Comparative study of fractional carbon dioxide laser with oral itraconazole versus oral itraconazole alone in the treatment of onychomycosis – A randomised controlled trial

INTRODUCTION

Onychomycosis, a fungal infection of the nail unit, is caused by dermatophytes, non-dermatophytic moulds and yeasts. The incidence of onychomycosis in India’s general population ranges from 0.5% to 5%.^[1] Dermatophytes are responsible for about 50% of fingernail infections and 90% of toenail infections.^[2] Due to its widespread occurrence, onychomycosis represents a significant health concern, leading to adverse effects such as pain, discomfort and physical disability. In addition, the psychological and social challenges associated with onychomycosis can negatively impact one’s professional and social interactions. Onychoscopy, the examination of the nail unit using a dermoscope, is a non-invasive method that helps to differentiate onychomycosis from other nail disorders. Various dermoscopic patterns seen in onychomycosis include onycholysis, jagged edges with spikes, chromonychia, transverse and longitudinal striations, distal irregular termination and ruin appearance.^[3]

Several oral and topical antifungal treatments are available for onychomycosis. Oral antifungal therapy is the gold standard in both children and adults due to its shorter treatment duration and higher cure rates, as compared to topical treatment. It is particularly recommended for cases where 50% or more of the nail is affected, multiple nails are infected, the nail matrix is involved or dermatophytoma is present.^[4] Amongst the oral therapies, itraconazole has a higher affinity for keratin with a broad spectrum of activity that can be used on an intermittent basis due to its fast absorption, effective concentration and prolonged presence in the nail plate. However, absorption of itraconazole is erratic, leading to wide fluctuations in blood concentration. This issue has been addressed with super bioavailable itraconazole (itraconazole SB), which features a non-pellet formulation containing hypromellose phthalate (HPMCP). This pH-dependent polymeric matrix improves intestinal absorption and dissolution, thereby increasing bioavailability and allowing for a reduced dosage.^[5]

In addition to topical, oral, chemical and mechanical treatments, laser therapy is emerging as a promising option for onychomycosis.^[6] Laser therapy operates on the principle of selective photo-thermolysis, with chitin augmenting the photothermal effect on fungi.^[1] Various lasers, such as fractional carbon dioxide (CO₂) lasers, short-pulsed 1064 nm neodymium-doped yttrium aluminium garnet (Nd:YAG) lasers, long-pulsed 1064 nm Nd:YAG lasers and near-infrared diode lasers, have been used for this purpose. Combining laser treatment with topical and systemic therapies has shown increased effectiveness, particularly in patients with systemic diseases such as diabetes, liver and kidney diseases.^[6]

However, studies demonstrating the efficacy of fractional CO₂ lasers and itraconazole in treating onychomycosis are limited. Therefore, we conducted a randomised controlled trial to assess the efficacy of itraconazole SB when used in conjunction with fractional CO₂ laser, clinically and dermoscopically, in the treatment of onychomycosis.

MATERIAL AND METHODS

A single centre, randomised controlled clinical trial was conducted at the outpatient department (OPD) of dermatology in a tertiary hospital at Bhavnagar from October 2022 to December 2023, after clearance from the Institutional Ethics Committee and informed written consent from the patient. The sample size was calculated using OpenEpi, Version 3, Open-source calculator – SSCohort. It was calculated with two-sided significance level (1-a) at 95%; power of the study (1-b, % chance of detecting) at 80%; ratio of unexposed/exposed at 1; approximate value of efficacy of oral itraconazole pulse therapy at 71 %; and approximate value of efficacy of fractional CO₂ laser treatment at 84%. The estimated sample size was 326 nails (163 each group); however, over the stipulated time, we were able to enroll 264 nails (132 each group).

Clinically diagnosed patients (>18 years of age) with fingernail onychomycosis were assessed for eligibility and included in the study. Pregnant and lactating females; patients with other nail disorders such as psoriasis, chronic eczema, lichen planus and subungual haematoma; those who had used topical and systemic antifungal in the preceding 3 months; those with a history of liver disease (transaminases more than thrice the normal range), cardiac disease patients and those with nail polish were excluded.

Clinical and dermoscopic pictures of the afflicted fingernails were taken at the time of enrollment, together with demographic information and pertinent medical history. Dermoscopic images were taken by DL-5 DERMLITE DERMOSCOPE at ×10 magnification attached to a smartphone. Routine blood investigations (complete blood count, renal function test and liver function test) were done at the time of enrolment and repeated at 3 months.

