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Abstract
Background: Cutaneous leishmaniasis (CL) is a vector-borne protozoal disease. Antimonial drugs remain the first-line treatment for CL despite the widespread drug resistance and high incidence of side effects. The present study aimed to compare the efficacy and safety of traditional intralesional sodium stibogluconate (SSG) alone and its combinations with trichloroacetic acid (TCA) 50% and fractional carbon dioxide (CO2) laser for the treatment of CL. Materials and Methods: An interventional study was carried out on 25 CL patients. In each patient, three lesions were assigned to treatment either by SSG alone (GI), SSG plus TCA 50% (GII), or SSG plus fractional CO2 laser (GIII). The overall clinical improvement and changes in the sizes of lesions and scars were assessed and compared among the three groups. Results: GIII patients had significantly lower treatment sessions as compared to GI patients (3.6 ± 1.29 versus 4.04 ± 2.11, P = 0.042). Moreover, GII and GIII patients had significantly shorter healing times when compared with GI (3.63 ± 1.35 and 3.46 ± 1.25, respectively, versus 4.0 ± 2.15 weeks, P = 0.019). Also, it was shown that GIII patients had significantly lower scar scores (1.40 ± 1.52) when compared with GI (3.00 ± 0.0) and GII (2.80 ± 1.10), P = 0.017. Conclusions: Intralesional SSG with TCA 50% is more effective than SSG alone and is comparable to SSG and fractional CO2 combination in the treatment of CL with better safety profile and patient satisfaction.
Keywords: Cutaneous leishmaniasis, fractional CO2 laser, sodium stibogluconate, trichloroacetic acid
Introduction 
Leishmaniasis is a vector-borne protozoal disease caused by more than 20 leishmania species. Through their bites, the infected female sandflies transmit the leishmania parasites from reservoirs (humans, desert rats, and dogs) to humans.[1] Leishmaniasis may present in cutaneous (CL), visceral (kala-azar), or mucocutaneous forms.[2],[3],[4] Temperature and humidity are the two most important climatic factors for sandfly survival, development, and activity. Higher temperatures are likely to accelerate the maturation of the parasite, thereby increasing the risk of infection. CL lesions develop within a period of weeks to several months after exposure to a sandfly bite. The bite presents as an erythematous papule that gradually enlarges to the size of a nodule and eventually becomes a crusted ulcer with raised and indurated borders.[4],[5],[6]
Several factors should be considered when choosing the optimal treatment for CL, including the leishmania species size, number, location of the lesions, availability of an appropriate treatment, and the experience of the medical personnel.[7] Pentavalent antimonials, for example, sodium stibogluconate (SSG) and meglumine antimoniate remain the first choice treatment for CL in most countries.[8] SSG is the most commonly used pentavalent anti-monial. Its exact mechanism of action is still obscure but it may inhibit the parasite's glycolytic and fatty acid oxidative activity resulting in diminished synthesis of adenosine triphosphate (ATP) and guanosine triphosphate (GTP).[9]
Trichloroacetic Acid (TCA) is a low-cost topical agent that induces the skin stress response resulting in the reconstitution of the epidermis and dermis through the wound healing process. This ability makes TCA peeling a potential therapeutic option for CL.[10] Combined CL treatment with meglumine antimoniate and TCA 50% was much more effective than meglumine antimoniate alone.[11]
Fractional CO2 laser alone has shown promising results against CL. Its thermolysis effect may inhibit and degrade the parasites; the channels it creates may allow for deeper penetration and greater bioavailability of the applied drug (referred to as laser-assisted drug delivery), and the multiple columns of epidermal and dermal microscopic thermal wounds (microthermal zones) exert an anti-scarring effect.[12],[13],[14] In a study by Asilian et al.,[15] continuous CO2 laser was found to be superior to meglumine antimoniate in the treatment of CL in terms of efficacy, healing time, and side effects.
The present study aimed to compare the efficacy and safety of traditional intralesional SSG alone and its combination with TCA 50% and fractional CO2 laser in the treatment of CL.
Materials and Methods The present interventional study was conducted during the period from November 2016 to February 2019. The study was approved by the local research ethical committee. A written informed consent was taken from all participants after a proper explanation of the study. Photography and biopsy to confirm the diagnosis were obtained from patients before enrollment.
The study included 25 consecutive patients with biopsy-confirmed CL with facial lesions away from the eyelids ≥2 cm. Patients were excluded if they had topical or systemic treatment for CL, immunosuppressive therapy, or if they showed serious side effects for any of the study medications. Before treatment, all patients were submitted to careful history taking and thorough dermatological examination. A 5-mm punch biopsy was taken from CL lesions and stained by Hematoxylin and Eosin and Giemsa stains to confirm the diagnosis before the study enrollment. In every patient, three comparable lesions of CL were assigned to treatment by SSB alone in one lesion (GI), SSG plus topical TCA 50% in the second lesion (GII), and by a combination of SSG and fractional CO2 laser in the third lesion (GIII).
Intralesional SSG was injected from the intact margin in an amount enough to cause complete blanching of the lesion and 1 mm of its surrounding normal skin. The injected amount was 100–500 mg (1–5 ml SSG) per session. The procedure was performed once weekly for 8 weeks or until complete healing.
