Anthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL. From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno) histopathological analyses were taken prior to EC (1st), after wound closure (2nd) and after 6 months (3rd). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43. 1 d) and II (54 patients, 42 d; p = 0. 83). In patients with Leishmania-positive 2nd biopsies DAC N-055 caused a more rapid wound epithelialization (37. 2 d vs. 58. 3 d; p = 0. 08). Superinfections occurred in both groups at the same rate (8. 8%). Except for one patient, reulcerations (10. 2% in group I, 18. 5% in group II; p = 0. 158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes. Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant future studies on the activity of DAC N-055. ClinicalTrails. gov NCT00947362
Human cutaneous leishmaniasis (CL) is a chronic infection caused by protozoan parasites of the genus Leishmania that are transmitted by sand fly vectors. In countries of the Near and Middle East such as Afghanistan Leishmania (L.) major and L. tropica are the principal parasite species that account for the development of the typical plaque-like or ulcerative skin lesions. The dermal lesions persist for months or even years, but eventually heal on their own (reviewed in [1]–[4]). However, the healing process can be complicated by superinfections, satellite lesions or a sporotrichoïd course of infection [1], [5]–[7] and commonly leads to disfiguring and socially stigmatizing scars [8]. From L. major mouse infections and from analyses of skin biopsies of patients suffering from L. major CL there is evidence that non-healing, ulcerative CL is linked to a diminished expression of genes involved in tissue remodeling [9] as well as to an upregulation of Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [10]. Afghanistan is the country with the highest prevalence of CL with an estimated annual incidence of new active cases of more than 200,000 [11]. During a prevalence survey in Kabul, 2. 7% of the population were found to have active disease in 2001 [12], which equals roughly 70,000 inhabitants and made Kabul the world capital of CL. The high prevalence of Phlebotomus sergenti and of L. tropica infections amongst humans accounts for the anthroponotic transmission mode of the disease in Kabul [12]–[14]. There is currently no standardized procedure for the management of CL following L. tropica or L. major infection. Whereas in the case of small or non-disfiguring lesions or in CL elicited by L. major a “wait and see” strategy can be practiced, ulcerative CL lesions leading to cosmetically relevant chronic wounds as well as lesions due to L. tropica infection usually require therapy. Local treatments recommended by WHO for the management of L. tropica infections include the intralesional injection of antimonials, the application of heat (thermotherapy, 50°C) or of liquid nitrogen (cryotherapy) [3]. In a randomized controlled trial (RCT) carried out in Kabul, thermotherapy using a radio-frequency generator was almost as effective as intralesionally administered sodium stibogluconate (SSG), leading to cure in 69. 4% compared to 75. 3% of the cases within 100 days after treatment initiation [15]. Other therapeutic strategies reported for L. tropica- or L. major-infected patients in Afghanistan include the use of oral hexadecylphosphocholin (miltefosine) or intravenous SSG [16], [17]. Overall, there is not only an urgent need for RCTs comparing the current therapeutic options for CL in the Old World [18], but also for the evaluation of novel treatments that are highly effective, well-tolerated, inexpensive and implementable in endemic countries [19]. A special pharmaceutical preparation of sodium chlorite (NaClO2) has been listed in the German Drug Codex as sodium chlorosum (DAC N-055) since 1990. It is produced in a chlorate-free manner by the reaction of chlorine dioxide (ClO2) with hydrogen peroxide (H2O2) under alkaline conditions and is saturated with carbonate. Besides the generation of NaClO2 the reaction of ClO2 and H2O2 presumably also leads to the formation of sodium salts of peroxychloric acid [20], [21]. In the presence of CO2/HCO3− and ClO2−, peroxychloric acid is thought to stabilize as catalase-resistant peroxide salts (i. e. NaO[O = ]COOClO2 and Na2Cl2O6) [22], in analogy to the reactions described for peroxynitrite [23]. The pharmaceutical monograph of DAC N-055 is based on a 12 mM NaClO2 solution (pH 10 to 11) containing 2. 