ORIGINAL
ARTICLE
Fractional carbon-dioxide (CO2) laser-assisted topical therapy for the treatment of onychomycosis Anil Kumar Bhatta, MD, Uma Keyal, MD, Xin Huang, PhD, and Jing Jun Zhao, PhD Shanghai, China Background: Inability of topical medications to penetrate via nail plate brings a great challenge to clinicians in treating onychomycosis. Furthermore, oral medications are not appropriate for all patients because of drug interactions, adverse effects, and contraindications. Objective: We sought to evaluate the clinical efficacy of fractional carbon-dioxide laser-assisted topical therapy for onychomycosis. Methods: In total, 75 patients with 356 onychomycotic nails confirmed by mycologic examination were included in this study. All the affected nails received 3 sessions of laser therapy at 4-week intervals and once-daily application of terbinafine cream for 3 months. Results: In all, 94.66% and 92% of the treated patients were potassium hydroxide and culture negative, respectively, after 3 months of treatment. However, only 84% and 80% were potassium hydroxide and culture negative, respectively, at 6 months of follow-up. Using Scoring Clinical Index for Onychomycosis electronic calculator, 73.33% of the patients scored higher than 6 and 26.66% of the patients scored 6 or less. Those who scored more than 6 were evaluated clinically and 98.18% of them showed response to treatment at 3 months and 78.18% of them at 6 months of follow-up. Limitation: Lack of control group and short duration of follow-up are limitations. Conclusions: Fractional carbon-dioxide laser therapy combined with topical antifungal was found to be effective in the treatment of onychomycosis. However, randomized clinical studies are needed before it can be widely used in clinics. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.12.002.) Key words: dermatophytes; fractional laser; onychomycosis; topical therapy.
O
nychomycosis, a fungal infection of the nail, is considered one of the most prevalent disorders of the nail. It occurs after primary infection of the nail bed, which may lead to subungual hyperkeratosis.1 Other than a cosmetic concern, onychomycosis is also frequently associated with tinea pedis, which can result in serious secondary infections such as osteomyelitis and cellulitis, particularly in diabetic patients.
From the Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine. Drs Bhatta and Keyal contributed equally to this article. Supported by the Natural Science Foundation of Science and Technology Commission of Shanghai Municipality (No.13ZR1437900). Presented orally at the sixth Five Continent Congress for Aesthetic and Laser Medicine, Cannes, France, September 3-6, 2015, and as a poster at the 24th European Academy of Dermatology and Venereology Congress, Copenhagen, Denmark, October 7-11, 2015.
Abbreviations used: CO2: DLSO: KOH: Nd:YAG: PSO: SCIO: SWO: TDO:
carbon dioxide distal lateral subungual onychomycosis potassium hydroxide neodymium:yttrium-aluminium-garnet proximal subungual onychomycosis Scoring Clinical Index for Onychomycosis superficial white onychomycosis total dystrophic onychomycosis
Conflicts of interest: None declared. Accepted for publication December 1, 2015. Reprint requests: Xin Huang, PhD, Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Putuo District, Shanghai China. E-mail: [email protected]. Published online February 9, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.12.002
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Etiologically, dermatophytes such as Trichophyton white onychomycosis [SWO], and total dystrophic rubrum and T mentagrophytes account for 80% to onychomycosis [TDO]) were considered for treat90% of all cases.2 Other causative organisms are ment. Only those affected nails that were positive nondermatophyte molds and yeasts. Candida for both potassium hydroxide (KOH) and culture albicans accounts for approximately 70% of were included in the study. Shanghai Tongji onychomycosis caused by yeasts. The predisposing Hospital Ethics Committee approved the research factors include advanced age, diabetes, peripheral (trial no. 244) and the research was registered vascular disease, low im(no. ChiCTR-OOC-14005547) mune status, HIV, obesity, in China Clinical Trials CAPSULE SUMMARY and smoking. Registry, a World Health The available treatment Organizationerecognized orTreatment options for onychomycosis options for onychomycosis ganization. are limited. are topical drugs such as ciclopirox, amorolfine, efiFractional carbon-dioxide laser-assisted naconazole, or tavaborole topical therapy provides an alternative to Scoring Clinical Index for in mild cases and systemic effectively treat onychomycosis. Onychomycosis drugs such as terbinafine, The Scoring Clinical Index This technique provides new treatment fluconazole, itraconazole, for Onychomycosis (SCIO) options for this condition. or griseofulvin in severe (range 1-30) was calculated cases.3 Topical antifungals using the clinical index are often ineffective because component and the growth of their inability to penetrate via nail plate. Systemic component in the following equation6: treatments, although effective, have limited applii1½ð2fÞð3fÞ=2 h cation because of adverse effects such as hepatoðd=3Þ3f ðf þ hð3 fÞÞ toxicity and potential drug interactions, especially Where d = depth of involvement, f = clinical form, in patients with comorbidities. Moreover, successful and h = degree of hyperkeratosis. therapy of onychomycosis has at least a 20% to 25% 4 We used an electronic calculator for SCIO and rate of relapse or reoccurrence. Therefore, many found that only 20 of 75 patients scored 1 to 6 and in vitro and in vivo therapeutic trials are being would receive topical treatment, whereas 55 patients conducted in a search of a safe and effective scored 6 to 30 indicating they would require systemic alternative therapy. therapy, combination therapy, or nail avulsion. Recently, photodynamic therapy and laser-based treatments have been explored as a possible alternative treatment for onychomycosis. LongKOH preparation and fungal culture pulse 1064-nm neodymium:yttrium-aluminiumFungal examination was done at the beginning of garnet (Nd:YAG) laser, diode