide, estimated to comprise 50% of all nail disorders, with a prevalence ranging from 2% to 18% worldwide, but some reports estimate up to 30%.¹,² Men are more commonly affected than women, and incidence increases with increasing age. Toenails are more commonly affected than fingernails, and there is a high rate of comorbid tinea pedis. Onychomycosis is considered a form of superficial mycosis, with the most common causative agent being the dermatophyte, comprising 90% of nail fungal infections. Onychomycosis is notoriously difficult to treat and maintain long-term mycological cure. Patient risk factors include increasing age, poor circulation, diabetes, smoking, nail trauma, immunosuppression, poor nail hygiene. Other patient factors such as drug-drug interactions, behavioral practices, and biochemical properties of the nail plate make treatment challenging.

PRESENTATION

Patients present with a variety of examination findings depending on the clinical subtype of onychomycosis. Common presentations include nail thickening, distal or lateral onycholysis, subungual keratinaceous debris, focal leukonychia, yellow or brown discoloration of the nail, proximal white subungual streaks, complete nail crumbling, and periungual scaling.

DIAGNOSIS

Clinical Diagnosis

Subungual keratotic yellow debris and/or the presence of white discoloration or yellow patches on the nail plate are the clinical indications of onychomycosis. More severe and long-standing cases manifest complete replacement of the nail with friable keratinaceous material.

There are 4 major clinical presentations for onychomycosis and are differentiated by the point of entry for the dermatophyte: distal/lateral subungual onychomycosis, superficial white onychomycosis (SWO), proximal subungual onychomycosis (PSO), and total dystrophic onychomycosis.

FIGURE 7.3.1 A patient with distal lateral subungual onychomycosis due to Trichophyton rubrum. This patient had onychomycosis of all toenails and several fingernails, tinea pedis, and tinea manuum.

Distal/Lateral Subungual

The most common presentation of onychomycosis is distal/lateral subungual onychomycosis (DLSO). In DLSO, the nail exhibits lateral and/or distal onycholysis with subungual debris and a hyperkeratotic nail bed (Figure 7.3.1). There may be linear yellow or white streaks progressing proximally, which represent a “dermatophytoma,” or dense collection of dermatophyte.¹ Often there is concomitant tinea pedis or tinea manuum (“one hand, two feet”). When proximal yellow streaks are present, this type of onychomycosis is more likely to fail because of lack of penetration of antifungal agent into the mass.

Superficial White

The next most common type is SWO, which is characterized by white patches on the outer surface of the nail plate that can be easily scraped or curetted off. The most common nail is the first toenail, and fingernail involvement of SWO is rare. The presence of tinea pedis or DLSO often predisposes to SWO.¹,²

Proximal Subungual

PSO is much less common and is characterized by subungual white patches that start at the proximal nail rather than distal. There is often associated paronychia, or edema and erythema of the proximal and lateral nail folds. PSO is more common in immunosuppressed
individuals and should prompt a consideration for human immunodeficiency virus (HIV) or other possible causes of immunosuppression.¹,²

FIGURE 7.3.2 An immunocompromised patient with total dystrophic onychomycosis of the fingernails caused by Trichophyton rubrum and colonized by Candida parapsilosis.

Total Dystrophic

Total dystrophic onychomycosis is characterized by involvement of the entire nail plate due to invasion of the nail matrix by fungus. The nail is crumbling and white, with thick irregular hyperkeratosis (Figure 7.3.2). Often periungual scaling is noted. This type represents a later stage of any of the above-mentioned forms of onychomycosis and is caused by nail matrix invasion of the fungus.¹,²

Laboratory Diagnosis

Diagnosis of onychomycosis is multifaceted. Periodic acid-Schiff (PAS) staining of a nail clipping from an affected nail that has been fixed in formalin is highly sensitive, estimated to be approximately 84% sensitive.³ For all diagnosis techniques, the specimen of nail clipped or of subungual debris should be taken from the most proximal portion of the onycholytic area. If the sample is taken from a distal portion, there will likely be contaminants. Fungal culture with speciation is highly specific but not very sensitive. Use of multiple test modalities increases sensitivity and specificity.³ A newer diagnostic modality is polymerase chain reaction (PCR) for the detection of the presence of DNA from fungus, yeast, or even bacteria if clinically indicated.⁴ However, the presence of a positive PCR result does not necessarily inform the clinician if the fungus is viable, just that the organism is present, whereas a positive fungal culture denotes a viable organism.