4% glycerol, which in 1983 was approved by the German Health Authorities for the topical treatment of chronic wounds under the trade name of Oxoferin®. In 1989, the German Health Authorities banned the designation of tetrachlorodecaoxygen anions (TCDO; Cl4O10n−) as the active ingredient of Oxoferin®. A recent spectroscopic analysis of the water disinfectant HydroXan® [24], a compound similar to Oxoferin® (now Oxovasin®) and other commercial preparations of pharmaceutical NaClO2 (e. g. , Ryoxon®, Oxilium®, WF10, or Immunokine™), confirmed that there is no evidence for the existence of the previously postulated TCDO complex consisting of chlorine (IV) -oxide and physically bound molecular oxygen [25]. Witke et al. [24] proposed a peroxide structure of ([ClO2]2O-O[ClO2]2) 2− for their “TCDO” preparation. However, this structure does not explain the strong chlorate-like Raman band they found and is therefore much less likely than the chlorine peroxide compound resulting from a chlorite stabilisation of peroxychlorate (e. g. ([ClIIIO2]O-O[ClVO2]) 2−) [22]. Under acidic conditions (pH≤6), in the presence of heme (Fe3+) [26] or manganese (Mn3+) -containing porphyrins [27], [28] or after exposure to ultraviolet A radiation the chlorite and/or the chlorine peroxide compound contained in DAC N-055 will release ClO2 and/or singlet oxygen (1O2), both of which are strong microbicidal oxidants [29], [30]. During the past 30 years in vitro analyses, animal studies and clinical trials have shown that preparations of pharmaceutical NaClO2 not only exerted antiviral and antimicrobial effects [31]–[34], but also promoted tissue regeneration and wound healing following radiation, chemotherapeutic, ischemic, metabolic, or infectious injuries [35]–[39]. Although the oxidative processes and molecular mechanisms underlying these findings have not yet been defined in detail, pharmaceutical NaClO2 clearly promotes cell proliferation, hematopoiesis, and microcirculatory blood and oxygen supply, modulates the functions of immune cells, and limits inflammatory responses [40]–[44]. Based on the hypothesis that ulcerative CL results from a defective wound healing response, the main goal of our study was to evaluate the effect of a careful wound management on the course and outcome of human CL. In the reported clinical trial carried out in Kabul, skin lesions of patients with CL were subjected to bipolar high-frequency electrocauterization (EC) followed by moist wound treatment (MWT) with or without DAC N-055. This new concept for the therapy of CL as well as preliminary results were first presented during an expert meeting at the Institute Pasteur, Paris, in 2006 [45].
The primary objective of this study was to evaluate the clinical efficacy of a new protocol for the treatment of L. tropica CL, which consisted of EC followed by MWT in the presence (group I) or absence (group II) of 0. 045% DAC N-055 (which equals 5 mM pharmaceutical NaClO2). As secondary objectives we aimed to assess, whether continuous wound care might represent a valuable improvement of the therapy of CL compared to current anti-parasitic treatments and whether EC/MWT would positively influence the anti-leishmanial immune response and thereby helps to prevent relapses. Our hypothesis was that EC plus MWT would lead to an acceleration of primary wound closure as compared to previous results obtained with the standard intralesional SSG injection. Furthermore, we hypothesized that EC plus MWT with DAC N-055 will be superior to EC plus MWT with physiological saline solution. The study was performed as a two-armed, randomized, controlled, double-blinded, mono-centric clinical phase IIa trial at the Leishmania Clinic of the German Medical Service (GMS), Darwaze-e-Lahory, 1st district, Kabul, Afghanistan, from 2004 to 2007. Prior to the actual start of the trial, a pilot study at the GMS Leishmania clinic unexpectedly revealed that women and children, who were initially thought to be difficult to treat and follow for sociocultural reasons, were extremely reliable patients, who strictly observed their appointments and the medical instructions. On the other hand, the original assumption that a sufficiently high number of patients with non-ulcerated lesions can be recruited did not hold true. Therefore, in deviation from the original trial protocol, male or female patients of the GMS Clinic, 5 years of age or older, with non-ulcerated (papule/nodule) or ulcerated lesions (ulcer with or without crust) were eligible to the trial. Further inclusion criteria were the presence of at least one parasitologically confirmed CL lesion and no prior history of leishmaniasis and/or anti-parasitic treatment. Inhabitants of Kabul and its suburban areas were preferentially chosen in order to minimize bad compliance and drop-outs, as daily visits were needed during therapy. Exclusion criteria were the presence of CL lesion (s) on or immediately adjacent to the nose, lips or eyes; pregnancy; and any kind of serious comorbidities. In patients with more than one lesion, all lesions were subjected to the same randomly assigned treatment, but only one of them was selected as target lesion for the biopsies, the follow-up assessments and the final analysis. The study protocol of the trial (ClinicalTrials. gov NCT00947362) was reviewed and provisionally approved on July 28,2004, by the Ethics Committee of the University of Freiburg, Germany. Following two requested amendments, the full approval was issued on August 24,2004 and submitted to the Afghan Ministry of Public Health in Kabul, Afghanistan on November 6,2004. There were no Ethics Committees or International Review Panels according to Western standards at that time in Afghanistan. The study was conducted following the ethical principles provided by the Declaration of Helsinki. As practically all patients could neither read nor write, an informed oral consent was obtained from them after detailed explanation of the