The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of onychomycosis. The document aims to (i) offer an appraisal of all relevant literature since January 2002, focusing on any key developments; (ii) address important, practical clinical questions relating to the primary guideline objective, for example accurate diagnosis and identification of cases, and suitable treatment to minimize the duration of disease and discomfort; (iii) provide guideline recommendations and, where appropriate, with some health economic implications; and (iv) discuss potential developments and future directions. The guideline is presented as a detailed review with highlighted recommendations for practical use in the clinic, in addition to an updated patient information leaflet [available on the British Association of Dermatologists' (BAD) website, www.bad.org.uk]. The guideline development group consisted of consultant dermatologists and a consultant mycologist. The draft document was circulated to the BAD membership, the British Dermatological Nursing Group, the Primary Care Dermatological Society and the North West Region Kidney Patient Association for comments, and was peer reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines Subcommittee) prior to publication. This set of guidelines has been developed using the BAD's recommended methodology1 and with reference to the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument (www.agreetrust.org).2 Recommendations were developed for implementation in the National Health Service using a process of considered judgement based on the evidence. The PubMed, Medline and Embase databases were searched for meta-analyses, randomized and nonrandomized controlled clinical trials, case series, case reports and open studies involving onychomycosis published in the English language from January 2002 to February 2014; search terms and strategies are detailed in Data S1 (see Supporting Information). Additional relevant references were also isolated from citations in the reviewed literature, as well as from additional, independent targeted literature searches carried out by the coauthors. The preliminary results were split into four, with each consultant coauthor screening the identified titles; those relevant for first-round inclusion were selected for further scrutiny. The abstracts for the shortlisted references were then reviewed and the full papers of relevant material were obtained. The structure of the guidelines was then discussed and different coauthors were allocated separate subsections. Each coauthor then performed a detailed appraisal of the relevant literature, and all subsections were subsequently collated and edited to produce the final guidelines. This document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared. It is recognized that under certain conditions it may be necessary to deviate from the guidelines and that the results of future studies may require some of the recommendations herein to be changed. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. Limiting the review to English language references was a pragmatic decision but the authors recognize that this may exclude some important information published in other languages. The proposed revision for this set of recommendations is scheduled for 2019; where necessary, important interim changes will be updated on the BAD website. The term tinea unguium is used to describe dermatophyte infections of the fingernails or toenails.3-5 Onychomycosis is a less specific term used to describe fungal disease of the nails. The condition is worldwide in distribution. In addition to dermatophytes, it can be caused by a number of other moulds and by Candida species. Some of the contributing factors causing this disease are occlusive footwear, repeated nail trauma, genetic predisposition and concurrent disease, such as diabetes, poor peripheral circulation and HIV infection, as well as other forms of immunosuppression. There is wide geographical and racial variation in the aetiological agents of onychomycosis, but in the U.K. 85–90% of nail infections are due to dermatophytes and about 5% are due to nondermatophyte moulds.4-6 The most commonly implicated dermatophyte is the anthropophilic species Trichophyton rubrum, followed by Trichophyton interdigitale. Zoophilic species are seldom involved, and usually only in fingernail infections. Onychomycosis is among the most common nail disorders in adults, accounting for 15–40% of all nail diseases.7 Onychomycosis is most prevalent in older adults but, because of the limited number of large-scale studies, the actual incidence of the condition is difficult to assess. Moreover, many reports do not distinguish between dermatophytosis and other forms of onychomycosis, or between infections of the fingernails and toenails. It has been estimated that onychomycosis occurs in about 3% of the adult population in the U.K.8 Many risk factors