laser, Q-switched treatment, at 3 months, and at 6 months. KOH Nd:YAG laser, titanium:sapphire laser, and shortpreparation showing septate hyphae or pseudohypulse Nd:YAG 1064-nm laser have all been phae was considered positive. Sabouraud dextrose studied and found to be safe and effective for agar medium was used for culture. treating onychomycosis. In our study we used fractional carbon-dioxide (CO2) laser and topical Photography terbinafine to treat onychomycosis. The fractional Photographs were taken using the same camera CO2 laser systems were developed to maximize the settings, lighting, nail position, and background effect of ablative laser therapies and minimize side on a digital single-lens camera (Power Shot, G12 effects.5 lens, 35 zoom, 10 megapixel [Canon, Tokyo, Japan]). Photographs were taken at the beginning of treatment, and at first, second, third, and sixth METHODS months. Patient selection Topical anesthesia In total, 75 patients with 356 onychomycotic Before laser therapy, 5% lidocaine cream (Beijing nails were enrolled in the study. Both fingernails Ziguang Zhiyao Youxian Co) was applied under and toenails with all 4 types of onychomycosis occlusion on the infected nail and periungual area (distal lateral subungual onychomycosis [DLSO], for 30 minutes. proximal subungual onychomycosis [PSO], superficial d
d
d
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Table I. Patient characteristics Total no. of patients
75
Sex
Age, y
Affected nails
Comorbid condition
Male
Female
#60
[60
Fingernails
Toenails
Diabetic
Liver cirrhosis
33 (44%)
42 (56%)
55 (73.33%)
20 (26.66%)
73 (20.50%)
283 (79.50%)
3
1
Fig 1. Nails before and after fractional carbon-dioxide laser treatment. There was substantial improvement in the nails 6 months after treatment. DLSO, Distal lateral subungual onychomycosis; PSO, proximal subungual onychomycosis; SWO, superficial white onychomycosis; TDO, total dystrophic onychomycosis.
Laser treatment All the infected nails were treated with fractional CO2 laser (2030CI, Wuhan Qi Zhi Laser Technology Co) using pulse energy of 99 mJ, a density of 410
spots/cm2, pulse interval of 0.5 mm, pulse duration of 0.1 milliseconds, and a rectangular spot size of 2to 10-mm length and 0.6- to 5-mm breadth. These parameters were chosen after a few clinical trials
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Fig 1. (continued).
with different parameters. Depending on the severity of the lesions, 2 to 6 passes were given at the same site in static operating mode over the affected area including 1-mm normal-appearing areas around them. Altogether 3 sessions of laser therapy were given, each at 4-week intervals.
software (SAS 9.4, SAS Institute Inc, Cary, NC). P value of less than .05 was considered to be significant.
RESULTS
Topical antifungal Patients were prescribed 1% terbinafine cream to apply once daily for 3 months.
Of 87 patients who were initially enrolled, 12 did not complete the study. Among 75 patients who completed the study (Table I), culture was positive for T rubrum in 35, T mentagrophytes in 2, C albicans in 23, C tropicalis in 3, C krusei in 4, Aspergillus niger in 5, and A fumigatus in 3 patients. The duration of disease ranged from 2 months to 40 years, with a mean duration of 6.4 years. All 4 types of onychomycosis were involved in the study with 36 patients having DLSO, 27 TDO, 4 PSO, and 8 SWO.
Statistical analysis Data were analyzed by x 2 test, Fisher exact test, Cochran-Mantel-Haenszel test, independent 2sample t test, and Wilcoxon rank sum test using
Clinical evaluation Clinical improvement (Fig 1) was evaluated as complete response, significant response ([60% improvement), moderate response (20%-60%
Pain assessment Pain experienced by patients was quantified using visual analog scale from 0 to 10, where ‘‘0’’ indicates no pain and ‘‘10’’ indicates worst possible pain.
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Fig 2. Evaluation of treatment clinical response after 6 months of treatment with fractional carbon-dioxide laser. NA, No response.
Bhatta et al 5
Fig 4. Comparison of treatment clinical response among different types of onychomycosis after 6 months of treatment with fractional carbon-dioxide laser. DLSO, Distal lateral subungual onychomycosis; NA, no response; PSO, proximal subungual onychomycosis; SWO, superficial white onychomycosis; TDO, total dystrophic onychomycosis.
patients (92%) and 60 patients (80%) were both KOH and culture negative at 3 months and 6 months, respectively. Subjective evaluation Subjective evaluation was done by the patients at 6 months of follow-up and reported as very satisfied, satisfied, slightly satisfied, and not satisfied by 50, 8, 10, and 7 patients, respectively (Fig 3). Fig 3. Evaluation of treatment response based on patient satisfaction after 6 months of treatment with fractional carbon-dioxide laser.
improvement), and no response (\20% improvement) in 11 (14.66%), 44 (58.66%), 19 (25.33%), and 1 (1.33%) patient, respectively, at 3 months of followup; and in 25 (33.33%), 30 (40%), 5 (6.66%), and 15 (20%) patients, respectively, at 6 months of followup (Fig 2). Mycologic evaluation In all, 71 patients (94.66%) were KOH negative and 69 patients (92%) culture negative at 3 months of treatment. Nevertheless at the 6-month follow-up, only 63 patients (84%) were KOH negative and 60 patients (80%) were culture negative because of recurrence of disease in few patients. In all, 69
Comparative evaluation among 4 different types of onychomycosis The treatment response among different types of onychomycosis was compared (Fig 4) and evaluated at 6 months of follow-up as complete response, significant response, moderate response, and no response. The maximum number of patients showing complete response was 17 patients with DLSO followed by 2 patients with TDO, 5 with SWO, and 3 with PSO. Similarly, the maximum number of patients showing significant response was 13 patients with DLSO, followed by 11 patients with TDO, 3 with SWO, and 1 with PSO. The number of patients showing moderate response was 2, 3, 0, and 0 for DLSO, TDO, SWO, and PSO, respectively. Similarly, the number of patients showing no response was 4, 11, 0, and 0 for DLSO, TDO, SWO, and PSO, respectively.