study protocol by the medical doctor before the start of the treatment. All medical services and drugs provided during the trial were free of charge for the patients. The patients received no remuneration. Prior to the treatment the medical history of each patient was taken and the present status of the lesion was recorded on a patient' s card according to GMS standards (portrait photo of the patient, sex, age; comorbidities; site, size, Giemsa smear result and wound status of the lesion). To document the lesion and scar development, digital photographs were taken before, throughout and after therapy during each visit of the patients. The inclusion of a scale in the photograph allowed calculating the wound area by digital analysis with the help of the DatInf® Image DB software (DatInf GmbH, Tübingen, Germany). After efficient cleaning of the skin with water and soap, the lesion site was disinfected with 70% ethanol and anesthetized with 1% lidocaine (AstraZeneca, Wedel, Germany) s. c. A 3 mm diameter punch biopsy (Stiefel Laboratorium GmbH, Offenbach, Germany) was taken from the edge of the lesion (1st biopsy) and processed as described in the section Parasitological Studies. Superficial coagulation and removal of lesion tissue was performed using bipolar high-frequency electrocauterization (EC; also termed high-frequency electrocoagulation) with the help of the electrosurgical Mini Cutter HMC 80 HF (max. current in the bipolar mode 70 mA, KLS Martin, Umkirch, Germany) constructed with a specially designed bi-polar angled forceps with a 2 mm distance holder. Superficial coagulation of the epidermis was carried out with the strongest relative current (position 10) for approximately 2 sec. A constantly renewed thin layer of physiological saline above the skin lesion prevented tissue carbonisation. After EC, a polyacrylate hydrogel with or without freshly prepared 0. 045% (w/w) pharmaceutical sodium chlorite (sodium chlorosum, DAC N-055, Waisenmedizin e. V. , Freiburg, Germany; formula and preparation of the gel see supporting information S3) was applied to the lesions with the help of a sterile plastic syringe without a needle to avoid the rapid decomposition of DAC N-055 after transition metal contact. The wounds were dressed with sterile gauze and fixed with a bandage rather than plaster wherever possible. The MWT dressing was replaced daily with a weekly pause on Fridays at the Leishmania Clinic of the GMS until wound closure was achieved; if necessary, gentle wound cleaning was performed. In case of clinical signs for a superinfection, a smear was taken, Gram stained and microscopically evaluated for the presence of bacteria and/or fungi. Systemic antibiotics were only given, if bacteria were detected and the wound infection was severe. Neither local nor systemic antifungal therapy was allowed to exclude anti-protozoal effects on the Leishmania infection. During the course of treatment Giemsa stainings of slit-skin smears were performed weekly. A 2nd and 3rd biopsy were taken after wound closure and 6 months later, respectively. The biopsies of the study patients were air-delivered with the help of diplomats and private passengers travelling from Kabul to Frankfurt/Main, Germany, and evaluated at the Department of Microbiology and Hygiene of the University Hospital of Freiburg or at the Microbiology Institute of the University Hospital Erlangen, Germany. The average transportation time was 4. 06±1. 90 days (mean ± SD). As primary outcome and end point for each patient within the study the time needed for complete epithelialization of the lesion wound was defined. The lesion status of all enrolled patients was routinely photo-documented when the MWT dressings were replaced and the number of healed wounds versus wounds that were still open was continuously recorded. As secondary outcome the parasite load within the lesion prior to the treatment start, at the time of wound closure and 6 months after wound healing was determined. In addition, adverse events such as bacterial or fungal superinfections of the wounds, the formation or scars and the rate of re-ulcerations were monitored during the treatment and follow-up period. Sample size was calculated based on the primary outcome (i. e. complete wound healing). Considering the results of an earlier wound healing trial with Oxoferin® in patients with venous, arterial or postoperative ulcers [35], a mean healing time of four weeks in the control patients (group II) and of two weeks in the patients treated with DAC N-055 (group I) was assumed, with the maximal time for endpoint analysis being 60 days. Based on these assumptions a number of 40 patients each was calculated to be necessary to obtain a power of 80% (significance level 5%). A presumed drop-out rate of 20% led to a minimum total number of 100 patients to be enrolled. The prolonged wound healing times observed during the later phase of the study (year 2006 and 2007; see results) did not invalidate the sample size calculation, as the follow-up period was adjusted accordingly, i. e. all patients were followed up until wound closure. In further specification of the original study protocol subjects were randomly assigned with the help of a GMS computer at a ratio of 1∶1 to group I (EC plus MWT with polyacrylate hydrogel including 0. 