The effectiveness of lasers in the treatment of onychomycosis: a systematic review Part 3 of 3.
This review of published papers has yielded 12 studies investigating the use of lasers in the treatment of onychomycosis. Sample sizes in all studies were generally small ranging from 8  to 131 patients , with six studies having 20 or fewer patients [26-28313334]. Only one paper offered a detailed design and protocol with a control (sham) intervention .
On review of the data available, a number of issues arise. Firstly, looking at early results it is clear that there is no consensus on laser effectiveness with conflicting study results being evident. This, in part, is due to the heterogeneity of the study designs at many stages. Although all papers reviewed onychomycosis in adults, selection criteria showed variation. Most focussed on older adult samples reflecting the fact that onychomycosis is a disease are more prevalent in this age group  however, definitive diagnosis for in- clusion relied on a single test result in some studies [25-29,31,32] or a combination of tests such as Periodic Acid-Schiff (PAS) stain, microscopy, positive fungal culture or polymerase Chain Reaction (PCR) in others [30,33,35,36,41]. The variability of these tests have been investigated. Weinberg et al.  examined 94 nail samples and suggested the sensitivities of KOH as 80%, PAS 92% and culture 59%. More recently developed PCR techniques are considered to the new standard technique in detecting dermatophyte presence  with detection rates similar to PAS staining technique . The research to date highlights the difficulty in what constitutes an effective "cure" in onychomycosis and how it is measured. Mycological cure is defined as clearance of the nail based on negative mycological test findings such as microscopy, culture and PAS staining, however this can be complicated when an individual may show mixed results when exposed to a range of different mycological tests. Moreover, a negative culture result may not equate to improvement in the nail appearance (known as "clinical cure"). A "complete cure" is a combination of mycological and clinical cure --effectively the nail is free from fungus and visually, returns to normal.
Visual appearance in some studies was based on patient satisfaction levels  whilst others measured clear nail emergence [25,31,34] or formalised the changes in the amount of nail plate surface affected and its associated changes. The OSI  was a commonly used in- strument [26,27,30] and categorised nails based on the amount of nail surface area affected. Other studies made no formal visual assessment [28,35]. As previous papers have discussed [45,46] assessing what constitutes a cure is difficult, requiring further work to provide a meaningful outcome for the clinician and the patient.
Another factor for consideration is the duration of the study. Most studies ran between 12-24 weeks [25,26,2830-36], with one recent study continuing to 36 weeks  and one to 12 months . In fully assessing the effectiveness of laser therapy, it is perhaps important to consider nail growth rate. In adults, toenails grow around 1.0 mm/month however in the elderly, the rate of nail growth decreases by approximately 0.5% per year between 25 to 100 years of age . In addition, it has been shown that nails infected with dermatophytes grow at a slower rate than uninfected nail plates, proportional to amount of nail affected . Consequently, for a full nail growth to occur post-intervention, a longer time period of up to 24 months maybe a more suitable way to assess effectiveness. The Hees et al. study , which suggested deterioration in the visual appearance of the some nails, had a longer follow up than most studies whilst Zhang and colleagues  reported rapid relapse in five patients (a total of 10 nails). Moreover, Hollmig et al.  noted that although modest improvement in nail clearance was observed in their laser treated group at 3 months compared to the control group, this was not sustained at 12 months, suggesting only a temporary effect.
To compound the issue, as studies become longer in duration the risks of relapse or reinfection potentially increase. Relapse is defined as a recurrence of the nail infection, resulting from insufficient clearing of the ori- ginal infection from the nail, whereas reinfection is a new infection occurring in a nail that has been previously cleared of all infection. It has been shown that re- infection is a common occurrence in onychomycosis [49,50] probably occurring as the patient reacquires dermatophytic fomites from previously worn footwear and hosiery. In such studies, the use of preventative measures such as shoe and sock disinfection or topical nail lacquers and antifungal creams may be a useful addition following completion of laser treatment to counteract the effect of reinfection. Only two studies in this review employed the use of a topical antifungal applied to the skin or nails after treatment deliberately to reduce reinfection [25,28].