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Table II. Comparison of 2 groups according to influencing factors DLSO, n = 36
Age, y Mean 6 SD Sex Male, n (%) Female, n (%) Duration of disease, mo Mean 6 SD SCIO Mean 6 SD Microscopic improvement KOH at first visit Negative n (%) Positive n (%) KOH after 12 wk Negative n (%) Positive n (%) KOH after 6 mo Negative n (%) Positive n (%) Culture reports First visit Trichophyton rubrum n (%) Trichophyton mentagrophytes n (%) Candida albicans n (%) Candida tropicalis n (%) Candida krusei n (%) Aspergillus niger n (%) Aspergillus fumigatus n (%) After 12 wk Negative n (%) Candida albicans n (%) After 6 mo Negative n (%) Trichophyton rubrum n (%) Trichophyton mentagrophytes n (%) Candida albicans n (%) Candida krusei n (%)
TDO, n = 27
44.83 6 16.68
49.48 6 17.92
16 (44.44) 20 (55.56)
Statistics
P value
t = 1.06
.2931
9 (33.33) 18 (66.67)
x 2 = 0.80
.3724
67.19 6 94.11
105.11 6 102.22
Z = 2.06
.0397
10.24 6 5.58
17.42 6 7.87
t = 4.24
\.0001
0 (0.00) 36 (100.00)
0 (0.00) 27 (100.00)
35 (97.22) 1 (2.78)
24 (88.89) 3 (11.11)
x 2 = 0.67
.4120
33 (91.67) 3 (8.33)
18 (66.67) 9 (33.33)
x 2 = 6.25
.0124
18 1 11 2 1 3 0
9 0 11 1 3 1 2
(33.33) (0.00) (40.74) (3.70) (11.11) (3.70) (7.41)
x 2 = 7.08
.3135
35 (97.22) 1 (2.78)
24 (88.89) 3 (11.11)
x 2 = 1.77
.1830
33 0 0 3 0
15 3 1 5 1
x 2 = 13.02
.0427
(50.00) (2.78) (30.56) (5.56) (2.78) (8.33) (0.00)
(91.67) (0.00) (0.00) (8.33) (0.00)
(55.56) (11.11) (3.70) (18.52) (3.70)
1.0000
DLSO, Distal lateral subungual onychomycosis; KOH, potassium hydroxide; SCIO, Scoring Clinical Index for Onychomycosis; TDO, total dystrophic onychomycosis.
Comparative evaluation between the 2 most common types of onychomycosis Because DLSO and TDO are the 2 most common types of onychomycosis, we statistically compared the effectiveness of therapy on these types on the basis of age and sex of patients, duration of disease, mycologic examination, SCIO, and clinical and subjective evaluation and found that the response in DLSO was superior to TDO (Tables II and III). SCIO evaluation The SCIO was evaluated using SCIO electronic calculator.6 Of 75 patients, 55 patients scored higher than 6 and 20 patients scored 6 or less. Those who scored greater than 6 were evaluated clinically for
treatment response. The number of patients showing complete, significant, moderate, and no response was 3, 35, 16, and 1, respectively, at 3 months and 13, 23, 7, and 12, respectively, at 6 months. On average, 98.18% of patients showed response to treatment at 3 months and 78.18% at 6 months. The results emphasize that patients who were candidate for systemic therapy according to the SCIO ([6) showed good clinical response to the laser-assisted topical treatment. Pain evaluation Pain experienced during laser therapy was assessed by visual analog scale. The mean visual analog scale score for pain was 1.93. As reported
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Table III. Comparison of clinical improvement and subjective evaluation between 2 groups Clinical improvement at 3 mo Complete response Significant response Moderate response No response Effective, % Clinical improvement at 6 mo Complete response Significant response Moderate response No response Effective, % Satisfaction evaluation Very satisfied Satisfied Slightly satisfied Not satisfied Effective, %
DLSO, n = 36
TDO, n = 27
Statistics
P value
6 (16.67) 24 (66.67) 5 (13.89) 1 (2.78) 83.33
1 (3.70) 14 (51.85) 12 (44.44) 0 (0.00) 55.56
x 2 = 5.36
.0206
x 2 = 5.74
.0166
17 (47.22) 13 (36.11) 2 (5.56) 4 (11.11) 83.33
2 (7.41) 11 (40.74) 3 (11.11) 11 (40.74) 48.15
x 2 = 13.10
.0003
x 2 = 8.68
.0032
27 (75.00) 4 (11.11) 5 (13.89) 0 (0.00) 86.11
12 (44.44) 3 (11.11) 5 (18.52) 7 (25.93) 55.56
x 2 = 9.87
.0017
x 2 = 7.20
.0073
Efficacy = (complete response 1 significant response)/total cases 3 100. Satisfaction = (extremely satisfied 1 very satisfied 1 satisfied)/total cases 3 100. DLSO, Distal lateral subungual onychomycosis; TDO, total dystrophic onychomycosis.
