What are the benefits and risks of different treatments for American (muco)cutaneous leishmaniasis (a parasitic disease of the skin and mucous membranes)?

Why this question is important

American (muco)cutaneous leishmaniasis (ACML) is a disfiguring disease that affects people in Central and South America. It is caused by parasites that are transmitted to humans by sandflies. Different forms of ACML have different symptoms. People with the cutaneous form develop skin sores that often heal within a few months without treatment, but can leave scars. In people with mucosal or mucocutaneous leishmaniasis, destructive sores develop in the protective lining (mucous membranes) of the nose, mouth and throat.

To compare the effectiveness and risks of the many treatments for ACML, we reviewed evidence from research studies (randomised controlled trials). We looked for information on the proportion of people whose sores had healed three months or more after treatment, unwanted effects, quality of life, re-appearance of sores, damage associated with the disease and prevention of scarring.

How we identified and assessed the evidence

First, we searched for all relevant studies. We then compared the results, summarised the evidence, and assessed the certainty of the evidence.

What we found

We found 75 studies on 6533 people (approximately 75% male; average age: 29 years).

- One study investigated children (2 to 12 years).
- Most studies (67) involved people with cutaneous leishmaniasis.
- Eight studies investigated people with mucosal or mucocutaneous leishmaniasis.
- The parasite Leishmania braziliensis caused the disease in 52 studies.
- Studies were conducted at regional hospitals, local clinics, and research centres.
- Studies lasted between 28 days and seven years.
- Most studies reported their funding source: the US army funded eight studies, industry funded 10, and institutional grants funded 33 (five of these also reported industry funding).

Treatments were mainly compared to a placebo (fake treatment) or meglumine antimoniate (an antimonial).

Here we report this review's main results. We were only able to report the risk of recurrence and side effects for the comparisons of meglumine antimoniate (MA) or miltefosine versus placebo and miltefosine versus MA.

Main results

Antimonials

Compared to placebo, MA may increase chances of complete healing of ACML, but treatment effects vary, so it is possible that it may make little to no difference. MA probably increases the likelihood of pain in the muscles or joints. There may be little to no difference in the risk of developing the disease again, but there is also a possibility of increased or reduced risk due to the wide range of effects seen.

Non-antimonials

Miltefosine probably improves chances of complete healing of American cutaneous leishmaniasis (ACL) compared to placebo, but there may be little to no difference compared to treatment with MA in ACML. Miltefosine may make little to no difference to the risk of developing ACL again when compared to placebo, but treatment effects on recurrence varied, so it may also increase or decrease the risk. Miltefosine probably increases the likelihood of vomiting or nausea when compared to either placebo or MA in ACML. We do not know the effect on recurrence of miltefosine compared to MA.

Azithromycin probably reduces chances of complete healing of ACML compared to MA.

Imiquimod in combination with MA probably makes little to no difference to the chance of complete healing of ACL compared to MA in combination with placebo.

Physical therapies

Thermotherapy lowers the chance of complete healing of ACL compared to MA.

Immuno-chemotherapy

Pentoxifylline plus MA probably makes little to no difference to chances of complete healing of ACML compared with MA plus placebo.

No study reported information about damage, prevention of scarring, or quality of life.

What this means

The main findings of this review suggest that:

- MA and miltefosine probably increase chances of complete healing; and
- vomiting or nausea are probably more common with miltefosine, and joint or muscle ache is probably more common with MA.

The evidence was mostly of moderate certainty, so the true results are likely close to what we found. Evidence was limited by the inclusion of very few people in some studies, and participants or investigators knowing which treatments they were receiving.

How-up-to date is this review?

The evidence in this Cochrane Review is current to August 2019.

Authors' conclusions: 

Evidence certainty was mostly moderate or low, due to methodological shortcomings, which precluded conclusive results. Overall, both IMMA and oral miltefosine probably result in an increase in cure rates, and nausea and vomiting are probably more common with miltefosine than with IMMA.

Future trials should investigate interventions for mucosal leishmaniasis and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.

Read the full abstract...
Background: 

On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites. Pentavalent antimonials remain the first-choice treatment. There are alternative interventions, but reviewing their effectiveness and safety is important as availability is limited. This is an update of a Cochrane Review first published in 2009.

Objectives: 

To assess the effects of interventions for all immuno-competent people who have American cutaneous and mucocutaneous leishmaniasis (ACML).

Search strategy: 

We updated our database searches of the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and CINAHL to August 2019. We searched five trials registers.

Selection criteria: 

Randomised controlled trials (RCTs) assessing either single or combination treatments for ACML in immuno-competent people, diagnosed by clinical presentation and Leishmania infection confirmed by smear, culture, histology, or polymerase chain reaction on a biopsy specimen. The comparators were either no treatment, placebo only, or another active compound.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. Our key outcomes were the percentage of participants 'cured' at least three months after the end of treatment, adverse effects, and recurrence. We used GRADE to assess evidence certainty for each outcome.