Onychomycosis can be diagnosed by bedside potassium hydroxide (KOH) preparation. Subungual debris scraping should be incubated with KOH or Chlorazol black for several minutes; heating on a hot plate will hasten the development. A positive prep will exhibit fungal hyphae in the debris. Fungal culture can take several weeks to result because dermatophytes are slow growers. To maximize the culture sensitivity, scraping of the proximal portion of subungual debris should be sent rather than a clipping of onycholytic nail. Ideally, Sabouraud dextrose agar with chloramphenicol with and without cycloheximide should be used. The presence of antibiotic (chloramphenicol) minimizes contamination by bacteria, and cycloheximide selects against fast growers, which can overgrow in a mixed culture and cause the other slower growing organisms to be missed. Fungal culture has a relatively high rate of false negative, and this author often sends a clipping for PAS and/or PCR in addition to the culture.

Histopathology

Nail clipping for histologic examination has a high sensitivity for diagnosing onychomycosis, up to 98% sensitive. Fixation of nail plate in formalin followed by PAS staining will demonstrate fungal hyphae and arthroconidia within and between the compact keratin layers of the nail plate.³

Subtypes

Dermatophyte onychomycosis
Candida onychomycosis
Nondermatophyte mold (NDM) onychomycosis

PATHOGENESIS

Several organisms can cause onychomycosis. The majority of cases of onychomycosis are caused by the dermatophyte group of fungi, including Trichophyton, Epidermophyton, and Microsporum, which are responsible for 90% of onychomycosis cases. The most common causes are Trichophyton rubrum and Trichophyton interdigitale. Less commonly, Candida yeast and NDMs can cause onychomycosis. Mixed infections can also occur, particularly when it is a dermatophyte and an NDM or Candida yeast. Until recently, it was controversial whether the NDMs and Candida are pathogenic in onychomycosis, but it is now becoming accepted that they can indeed be causative agents and, in some cases, represent particular challenges in treatment. It is important to determine the causative species because treatment decisions will depend on what organism is being targeted.¹,²

Onychomycosis occurs when a fungus invades the nail plate. Dermatophytes and other fungi secrete keratinases, elastases, acid proteases, and other proteases, which breakdown the keratin in the nail plate and allow for invasion. The clinical presentation varies based on the anatomic location of the initial invasion. For example, DLSO is caused by distal invasion of the fungus from the hyponychium and lateral nail folds. PSO is caused by proximal invasion through the eponychium, and SWO is due to superficial plate invasion.

Once the nail has been invaded by the fungus, it becomes weak with increased spaces within the compact keratin of the nail plate, allowing for dystrophy, loss of attachment to the nail bed (onycholysis), decreased structural integrity (crumbling), and invasion of surrounding skin (tinea pedis).

Common species of pathogenic fungi include the dermatophytes: T. rubrum, Trichophytum menagrophytes, T. interdigitale, Epidermophyton floccosum; NDMs: Acremonium spp., Alternaria spp., Aspergillus spp., Botryoduplodia spp., Scytalidium hyalinum, Scytalidium dimidiatum, Cladosporum spp., Scopulariopsis spp.; yeast: Candida albicans, Candida parapsilopsis, and Candida tropicalis.