Table IV. Effectiveness of different treatment modalities in past and current studies Treatment method
Efficacy
Topical7
Oral7
16%-46%
38%-76%
by the patients, treatments were well tolerated by most of them. Although some patient experienced mild pain during laser treatment, no adverse events such as bleeding or oozing were reported. Complications such as bacterial infections or contact dermatitis were also not reported.
DISCUSSION Onychomycosis is the most common nail disorder in adults, accounting for up to 50% of all nail diseases and evidence suggests that incidence of onychomycosis is increasing.1 Therapeutic options for the treatment of onychomycosis include palliative care, mechanical or chemical debridement, topical and systemic antifungal agents, and various combinations of these modalities. Treatment of advanced onychomycosis is timeconsuming, is cost-intensive, and has relatively high failure rates. Even potent systemic antimycotics delivered over a period of several months have cure rates of only 40% to 80%.7 Moreover, systemic drugs are associated with side effects. Headache, rash, and gastrointestinal symptoms were reported in about 7% of patients treated with itraconazole8
Oral 1 topical7
Laser treatment9
71%-86%
33%-70%
Current study
80%
and about 5% of patients treated with fluconazole experienced nausea, headache, pruritus, and liver enzyme abnormalities.7 Now, many laser systems have been studied for the treatment of onychomycosis and were found to be effective.9 Lim et al10 used fractional CO2 laser and a topical antifungal to treat toenail onychomycosis and found it to be effective. In our study, too, using fractional CO2 laser and topical antifungal cream, of 75 patients, 71 were KOH negative and 69 were culture negative after 12 weeks of treatment. However, at 6 months of follow-up, only 63 patients remained KOH negative and 60 remained culture negative. The patients not showing mycologic cure were mostly those who had C albicans grown in the culture. This could be because of terbinafine’s poor efficacy against Candida. Meral and colleagues11 reported the fungicidal effect of Nd:YAG laser on C albicans. In another in vitro study, the diode laser Noveon (870/930 nm; Nomir Medical Technologies, Inc, Woodmere, NY) was found to have a fungicidal and bactericidal effect on Staphylococcus aureus, Escherichia coli,
8 Bhatta et al
C albicans, and T rubrum.12 The successful use of lasers largely depends on the wavelength, output power, pulse duration, exposure time, spot size, type, and color of the targeted tissue.13 Laser light causes local hyperthermia, destruction of pathogenic micro-organisms, and stimulation of the reparative process.14 Studies of different treatment modalities for onychomycosis to date are summarized in Table IV. The studies showed that the best response is seen with combination therapy (topical plus oral), followed by oral therapy, then laser therapy and at last topical therapy. To be noted is that our study and other similar studies have shown laser-assisted topical therapy could be as effective as combination therapy. Moreover, laser-assisted topical therapy has many advantages over combination therapy, such as no serious adverse effects, comparatively short treatment course, use in patients with comorbid conditions, and no risk of development of resistance.
Conclusion Laser treatment of onychomycosis has satisfactory results. It can treat different types of onychomycosis safely and effectively, and is especially suitable for older patients with low immunity or liver and renal dysfunction who are not appropriate candidates for systemic antifungal agents. Thus, it can be considered an alternative treatment modality. Unfortunately, there are few studies demonstrating efficacy and no randomized controlled clinical trials comparing efficacy with oral antifungal agents. We believe that this area of study will continue to expand and provide new insights of treatment options for onychomycosis. We believe that sufficient evidence is still lacking for laser therapy for routine treatment of onychomycosis, as has been advertised and
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propagated by laser manufacturers and franchises. Randomized clinical studies are urgently needed. REFERENCES 1. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43(4): 641-648. 2. Thomas J, Jacobson GA, Narkowicz CK, Peterson GM, Burnet H, Sharpe C. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35(5):497-519. 3. Baran R, Gupta AK, Pierard GE. Pharmacotherapy of onychomycosis. Expert Opin Pharmacother. 2005;6(4):609-624. 4. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol. 2010;62:411-414. 5. Tierney EP, Eisen RF, Hanke CW. Fractionated CO2 laser skin rejuvenation. Dermatol Ther. 2011;24:41-53. 6. Sergeev AY, Gupta AK, Sergeev YV. The Scoring Clinical Index for Onychomycosis (SCIO Index). Skin Therapy Lett. 2002;1(7 Suppl):6-7. 7. Scher RK. Onychomycosis: therapeutic update. J Am Acad Dermatol. 1999;40(6 pt 2):S21-S26. 8. Gupta AK, De Doncker P, Scher RK, et al. Itraconazole for the treatment of onychomycosis. Int J Dermatol. 1998;37:303-308. 9. Bhatta AK, Huang X, Keyal U, Zhao JJ. Laser treatment for onychomycosis: a review. Mycoses. 2014;57:734-740. 10. Lim EH, Kim HR, Park YO, et al. Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream. J Am Acad Dermatol. 2014;70(5):918-923. 11. Meral G, Tasar F, Kocagoz S, Sener C. Factors affecting the antibacterial effects of Nd:YAG laser in vivo. Lasers Surg Med. 2003;32:197-202, 22. 12. Bornstein E, Hermans W, Gridley S, Manni J. Near-infrared photo inactivation of bacteria and fungi at physiologic temperatures. Photochem Photobiol. 2009;85:1364-1374. 13. Brooks SG, Ashley S, Fisher J, et al. Exogenous chromophores for the argon and Nd:YAG lasers: a potential application to laser-tissue interactions. Lasers Surg Med. 1992;12(3): 294-302. 14. Dayan S, Damrose JF, Bhattacharyya TK, et al. Histological evaluations following 1,064-nm Nd:YAG laser resurfacing. Lasers Surg Med. 2003;33:126-131.