Other issues worthy of discussion, include nail thickness and severity of the infection. Increased nail thick- ness in any type of treatment for onychomycosis acts as a potential barrier. Noguichi et al.  measured nail thickness and excluded those with a nail thickness of greater than 3 mm suggesting that the 1064 nm laser can only penetrate down to this depth. Kalokasidis et al.  employed the use of a nail drill prior to treatment in their study, Hees et al. stated that they did not in their study deliberately seek to drill nails prior to therapy . All other studies did not state, either way, if nail reduction was employed [2526,28,29,31-33,3536]. The use of nail drilling prior to antifungal drug use has been shown to be effective in improving cure rates [51,52] but its effect in laser treatment remains a point to be tested.
The type of onychomycosis is a factor which may the affect the outcome of treatment. The four main types are distal lateral subungual onychomycosis (DLSO), superficial white onychomycosis (SWO), proximal white sub-ungual onychomycosis (PWSO) and total dystrophic onychomycosis (TDO). The extent of the nail infection will potentially have a bearing on the treatment success. The DLSO and PWSO varieties showed in some studies being more responsive to treatment possibly owing to their mild to mod- erate presentation when compared to the more severe proximal PSO and TDO varieties. Clear documentation of the profile of type of onychomycosis presenting in study cohorts would permit a clearer judgement on the lasers effectiveness. Four studies [28,29,35,36] did not profile the onychomycosis at presentation whilst two only included DLSO or SWO [26,34]. The remaining five studies included all types [25,27,30-32], however in four of these studies, the vast majority were DLSO cases [2530-32].
Setting up and running clinical trials for new laser technologies can be costly and time consuming. To that end, sponsorship from industry may not be entirely objectionable in researching new devices  but it is an important factor to be considered in judging the validity of any study. Of the 11 included studies, only one paper made no declaration of competing interests  whilst four papers declared competing interests ranging from loan of equipment , to individual author involve- ments with associated companies [26,35], through to full sponsorship and involvement in study design and authorship in one study .
This paper set out to systematically review current evidence in the treatment of onychomycosis employing laser technologies. However, there are potential limitations to this work. Firstly, whilst this review includes papers published and indexed on two large databases (Web of Science[R] and PubMed), it must be stated that these libraries are not exhaustive and therefore cannot cover all relevant publications. As an emerging modality, searches of the internet reveal much more literature in the form of documents, papers and posters but it is difficult to objectively ascertain their origins, peer review status or whether any conflicts of interest exist. Therefore, only recognised databases have been used for this review. In addition, only studies written in English and which are readily accessible through normal methods have been included.
In the last five years, papers have been published investigating the application of lasers in treating onychomycosis. Twelve studies were identified and included in this review. Most of the published data to date is reported at a low level of evidence predominantly case series involving small numbers of patients and with only two small randomized controlled studies. Outcomes appeared to be measured on visual nail clearance measurements following treatment, mycological evidence of cure or both. Studies with longer follow up periods suggest nail infection relapse occurring in those treated with laser which warrants further investi- gation. However, overall conflicting results are shown in this review of studies with no clear evidence of efficacy. There were no studies published comparing laser with more traditional therapies in the treatment of onychomycosis. Comparative studies are required with improved design such as longer follow up periods, classification of the type of nail infection and control interventions to truly assess the effectiveness of laser devices in the management of onychomycosis.
References and End Notes (for part 3)
AOTA: American Occupational Therapy Association; DLSO: Distal lateral subungual onychomycosis; FDA: Food and Drug Administration; Nd: YAG: Neodymium:Yttrium Aluminum Garnet (laser); OSI: Onychomycosis severity index; PAS: Periodic Acid-Schiff stain; PCR: Polymerase Chain Reaction; PWSO: Proximal white subungual onychomycosis; RCT: Randomised Controlled Trial; SWO: Superficial white onychomycosis; TDO: Total dystrophic onychomycosis.
The author declares he has no competing interests.
IB was responsible for the drafting of the paper and conducting the review. All authors read and approved the final manuscript.
Received: 15 April 2014 Accepted: 17 July 2014
Published: 27 July 2014
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Bristow: The effectiveness of lasers in the treatment of onychomycosis: a systematic review. Journal of Foot and Ankle Research 2014 7:34.Submit
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