TREATMENT

Medical

The decision to use topical versus oral antifungal therapy is often made based on patients’ or physicians’ fear of systemic toxicity of oral antifungals. The ideal patient for topical antifungal therapy is a patient with thin nails (<2 mm thick), with <50% of nail plate involvement, and only a few nails involved. Thicker nails, or more severe involvement will often be recalcitrant to topical therapy. Concomitant and ongoing topical treatment with antifungal cream to the feet and toes, as well as antifungal hygiene to socks and shoes, assists in maintaining clearance with both topical and systemic antifungal treatment. Algorithm 7.3.1 outlines treatments for onychomycosis.

Topical

Ciclopirox Olamine. Ciclopirox olamine 8% solution lacquer (Penlac) is a hydroxypyridine antifungal that is Food and Drug Administration (FDA) approved in the United States for onychomycosis. It is effective against dermatophytes, yeasts, NDMs, and some bacteria. The lacquer formulation allows for longer contact with the nail and increases absorption through the nail plate. It should be applied to the top of the nail, any accessible undersurface of the nail, as well as 5 mm of surrounding periungual skin daily. After 1 week of application, the lacquer should be removed and then the cycle repeated until the nail is clear, which can take up to 18 months with toenails. Package insert rates of mycological cure range from 29% to 36% and complete cure from 5.5% to 8.5%.⁵

Tavaborole. Tavaborole solution (Kerydin) is a newer boron-based antifungal agent that is FDA approved for toenail onychomycosis caused by T. rubrum and T. mentagrophytes. It is a benzoxaborole agent that is active against dermatophytes, yeasts, and NDMs and applied using a brush applicator to the nail plate daily. Phase III clinical trial study of mild to moderate DSO reports rates of mycologic cure up to 35.9% and complete cure rates up to 17.8% after 52 weeks. Duration of follow-up is listed as a limitation of the study.⁶ Tavaborole has been shown to penetrate nail lacquer in cadaver studies, but there are no human trials of its efficacy in the presence of nail lacquer, and general recommendations are to use it without nail polish, gel, or lacquer.

ALGORITHM 7.3.1 Treatment of onychomycosis. Er, erbium; Nd:YAG, neodymium-doped yttrium aluminum garnet; QS, Q-switched.

Efinaconazole. Efinaconazole solution (Jublia) was FDA approved in 2014 for onychomycosis due to T. rubrum and T. mentagrophytes. It is a triazole antifungal and has activity against dermatophytes, Candida, and NDMs. In phase III clinical trials of patients with mild to moderate DLSO, rates of mycologic cure were 53.4% to 55.2% and rates of complete cure were 15.2% to 17.8%.⁷ Similar to tavaborole clinical trials, the duration of the study was 52 weeks, which may be too short to evaluate for recurrence. A recent single-center prospective study evaluating efficacy of efinaconazole in the setting of nail polish showed that efficacy was not reduced in the presence of nail polish but the application of the treatment over nail polish led to diminished cosmesis of the nail polish.⁸

Combination Therapies. The use of light-based technologies in onychomycosis will be discussed later, but the use of lasers as a technique to assist in topical drug delivery has been examined in several studies.⁹,¹⁰,¹¹,¹² One group examined the use of the 1064-nm diode laser with topical amorolfine or ciclopirox olamine versus laser alone and showed that there was improvement in clinical cure as well as mycological cure with combination laser and topical antifungals.¹²

Similarly, physical drilling of small holes into the nails as an adjunct to topical terbinafine therapy was shown by Shemer and colleagues to enhance penetration of the drug and increase efficacy.¹³ Other means to enhance topical drug delivery include putting the agent into a vehicle such as lacquer that allows for long contact duration, using nanoemulsions or nanoparticles to deliver the antifungal, nail poration, or iontophoresis to drive penetration of the drug through the nail plate.

Keratolytics. Keratolytics alone may also be useful to treat onychomycosis. One open-label trial evaluated the efficacy of K101-03, a marketed keratolytic containing urea, lactic acid, propylene glycol, and glycerol in cosmetic improvement of onychomycotic nails and demonstrated that 92% of patients reported improvement in the appearance of the treated nail, with multiple patients exhibiting improvement within 1 week.¹⁴ A similar agent, K101-01, is available over the counter as Kerasal Nail.