ARTICLE
Fractional carbon-dioxide (CO2) laser-assisted topical therapy for the treatment of onychomycosis Anil Kumar Bhatta, MD, Uma Keyal, MD, Xin Huang, PhD, and Jing Jun Zhao, PhD Shanghai, China Background: Inability of topical medications to penetrate via nail plate brings a great challenge to clinicians in treating onychomycosis. Furthermore, oral medications are not appropriate for all patients because of drug interactions, adverse effects, and contraindications. Objective: We sought to evaluate the clinical efficacy of fractional carbon-dioxide laser-assisted topical therapy for onychomycosis. Methods: In total, 75 patients with 356 onychomycotic nails confirmed by mycologic examination were included in this study. All the affected nails received 3 sessions of laser therapy at 4-week intervals and once-daily application of terbinafine cream for 3 months. Results: In all, 94.66% and 92% of the treated patients were potassium hydroxide and culture negative, respectively, after 3 months of treatment. However, only 84% and 80% were potassium hydroxide and culture negative, respectively, at 6 months of follow-up. Using Scoring Clinical Index for Onychomycosis electronic calculator, 73.33% of the patients scored higher than 6 and 26.66% of the patients scored 6 or less. Those who scored more than 6 were evaluated clinically and 98.18% of them showed response to treatment at 3 months and 78.18% of them at 6 months of follow-up. Limitation: Lack of control group and short duration of follow-up are limitations. Conclusions: Fractional carbon-dioxide laser therapy combined with topical antifungal was found to be effective in the treatment of onychomycosis. However, randomized clinical studies are needed before it can be widely used in clinics. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.12.002.) Key words: dermatophytes; fractional laser; onychomycosis; topical therapy.
O
nychomycosis, a fungal infection of the nail, is considered one of the most prevalent disorders of the nail. It occurs after primary infection of the nail bed, which may lead to subungual hyperkeratosis.1 Other than a cosmetic concern, onychomycosis is also frequently associated with tinea pedis, which can result in serious secondary infections such as osteomyelitis and cellulitis, particularly in diabetic patients.
From the Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine. Drs Bhatta and Keyal contributed equally to this article. Supported by the Natural Science Foundation of Science and Technology Commission of Shanghai Municipality (No.13ZR1437900). Presented orally at the sixth Five Continent Congress for Aesthetic and Laser Medicine, Cannes, France, September 3-6, 2015, and as a poster at the 24th European Academy of Dermatology and Venereology Congress, Copenhagen, Denmark, October 7-11, 2015.
Abbreviations used: CO2: DLSO: KOH: Nd:YAG: PSO: SCIO: SWO: TDO:
carbon dioxide distal lateral subungual onychomycosis potassium hydroxide neodymium:yttrium-aluminium-garnet proximal subungual onychomycosis Scoring Clinical Index for Onychomycosis superficial white onychomycosis total dystrophic onychomycosis
Conflicts of interest: None declared. Accepted for publication December 1, 2015. Reprint requests: Xin Huang, PhD, Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Putuo District, Shanghai China. E-mail: [email protected]. Published online February 9, 2016. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.12.002
1
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Etiologically, dermatophytes such as Trichophyton white onychomycosis [SWO], and total dystrophic rubrum and T mentagrophytes account for 80% to onychomycosis [TDO]) were considered for treat90% of all cases.2 Other causative organisms are ment. Only those affected nails that were positive nondermatophyte molds and yeasts. Candida for both potassium hydroxide (KOH) and culture albicans accounts for approximately 70% of were included in the study. Shanghai Tongji onychomycosis caused by yeasts. The predisposing Hospital Ethics Committee approved the research factors include advanced age, diabetes, peripheral (trial no. 244) and the research was registered vascular disease, low im(no. ChiCTR-OOC-14005547) mune status, HIV, obesity, in China Clinical Trials CAPSULE SUMMARY and smoking. Registry, a World Health The available treatment Organizationerecognized orTreatment options for onychomycosis options for onychomycosis ganization. are limited. are topical drugs such as ciclopirox, amorolfine, efiFractional carbon-dioxide laser-assisted naconazole, or tavaborole topical therapy provides an alternative to Scoring Clinical Index for in mild cases and systemic effectively treat onychomycosis. Onychomycosis drugs such as terbinafine, The Scoring Clinical Index This technique provides new treatment fluconazole, itraconazole, for Onychomycosis (SCIO) options for this condition. or griseofulvin in severe (range 1-30) was calculated cases.3 Topical antifungals using the clinical index are often ineffective because component and the growth of their inability to penetrate via nail plate. Systemic component in the following equation6: treatments, although effective, have limited applii1½ð2fÞð3fÞ=2 h cation because of adverse effects such as hepatoðd=3Þ3f ðf þ hð3 fÞÞ toxicity and potential drug interactions, especially Where d = depth of involvement, f = clinical form, in patients with comorbidities. Moreover, successful and h = degree of hyperkeratosis. therapy of onychomycosis has at least a 20% to 25% 4 We used an electronic calculator for SCIO and rate of relapse or reoccurrence. Therefore, many found that only 20 of 75 patients scored 1 to 6 and in vitro and in vivo therapeutic trials are being would receive topical treatment, whereas 55 patients conducted in a search of a safe and effective scored 6 to 30 indicating they would require systemic alternative therapy. therapy, combination therapy, or nail avulsion. Recently, photodynamic therapy and laser-based treatments have been explored as a possible alternative treatment for onychomycosis. LongKOH preparation and fungal culture pulse 1064-nm neodymium:yttrium-aluminiumFungal examination was done at the beginning of garnet (Nd:YAG) laser, diode laser, Q-switched