Nd:YAG 1064 nm laser treatment for onychomycosis ‐ is it really effective? A prospective assessment for efficiency and factors contributing to response

Onychomycosis is a highly prevalent and persistent nail disorder primarily caused by dermatophytes. The effectiveness of current topical and systemic antifungals is limited by the extent and severity of the infection, patient demographics and health status, hepatic toxicity, drug interactions and low compliance. Laser therapy is a promising modality for safe and cost‐effective removal of mycotic nail. This prospective study assessed the performance of a multi‐series long‐pulsed Nd:YAG 1064 nm regimen (30–40 J/cm2, 1 Hz) in the treatment of 213 mycotic nails in 31 patients. Pain and discomfort were scored at each treatment session and mycological and clinical cure rates were determined 3 months after the last treatment session. Patients presented with mostly severe (mean SCIO score: 21.9 ± 8.9), T. rubrum‐positive (87.1%) infections. Most (61%) had a family history of onychomycosis and a significant proportion had comorbidities, including hypertension (38.7%), hyperlipidemia (35.5%) and/or diabetes (12.9%). Treatment was well tolerated and there were no reports of nail deformity or burns. By 3 months post‐treatment, mycological cure was achieved by 4 (12.9%) and visual improvements were noted for 10 (32.3%) patients, including 3 (9.7%) with moderate to significant improvements. Clinical response correlated with baseline SCIO ≤ 20 (OR: 0.9 [0.13–6.52]), family history of onychomycosis (OR: 0.27 [0.04–1.50]) and comorbidities (OR: 0.44 [0.05–3.74]). In conclusion, Nd:YAG 1064 nm laser is safe and effective for the management of mild‐to‐moderate onychomycosis in diverse populations. Further studies will be necessary to adjust treatment parameters to patient and nail profiles and to determine the impact of combined laser and topical therapies.

and depression, all of which can markedly impact daily activities and social interactions. 3Dermatophytes, most frequently Trichophyton rubrum, are the causative pathogens in the vast majority of cases, while nondermatophytes and yeast are less commonly isolated from affected nails.Predisposing factors include advanced age, compromised immunity, diabetes mellitus, poor nail grooming and occupations with increased risk of nail trauma and/or exposure to fungal pathogens and warm, humid climates. 4,5eatments aim to eliminate the infecting fungus, restore the nail and improve quality of life and are generally recommended to prevent spread and secondary infections.Management protocols are highly individualised and tailored to the extent and severity of nail involvement, infecting species, known drug interactions, comorbidities and patient preferences.Due to inherently slow nail growth rate (~2 mm/month) and the thick keratin structure of the nail, treatment is generally prolonged, which is often mirrored by poor patient compliance.
Several new-generation oral antifungal drugs (terbinafine, itraconazole, fluconazole) are considered relatively potent, safe and cost-effective, owing to their improved penetration into and residence time in the nail matrix, and the commonly prescribed intermittent regimens. 6,7][10] Common side effects include headache, gastrointestinal symptoms and rash and rarely hepatotoxocity and taste disturbances.Moreover, in light of their significant interactions with various drug classes, absolute contraindications exist for polypharmacy patients.While topical agents have fewer side effects, subtherapeutic concentrations of the antifungal components penetrate the keratin-rich nail.As a result, they are less effective, require considerably longer treatment periods and are associated with high relapse rates.
Physical treatment modalities, such as laser, photodynamic, ultrasound and iontophoretic therapies, are being investigated to enhance transungual penetration of topically applied drugs, avoid systemic side effects, broaden patient eligibility and/or overcome adherence-related barriers of drug therapies, with the ultimate goal of improving cure and recurrence rates. 7The fungicidal effect of laser systems has been proposed to be elicited by selective photothermolysis of chromophores in the fungal mycelium [11][12][13][14] and mechanical disruption of treatment-resistant fungal biofilms. 15,16ximal penetration of the nail plate and activation of the target fungal chromophores is achieved at wavelengths of 750-1300 nm, rendering Nd-YAG, near-infrared and dual-wavelength diode and fractional CO 2 lasers suitable systems.Thus far, they have been demonstrated effective in improving the aesthetic appearance of affected nails. 17,18Moreover, a meta-analysis of 35 reports of laser applications to treat onychomycosis in over 1700 patients, found them to be well tolerated, with mild to moderate burning sensation being the most common adverse effect. 19The current prospective study assessed the efficacy of a new multi-series Nd:YAG 1064 nm treatment protocol for the treatment of onychomycosis in adults.