Menthol. Mentholated ointment, or topical cough suppressant (eg, Vicks VapoRub) has been anecdotally reported to be effective in onychomycosis as a safe, inexpensive alternative to topical and oral antifungal medication.¹⁵ These treatments contain thymol, menthol, camphor, oil of Eucalyptus, turpentine oil, cedar leaf oil, nutmeg oil, and petrolatum, some of which have antifungal properties as demonstrated in in vitro studies.¹⁶,¹⁷,¹⁸ A small pilot case series in 2011 examined 18 patients with culture-confirmed onychomycosis who were treated with topical Vicks VapoRub for 48 weeks. Of this group, 83% had some improvement, with 27.8% showing mycological cure and 22.2% showing complete cure (clinical and mycological cure). Patient satisfaction with treatment was very high, despite a 16.7% failure rate (positive cultures at the end of treatment).¹⁹ Dilute acetic acid (vinegar) soaks have been anecdotally recommended to treat onychomycosis and tinea pedis, but there are no published clinical studies to support this.²⁰

Plant-Derived Agents. Other natural products have also been shown in in vitro studies to have antifungal activity and include tea tree oil, natural coniferous resin (Norway spruce tree), Ageratina pichinchensis extract (asteraceae family), and ozonized sunflower oil.²¹

Oral

Terbinafine. Terbinafine is FDA approved to treat dermatophyte-induced onychomycosis. It is an allylamine and has activity against dermatophytes, some yeasts, and NDMs. Dosing is 250 mg oral daily for 6 weeks (fingernails) or 12 weeks (toenails). Mycological cure rates are 79% for fingernails and 79% for toenails, and complete cure rates are 59% for fingernails and 38% for toenails.²² Reduced dosing, such as pulse dosing, may be used in cases in which drug interaction or patient comorbidities may increase toxicity of the medication. A meta-analysis for pulse-dosing terbinafine showed that in general pulse regimens are slightly inferior to continuous dosing, but regimens using 2 pulses of 250 mg daily for 4 weeks on and 4 weeks off were comparable with 12 week continuous dosing.²³

Adverse effects of terbinafine include headache, gastrointestinal symptoms, and dermatitis. Less common but serious adverse effects including liver toxicity, dysgeusia, myelosuppression, hair loss, severe skin reactions including but not limited to acute generalized exanthematous pustulosis (AGEP), erythema multiforme, lupus erythematosus, and toxic epidermal necrolysis have been reported. Although it is controversial whether routine laboratory monitoring is required, many dermatologists monitor liver functions throughout the course of treatment.

Itraconazole. Itraconazole is a triazole antifungal agent that is FDA approved for the treatment of onychomycosis. Itraconazole has broad antifungal activity, including dermatophyte, Candida, and NDMs. The recommended dosing is 200 mg orally daily for 12 weeks (toenails) or 200 mg twice daily for 1 week a month for 2 months (fingernails). The reported complete cure rate is 47% for fingernail onychomycosis and 14% for toenails.²⁴ Itraconazole is a strong CYP3A4 inhibitor and therefore has multiple important drug interactions and a long list of drugs of which concomitant therapy with itraconazole is contraindicated. Some of these drugs include simvastatin, lovastatin, methadone, ergot alkaloids, and midazolam. Itraconazole increases the plasma concentration of a number of medications, and great care must be taken to screen for the use of these medications when considering itraconazole. Common medications whose metabolism is altered include warfarin, atorvastatin, verapamil, digoxin, glyburide, glipizide, carbamazepine, and many others.