A computerised random number generator was used to assign patients to either Group A or Group B. Group A patients received fractional CO₂ laser with oral itraconazole SB 100 mg twice a day for 7 days of pulse therapy every month for 2 months. Group B patients received oral itraconazole SB 100 mg twice a day for 7 days of pulse therapy every month for 2 months. A total of three laser therapy sessions were given at an interval of 4 weeks, with deep mode, triple-pass, pulse energy of 10-15mJ, a density of 10%, pulse duration of 0.5ms, and pulse width of 0.5-1.0mm. Post laser treatment, ice application for 5-10 minutes was done in case of pain and erythema.

Patients were followed up every month till 3 months with clinical assessment using onychomycosis severity index (OSI), and dermoscopic evaluation. Clinical response was graded as no improvement, mild improvement, moderate improvement, near complete, and complete improvement. Side effects of fractional CO₂ laser and itraconazole SB were monitored based on the patient’s complaints at every follow-up visit.

All data were entered in a Microsoft Excel^® sheet and statistical analysis was carried out using GraphPad INSTAT software version 3.06. Categorical data were expressed as frequencies, while quantitative data were expressed as means. Comparisons between the two groups were done using Mann–Whitney test (non-parametric distribution) and unpaired t-test (parametric distribution). The differences in the parameters within a group at different time points was compared using the Wilcoxon-matched pair test (non-parametric distribution). Proportional data were calculated by the Z-test using the Z-score calculator for 2 population proportions (https://www.socscistatistics.com/tests/ztest/). A p value of < 0.05 was considered statistically significant, and p < 0.001 was considered highly significant.

RESULTS

A total of 60 patients (264 nails) fulfilling the eligibility criteria were enrolled in our study, with 30 patients in each group. Amongst them, 22 patients (101 nails) and 21 patients (102 nails) completed the study in group A and group B, respectively. Of the 60 patients enrolled, 46 were females and 14 were males, with the majority in the age group of 40–59 years [Table 1]. The most common type of onychomycosis was distal lateral subungual onychomycosis (DLSO), followed by total dystrophic onychomycosis (TDO). Of these 60 patients, 23 (38.34%) had dermatophytic infection at other sites.

The mean reduction in OSI in group A was 3.53±5.09, while in group B it was 0.86±4.22 [Table 2]. This difference was found to be statistically significant (p<0.0043). Significant improvement was seen in DLSO on treatment with combination therapy (P = 0.0004). A higher mean reduction in OSI was seen with combination laser therapy in patients with multiple afflicted nails, diabetics, hypertensives, and housewives. Patients more than 60 years of age showed a significantly better response with combination therapy (p=0.0006) [Table 3].

We also studied the various onychoscopic findings [Figure 1] and observed that chromonychia and onycholysis were most common features while transverse striations and ruin patterns were least commonly seen [Table 4]. Onychoscopy at 3 months showed significant improvement in group A as compared to group B, with respect to various changes including onycholysis, spiked pattern, chromonychia, longitudinal and transverse striations.

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Figure 1:

Dermoscopic findings seen in onychomycosis (Dermlite DL5, × 10 polarised mode). (a) Red arrow - black colour, White arrow - brown colour, Yellow arrow - distal irregular termination, Dark blue arrow - dryness and scaling, Black arrow - ruin pattern, Black circle - spiked pattern. (b) Red arrow - brown colour, Yellow arrow - orange colour, White arrow - white colour, Black arrow - dryness and scaling, White circle - transverse striation, Red square -onycholysis with spiked pattern. (c) Red arrow - distal irregular termination, White arrow - orange colour, Black arrow - dryness and scaling, Black square - transverse striations, White circle - spiked pattern with chromonychia.

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DISCUSSION

Up to 50% of nail disorders are caused by onychomycosis, considered the most prevalent nail disorder in adults with an increasing incidence.^[7] Topical and systemic antifungals, mechanical or chemical debridement, and various combinations of these are the treatment modalities commonly used. However, the cure rates with systemic therapy range from 40% to 80%.^[8] Furthermore, side effects linked to systemic medications such as rashes, headaches and gastrointestinal problems, are reported in up to 7% of itraconazole-treated patients.^[9] Super-bioavailable itraconazole offers an advantage by overcoming the challenges of conventional itraconazole, such as variations in bioavailability and requirement of food for optimal absorption, due to a consistent nonpellet formulation that contains HPMCP, a pH-dependent polymeric matrix, that improves intestinal absorption and dissolution. Thus, it requires lesser dosage and has better tolerability as compared to conventional itraconazole.^[5,10]

Laser therapy when combined with topical or oral antifungals can enhance the efficacy of these treatments. Fractional CO₂ exerts its effect in onychomycosis through “selective photo-thermolysis,” delivering a burst of laser light energy, creating microthermal zones that rapidly heat and kill the mycelium. Furthermore, the nail tissue is exfoliated by the fractional CO₂ laser, which encourages remodelling, eliminating the environment conducive to fungal growth.^[11] As a result, it improves patient compliance by reducing medication duration and increasing antifungal effectiveness.