| PATIENTS AND ME THODS
This study was approved by the Rambam Medical Center Ethics Committee (approval number: 0694-19-RMB) and was conducted in accordance with the principles of the Declaration of Helsinki.Signed consent was obtained from all participants before execution of any study-related procedures.

| Patients
Adult patients aged 18-75 years, presenting with finger or toe onychomycosis confirmed by potassium hydroxide (KOH) smear and mycological culture, were eligible to participate in the study.Patients treated with a topical antifungal within the preceding 2 weeks or with systemic antifungal in the past 6 months, with hyperkeratotic nails (>4-mm-thick) or with another nail disorder, such as Lichen planus, psoriasis, atopic dermatitis, or bacterial infection, were not eligible to participate in the study.In addition, pregnant and breastfeeding women were excluded.

| Study design
After providing signed consent, medical and treatment histories were documented, nails were evaluated and photographed, and a confirmatory KOH smear or mycological culture was performed.
Nails were subjected to eight Nd:YAG 1064 nm laser treatment sessions (HARMONY XL PRO, Alma Laser Ltd.), scheduled once a week for four consecutive weeks and then once every 2 weeks over 8 consecutive weeks.Nails were reevaluated and photographed 3 months after the last treatment session (6 months after the first treatment session) and samples were collected for KOH smear and/or mycological culture.

| Laser treatment procedure
Before each session, thick nails were filed.Each laser treatment session was comprised of two intervals of spiral-pattern illumination, separated by a 1-min pause.The laser was set to a fluence of 30-40 J/cm 2 , depending on nail thickness, pulse duration of 35-45 ms, spot size of 6 mm and 1 Hz frequency.Nails were cooled with a Zimmer Cryo 5 (Zimmer Inc.) for 5 min before each treatment session, during the 1-min pause between intervals and for 2 min at the end of each session.

| Assessments
Nail specimens were incubated for 30 min in 30% KOH solution and then microscopically examined for fungal presence.For mycological cultures, each sample was inoculated in Sabouraud dextrose agar with cycloheximide and chloramphenicol and incubated at 29-30°C until colonies formed.Identification of microorganisms was based on macroscopic and microscopic characteristics of colonies.
Pain and discomfort were scored at the completion of each treatment session using the 10-point visual analogue scale (VAS).
In addition, before and after photos and mycological cultures were compared.Nails were evaluated using an online Scoring Clinical Index for Onychomycosis (SCIO) calculator (www.onychoindex.com), which provides a composite severity score that considers onychomycosis clinical form, location and extent of involvement, subungual hyperkeratosis thickness and patient age.Responders were defined as those with nails showing any degree of improvement from baseline SCIO.

| Statistical analysis
Descriptive statistics were summarised, with continuous variables presented as mean, median, minimum, maximum and percentage and categorical variables presented as count and percentage.A logistic regression model was applied to identify factors relating to response.A two-sided p value of <.05 was used to define statistical significance.Analyses were performed using the R-4.1.3(R Foundation for Statistical Computing).