for onychomycosis have been identified. They include increasing age, peripheral vascular disease, trauma and hyperhidrosis. Fungal nail disease is more prevalent in men and in individuals with other nail problems such as psoriasis, in persons with immunosuppressive conditions such as diabetes mellitus or HIV infection, and in those taking immunosuppressive medications. Tinea unguium is associated with tinea pedis in up to one-third of cases. The difference between the incidence of onychomycosis in men and women might be a reflection of the degree to which individuals are concerned about the appearance of their nails. Likewise, the higher incidence of onychomycosis in older individuals could be due to the greater likelihood of younger patients seeking treatment at an earlier stage. Although infrequent, onychomycosis can affect children and is most likely due to the wearing of occlusive footwear. There are few reports studying the aetiology of onychomycosis in children. A recent study from Spain illustrates the spectrum of causal agents and disease patterns.9 To study childhood dermatophyte onychomycosis, a retrospective study was carried out of children < 16 years of age, with dermatophyte onychomycosis diagnosed between 1987 and 2007. Of 4622 nail samples from 3550 patients, 218 came from 181 children up to 16 years old. Onychomycosis caused by dermatophytes was demonstrated in 28 cases (15·5%). T. rubrum (18 cases) was the most prevalent species, followed by T. tonsurans (five cases), T. mentagrophytes var. interdigitale (four cases) and T. mentagrophytes var. mentagrophytes (one case). Concomitant dermatophytosis at other locations was confirmed in seven cases (25%). Toenail onychomycosis was associated with tinea pedis in five cases. Distal and lateral subungual onychomycosis was the most common clinical pattern. The superficial white type was found in two cases of toenail onychomycosis caused by T. rubrum and T. tonsurans. During the period of study, only 5·1% of all investigated people were children aged up to 16 years. Onychomycosis tended to increase in prevalence over the years and represented 15·5% of all nail dystrophies in children. The findings emphasized that dermatologists must consider onychomycosis in the differential diagnosis of nail alterations in children and always perform a mycological study to confirm the diagnosis. Specific aspects of athletics lead to a higher prevalence of onychomycosis in athletes, such as trauma, previous tinea pedis infection, increased sweating and increased exposure to infectious dermatophytes.10 A study of Icelandic swimmers observed a threefold increase in the occurrence of onychomycosis in swimmers (23%) compared with the general population (8%),11 and the Achilles survey demonstrated a 1·5 times higher prevalence of onychomycosis in athletes compared with nonathletes.12 Fungus invading the nail can spread to the foot to cause tinea pedis when activated by periods of increased warmth and humidity or impaired immunity. Moreover, the presence of one infection may increase the risk of the other occurring. The key predisposing factors that contribute to infection in sports persons are the speed/intensity involved with sport (runners), the sudden starting and stopping nature of the sport (e.g. tennis, squash, football, cricket and ice skating), practising sports without protective footwear (e.g. gymnasts, ballet dancers), frequency of nail injuries, prevalent use of synthetic clothing and shoes that retain sweat, water sports and communal bathing.10 Diabetics are almost three times more likely to develop onychomycosis than nondiabetics.13 Diabetics may have increased difficulty in doing regular foot check-ups due to obesity or complications of diabetes such as retinopathy and/or cataracts. This may contribute to diabetics (typically with poor circulation of the lower extremities, neuropathy and impaired wound healing) having a generally higher risk of developing complications from onychomycosis. Diseased nails, with thick sharp edges, can injure the surrounding skin tissue and result in pressure erosion of the nail bed, injuries that may go unnoticed in diabetics due to sensory neuropathy. The injury may act as an entry point for bacteria, fungi or other pathogens, leading to limb-threatening complications or even possible amputation of the lower extremities. Approximately 34% of all diabetics have onychomycosis, as the worldwide diabetic population displays many of the risk factors associated with increased prevalence of the disease.14 Studies investigating the dermatophyte species in diabetic individuals are limited.13 In agreement with the majority of previous studies, recent reports have found that the most common causative agent for tinea pedis and onychomycosis was T. rubrum, followed by T. mentagrophytes in diabetic patients.15 The types and frequency patterns of dermatophyte species in diabetic patients