045% DAC N-055) and group II (EC plus MWT with polyacrylate hydrogel without DAC N-055). The participants, the medical personnel treating and evaluating the patients, the investigators analyzing the clinical course of treated lesions, as well as the lab members performing the parasitological analyses were blinded. The preparation of the two different gels (marked as jelly A and B), which could not be visually distinguished, was performed by a technician who was not involved in the treatment of patients. RS and KWS were responsible for the enrollment of the patients and their assignment to the treatment groups. All patient data were entered into Excel software (Microsoft) and statistically analyzed with SPSS (IBM® SPSS® Statistics version 20, SPSS Inc. , Chicago, IL, USA) or GraphPad Prism version 4. 0 (Graphpad Software Inc.). With respect to baseline and clinical data, the two randomized groups were compared using the Fisher' s Exact test, the Mann Whitney test, the t-test or the Pearson Chi-Square test. The analysis of primary as well as secondary outcomes was planned on an intention-to treat basis (ITT) in this phase IIa trial. As we excluded those patients, who were lost during the follow-up period, the analysis of efficacy was de facto a per-protocol (PP) analysis. To compare the healing curves for the two treatment groups, the non-parametric log-rank test (Mantel-Cox test) was used; the Kaplan-Meier method was applied to evaluate the absolute wound closure time. The evaluation of differences in the parasite load between the two groups was performed with the help of a t-test. All p values are two-sided and p<0. 05 was considered statistically significant.
As detailed in Fig. 1, a total of 135 CL patients with at least one lesion, which was confirmed to be Leishmania-positive by Giemsa smear analysis, were included in the study. 73 of them were randomized to group I, 62 to group II. Out of the 135 patients, 14 patients of group I and 8 patients of group II were retrospectively excluded due to deviations from the study protocol (e. g. missing documentation, wrong wound treatment or interruption of the treatment by the patient). Thus, a total of 113 patients (59 in group I and 54 in group II) completed the assigned treatment and therefore were included in the PP analysis. For the follow-up analysis 6 months after wound healing, only 70 patients could be included, as 21 patients of group I and 22 patients of group II did not observe their appointments (Fig. 1). Leishmania parasites were detected within all biopsies taken from the patients of group I and group II prior to treatment by (immuno) histology of formalin-fixed tissue (not shown). With the exception of a few samples secondarily contaminated by bacteria or fungi, all biopsies yielded the growth of Leishmania parasites. Genomic DNA was prepared from 58 parasite isolates, of which 28 were derived from group I and 30 from group II patients, covering the entire study period (11,11,21 or 15 isolates in the years 2004,2005,2006 or 2007, respectively). In each case L. tropica was identified as the underlying parasite species. Patients were enrolled from August 2004 until August 2007. The numbers of patients recruited per year were 19 (August–December 2004), 13 (January to December 2005), 29 (January to December 2006) and 52 (January to August 2007). The slow recruitment in 2005 and 2006 was due to a temporary lack of qualified personnel at the GMS. The baseline demographic characteristics, the localization and size of the lesion, the lesion type as well as the parasite load within the lesion before treatment start were comparable in the two treatment groups I and II (Tab. 1 and Fig. 2). The quantity of Leishmania parasites per gram tissue in the 1st biopsies was highly variable, ranging from 4. 42×103 to 8. 75×108 parasites/g in group I and from 8. 9×101 to 3. 71×109 parasites/g in group II, but was not significantly different between both treatment groups (Tab. 1 and Fig. 2). The fact that 0. 045% DAC N-055 (which equals 5 mM pharmaceutical NaClO2), showed beneficial effects especially in patients with high and persistent parasite loads, prompted us to investigate whether DAC N-055 has direct effects on extra- and/or intracellular L. tropica parasites. To this end, L. tropica promastigotes were cultured in the absence or presence of increasing concentrations of DAC N-055 (0. 4–400 µM). The data revealed a clear cytotoxic effect of DAC N-055 on promastigotes, with a half maximal effective concentration (EC50) of 13. 7 µM (Fig. 7A). Next, we analyzed whether this also holds true for intracellular L. tropica. Adherent human monocytes were infected with L. tropica promastigotes. Similar to the positive control IFN-γ, which is a known inducer of leishmanicidal activity in human mononuclear phagocytes [49], [50], DAC N-055 at concentrations of 40 to 400 µM that were non-toxic for the monocytes lowered the infection rate and blocked the replication of intracellular L. tropica parasites (Fig. 7B). Thus, the beneficial effect of DAC N-055 in human L. tropica CL might be partly related to its direct antileishmanial activity.