Topical TCA was applied to the lesion with a cotton swab till frosting occurred. When the lesion was frosted, the acid was neutralized by water, and the scar site was covered with Vaseline. Patients were asked to apply zinc oxide ointment twice daily and not to remove the crustations or the peeled layers of the skin. The procedure was repeated once a week for 8 weeks or until complete healing.
The fractional CO2 laser was applied using SmartXide DOT (DEKA, Italy) with the following parameters: power: 15 watts; stack: 2; dwelling time: 500 μsec; spacing: 1000 μm and pass: 1. The procedure was performed for 2 sessions at 2-week intervals. Patients were asked to apply zinc oxide ointment twice daily after the laser session.
Patients in the three groups were followed up weekly and any side effects or complications were recorded. Standard digital photographs were taken before and after treatment sessions. The degree of clinical improvement of the lesions was evaluated with the aid of photos. All patients were asked to record their opinion regarding the efficacy and safety of the three therapeutic approaches. Their level of satisfaction with treatment response was graded as poor response (0%–25%), good response (25%–50%), very good response (50%–80%), and excellent response (80%–100%). Clinical assessment of the scar was done using Vancouver Scar Scale which assesses four variables: vascularity, height/thickness, pliability, and pigmentation.[16]
Data presented by this study were statistically analyzed using the statistical package for social sciences (SPSS) version 20 (IBM, Chicago, Illinois, USA). Quantitative data were expressed as mean ± standard deviation (SD) and compared using one-way ANOVA with post-hoc analysis while qualitative data were expressed as frequency and percentage and compared using the Chi-square test. P value <0.05 was considered statistically significant.
Results The present study included 25 male CL patients with an age of 23.88 ± 3.96 years and a disease duration of 2.6 ± 1.27 months. Types and locations of CL lesions are shown in [Table 1]. Histopathological analysis of the 25 skin biopsies of patients showed histopathological alterations in the superficial and deep dermis [Figure 1]. Comparison between the studied groups regarding treatment and outcome parameters revealed that GIII patients had significantly lower treatment sessions as compared to GI patients (3.6 ± 1.29 versus 4.04 ± 2.11, P = 0.042). Moreover, GII and GIII patients had significantly shorter healing time when compared with GI (3.63 ± 1.35 and 3.46 ± 1.25, respectively, versus 4.0 ± 2.15 weeks, P = 0.019). Also, it was shown that GIII patients had significantly lower scar score (1.40 ± 1.52) when compared with GI (3.00 ± 0.0) and GII (2.80 ± 1.10), P = 0.017 [Table 2].
Figure 1: (a) The epidermis shows marked hyperkeratosis and acanthosis, the dermis shows dense dermal infiltrate of lymphocytes, histocytes, and plasma cells with intracytoplasmic rounded formations inside the histocytes suggestive of amastigotes (hematoxylin and eosin stain ×400) (b) Amastigotes are visible in the cytoplasm of some histocytes (Giemsa stain ×400)Comparison between the studied groups regarding the reported side effects showed that GII and GIII patients had significantly lower edema and total side effects when compared with GI [Table 3]. Also, it was shown that GII and GIII patients reported significantly higher rate of excellent satisfaction with treatment outcome when compared with GI patients (28.0 and 48.0%, respectively, versus 0%, P = 0.002) [Table 4]. The treatment outcome of the three groups of lesions is shown in [Figure 2], [Figure 3], [Figure 4].
Figure 2: (a) CL lesion of the left ankle before treatment by intralesional SSG alone (b) same lesion after treatment, with the appearance of satellite nodules after 3 sessions
Figure 3: (a) The same patient with other CL lesion on the left foot before treatment by TCA + SSG (b) the same lesion after treatment
Figure 4: (a) The same patient with CL lesion on the right elbow before treatment by fractional laser + SSG (b) same lesion after treatment Discussion CL is endemic in 88 countries with an estimated 1.5–2 million new cases every year and a total of 12 million cases worldwide.[17] Antimonial agents remain the first-line treatment for CL despite the widespread drug resistance and high incidence of side effects. However, over the past decade, multiple clinical trials have been performed to find alternatives.[18]
Our current results indicate that the combined treatment of SSG with TCA 50% or fractional CO2 laser is much more effective than SSG alone in terms of required treatment sessions, healing time, scar score, reported side effects, and patient satisfaction. These conclusions are supported by multiple previous reports.
Iraji et al.[19] successfully used CO2 laser plus TCA for the treatment of CL. Moreover, Jaffary et al.[20] confirmed that the combination therapy of intralesional glucantime and TCA 50% or fractional CO2 laser is much more effective than intralesional glucantime alone in the treatment of CL with fewer side effects. Interestingly, the study of Nilforoushzadeh et al.[21] noted that TCA 50% is comparable to CO2 laser with the advantage of low cost.
In another study, Hilerowicz et al.[22] used fractional ablative CO2 laser followed by topical SSG application and showed that the side effects were minimal and self-limited. The same study showed better treatment tolerance and patient satisfaction with treatment outcomes with fractional ablative CO2 laser as compared to topical SSG application.
In conclusion, the present study found that SSG with TCA 50% is more effective than SSG alone and is comparable to SSG and fractional CO2 combination in the treatment of CL with better safety profile and patient satisfaction.
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Conflicts of interest
There are no conflicts of interest.
References 
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