Intermittent pulse therapy with itraconazole can decrease the risk of drug-drug interactions. One randomized control trial for severe onychomycosis examined a variety of pulse dose regimens and compared
standard pulse therapy (200 mg twice daily 1 week a month for 3 months), long-term pulse therapy (200 mg twice daily 1 week a month for 6 months), or low-dose long-term therapy (200 mg daily 1 week a month for 6 months). Complete cure rates were higher for the longer-duration pulse therapy regimens, and there was no statistically significant difference between standard dosing of 200 mg twice daily and 200 mg daily.²⁵

Common adverse effects of itraconazole include headache, diarrhea, upper respiratory tract infection symptoms, rhinitis, abdominal pain, hypertriglyceridemia, and transaminitis. Severe adverse effects include liver injury/failure, bone marrow suppression, congestive heart failure, peripheral neuropathy, pancreatitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

Fluconazole. Fluconazole, a triazole antifungal medication, is not FDA approved for onychomycosis but is often used off-label for this purpose. The dosing regimen is 150 mg once a week for 6 to 9 months for fingernails and 12 to 18 months for toenails. Common side effects include headache, nausea, diarrhea, transaminitis, and abdominal pain. Severe adverse effects include liver injury, QT prolongation, anaphylaxis, seizures, myelosuppression, agranulocytosis, and SJS-TEN. In a comprehensive network analysis, fluconazole 150- to 450-mg dosing regimens were not deemed superior to terbinafine or itraconazole, and therefore the lowest dosing of 150 mg is recommended.²⁶ Similar to itraconazole, fluconazole has a great number of drug interactions, and caution should be taken to screen for potential interactions before starting a long course of fluconazole.

Cosmetic

Laser

Lasers are emerging as a potential treatment of onychomycosis, independent of their use as a device to enhance topical drug delivery. There are many reports of lasers being used in onychomycosis treatment, but these studies have generally been limited by small size, short follow-up duration, lack of standardization of end point evaluation, and wide variety of laser energy settings and treatment protocols between studies and within studies.²⁷,²⁸ In this section, the current status of lasers in onychomycosis will be discussed.

Nd:YAG Laser. The neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is the most widely reported laser used for the treatment of onychomycosis and has been FDA approved for the treatment of onychomycosis; however, the specific FDA indication is for the cosmetic temporary improvement in nail appearance in onychomycosis. The target chromophore is water, which by selective photothermolysis is heated by exposure to the laser and is thought to cause thermal damage to the fungus. In general, the studies using the Nd:YAG laser have shown variable degrees of improvement in onychomycotic nails, either with or without concurrent antifungal therapy. There are no standard energy settings, treatment frequencies, or length of follow-up among these reports, which is a well-described drawback in the criticism of these reports.²⁹ Standardization of clinical evaluation and treatment protocols will need to be a major focus in future studies to truly determine the efficacy of these devices in treatment or cure of fungal infection, rather than simply cosmetic improvement.³⁰

The 1064-nm Nd:YAG. Numerous studies have used the 1064-nm Nd:YAG laser in onychomycosis.¹¹,¹²,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹ A few studies are discussed in this section. In 2018, Bonhert et al reported the use of the 1064-nm Nd:YAG laser in combination with efinaconazole 10% topical solution in toenail onychomycosis. Laser energy settings were 2 to 5 mm spot size, 12 to 324 J/cm² fluence, 0.3 to 35 ms pulse duration, and 1 to 5 Hz frequency.¹¹ Hallux nails were treated with 100 pulses per pass, with 4 passes each treatment, whereas small toes received 100 cumulative pulses per session. The authors found that in comparison with efinaconazole alone, the addition of 4 monthly laser treatments with the 1064-nm Nd:YAG laser led to faster onset of improvement and higher rates of clinical improvement but no statistical difference in mycological cure rates by the 52-week follow-up.¹¹ Kim and colleagues reported 40 patients treated over 4 sessions with the 1064-nm Nd:YAG, with settings of pulse width 35 ms, 1 Hz pulse frequency, and 35 to 40 J/cm² fluence, and showed 90% mycological cure and over 100% of nails showing >75% clinical improvement.³⁵

The 1444-nm Nd:YAG. One group studied the effect of a 1444-nm Nd:YAG laser in onychomycosis, citing the idea that this particular wavelength has a higher degree of absorption in water and fat than the 1064-nm laser, and hypothesized a potential use in treatment of onychomycosis. Although they did observe significant damage to fungal elements and reduction in fungal activity, a great deal of damage was also seen to
the nail. The authors cautioned that there is a high risk of damage to surrounding tissue, and further investigation is warranted.⁴⁰