were similar to those in the immunocompetent group. Onychomycosis is reported to be more prevalent in the elderly and appears to occur more frequently in men.5, 16 Approximately 20% of the population aged over 60 years, and up to 50% of subjects aged over 70 years are reported to have onychomycosis.5 The correlation between increasing age and onychomycosis may be attributed to reduced peripheral circulation, inactivity, suboptimal immune status, diabetes, larger and distorted nail surfaces, slower-growing nails, difficulty in grooming the nails and maintaining foot hygiene, frequent nail injury and increased exposure to disease-causing fungi. Some recent studies suggest a genetic basis for susceptibility to onychomycosis.17 Familial patterns of distal lateral onychomycosis were caused by T. rubrum infection that appeared to be unrelated to interfamilial transmission. Several studies have reported the autosomal dominant pattern of inheritance associated with T. rubrum infection and highlighted the increased risk of developing onychomycosis in subjects where at least one parent had onychomycosis.17 Individuals infected with HIV have an increased risk of developing onychomycosis when their T-lymphocyte count is as low as 400 cells mm−3 (normal range 1200–1400), and their onychomycoses tend to be more widespread, usually affecting all fingernails and toenails.5 Proximal subungual onychomycosis has been considered as an indication of HIV infection. However, transplant recipients, individuals on immunosuppressive treatments and individuals with defective polymorphonuclear chemotaxis may exhibit a similar type of infection. T. rubrum is the causative fungus in most cases, except for cases of superficial white onychomycosis (SWO), which are usually caused by T. mentagrophytes. Experimental human infection has been developed using different morphological forms of dermatophytes on different tissue substrates.18 Infection of the nail plate has been induced with macroconidia, microcondia, arthrospores from natural infection, fragments of agar cultures, and dermatophyte-infected skin scales. From these studies it can be concluded that all of the different morphological forms of dermatophytes have the potential to cause human infection, but arthroconidia, because of their in vivo formation and shedding from the skin and nail, are likely to be the forms involved in the spread of infection.18, 19 In the direct mode of dermatophyte spread – contact with exfoliated infected material – the role of arthrospores is substantiated by the fact that besides being spores, i.e. nonvegetative and thus having no exogenous nutritional requirements, they are resistant to adverse conditions. They can also be produced in large numbers. As arthrospores are produced by fragmentation of hyphae, it is suggested that these fungal cells are the most suitable of the dermatophyte spores for the growth of dermatophytes in the nail plate. It is a common misconception among physicians that as onychomycosis is a cosmetic problem it need not be treated. However, it is clear that onychomycosis can have a significant impact on the quality of life of patients.20 Problems associated with onychomycosis include discomfort, difficulty in wearing footwear and walking, cosmetic embarrassment and lowered self-esteem.4 Infected nails may serve as a reservoir of fungi with a potential for spread to the feet, hands and groin. Fungal diseases are contagious and may spread to other family members, if not treated. Onychomycosis can result in disruption of integrity of the skin, providing an entry point for bacteria leading to the development of foot ulcers, osteomyelitis, cellulitis and gangrene in diabetic patients.21 Furthermore, there can be huge financial implications of neglecting onychomycosis in this group of patients.4 In addition, the presence of sensitizing fungal/dermatophytic antigens in the nail plate may predispose to other clinical conditions in subjects with onychomycosis. These include asthma/sensitization of the respiratory tract, and skin conditions, such as atopic dermatitis, urticaria and erythema nodosum. Nail changes are an important medical concern for patients and, therefore, nail diseases should raise attention and receive proper care from both physicians and other healthcare providers.22 Approximately half of all patients with onychomycosis experience pain or discomfort. About 30% of the patient population have difficulty in wearing footwear. Although onychomycosis is not a life-threatening condition, many important functional purposes of the nails may be severely compromised. Difficulty in walking, emotional embarrassment and work-related difficulties are the most commonly reported issues. However, severe cases appear even to have a negative influence on patients' sex lives. Socks and stockings may frequently be damaged, due to the constant friction with sharp, dystrophic diseased nails in