The molecular mechanisms that account for the accelerated wound healing following MWT are only partially understood. First, early studies in pigs and humans provided convincing evidence that the epithelialization of covered, moist wounds progressed twice as fast as of wounds exposed to air. In wounds kept moist the newly formed epidermal cell layer migrated above rather than through the fibrous tissue deposited on the dermis; formation of scab and eschar was virtually absent [59], [60]. Second, loss of the integrity of the epidermis causes the immediate generation of an electric current in the skin [61]. Recently, it was shown that electric fields of a comparable order of magnitude directly alter the movement of epithelial cells in vitro via modulation of Src and inositol-phospholipid signaling pathways [62]. It is conceivable that MWT helps to maintain an electric gradient in the wound and thereby accelerates the migration of immune and epithelial cells. Finally, it has been proposed that MWT and occlusive dressings support the accumulation of wound fluid [63], which contains a cocktail of growth factors and cytokines essential for the repair processes [64]. The EC, which we performed prior to the MWT, resembles a surgical debridement practiced on chronic wounds with areas of necrosis and heavy slough. Presumably, it had two major effects: it caused a reduction of the parasite load, due to the coagulation and physical removal of tissue by heating the lesions with a high-frequency current; and it created a fresh wound bed for subsequent granulation and epithelialization. Unlike to the radio-frequency-induced heat therapy (50°C), which also proved effective in endemic areas such as Iran and Afghanistan [15], [19], [65], the sensitivity of Leishmania parasites to temperatures above 39°C is not the primary mechanism of action of our EC approach. Considering the known tissue-regenerative activity of pharmaceutical NaClO2 [35]–[39], [65]–[67] and its cytotoxicity against extra- and intracellular L. tropica parasites (reported here), it was unexpected to see that the therapeutic benefit of including DAC N-055 in the EC/MWT protocol was confined to a subgroup of patients with a persistently high parasite loads in the 2nd biopsy and to the partial prevention of relapses. A plausible explanation is that EC/MWT alone already exerted a strong anti-parasitic and wound healing effect, which in most patients could not be further enhanced by the addition of DAC N-055. The current routine treatment for L. tropica-induced CL in Afghanistan consists of a course of intralesional or intramuscular injections of pentavalent antimony preparations (i. e. SSG or meglumine antimonate). To date, there is no RCT with a placebo group to directly support this standard therapy [19], [68], but clinical observations and two recent RCTs comparing antimony treatment and thermotherapy argue for the effectiveness of antimony in anthroponotic CL in Afghanistan [15], [65]. Nevertheless, there are several problems with the use of antimony-containing drugs. First, both the local and the systemic application can cause severe adverse reactions [69]. Second, the use of antimony has been linked to the emergence of drug-resistant parasites; antimony-resistant L. tropica strains and treatment failures have been reported from Iran [70]. Third, there have been recent incidences of limited supply and poor manufactural quality of antimony preparations in some countries [71], [72]. None of these concerns applies to our EC/MWT approach. The only possible side effects associated with MWT, especially if practiced with occlusive dressings, are superinfections and very rarely chloracne due to chlorine dioxide, which can be released from DAC N-055 under the acidic conditions of the skin. The incidence of superinfections, however, can be strongly reduced if a water-vapor permeable foil is used or the moist wound coverage is performed without foil as was the case in almost all of our patients. In the group of patients with MWT containing DAC N-055 no case of chloracne was observed. A possible alternative to the high-frequency EC of the leishmanial skin lesions is the use of a CO2 laser [73], [74]. In Iran, the CO2 laser was more effective than systemic meglumine antimonate [75] or cryotherapy combined with intralesional meglumine antimonate in patients with CL [76]. However, for Afghanistan, one of the lowest developed countries in the world with an unstable electrical power supply even in the big cities and no infrastructure for technical maintenance, a CO2 laser is not the instrument of first choice for the treatment of CL lesions. Instead, the instrument for bipolar high-frequency EC used in this study is cheap and robust, needs no special maintenance, is suitable for small- and medium-sized CL ulcers and can be run with an easily rechargeable car battery. Recently, two studies reported on the effect of wound care procedures in CL