Of the 60 patients (264 nails) enrolled, 22 patients (101 nails) and 21 patients (102 nails) completed the study protocol in group A and group B, respectively. Majority of the patients were females (76.67%) within the age group of 40–59 years (55%). This is consistent with the findings of Ranjan et al.^[1] and Bhatta et al.^[10] Amongst the various clinical types, DLSO and TDO were the most common types of onychomycosis observed, aligning with the findings from other published studies.^[1,10,12] Overall, nails treated with combination of fractional CO₂ laser and oral itraconazole showed a significantly better response as reflected in the mean reduction in OSI scores in both the groups [Figures 2 and 3]. This could be attributed to the ablative and thermal effects of fractional CO₂ laser, which provides a faster cure compared to oral or topical therapy alone. Ranjan et al.^[1] compared monthly fractional CO₂ laser with 1% terbinafine cream application twice daily versus oral itraconazole pulse therapy and found the mean reduction in OSI to be 8.65±7.09 and 7.36±6.65, respectively (p=0.157). Increased efficacy of combined therapy was also supported by Bashir et al.,^[11] who reported a 77.3% improvement with three weekly sessions of fractional CO₂ laser therapy combined with topical luliconazole 5% lotion twice daily for 3 months.

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Figure 2:

Right middle finger (a) before treatment (b) at 3^rd month after combined therapy (c) dermoscopic image before treatment (d) dermoscopic image at 3^rd month after combined therapy. (Dermlite DL5, ×10 polarised mode).

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Figure 3:

Right thumb (a) before treatment (b) at 3^rd month after itraconazole pulse therapy (c) dermoscopic image before treatment (d) dermoscopic image at 3^rd month after itraconazole pulse therapy (Dermlite DL5, ×10 polarised mode).

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We found the response to combination therapy to be better amongst the elderly (>60 years) having diabetes mellitus and hypertension. This could be particularly beneficial in reducing the required dosage of oral medication and providing a faster cure. Patients with multiple affected nails responded significantly better to combination therapy, showing an impressive mean reduction in OSI of 5.39±6.70 as compared to baseline. In stark contrast, those treated solely with itraconazole pulse therapy experienced a deterioration, with a mean OSI change of −0.46±5.47 (p=0.0028). This compelling evidence highlights that when multiple nails are involved, the addition of laser therapy to the oral treatment regimen can be remarkably beneficial with increased patient satisfaction due to effective and faster results. Combination therapy also led to a statistically significant improvement in nails with subungual hyperkeratosis (>2 mm), resulting in a substantial decrease in the OSI (p=0.0014).

Interestingly, males exhibited a comparable response to both oral therapy and combination therapy, with a greater reduction in OSI amongst farmers and diamond workers as compared to office workers. On the other hand, females, particularly houseworkers, experienced a marked improvement with combination therapy as compared to oral therapy alone. By accelerating the cure, reducing medication requirements and enhancing the overall quality of life, this approach can significantly improve compliance. This is especially advantageous for women balancing demanding roles at home and work.

We also documented various onychoscopic patterns in onychomycosis, including onycholysis, spiked pattern, chromonychia, transverse and longitudinal striations, distal irregular termination, dryness and scaling and subungual hyperkeratosis with a ruin pattern. Amongst these, chromonychia was the most common finding, aligning with the results reported by Vasava et al.^[13] and Kaur et al.^[2] Reassessment at 3 months showed a greater improvement across all onychoscopic patterns in Group A as compared to Group B. Significant improvement was particularly noted in onycholysis, spike pattern, chromonychia and both longitudinal and transverse striations. These findings can be utilised to assess the improvement in onychomycosis. Onychoscopy holds significant potential of diagnosing and monitoring various nail disorders, offering clinicians an efficient method to evaluate treatment efficacy and disease progression.

Importantly, no side effects were noted in any patient receiving either fractional CO₂ laser or oral itraconazole SB during or after the treatment. After the laser treatment, a temporary grid pattern was observed, which disappeared gradually during the monthly follow-up visits.

CONCLUSION

Our study demonstrated that combination of fractional CO₂ laser and oral itraconazole is significantly more effective as compared to oral therapy alone, particularly in patients with multiple affected nails, older patients, those with co-morbidities (diabetes, hypertension) and housewives. Furthermore, onychoscopy can be exceptionally useful in evaluating treatment response in onychomycosis by allowing a detailed visualisation of nail structures, enabling clinicians to monitor improvement and detect subtle changes throughout the course of therapy. This can enhance the accuracy of treatment assessment and overall patient care. Importantly, fractional CO₂ laser therapy proved to be safe, with no side effects observed. In addition, oral itraconazole SB showed no side effects, unlike conventional itraconazole, which may cause nausea and diarrhoea.