patients with onychomycosis. Onychomycosis is a fungal infection caused by various pathogens, which can adopt any of several clinical patterns. The five main clinical patterns are (i) distal and lateral subungual onychomycosis (DLSO), (ii) SWO, (iii) proximal subungual onychomycosis (PSO), (iv) endonyx onychomycosis and (v) total dystrophic onychomycosis (TDO). DLSO is the most common presentation of dermatophyte nail infection. Toenails are more commonly affected than fingernails. The fungus invades the nail and nail bed by penetrating the distal or lateral margins. The affected nail becomes thickened and discoloured, with a varying degree of onycholysis (separation of the nail plate from the nail bed), although the nail plate is not initially affected. The infection may be confined to one side of the nail or spread to involve the whole of the nail bed. In time the nail plate becomes friable and may break up. The most common causative organism is T. rubrum. As DLSO has a similar clinical presentation whether caused by dermatophytes or nondermatophytes, it is important to obtain a nail sample for mycological examination so that the causative organism can be identified. Tinea unguium of the toenails is usually secondary to tinea pedis, while fingernail infection often follows tinea manuum, tinea capitis or tinea corporis. Tinea unguium may involve a single nail, more than one nail, both fingernails and toenails, or, in exceptional circumstances, all of them. The first and fifth toenails are more frequently affected, probably because footwear causes more damage to these nails. Dermatophyte infection of the fingernails occurs in a similar pattern to that in the toenails, but is much less common. Fingernail infections are usually unilateral. In SWO, the infection usually begins at the superficial layer of the nail plate and spreads to the deeper layers. Crumbling white lesions appear on the nail surface, particularly the toenails. These gradually spread until the entire nail plate is involved. Some forms of superficial infection emerge as linear bands from the proximal nail fold, but are superficial. Also some forms show deep penetration. Neither of these will respond well to topical therapy. This condition is most commonly seen in children and is usually due to T. interdigitale infection. Most cases of PSO involve the toenails. This infection can originate either in the proximal nail fold, with subsequent penetration into the newly forming nail plate, or beneath the proximal nail plate. The distal portion of the nail remains normal until late in the course of the disease. T. rubrum is the usual cause. Although PSO is the least common presentation of dermatophyte nail infection in the general population, it is common in persons with AIDS, and has sometimes been considered a useful marker of HIV infection. In patients with AIDS, the infection often spreads rapidly from the proximal margin and upper surface of the nail to produce gross white discoloration of the plate without obvious thickening. In endonyx onychomycosis, instead of invading the nail bed through the nail plate margin, the fungus immediately penetrates the nail plate keratin. The nail plate is discoloured white in the absence of onycholysis and subungual hyperkeratosis. The most common causative organisms are T. soudanense and T. violaceum. Any of the above varieties of onychomycosis may eventually progress to total nail dystrophy (TDO), where the nail plate is almost completely destroyed. Primary TDO is rare and is usually caused by Candida species, typically affecting immunocompromised patients. Different patterns of nail plate infection may be seen in the same individual. The most common combinations include PSO with SWO, and DLSO with SWO.23 Infection of the nail apparatus with Candida yeasts may present in one of four ways. Chronic paronychia of the fingernails generally occurs only in patients with wet occupations and in children due to thumb sucking. Swelling of the posterior nail fold occurs secondary to chronic immersion in water or possibly due to allergic reactions to some foods, and the cuticle becomes detached from the nail plate thus losing its water-tight properties. Microorganisms, both yeasts and bacteria, enter the subcuticular space causing further cuticular detachment, thus generating a vicious circle. Infection and inflammation in the area of the nail matrix eventually lead to a proximal nail dystrophy. Distal nail infection with Candida yeasts is uncommon, and virtually all patients have Raynaud phenomenon or some other form of vascular insufficiency, or are on oral corticosteroids. It is unclear whether the underlying vascular problem gives rise to onycholysis as the initial event or whether yeast infection causes the onycholysis. Although candidal onychomycosis cannot be clinically differentiated from DLSO with certainty, the absence of toenail involvement and typically a lesser degree