Main results: 

We included 75 studies (37 were new), totalling 6533 randomised participants with ATL. The studies were mainly conducted in Central and South America at regional hospitals, local healthcare clinics, and research centres. More male participants were included (mean age: roughly 28.9 years (SD: 7.0)). The most common confirmed species were L. braziliensis, L. panamensis, and L. mexicana. The most assessed interventions and comparators were non-antimonial systemics (particularly oral miltefosine) and antimonials (particularly meglumine antimoniate (MA), which was also a common intervention), respectively.

Three studies included moderate-to-severe cases of mucosal leishmaniasis but none included cases with diffuse cutaneous or disseminated CL, considered the severe cutaneous form. Lesions were mainly ulcerative and located in the extremities and limbs. The follow-up (FU) period ranged from 28 days to 7 years. All studies had high or unclear risk of bias in at least one domain (especially performance bias). None of the studies reported the degree of functional or aesthetic impairment, scarring, or quality of life.

Compared to placebo, at one-year FU, intramuscular (IM) MA given for 20 days to treat L. braziliensis and L. panamensis infections in ACML may increase the likelihood of complete cure (risk ratio (RR) 4.23, 95% confidence interval (CI) 0.84 to 21.38; 2 RCTs, 157 participants; moderate-certainty evidence), but may also make little to no difference, since the 95% CI includes the possibility of both increased and reduced healing (cure rates), and IMMA probably increases severe adverse effects such as myalgias and arthralgias (RR 1.51, 95% CI 1.17 to 1.96; 1 RCT, 134 participants; moderate-certainty evidence). IMMA may make little to no difference to the recurrence risk, but the 95% CI includes the possibility of both increased and reduced risk (RR 1.79, 95% CI 0.17 to 19.26; 1 RCT, 127 participants; low-certainty evidence).

Compared to placebo, at six-month FU, oral miltefosine given for 28 days to treat L. mexicana, L. panamensis and L. braziliensis infections in American cutaneous leishmaniasis (ACL) probably improves the likelihood of complete cure (RR 2.25, 95% CI 1.42 to 3.38), and probably increases nausea rates (RR 3.96, 95% CI 1.49 to 10.48) and vomiting (RR 6.92, 95% CI 2.68 to 17.86) (moderate-certainty evidence). Oral miltefosine may make little to no difference to the recurrence risk (RR 2.97, 95% CI 0.37 to 23.89; low-certainty evidence), but the 95% CI includes the possibility of both increased and reduced risk (all based on 1 RCT, 133 participants).

Compared to IMMA, at 6 to 12 months FU, oral miltefosine given for 28 days to treat L. braziliensis, L. panamensis, L. guyanensis and L. amazonensis infections in ACML may make little to no difference to the likelihood of complete cure (RR 1.05, 95% CI 0.90 to 1.23; 7 RCTs, 676 participants; low-certainty evidence). Based on moderate-certainty evidence (3 RCTs, 464 participants), miltefosine probably increases nausea rates (RR 2.45, 95% CI 1.72 to 3.49) and vomiting (RR 4.76, 95% CI 1.82 to 12.46) compared to IMMA. Recurrence risk was not reported.

For the rest of the key comparisons, recurrence risk was not reported, and risk of adverse events could not be estimated.

Compared to IMMA, at 6 to 12 months FU, oral azithromycin given for 20 to 28 days to treat L. braziliensis infections in ACML probably reduces the likelihood of complete cure (RR 0.51, 95% CI 0.34 to 0.76; 2 RCTs, 93 participants; moderate-certainty evidence).

Compared to intravenous MA (IVMA) and placebo, at 12 month FU, adding topical imiquimod to IVMA, given for 20 days to treat L. braziliensis, L. guyanensis and L. peruviana infections in ACL probably makes little to no difference to the likelihood of complete cure (RR 1.30, 95% CI 0.95 to 1.80; 1 RCT, 80 participants; moderate-certainty evidence).

Compared to MA, at 6 months FU, one session of local thermotherapy to treat L. panamensis and L. braziliensis infections in ACL reduces the likelihood of complete cure (RR 0.80, 95% CI 0.68 to 0.95; 1 RCT, 292 participants; high-certainty evidence).

Compared to IMMA and placebo, at 26 weeks FU, adding oral pentoxifylline to IMMA to treat CL (species not stated) probably makes little to no difference to the likelihood of complete cure (RR 0.86, 95% CI 0.63 to 1.18; 1 RCT, 70 participants; moderate-certainty evidence).

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