Leishmaniasis is a parasitic, non-contagious disease caused by different species of protozoa of the genus Leishmania¹. The WHO estimates the incidence of Leishmaniasis at approximately 2 million new cases per year², with deaths from Leishmaniasis reaching 67,000 per year worldwide³. In South America, the disease is present in almost all countries except Chile and Uruguay³. Leishmaniasis has three clinical forms: visceral, cutaneous and mucocutaneous. The cutaneous form is the most common and consists of chronic ulcers that leave lifelong scars, and the mucocutaneous form is more aggressive and causes partial or complete destruction of the mucous membranes of the nose, mouth and larynx³. In Bolivia, the most frequent species responsible for 85% of cases of cutaneous Leishmaniasis is L. braziliensis⁴. This species is also responsible for mucosal leishmaniasis, which generally occurs after an episode of cutaneous leishmaniasis due to systemic dissemination of the parasite⁵.

Pentavalent antimonials are the first-line drugs for the treatment of cutaneous leishmaniasis and are administered systemically (intravenously or intramuscularly) at a dose of 20 mg/kg/day for 20 days. According to a meta-analysis conducted in 2008, this treatment has a clinical cure efficacy of 76.5%⁷. However, the disadvantage of this therapy is the use of multiple injections and large volumes of drug, causing adverse effects such as myalgia, arthralgia, gastrointestinal symptoms and significant cardiac, hepatic, pancreatic and renal toxicity. Adverse reactions and toxicity associated with this treatment are responsible for treatment abandonment by the patient, as well as partial or total treatment interruptions by medical staff, situations that give rise to problems of therapeutic failure that are much more complicated to manage^8,9.

Intralesional application of pentavalent antimonials is a widely used technique to treat Leishmaniasis worldwide with a clinical cure rate of 70%⁷, which is why it is currently recommended by PAHO/WHO⁶; this is why Brazil, which has the same strain responsible for mucosal Leishmaniasis, has included a management manual for the use of intralesional antimonials for the disease¹⁰. Additionally, in Bolivia, our working group has developed its own experiences in this type of treatment⁴, however, this treatment has not yet been sufficiently accepted or implemented in Bolivia by the authorities of the Ministry of Health, due to excessive mistrust regarding the success of this treatment, arguing that there is little evidence to support the safety of the treatment¹¹. In the interest of contributing more evidence on this issue, the aim of this study was to evaluate the safety of intralesional treatment with pentavalent antimonials for cutaneous leishmaniasis against the risk of long-term mucosal complications.

Material and methods

This is a retrospective longitudinal quantitative observational study. Exclusion criteria for the study included having received treatment other than intralesional or systemic treatment and the impossibility of post-treatment follow-up. On the other hand, inclusion criteria included having received pentavalent antimonial-based treatment (intralesional or systemic) within the follow-up period and their acceptance to voluntarily participate in the study.

Sixty-six clinical records were selected for the study of patients with a laboratory-confirmed diagnosis of cutaneous leishmaniasis who received intralesional treatment or systemic treatment with pentavalent antimonials during the period 2012 to 2016 and who corresponded to a community in the Isiboro Sécure Park in the Municipality of Villa Tunari. Of the 66 patients, 46 received systemic treatment and 20 received intralesional treatment. The latter consisted of the local application of 3 and 6 doses of pentavalent antimonials at the edge of the lesion every other day. The amount of drug applied was calculated by multiplying the width by the length of the lesion and by a constant factor of 0.008, according to the Bolivian operational guide⁴. Intralesional treatment was performed on the basis of two schedules: nine patients received three applications in a first clinical trial in 2012-2013 with a 7-year follow-up, and the other 11 received six applications as part of a second clinical trial conducted in 2014-2015 with a 4-year follow-up^4,5.

Data collection

Clinical information on study participants was collected from records available at health centres throughout the Isiboro Sécure Park territory, in conjunction with a new on-site clinical assessment of patients previously notified for this purpose.

Post-healing clinical evaluation participants were evaluated by means of a complete physical examination in search of complications that could occur after the completion of the treatment. Specifically, participants were assessed for: 1) the presence of parasitic activity (characterised by recurrence of the ulcer or inflammation of the scar edges); 2) the occurrence of a new episode in areas of the skin other than where the healed lesion was located; and 3) the presence of mucosal ulcers in the nose, mouth, changes in voice tone as a sign of mucosal complication.

Ethical considerations

The study was approved by the Bolivian Ethics Committee of the Faculty of Medicine of the Universidad Mayor de San Simón. All study participants gave their voluntary written consent agreeing to participate in the study.

Results

Sixty-six patients with cutaneous leishmaniasis who received systemic or intralesional treatment between 2012 and 2016 were contacted. Of this total, the highest percentage were women and the age range was between 4 and 67 years of age, with a mean of 26 years(Table 1).

Table 1
Demographic and clinical data of patients with cutaneous leishmaniasis who received systemic or intralesional treatment with pentavalent antimonials. Data presented as frequencies (%).

