It is said that laws are like sausages, in that it is best not to see them made. Literature reviews can arguably be added to this list, as investigators are faced with retrieving data from disparate published studies and amalgamating them into a coherent analysis. Differences in study design, study population, disease presentation, intervention, outcome measures, and follow-up are but a few of the variables that can confound the investigator.
Performing a review on the treatments for cutaneous leishmaniasis and mucocutaneous leishmaniasis (CL/MCL) is particularly challenging, as the disease is complex and much of the existing literature is limited. Difficulties in harmonizing data can be grouped into the epidemiological, diagnostic, clinical, and therapeutic aspects of the disease.
Epidemiologically, CL/MCL are neglected tropical diseases, and their burden falls most heavily on the poorest regions of the world, making clinical research difficult.
Diagnostically, existing methods can be imprecise. Molecular methods for both diagnosis and taxonomy assignment are increasingly reported, with the potential for real-time diagnosis and species identification, but are not widely available.
Clinically, the presentation of CL can be frustratingly diverse. Self-healing lesions are relatively common, making the evaluation of therapeutic interventions difficult. Relapse after initial healing can occur, so adequate follow-up is required. The clinical course appears to be related to the infecting strains (eg, Leishmania major and Leishmania braziliensis being related to greater and fewer, respectively, spontaneous cures), but the influence of other factors such as the presence of leishmania virus and host factors likely also play a role.[3-7]
Finally, interpreting the actual effectiveness of therapy for CL is challenging. Lesion “reepithelialization” has often been used to define cure, but the time-points at which lesions are evaluated vary among studies, and the end-point is unhelpful for nodular lesions. Repeat biopsy at the end of treatment to document sterility has been used, but data suggest that lesions can cure even in the presence of viable parasites.
Given these challenges, recent Cochrane reviews for the treatment of Old World CL and American CL and MCL concluded that “most trials have been designed and reported so poorly that they are inconclusive.”[9, 10] So why would readers be interested in the current treatment recommendations from the LeishMan group? Because, in my opinion, despite the lack of definitive data, practitioners are still faced with patients afflicted with CL/MCL and need to choose therapies that are believed to be safe and effective. The LeishMan group provides guidance based on data reviewed between 1960 and 2013, as well as unpublished evidence and the group's own personal experience, and uses the Oxford evidence grading system to assign weight to their recommendations.
The LeishMan group provides several practical approaches for the treatment of CL. The group advises “primum non nocere,” with simple wound care recommended for minor infections secondary to strains that tend to self-heal, such as L. major, Leishmania tropica, Leishmania infantum/donovani, Leishmania aethiopica, and Leishmania mexicana. For moderate disease, local therapies are advised. Should patients require systemic therapy for extensive disease, the authors provide several options, but list as last the use of a pentavalent antimonial. I think this step-wise approach is reasonable, and agree that minor, self-limited lesions should not be treated with a drug known to cause pancreatitis, abnormalities in cardiac conduction, and months of disabling arthralgias and myalgias.
The treatment recommendations for CL caused by L. braziliensis and Leishmania panamensis suggest local therapy for selected cases. As both these strains can be associated with MCL, some providers may feel more comfortable with prescribing systemic therapy. However, emerging data, albeit limited, suggest that local therapy may be safe.[7, 13]
Finally, treatment recommendations for MCL all involve systemic agents, which is appropriate for this complex disease.
There are several limitations to the LeishMan review. The article is not a meta-analysis, and is more of a narrative than systematic review. The reviewed articles are assessed solely by the Oxford grading system, there is no assessment of other quality measures or risk of bias, and the authors do not report a statistical analysis in an attempt to compare cure rates among the various trials. The ranking of suggested treatments seems arbitrary, as the authors often list lower quality (C or D) ahead of higher quality interventions (A or B). Finally, depending on practice location, some of the recommended therapies remain unavailable or difficult to obtain (eg, miltefosine, pentavalent antimonial, local heat therapy, and paromomycin ointment in the United States).
In summary, given the limitations of the existing data, the LeishMan recommendations provide physicians with a species-specific approach to the treatment of CL/MCL, with suggested interventions based on disease severity. For CL, this flexible approach seeks to minimize toxicity, which is appropriate for what is usually a slowly progressive, often self-resolving infection. Practitioners need to recognize that CL/MCL are complicated diseases, and that the available data limit the ability to make firm conclusions regarding the ideal therapy. Hopefully, future studies will improve our understanding of CL/MCL, but until then the LeishMan recommendations can serve as food for the busy practitioner.