patients. In a three-arm clinical trial carried out in Iran with L. major-infected CL patients the additional administration of a triglyceride ointment dressing with or without silver impregnation failed to promote the healing of the lesions as compared to local injections of meglumine antimonate alone [77]. Although certain silver complexes might exert antileishmanial effects [78], [79], silver-containing dressings are no better or even worse than controls dressings in promoting wound healing [80]. In the second study, a highly heterogenous group of French travellers with CL (infections with 10 different species of Leishmania contracted in 29 different countries) either received simple wound care, cryotherapy plus intralesional antimony, or systemic drug therapy following the instructions by a reference center. Of 109 patients, only 25 patients were categorized to have simple lesions and received topical wound care, which led to cure in 23 patients. Unfortunately, no information was provided on the frequency and type of wound care performed [81]. In addition to pentavalent antimony other local or systemic drug treatments have been reported for L. tropica-induced CL. Both oral miltefosine and liposomal intravenous amphotericin B were effective in a few L. tropica CL cases reported [16], [82]–[84], but controlled trials are still missing. In addition, the current prices for these medications essentially prohibit their use in Afghanistan. The local treatment with paromomycin-based ointments, which have proven effective in ulcerative L. major-induced CL [85]–[87], did not yield convincing results in L. tropica infections (reviewed in [68]). Due to the limited sample size of 59 and 54 patients we cannot firmly exclude the possible antagonistic influence of covariates (such as parasite load, age and gender), which might camouflage a significant difference between the placebo (EC/MWT without DAC N-055) and the verum group (EC/MWT plus DAC N-055) of the study [88]. Likewise, subsequent trials with a larger number of CL patients have to tell, whether non-desired effects of EC, such as keloïd formations and relapses of the Leishmania infection, are in the range of those observed with cryotherapy, thermotherapy, laser therapy, or local or systemic chemotherapy. Finally, the study design did not allow to judge the differential therapeutic contribution of the EC (reduction of parasite load by removal of lesion tissue) and of the MWT. In a follow-up three-arm study we therefore compared the therapeutic effect of EC plus MWT containing DAC N-055 with a wound-moistening treatment with DAC N-055 alone and with the standard intralesional injections of SSG (Stahl HC et al. , in preparation). In summary, the present study demonstrated that EC plus MWT is a straight-forward and clinically highly efficient method for treating CL lesions due L. tropica infections, which can be successfully implemented in a country such as Afghanistan, where infrastructural, financial and medical resources are limited. We strongly believe that MWT with DAC N-055 is a therapeutic approach that is likely to be also effective in patients with other forms of CL (e. g. , infections with L. major, L. mexicana or L. braziliensis).
In many countries of the Middle East such as Afghanistan, cutaneous leishmaniasis is a highly prevalent, chronic and stigmatizing skin disease. Poor hygiene conditions frequently aggravate the lesions due to bacterial and fungal superinfections. Classical treatments with injections of pentavalent antimony are hampered by costs, side effects, resistance development, supply and manufactural quality problems. In the present study on Afghan patients with Leishmania tropica-induced skin lesions we evaluated the clinical effect of an initial removal of lesion tissue by electrocoagulation using a bipolar high-frequency electrosurgery instrument, followed by daily moist wound treatment with or without a preparation of pharmaceutical sodium chlorite (DAC N-055). DAC N-055 is a compound with anti-infective, immunomodulatory and tissue repair-promoting effects. Our analysis revealed that the carefully performed moist wound treatment led to a rapid healing of the wounds within an average period of 6 weeks, even in the absence of the sodium chlorite preparation. This is considerably faster than the time spans previously reported for local or systemic antimony treatment. We believe that the current standard for local care of chronic wounds should also be applied to Leishmania skin lesions. If combined with an initial single high-frequency electrocoagulation, it is a highly effective, inexpensive and well-tolerated treatment option for cutaneous leishmaniasis.
medicine
infectious diseases
skin infections
leishmaniasis
neglected tropical diseases
Rapid Healing of Cutaneous Leishmaniasis by High-Frequency Electrocauterization and Hydrogel Wound Care with or without DAC N-055: A Randomized Controlled Phase IIa Trial in Kabul