treatment, at 3 months, and at 6 months. KOH Nd:YAG laser, titanium:sapphire laser, and shortpreparation showing septate hyphae or pseudohypulse Nd:YAG 1064-nm laser have all been phae was considered positive. Sabouraud dextrose studied and found to be safe and effective for agar medium was used for culture. treating onychomycosis. In our study we used fractional carbon-dioxide (CO2) laser and topical Photography terbinafine to treat onychomycosis. The fractional Photographs were taken using the same camera CO2 laser systems were developed to maximize the settings, lighting, nail position, and background effect of ablative laser therapies and minimize side on a digital single-lens camera (Power Shot, G12 effects.5 lens, 35 zoom, 10 megapixel [Canon, Tokyo, Japan]). Photographs were taken at the beginning of treatment, and at first, second, third, and sixth METHODS months. Patient selection Topical anesthesia In total, 75 patients with 356 onychomycotic Before laser therapy, 5% lidocaine cream (Beijing nails were enrolled in the study. Both fingernails Ziguang Zhiyao Youxian Co) was applied under and toenails with all 4 types of onychomycosis occlusion on the infected nail and periungual area (distal lateral subungual onychomycosis [DLSO], for 30 minutes. proximal subungual onychomycosis [PSO], superficial d
d
d
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VOLUME jj, NUMBER j
Table I. Patient characteristics Total no. of patients
75
Sex
Age, y
Affected nails
Comorbid condition
Male
Female
#60
[60
Fingernails
Toenails
Diabetic
Liver cirrhosis
33 (44%)
42 (56%)
55 (73.33%)
20 (26.66%)
73 (20.50%)
283 (79.50%)
3
1
Fig 1. Nails before and after fractional carbon-dioxide laser treatment. There was substantial improvement in the nails 6 months after treatment. DLSO, Distal lateral subungual onychomycosis; PSO, proximal subungual onychomycosis; SWO, superficial white onychomycosis; TDO, total dystrophic onychomycosis.
Laser treatment All the infected nails were treated with fractional CO2 laser (2030CI, Wuhan Qi Zhi Laser Technology Co) using pulse energy of 99 mJ, a density of 410
spots/cm2, pulse interval of 0.5 mm, pulse duration of 0.1 milliseconds, and a rectangular spot size of 2to 10-mm length and 0.6- to 5-mm breadth. These parameters were chosen after a few clinical trials
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Fig 1. (continued).
with different parameters. Depending on the severity of the lesions, 2 to 6 passes were given at the same site in static operating mode over the affected area including 1-mm normal-appearing areas around them. Altogether 3 sessions of laser therapy were given, each at 4-week intervals.
software (SAS 9.4, SAS Institute Inc, Cary, NC). P value of less than .05 was considered to be significant.
RESULTS
Topical antifungal Patients were prescribed 1% terbinafine cream to apply once daily for 3 months.
Of 87 patients who were initially enrolled, 12 did not complete the study. Among 75 patients who completed the study (Table I), culture was positive for T rubrum in 35, T mentagrophytes in 2, C albicans in 23, C tropicalis in 3, C krusei in 4, Aspergillus niger in 5, and A fumigatus in 3 patients. The duration of disease ranged from 2 months to 40 years, with a mean duration of 6.4 years. All 4 types of onychomycosis were involved in the study with 36 patients having DLSO, 27 TDO, 4 PSO, and 8 SWO.
Statistical analysis Data were analyzed by x 2 test, Fisher exact test, Cochran-Mantel-Haenszel test, independent 2sample t test, and Wilcoxon rank sum test using
Clinical evaluation Clinical improvement (Fig 1) was evaluated as complete response, significant response ([60% improvement), moderate response (20%-60%
Pain assessment Pain experienced by patients was quantified using visual analog scale from 0 to 10, where ‘‘0’’ indicates no pain and ‘‘10’’ indicates worst possible pain.
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Fig 2. Evaluation of treatment clinical response after 6 months of treatment with fractional carbon-dioxide laser. NA, No response.
Bhatta et al 5
Fig 4. Comparison of treatment clinical response among different types of onychomycosis after 6 months of treatment with fractional carbon-dioxide laser. DLSO, Distal lateral subungual onychomycosis; NA, no response; PSO, proximal subungual onychomycosis; SWO, superficial white onychomycosis; TDO, total dystrophic onychomycosis.
patients (92%) and 60 patients (80%) were both KOH and culture negative at 3 months and 6 months, respectively. Subjective evaluation Subjective evaluation was done by the patients at 6 months of follow-up and reported as very satisfied, satisfied, slightly satisfied, and not satisfied by 50, 8, 10, and 7 patients, respectively (Fig 3). Fig 3. Evaluation of treatment response based on patient satisfaction after 6 months of treatment with fractional carbon-dioxide laser.
improvement), and no response (\20% improvement) in 11 (14.66%), 44 (58.66%), 19 (25.33%), and 1 (1.33%) patient, respectively, at 3 months of followup; and in 25 (33.33%), 30 (40%), 5 (6.66%), and 15 (20%) patients, respectively, at 6 months of followup (Fig 2). Mycologic evaluation In all, 71 patients (94.66%) were KOH negative and 69 patients (92%) culture negative at 3 months of treatment. Nevertheless at the 6-month follow-up, only 63 patients (84%) were KOH negative and 60 patients (80%) were culture negative because of recurrence of disease in few patients. In all, 69
Comparative evaluation among 4 different types of onychomycosis The treatment response among different types of onychomycosis was compared (Fig 4) and evaluated at 6 months of follow-up as complete response, significant response, moderate response, and no response. The maximum number of patients showing complete response was 17 patients with DLSO followed by 2 patients with TDO, 5 with SWO, and 3 with PSO. Similarly, the maximum number of patients showing significant response was 13 patients with DLSO, followed by 11 patients with TDO, 3 with SWO, and 1 with PSO. The number of patients showing moderate response was 2, 3, 0, and 0 for DLSO, TDO, SWO, and PSO, respectively. Similarly, the number of patients showing no response was 4, 11, 0, and 0 for DLSO, TDO, SWO, and PSO, respectively.