| RE SULTS
Thirty-one patients were enrolled in the study.These included 16 males and 15 females of a mean age of 53.5 ± 13.1 years.Hypertension (38.7%), hyperlipidemia (35.5%) and diabetes (12.9%) were the most common comorbidities.Personal or family history of onychomycosis was reported by 2 (6.5%) and 19 (61.3%) patients, respectively.Fungal infection in treated nails was confirmed by either direct smear or mycology culture.In total, 204 toenail infections, mostly in toe 1 (26.0%), in 30 patients and 9 fingernail infections in 3 patients were treated.Distal/lateral subungual onychomycosis (DLSO) was documented in 141 (66.2%) nails, while the remaining were mixed-pattern infections.T. rubrum was the sole etiological factor identified in 27 (87.1%)clinical samples and T. mentagrophyte was identified in 1 (3.2%) sample.Onychomycosis was mostly severe, with a mean SCIO score of 21.9 ± 8.9 at baseline.For 16 patients, the current treatment was the first line of treatment, while the remaining patients had previously been treated with topical medication (n = 9), laser therapy (n = 6), terbinafine (n = 6), itraconazole (n = 1) and/or fluconazole (n = 1).Baseline clinical characteristics are summarised in Table 1.
All patients completed the full course of treatment.Posttreatment culture was negative in four patients.Significant and moderate clinical improvements were noted for one and two patients, respectively (Figure 1) and slight improvements were noted for seven patients.For five of the six patients with mycological or clinical cure, this was the first line of treatment.Median baseline SCIO was slightly lower in the responders (20 [11.7-24.8])as compared to the non-responders (30 [20-30]) group.Among the patients with baseline SCIO ≤ 20, 42.9% were responders, while only 24% of the patients with baseline SCIO > 20 were responders (OR: 0.9 [0.13-6.52])(Figure 2).A correlation was also found between response to treatment and family history of onychomycosis; 21% of the patients with a family history of the fungal infection achieved a response, while 50% of the patients without a family history achieved a response (OR: 0.27 [0.04-1.50]).In addition, responses were documented among 21% of the patients with comorbidities versus 41% of the patients without comorbidities (OR: 0.44 [0.05-3.74]).
Treatment was well tolerated by all subjects, as reflected by mean pain scores ≤1.3 at each session, with mild discomfort reported by up to 5 patients per session.There were no reports of nail deformity or burns throughout the treatment phase.elderly patients and low performance in all three parameters in patients with higher nail involvement. 22Common denominators between these medical conditions include slower nail growth, poor circulation, impaired wound healing and a higher prevalence of mixed infections. 23veral earlier works assessed the clinical benefits of Nd:YAG lasers in treating onychomycosis and have produced mixed results.