All of them achieved healing of their skin ulcers within 6 months of follow-up after completion of treatment, regardless of the type of treatment received (Figure 1). It should be noted that the ulcer area was less than 900 mm² (30x30 mm) in all cases included in the study (systemic or intralesional treatment). The time in which the lesions reached healing, according to the reports reviewed, was in the range of 6 months after completion of treatment.

Figure 1.
Area of the lesion of patients with cutaneous leishmaniasis before and after therapeutic intervention. Tx. Systemic = Conventional treatment for 20 days of intramuscular application dose /kg/weight (n=46); Tx. Intralesional (A) = Six Intralesional drug applications (n=9); Tx. Intralesional (B) = Three Intralesional drug applications (n=11). Data expressed as Median (RIC)

Regarding post-treatment clinical follow-up, both for those who received systemic and intralesional treatment (3 and 6 applications respectively), the clinical review showed the absence of mucosal lesions after completion of treatment for cutaneous leishmaniasis regardless of treatment (Figure 2), as well as the absence of other cutaneous involvement compatible with therapeutic failure, the presence of relapses and/or the occurrence of new episodes (Table 2).

Figure 2.
Clinical follow-up for Leishmania mucosal lesions, after clinical cure (scar) of cutaneous leishmaniasis. Systemic Tx = Conventional treatment for 20 days of intramuscular application dose /kg/weight (n=46); Intralesional Tx (A) = Six applications of intralesional drug (n=9); Intralesional Tx (B) = Three applications of intralesional drug (n=11).

Table 2.
Clinical involvement following treatment with pentavalent antimonials in patients with cutaneous leishmaniasis. Data are expressed as frequency of cases. Data are expressed in frequency (%).

Finally, regarding adverse effects caused by systemic or intralesional treatments, the most frequent was pain at the site of application for both treatments used (systemic or intralesional). However, cases receiving systemic treatment also presented with myalgia, fever and headache in about 11% of patients (Table 3). No data on liver, cardiac and pancreatic alterations are available because laboratory tests were not available in the medical services where the treatments were performed.

Table 3.
Adverse effects presented during treatment with pentavalent antimonials in patients with cutaneous leishmaniasis. Data are expressed in frequency of cases. Data are expressed in frequency (%).

Discussion

Long-term clinical evaluation of patients treated with systemic and intralesional pentavalent antimonials showed the absence of mucosal complications of Leishmaniasis in all cases, regardless of the treatment regimen administered. Although there are few studies in Latin America that perform long-term follow-up of patients treated with systemic or intralesional pentavalent antimonials, the few that exist showed similar results to this study, highlighting the absence of development of mucosal lesions^12-14. Although the reasons for the development of mucosal complications are not sufficiently clear, different evidence points to dysregulation of the individual’s immune system as an important factor for this development^15-18. In this respect, the immunomodulatory effect of pentavalent antimonials is as important as their leishmanicidal effect. Pentavalent antimonials modify the specific immune response by favouring the activation of macrophages and thus facilitating phagocytosis of intracellular parasites¹⁹. On the other hand, in the absence of a functional immune system, the response to pentavalent antimonials is reduced for ulcer healing and the likelihood of mucosal complications increases²⁰, due to the modification of the cell-mediated immune response^21,22 of the individual with Leishmaniasis. Another important finding was the absence of relapses or reinfections in the group of patients who received three intralesional applications of the drug, and although new skin lesions were identified in other anatomical regions, these corresponded to a new episode.

The adverse effects produced by the drugs were more frequent among patients who received systemic treatment (Table 3), the most common being myalgia, fever and headache, which are probably due to the toxicity of the antimony or of the additives contained in the pharmaceutical formulation^23,24. In contrast, these types of adverse effects in intralesional application are considered rare²⁵. Local pain was present in all cases regardless of whether treatment was by systemic or intralesional application due to local hypersensitivity of the inflamed tissue due to antimony toxicity^26,27 and in the case of intralesional application the inflammation also responds to the activity of the parasite present at the edge of the lesions^28,29.

The results presented in this study have two limitations related to sample size, due to the difficulties of access to the communities, and the follow-up time (4-7 years), which, although long-term, is not long enough to completely rule out the risk that these patients may develop mucosal leishmaniasis in a period longer than that evaluated as a result of changes in the behaviour of their immune system,¹⁵ which could be triggered by multiple causes. However, despite these limitations, this is the first study with a follow-up longer than four years for this type of treatment in Latin America.

Conclusions

This study is the first in Bolivia to explore the effect of intralesional and systemic treatment with a clinical follow-up of more than four years in all patients evaluated.

Treatment with intralesional pentavalent antimonials is a reliable option in relation to future complications of the disease, as well as in terms of its clinical efficacy, since it achieves a similar percentage of cure to that obtained with systemic treatment. Its long-term safety, characterised by its low toxicity, minimal risk of relapses and reinfections and the absence of mucosal complications, reinforces the conclusions that it is a more cost-effective alternative for health systems in the management of cutaneous leishmaniasis.

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Author notes

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