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Table II. Comparison of 2 groups according to influencing factors DLSO, n = 36
Age, y Mean 6 SD Sex Male, n (%) Female, n (%) Duration of disease, mo Mean 6 SD SCIO Mean 6 SD Microscopic improvement KOH at first visit Negative n (%) Positive n (%) KOH after 12 wk Negative n (%) Positive n (%) KOH after 6 mo Negative n (%) Positive n (%) Culture reports First visit Trichophyton rubrum n (%) Trichophyton mentagrophytes n (%) Candida albicans n (%) Candida tropicalis n (%) Candida krusei n (%) Aspergillus niger n (%) Aspergillus fumigatus n (%) After 12 wk Negative n (%) Candida albicans n (%) After 6 mo Negative n (%) Trichophyton rubrum n (%) Trichophyton mentagrophytes n (%) Candida albicans n (%) Candida krusei n (%)
TDO, n = 27
44.83 6 16.68
49.48 6 17.92
16 (44.44) 20 (55.56)
Statistics
P value
t = 1.06
.2931
9 (33.33) 18 (66.67)
x 2 = 0.80
.3724
67.19 6 94.11
105.11 6 102.22
Z = 2.06
.0397
10.24 6 5.58
17.42 6 7.87
t = 4.24
\.0001
0 (0.00) 36 (100.00)
0 (0.00) 27 (100.00)
35 (97.22) 1 (2.78)
24 (88.89) 3 (11.11)
x 2 = 0.67
.4120
33 (91.67) 3 (8.33)
18 (66.67) 9 (33.33)
x 2 = 6.25
.0124
18 1 11 2 1 3 0
9 0 11 1 3 1 2
(33.33) (0.00) (40.74) (3.70) (11.11) (3.70) (7.41)
x 2 = 7.08
.3135
35 (97.22) 1 (2.78)
24 (88.89) 3 (11.11)
x 2 = 1.77
.1830
33 0 0 3 0
15 3 1 5 1
x 2 = 13.02
.0427
(50.00) (2.78) (30.56) (5.56) (2.78) (8.33) (0.00)
(91.67) (0.00) (0.00) (8.33) (0.00)
(55.56) (11.11) (3.70) (18.52) (3.70)
1.0000
DLSO, Distal lateral subungual onychomycosis; KOH, potassium hydroxide; SCIO, Scoring Clinical Index for Onychomycosis; TDO, total dystrophic onychomycosis.
Comparative evaluation between the 2 most common types of onychomycosis Because DLSO and TDO are the 2 most common types of onychomycosis, we statistically compared the effectiveness of therapy on these types on the basis of age and sex of patients, duration of disease, mycologic examination, SCIO, and clinical and subjective evaluation and found that the response in DLSO was superior to TDO (Tables II and III). SCIO evaluation The SCIO was evaluated using SCIO electronic calculator.6 Of 75 patients, 55 patients scored higher than 6 and 20 patients scored 6 or less. Those who scored greater than 6 were evaluated clinically for
treatment response. The number of patients showing complete, significant, moderate, and no response was 3, 35, 16, and 1, respectively, at 3 months and 13, 23, 7, and 12, respectively, at 6 months. On average, 98.18% of patients showed response to treatment at 3 months and 78.18% at 6 months. The results emphasize that patients who were candidate for systemic therapy according to the SCIO ([6) showed good clinical response to the laser-assisted topical treatment. Pain evaluation Pain experienced during laser therapy was assessed by visual analog scale. The mean visual analog scale score for pain was 1.93. As reported
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Table III. Comparison of clinical improvement and subjective evaluation between 2 groups Clinical improvement at 3 mo Complete response Significant response Moderate response No response Effective, % Clinical improvement at 6 mo Complete response Significant response Moderate response No response Effective, % Satisfaction evaluation Very satisfied Satisfied Slightly satisfied Not satisfied Effective, %
DLSO, n = 36
TDO, n = 27
Statistics
P value
6 (16.67) 24 (66.67) 5 (13.89) 1 (2.78) 83.33
1 (3.70) 14 (51.85) 12 (44.44) 0 (0.00) 55.56
x 2 = 5.36
.0206
x 2 = 5.74
.0166
17 (47.22) 13 (36.11) 2 (5.56) 4 (11.11) 83.33
2 (7.41) 11 (40.74) 3 (11.11) 11 (40.74) 48.15
x 2 = 13.10
.0003
x 2 = 8.68
.0032
27 (75.00) 4 (11.11) 5 (13.89) 0 (0.00) 86.11
12 (44.44) 3 (11.11) 5 (18.52) 7 (25.93) 55.56
x 2 = 9.87
.0017
x 2 = 7.20
.0073
Efficacy = (complete response 1 significant response)/total cases 3 100. Satisfaction = (extremely satisfied 1 very satisfied 1 satisfied)/total cases 3 100. DLSO, Distal lateral subungual onychomycosis; TDO, total dystrophic onychomycosis.