of subungual hyperkeratosis are helpful diagnostic features. Chronic mucocutaneous candidosis has multifactorial aetiology, leading to diminished cell-mediated immunity. Clinical signs vary with the severity of immunosuppression, but in more severe cases gross thickening of the nails occurs, amounting to a Candida granuloma. The mucous membranes are almost always involved in such cases. Secondary candidal onychomycosis occurs in other diseases of the nail apparatus, most notably psoriasis. Various filamentous fungi other than dermatophytes have been isolated from abnormal nails.5, 24, 25 Often these are casual, transient contaminants, and direct microscopic examination of nail clippings and scrapings is negative. However, certain environmental moulds that are found in soil or plant material are capable of causing nail infection, and when this is so it is important that their significance is recognized. Unlike dermatophytes, these moulds, with the exception of Neoscytalidium species, are not keratinolytic and they are generally considered to be secondary invaders rather than primary pathogens of the nail plate. There is wide geographical variation in the causative organisms, but Scopulariopsis brevicaulis, a ubiquitous soil fungus, is the most common cause of nondermatophyte nail infection. Neoscytalidium dimidiatum (formerly called Scytalidium dimidiatum or Hendersonula toruloidea) has been isolated from diseased nails as well as from skin infections of the hand and foot in patients from the tropics. Other causes of nail infection include Acremonium species, Aspergillus species, Fusarium species and Onychocola canadensis. Mould infections of nails have been reported in all age groups, but are most prevalent in older individuals. Men are more commonly affected than women, and toenails are more frequently involved than fingernails. The incidence of mould infection of the nails is difficult to assess from published work, because many reports do not distinguish between dermatophytosis and other forms of onychomycosis. However, it has been estimated that nondermatophyte moulds account for about 5% of cases of onychomycosis diagnosed in the U.K., and around 20% of cases diagnosed in North America.26 Unlike dermatophytosis, these mould infections are not contagious, but many of them will not respond to the standard treatments for dermatophyte or Candida onychomycosis. Similarly to dermatophytic onychomycosis, many risk factors for nondermatophytic disease have been identified.5 They include increasing age, occlusive footwear, local trauma, peripheral vascular disease, hyperhidrosis and psoriasis. Mould infections of the nails are more prevalent in individuals with other nail problems, in persons with immunosuppressive conditions such as diabetes mellitus or HIV infection, and in those taking immunosuppressive medications. With the exception of Neoscytalidium infection, nondermatophyte moulds occur usually as secondary invaders in nails that have previously been diseased or traumatized. This may account for the fact that these infections often affect only one nail.26 The toenails, especially the big toenail, are more frequently affected than the fingernails. A nondermatophyte mould should be suspected as the aetiological agent of onychomycosis when previous antifungal treatment has failed on several occasions, direct microscopic examination has been positive but no dermatophyte has been isolated, and there is no sign of associated skin infection.26 The clinical signs of tinea unguium are often difficult to distinguish from those of a number of other infectious causes of nail damage, such as Candida, mould or bacterial infection.5 Unlike dermatophytosis, candidosis of the nails usually begins in the proximal nail plate, and nail fold infection (paronychia) is also present. Bacterial infection, particularly when due to Pseudomonas aeruginosa, tends to result in green or black discoloration of the nails. Sometimes bacterial infection can coexist with fungal infection and may require treatment in its own right. Many noninfectious conditions can produce nail changes that mimic onychomycosis, but the nail surface does not usually become soft and friable as in a fungal infection. Nonfungal causes of nail dystrophies include chronic trauma, psoriasis, onycholysis, onychogryphosis, subungual malignant melanoma and lichen planus. Other less common dystrophic nail conditions mimicking onychomycosis are Darier disease and lichen planus, and ichthyotic conditions such as keratosis, ichthyosis and deafness syndrome. Approximately 10% of subjects affected with lichen planus have abnormal nails, but in the majority of cases they are associated with clinical signs such as thinning of the nail plate, subungual hyperkeratosis, onycholysis and dorsal pterygium.5 Often yellow nail syndrome is falsely identified as a fungal infection. Light green-yellowish pigmentation of the nail