Kozarev reported on clearance of all fungal nail infections among
95.8% of a 72-patient cohort within 3 months of a four-session Nd:YAG laser treatment regimen. 24Apart from failure to present information relating to comorbidities and personal and family history of onychomycosis, patients over the age of 45 years were not eligible to participate in the study, which raises the likelihood of positive response to treatment. 2,25Furthermore, the collected nail isolates included a relatively high percentage of T. mentagrophytes, which may be more susceptible to 1064 nm laser therapy.Okan et al. measured 60% mycological cure and 47% clinical improvement rates in mycotic nails subjected to spiral long-pulsed Nd:YAG laser illumination. 26Over 70% of the nails were infected with Trichophyton sp., but no subspecies details were provided.In addition, the patient age and medical profiles were not detailed.Zhong et al. found that weekly treatment of onychomycosis with a long-pulsed Nd:YAG 1064 nm laser in 22 patients yielded a 29% mycological cure rate within 2 months, which rose to 69% after continued treatment once per month for 4 months. 27Another study measured 9.4% complete cure and a gradual decrease in the extent of involvement in all nails, with 18.6% reaching excellent and 72% reaching good outcomes following treatment of onychomycosis with five long-pulsed 1064 nm Nd:YAG laser treatment sessions conducted at 4-week intervals. 28 sharp contrast to the current study, a large percentage (39%) of the treated nails were fingernails, which are faster growing and generally in more heal-favourable conditions than toenails, and consequently more responsive to treatment. 25Of note, the authors provide no account of patient comorbidities.Short-pulsed Nd:YAG laser treatments delivered at 1-to 3-week intervals achieved high rates of mycological cure (88-95%) and substantially improved visual appearance. 29,30In both reports, patient health status and nail involvement are not detailed.Another group reporting on the performance of a sub-millisecond Nd:YAG 1064 nm laser treatments measured complete clearance in 51% of the treated nails, of which all tested negative in direct smear analyses. 31While significant and even complete clearance was also achieved in nails with high baseline turbidity, the authors noted that all the nails that failed to show any improvement had a baseline turbidity score of 10.In addition, none of the great toenails with a baseline turbidity of 10 showed a full response.Another group failed to find significant differences in mycological cure rates and toenail plate clearance following a two-treatment series of 1064 nm Nd:YAG laser therapy delivered at a 2-week interval compared to untreated controls. 32Yet, the cohort receiving active treatment was significantly older than the control cohort and comorbidities were not considered or compared between groups.[35] Taken together, the medical literature presents an inconsistent picture with regards to the clinical effectiveness of laser management of onychomycosis.The diverse range of factors impacting treatment outcomes and assessment, 25 including patient characteristics, infection and treatment history, extent, severity and mycological profile and laser parameters as well as study design and lack of standardised definitions of efficacy endpoints 36 complicate comparisons across studies.Yet common to all studies is the high safety profile, with no reports of severe or serious adverse effects.
Both in vitro and clinical studies have demonstrated significant growth inhibition of T. rubrum and other species by Nd:YAG laser treatment. 24,37,38The microbiocidal impact of the deeply penetrating Nd:YAG 1064 nm laser has been linked to the resulting hyperthermia and its denaturing effect on critical cellular proteins and structures. 39,402][43] Together, these mechanisms deter fungal proliferation and lead to nail disintegration without affecting untreated tissue.
The cooling device was integrated into the treatment protocol to avoid severe pain and thermal injury expected from the 35-ms pulse duration, which exceeds the 0.7-ms thermal relaxation time of skin tissue. 44The intermittent cooling proved sufficient, as reflected by the low pain and discomfort levels reported by patients and by absence of any visible signs of burns.Yet, at the same time, it may have reduced laser treatment efficacy.
The present study was limited by the lack of a control group.In addition, mycological cure rates determined by assessing superficial nail layers may not accurately reflect the effect of the laser on deeper layers.Other design limitations included failure to monitor complete cure rates as well as the relatively short follow-up period which may

TA B L E 1
Patient demographics and baseline clinical characteristics.

4 |
DISCUSS ION Pharmacological treatments traditionally prescribed for onychomycosis generally require months of therapy and are limited by drug interactions, side effects, poor patient compliance and suboptimal outcomes.The current prospective study demonstrated the safety and efficacy of an eight-session Nd:YAG 1064 laser treatment series delivered over a 12-week period, in managing toenail and fingernail onychomycosis.Treatment was well tolerated and no serious or long-term complications or damage to surrounding tissue were reported throughout the study.Within 3 months of treatment completion, mycological cure was achieved by 12.9% of patients and marked visual improvements by 9.7% of patients.Improvement of any degree was measured in 32.3% of the treated patients.Odd ratios of clinical improvement were negatively impacted by infection severity at baseline, family history of onychomycosis and comorbidities.These findings align with previous reports correlating between limited treatment success and the likelihood clinical cure and multiple systemic factors, history of infection, age and concurrent disease and medications. 2,20,21For example, a retrospective analysis of 207 medical records of patients with onychomycosis who completed a full course of treatment with oral antifungal and/or an antifungal nail lacquer, found longer time to complete cure and higher recurrence rates among diabetes patients, lower cure rates and longer time to complete cure among F I G U R E 1 Clinical improvements following multi-session Nd:YAG 1064 nm treatment of mycotic nails.The toenails of the patients showed significant and moderate responses to treatment.Scoring Clinical Index for Onychomycosis (SCIO) scores before and 3 months after the last of the 8 treatment sessions are indicated.

F I G U R E 2
Higher response rates to laser therapy in patients with lower baseline onychomycosis severity.Mycotic nails were subjected to eight Nd:YAG 1064 nm laser treatment sessions over a 12-week period.Patients with nails showing any degree of visual improvement 6 months after the start of treatment were categorised by baseline Scoring Clinical Index for Onychomycosis (SCIO) score.