The effectiveness of laser treatments for onychomycosis in adults in the community: a systematic review protocol

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Review question/objectiveThe objective of this review is to investigate if laser treatments can effectively treat onychomycosis of the nails in healthy adults living in the community. More specifically, the objectives are to identify: whether the investigated experimental methods, modes and treatment regimens utilizing laser interventions, applied to adults (> 18 years) living in the community with at least one nail infected with onychomycosis, produce outcomes comparable to the current 'gold standard treatment' of oral terbinafine over a minimum 12-week treatment period.BackgroundOnychomycosis (tinea unguium) is an extremely common and specific fungal infection caused by a keratinophilic dermatophyte Trichophyton rubrum that infects the nail plate, nail bed and matrix.1Dermatophytes were present in 82% of onychomycosis isolates in an epidemiologic survey of superficial fungal infections2 and are the major causal agents of tinea pedis and onychomycosis.1,2Traditionally, the term onychomycosis was used to describe nondermatophytic nail infection.3 Current research has shown that onychomycosis etiologically comprises of a suite of dermatophytic fungi, yeasts, saprophytic moulds and/or bacteria which colonize different ecological niches on a human.4Onychomycosis prevalence has been estimated to be between 14-20% of the North American population5 and in the range of 3-22% in European countries.6-8 In 1999, Scher9 estimated a 2-18% incidence of onychomycosis in the global population.Due to the increasing numbers of immunocompromised individuals, extensive use of broad-spectrum antibiotics and chemotherapy,10 increasing numbers of older aged people and individuals engaged in personal fitness programs utilizing public facilities,11 more recent research implicates onychomycosis caused by a fungus in about half of all nail infections worldwide.12-14T. rubrum is the major pathogen in tinea unguium infection in most surveys with incidence rates reported between 68% to as high as 90% in Europe.6,11,15-17 The economic burden of treatment is high18 and the social impact on individuals is significant.19,20The incidence of dermatophytes and saprophytes isolated from infected individuals varies over geographic and demographic regions worldwide with onychomycosis skin infections reportedly affecting up to 30% of the adult population.1,21,22 The close relationship between tinea pedis and T.rubrum infection is well established and widely acknowledged.23,24 Hence it is necessary to confirm the diagnosis of the causal agent prior to starting a treatment regime.1,13,14Traditionally, testing involves fungal culture and direct microscopy techniques3,10 such as a KOH wet mount performed in an office-based situation or a laboratory.13,14 Samples are taken from the active areas of a lesion, mounted onto a glass slide with a 20% KOH solution and the solution is heated such that the epidermal cell keratin is dissolved and the fungal elements are left. Microscopic examination for septate or branching hyphae, budding cells and spores are evidence of fungal infection.14 Direct microscopy alone can result in false-negative results25 and the presence of nondermatophytes in culture specimens can further confound the identification of the causal organism.25 Cumulative evidence using direct microscopy techniques together with careful examination of a culture specimen provide unequivocal evidence of the causal agent.3More recently, the efficacy of periodic acid-Schiff (PAS) stain; which stains fungal wall glycoprotein, basement membrane material and mucosubstances bright red clearly delineating these elements from the pink-blue background used for testing, has been demonstrated.26 PAS is a very sensitive diagnostic test for onychomycosis in nail plate biopsy27,28 providing a definitive diagnosis of dermatophyte infection.26There are four recognized types of onychomycosis13 differentiated by infection pathway and clinical presentation.3Distal subungual onychomycosis (DSO) invades the distal nail plate progressing proximally to invade the nail bed and underside of the nail plate and is the most common form of onychomycosis caused by T. rubrum.3 Nails can become brittle, thickened, and discolored with pieces of nail breaking away.3White superficial onychomycosis (WSO) results in superficial infection of the nail plate indicated by the presence of 'white islands'; it occurs mainly on toenails.13,29 As the infection consolidates, onycholysis can occur as the keratin breaks down.30T. rubrum colonization of the newly formed nail plate via the proximal nail fold, progressing distally with fingernails and toenails equally affected, is the least common form of onychomycosis in healthy adults; but is commonly isolated from immunocompromised individuals.13 Proximal subungual (white) onychomycosis (PSO) or (PSWO) is an early clinical marker for HIV.13,31,32Individuals who often have their hands in water or suffer from hyperhydrosis, and wear occlusive footwear can be infected with candidal onychomycosis, caused by Candida spp.33 Seventy percent of onychomycosis caused by yeast are attributed to Candida albicans.33 Total dystrophic onychomycosis (TDO) can be primarily due to chronic mucocutaneous candidiasis.34 One study on a geriatric population suggested that mixed saprophytic infections may be more prevalent than the isolated dermatophyte infection as the causal agent of onychomycosis.35Onychomycosis is more likely to occur in the elderly36,37 and incidence is higher in males38 than females. Infections tend to increase in severity and prevalence (number of nails infected and area of nail affected) as individuals age,24 and are compounded by pre-existing health conditions such as diabetes,39 HIV,40 cancer and obesity.41Poor cosmetic appearance of nails can seriously impact an individual's employment prospects, personal relationships and general lifestyle.42,43 Onychomycotic toe nails which become very thick and malformed can significantly impact mobility and limit footwear choice.33 Onychomycotic infections tend to be long term (>12 months) and recalcitrant. Current therapies show poor efficacy with recurrence/reinfection rates around 25%. 