Table IV. Effectiveness of different treatment modalities in past and current studies Treatment method
Efficacy
Topical7
Oral7
16%-46%
38%-76%
by the patients, treatments were well tolerated by most of them. Although some patient experienced mild pain during laser treatment, no adverse events such as bleeding or oozing were reported. Complications such as bacterial infections or contact dermatitis were also not reported.
DISCUSSION Onychomycosis is the most common nail disorder in adults, accounting for up to 50% of all nail diseases and evidence suggests that incidence of onychomycosis is increasing.1 Therapeutic options for the treatment of onychomycosis include palliative care, mechanical or chemical debridement, topical and systemic antifungal agents, and various combinations of these modalities. Treatment of advanced onychomycosis is timeconsuming, is cost-intensive, and has relatively high failure rates. Even potent systemic antimycotics delivered over a period of several months have cure rates of only 40% to 80%.7 Moreover, systemic drugs are associated with side effects. Headache, rash, and gastrointestinal symptoms were reported in about 7% of patients treated with itraconazole8
Oral 1 topical7
Laser treatment9
71%-86%
33%-70%
Current study
80%
and about 5% of patients treated with fluconazole experienced nausea, headache, pruritus, and liver enzyme abnormalities.7 Now, many laser systems have been studied for the treatment of onychomycosis and were found to be effective.9 Lim et al10 used fractional CO2 laser and a topical antifungal to treat toenail onychomycosis and found it to be effective. In our study, too, using fractional CO2 laser and topical antifungal cream, of 75 patients, 71 were KOH negative and 69 were culture negative after 12 weeks of treatment. However, at 6 months of follow-up, only 63 patients remained KOH negative and 60 remained culture negative. The patients not showing mycologic cure were mostly those who had C albicans grown in the culture. This could be because of terbinafine’s poor efficacy against Candida. Meral and colleagues11 reported the fungicidal effect of Nd:YAG laser on C albicans. In another in vitro study, the diode laser Noveon (870/930 nm; Nomir Medical Technologies, Inc, Woodmere, NY) was found to have a fungicidal and bactericidal effect on Staphylococcus aureus, Escherichia coli,
8 Bhatta et al
C albicans, and T rubrum.12 The successful use of lasers largely depends on the wavelength, output power, pulse duration, exposure time, spot size, type, and color of the targeted tissue.13 Laser light causes local hyperthermia, destruction of pathogenic micro-organisms, and stimulation of the reparative process.14 Studies of different treatment modalities for onychomycosis to date are summarized in Table IV. The studies showed that the best response is seen with combination therapy (topical plus oral), followed by oral therapy, then laser therapy and at last topical therapy. To be noted is that our study and other similar studies have shown laser-assisted topical therapy could be as effective as combination therapy. Moreover, laser-assisted topical therapy has many advantages over combination therapy, such as no serious adverse effects, comparatively short treatment course, use in patients with comorbid conditions, and no risk of development of resistance.
Conclusion Laser treatment of onychomycosis has satisfactory results. It can treat different types of onychomycosis safely and effectively, and is especially suitable for older patients with low immunity or liver and renal dysfunction who are not appropriate candidates for systemic antifungal agents. Thus, it can be considered an alternative treatment modality. Unfortunately, there are few studies demonstrating efficacy and no randomized controlled clinical trials comparing efficacy with oral antifungal agents. We believe that this area of study will continue to expand and provide new insights of treatment options for onychomycosis. We believe that sufficient evidence is still lacking for laser therapy for routine treatment of onychomycosis, as has been advertised and
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propagated by laser manufacturers and franchises. Randomized clinical studies are urgently needed. REFERENCES 1. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43(4): 641-648. 2. Thomas J, Jacobson GA, Narkowicz CK, Peterson GM, Burnet H, Sharpe C. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35(5):497-519. 3. Baran R, Gupta AK, Pierard GE. Pharmacotherapy of onychomycosis. Expert Opin Pharmacother. 2005;6(4):609-624. 4. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol. 2010;62:411-414. 5. Tierney EP, Eisen RF, Hanke CW. Fractionated CO2 laser skin rejuvenation. Dermatol Ther. 2011;24:41-53. 6. Sergeev AY, Gupta AK, Sergeev YV. The Scoring Clinical Index for Onychomycosis (SCIO Index). Skin Therapy Lett. 2002;1(7 Suppl):6-7. 7. Scher RK. Onychomycosis: therapeutic update. J Am Acad Dermatol. 1999;40(6 pt 2):S21-S26. 8. Gupta AK, De Doncker P, Scher RK, et al. Itraconazole for the treatment of onychomycosis. Int J Dermatol. 1998;37:303-308. 9. Bhatta AK, Huang X, Keyal U, Zhao JJ. Laser treatment for onychomycosis: a review. Mycoses. 2014;57:734-740. 10. Lim EH, Kim HR, Park YO, et al. Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream. J Am Acad Dermatol. 2014;70(5):918-923. 11. Meral G, Tasar F, Kocagoz S, Sener C. Factors affecting the antibacterial effects of Nd:YAG laser in vivo. Lasers Surg Med. 2003;32:197-202, 22. 12. Bornstein E, Hermans W, Gridley S, Manni J. Near-infrared photo inactivation of bacteria and fungi at physiologic temperatures. Photochem Photobiol. 2009;85:1364-1374. 13. Brooks SG, Ashley S, Fisher J, et al. Exogenous chromophores for the argon and Nd:YAG lasers: a potential application to laser-tissue interactions. Lasers Surg Med. 1992;12(3): 294-302. 14. Dayan S, Damrose JF, Bhattacharyya TK, et al. Histological evaluations following 1,064-nm Nd:YAG laser resurfacing. Lasers Surg Med. 2003;33:126-131.