QS Nd:YAG. Kalokasidis et al. examined a Q-switched 1064/532-nm laser system in onychomycosis, suggesting that, in addition to water as a chromophore, the 2 different wavelengths also function to target different pigments within the fungi, potentially enhancing the antifungal effect. This group examined 131 patients treated with QS Nd:YAG over 2 treatments along with adjunctive nail debridement, with energy settings of 9 ns pulse duration, 5 Hz pulse frequency, and 14 J/cm² fluence, and found 95% mycological cure with >75% of the nail showing clinical improvement in 9.2% of patients.⁴¹

Diode Laser with Topical Antifungals. A prospective open trial evaluated the 1064-nm diode laser efficacy in patients with onychomycosis who had failed to have clinical improvement after at least 8 weeks of topical or oral antifungal treatment.⁴² Patients who had not had prior antimycotic treatment were also included. Nails were treated with laser either 2 or 3 times at 8-week intervals, with energy settings of 4 mm spot size, 8 W, 80 ms pulse duration with 5.6 Hz repetition rate, and fluence 5.1 J/cm². Nails were evaluated using onychomycosis severity index (OSI) before and after treatment. The authors observed that all patients showed mean improvement by 25% after laser treatments.⁴² Patients with and without ongoing onychomycosis treatment exhibited a 25% improvement in the OSI. The take home conclusion was that laser treatment did improve overall onychomycosis severity, but a longer follow-up period is needed.⁴²

In a recent retrospective analysis, Weber et al examined the efficacy of a long-pulsed 1064-nm diode laser with or without topical antifungals (ciclopirox olamine or amorolfine) in 56 patients.¹² Energy settings were spot size 4 mm, pulse duration 80 ms, and power 8 W. Before treatment sessions, dystrophic nail was debrided by a podiatrist. The patients were treated an average of 3.9 treatments at 2- to 6-week intervals. In laser-only treated patients, mycologic cure was attained in 63% (after mean of 5.4 treatments), whereas 86% of patients treated with laser and topical antifungals (average of 4.8 treatments) achieved mycologic cure. Clinical clearance was achieved in fewer treatments with laser plus topical antifungals compared with laser alone. The conclusion was that the 1064-nm diode laser is an effective adjunctive treatment to topical antifungals that will enhance efficacy and speed up mycological and clinical cure in dermatophyte onychomyosis.¹²

Er:YAG Laser. The use of the fractional ablative Er:YAG laser is also undergoing clinical trials for onychomycosis with promising results.⁴³,⁴⁴ In 2016, Zhang et al examined the efficacy of a fractional ablative 2940-nm Er:YAG laser with 5% amorolfine lacquer versus amorolfine alone and showed that, with the combination treatment 75% of nails showed mycological cure compared with 20% of amorolfine alone treated nails after 24 weeks.⁴⁴

CO₂ Laser. Several studies have examined the CO₂ ablative laser in onychomycosis.⁹,¹⁰,⁴⁵,⁴⁶ In 2014, Lim and colleagues reported the use of fractional CO₂ laser with topical amorolfine cream.⁴⁵ Patients were treated with 3 monthly sessions, with settings of pulse energy 160 mJ and 150 spots/cm² followed by topical antifungal cream daily. About 50% of patients showed complete response (clinical and mycological), with 92% of patients exhibiting clinical response and 8% with no response after 3 months.⁴⁵ Another study examined the fractional CO₂ laser on 75 patients in combination with terbinafine cream using 0.1-ms pulse width, 99 mJ, and 140 spots/cm². They reported 80% patients with mycological cure and 33% patients with clinical cure.⁴⁶ Another group examined the CO₂ laser with terbinafine cream over a 6-month period and found clinical improvement in 68.5% 3 months after completion and 74.2% mycologic response rate 3 months after completion.⁹

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