21,44The most commonly utilized current treatment methods are topical and oral pharmacotherapies;45 the former being less costly and causing less side effects than the latter. Oral medications can have side effects such as altered liver function.24 However, a 93% complete cure rate has been reported with a treatment regime of 250mg of terbinafine daily for seven days every three months.46 Treatment with oral terbinafine at the dosage of 250mg daily for twelve weeks resulted in a mycological cure rate between 77-82%, and a clinical cure rate of 60-70%.47,48 Terbinafine has been government approved for treatment of onychomycosis in all countries49 and is the current gold standard oral treatment.21,34Topical treatments for nail infections are problematic for several reasons. They require chemical penetration of the nail plate and bed to reach the target infected tissue,45 resulting in reported efficacy rates between 5% and 8%.3,50 A lengthy treatment period of three to 12 months is required45 and patients are generally non-compliant13,51 Topical applications are not a treatment option for obese clients, individuals who are unable to reach their feet, and older individuals with poor eyesight and reduced manual dexterity. Thus there is need for more effective treatment options.In recent years, device based non-invasive therapies such as laser, ultrasound, iotophoresis and photodynamic therapies have been applied to onychomycotic infections.52Compared to current pharmaceutical options, laser therapy offers a non-invasive, short-term treatment regime provided by a medical professional in a clinical setting; thereby reducing or eliminating negative patient experiences.52'Laser' is an acronym for 'light amplification by stimulated emission of radiation'.53 Lasers produce coherent light that can be spot focused while maintaining very high irradiance.53 Lasers derive their name, and emit light with characteristics specific to the 'lasing material' that is activated.53 The light beam produced by a laser can be pulsed, pseudo-continuous or continuous, and has wavelengths in the ultraviolet, visible and infrared ranges for dermatological uses.53 Biological responses can be targeted precisely by the careful choice of light wavelength, pulse duration and fluence.51,53,54Laser application to the medical field did not flourish until the 1990s when it was discovered that solid state lasers that utilized the alexandrite crystal produced photons of 755-nm light in the near infrared spectrum;55 and quality switching55 enabled a pulse width range from 50-100ns.56Effective laser treatment relies on the theory of selective photothermolysis.22 Chromophores are substances which selectively absorb a particular light wavelength. Melanin, present in skin22,55 and Trichophyton species cell walls,57 absorbs the 1064 nm wavelength produced by the Q-switched Nd:YAG laser. Whereas the 532 nm wavelength of the Q-switched Nd:YAG laser is absorbed by the red chromophore xanthomegnin abundant in T. rubrum.22,53,55,57 Each chromophore has a unique thermal relaxation time (TRT).58 The TRT of a substance is defined as the time taken for the object to cool after absorbing heat.59 This means that if the target chromophore is unable to cool faster than heat is delivered, then the target substance is hotter than its environment and is destroyed.55 In the case of fungi, this means that targeted laser treatment can be fungistatic.60Conversely, heat is transferred to the surrounding environment if heat is delivered more slowly than the chromophore can cool.55,58 Essentially, as target size reduces, the TRT reduces, which in turn requires reduced laser pulse duration to confine the heat energy produced to the target tissue only.55 Advances in laser technology suggest that the longer wavelength of the neodymium-doped yttrium aluminum garnet (Nd:YAG) laser enables a deeper penetration of tissues and thus it can target fungal elements in the nail bed,51 specifically xanthomegnin.58 The Nd:YAG laser emits 1064-nm wavelength but can emit light at 1440-nm,1320-nm and 940-nm wavelengths and has the capacity to be modified such that the beam can be continuous, Q-switched, long-pulsed or potassium titanyl phosphate (KTP) modes to emit a range of medically useful wavelengths.55The carbon dioxide, Nd:YAG, 870/930-nm combination and femtosecond infrared 800-nm lasers, Flash pumped short pulsed Nd:YAG 1064-nm, Nd:YAG 1320-nm, modelocked femtosecond pulse titanium sapphire lasers (Ti:Sapphire) laser, near infrared Diode lasers and low level laser light all offer the potential of an alternative to current pharmaceutical treatments for onychomycosis.Recently published reviews51,52,61 have highlighted the potential laser therapies have to offer effective, convenient, short duration treatment regimens, and the need for further detailed research; but have not systematically evaluated the effectiveness of different laser types and treatment modalities.This systematic review of effectiveness of current laser treatments for onychomycotic infections of nails among adults living in the community will provide information to assist medical professionals, such as podiatrists, dermatologists, and general practitioners, to develop their client treatment plan.

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