Background
Old World cutaneus leishmaniasis (OWCL) is an infection caused by the Leishmania parasite, which is passed onto humans by the bite of sandflies. It is a serious skin disease associated with a broad range of signs, symptoms, and degrees of severity. We wanted to assess the competence and safety of all available treatments for OWCL.
Review question
We assessed participants with a healthy immune response who had OWCL diagnosed by laboratory methods. Treatments had to be given alone or in combination with another treatment, and they were compared against no treatment, placebo (an inactive substance) only, or another active treatment. Some of the main outcomes we were interested in included the percentage of wounds cured after the end of treatment, the number of participants completely cured after the end of treatment, speed of healing, side-effects of treatment, and clearance of parasites (i.e. infection).
Study characteristics
We reviewed 89 clinical trials, which included 10,583 people, in total, with OWCL. We included participants of both sexes and all ages (mean 24.5 years); most participants were over 18 years of age. Most studies were carried out in single centres in different countries, mainly in the Far or Middle East, and lasted between two to six months. We included a variety of treatments, such as antimonials, antifungals, and antibiotics, which were administered either directly onto the skin or into a wound, taken by mouth, or physically applied (e.g. laser treatment, heat therapy, etc.). Most of the included studies assessed OWCL caused by two species of parasites known as Leishmania major (L. major) and Leishmania tropica (L. tropica).
Key results
The evidence is current to November 2016.
Two of the most important treatments that we assessed in this review were itraconazole, an antifungal drug taken by mouth, and paromomycin, an antibiotic applied as an ointment. Trials compared both to a placebo tablet or inactive cream (vehicle).
Participants received 200 mg itraconazole for six to eight weeks or paromomycin ointment at a concentration of 15% plus 10% urea, twice daily for 14 days.
When assessed on average 2.5 months after treatment, more participants were completely cured and cleared of the infection-causing parasites with itraconazole than placebo, but they also had more side effects (mild stomach pain, sickness, and abnormal liver function, as well as headaches and dizziness).
When paromomycin ointment was compared with placebo, there was no difference in the number of completely cured participants or the number who were found to be cleared of parasites when assessed on average 2.5 months after treatment, but those in the paromomycin treatment group had more contained skin reactions (such as swelling, blistering, pain, redness, or itch).
However, as the certainty of the evidence for these outcomes for these particular comparisons was very low, we are not sure of the accuracy of these results.
Neither of our key treatment comparisons assessed the percentage of wounds cured after the end of treatment and speed of healing (i.e. time taken to be cured).
Quality of the evidence
The overall certainty of the evidence for the different outcomes in the two main comparisons was very low. Important reasons for this were that studies were not blinded, or had a small sample size, making the results less precise. Some of the evidence only focused on young people, and the results greatly varied between each study.
We need more research to fill in the following research gaps: 1) trials of OWCL caused by other types of infection such as L. infantum, L. aethiopica, or L. donovani; 2) involving specific subgroups of people such as children; 3) assessing effectiveness and safety of different anti-Leishmania drugs compared with placebo in self-healing forms of leishmaniasis or with traditional first-choice antimonial treatment in complicated form (defined as more than four lesions over 4 cm in size, located close to an opening or small joints, for which previous treatment has failed); and 4) assessing areas such as wound healing and patient-reported outcomes, such as quality of life. In addition, few studies assessed relevant issues such as drug resistance. International collaboration is required to improve the quality and standardisation of future trials in order to develop a better evidence-based approach.
There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.
We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, and L donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.
It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.
Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.
To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.
We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.
Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.
Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.
We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.
Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.
In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.
When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.
Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.