plate, hardness and elevated longitudinal curvature are the key clinical characteristics of this nail disease. Repetitive trauma to the nail plate can also result in the abnormal appearance of nails. It can result in distal onycholysis leading to the colonization of the affected space by infectious pathogens and discoloration of the nail plate. A clipping of the infected nail area followed by examination of the nail bed will help to differentiate between nail trauma and onychomycosis. The nail bed will appear normal if the symptoms are caused by trauma rather than onychomycosis, with a characteristic pattern of intact longitudinal epidermal ridges stretching to the lunula. The clinical characteristics of dystrophic nails must alert the clinician to the possibility of onychomycosis. Laboratory confirmation of a clinical diagnosis of tinea unguium should be obtained before starting treatment. This is important for several reasons: to eliminate nonfungal dermatological conditions from the diagnosis; to detect mixed infections; and to diagnose patients with less responsive forms of onychomycosis, such as toenail infections due to T. rubrum. Good nail specimens are difficult to obtain but are crucial for maximizing laboratory diagnosis. Material should be taken from any discoloured, dystrophic or brittle parts of the nail. The affected nail should be cut as far back as possible through the entire thickness and should include any crumbly material. Nail drills, scalpels and nail elevators may be helpful but must be sterilized between patients. When there is superficial involvement (as in SWO) nail scrapings may be taken with a curette. If associated skin lesions are present, samples from these are likely to be infected with the same organism, and are more likely to give a positive culture.27 Traditionally, laboratory detection and identification of dermatophytes consists of culture and microscopy, which yields results within approximately 2–6 weeks.5, 27 Calcofluor white is exceedingly useful for direct microscopic examination of nail specimens, as the fungal elements are seen much more easily than with potassium hydroxide, thereby increasing sensitivity.27 Newer diagnostic techniques have been developed in recent years using molecular genetic tools for diagnosing dermatophytes, Candida species and nondermatophytic moulds.28 Many mycology diagnostic laboratories have implemented a molecular method for the detection of dermatophytes.29, 30 Real-time polymerase chain reaction (PCR) assays have been developed, which simultaneously detect and identify the most prevalent dermatophytes directly in nail, skin and hair samples and have a turnaround time of < 2 days.31-34 It appears that real-time PCR significantly increased the detection rate of dermatophytes compared with culture. However, PCR may detect nonpathogenic or dead fungus, which could limit its use in identifying the true pathogen. Restriction fragment length polymorphism analysis, which identifies fungal ribosomal DNA, is very helpful for defining whether the disease is caused by repeat infection or another fungal strain when there is a lack of response to treatment.35 However, this technique has not been implemented into routine clinical practice. Recent studies have shown that histopathological analysis using periodic acid–Schiff staining is more sensitive than direct microscopy or culture.36 However, this technique is not currently available in the majority of dermatology clinics or mycology laboratories. Other diagnostic techniques under investigation include flow cytometry and confocal and scanning electron microscopy. Candida infection accounts for 5–10% of all cases of onychomycosis.5 Three forms of infection are recognized: infection of the nail folds (or Candida paronychia), distal nail infection and total dystrophic onychomycosis. The last is a manifestation of chronic mucocutaneous candidosis. Nail and nail fold infections with Candida are more common in women than in men. Fingernails are more commonly affected than toenails. These infections often occur in individuals whose occupations necessitate repeated immersion of the hands in water, and the nails affected tend to be those of the dominant hand. The fourth and fifth fingers are involved less frequently than the thumbs and middle fingers. Among the various species implicated, C. albicans and C. parapsilosis are the most common. Candida paronychia usually starts in the proximal nail fold, but the lateral margins are sometimes the first site to be affected. The periungual skin becomes swollen, erythematous and painful, and a prominent gap often develops between the fold and the nail plate. Nail plate involvement often follows, with infection usually commencing in the proximal section. White, green or black marks appear in the proximal and lateral portions of the nail and then in the distal parts. The nail becomes more opaque, and transverse or longitudina
