Disseminated Leishmaniasis, a Severe Form of Leishmania braziliensis Infection.

Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and therapeutic outcomes, we studied 101 DL and 101 cutaneous leishmaniasis (CL) cases and determined cytokines and chemokines in supernatants of mononuclear cells stimulated with leishmania antigen. Patients were treated with meglumine antimoniate (20 mg/kg) for 20 days (CL) or 30 days (DL); 19 DL patients were instead treated with amphotericin B, miltefosine, or miltefosine and meglumine antimoniate. High levels of chemokine ligand 9 were associated with more severe DL. The cure rate for meglumine antimoniate was low for both DL (44%) and CL (60%), but healing time was longer in DL (p = 0.003). The lowest cure rate (22%) was found in DL patients with >100 lesions. However, meglumine antimoniate/miltefosine treatment cured all DL patients who received it; therefore, that combination should be considered as first choice therapy.

A Double-blind, Randomized Trial to Evaluate Miltefosine and Topical Granulocyte Macrophage Colony-stimulating Factor in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil.

BACKGROUND: The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. METHODS: A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. RESULTS: The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. CONCLUSIONS: Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. CLINICAL TRIALS REGISTRATION: NCT03023111.

Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial.

OBJECTIVES: There is a clear need for new strategies of leishmaniasis treatment. This work was conducted to evaluate the efficacy of the co-administration of tamoxifen and meglumine antimoniate (SbV ) in a phase II pilot clinical trial in localised cutaneous leishmaniasis patients. METHODS: A randomised controlled pilot clinical trial was conducted to evaluate the efficacy and safety of oral (40 mg/day for 20 days) or topical tamoxifen (0.1% tamoxifen citrate for 20 days) combined with meglumine antimoniate (20 mg SbV /kg/day for 20 days) vs. a standard SbV protocol (20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis. Primary outcome was complete epithelisation of the lesion 6 months after the end of treatment. Secondary outcomes were lesion healing 2 months after the end of treatment and frequency and severity of adverse events. RESULTS: A total of 38 subjects were included in the trial, 15 were treated with standard SbV and 23 with the combination of tamoxifen and SbV . Of the patients treated with the co-administration scheme, 12 received tamoxifen orally and 11 were treated with topical tamoxifen. Tamoxifen administered by the oral or topical routes was well tolerated. Cure rates 6 months after the end of treatment per intention to treat were 40% in the group treated with the standard SbV scheme, and 36.4% and 58%, respectively, for groups treated with SbV plus topical or oral tamoxifen. CONCLUSIONS: In the doses and schemes used in this study, co-administration of oral tamoxifen and SbV resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.

Fluconazole in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis: A Randomized Controlled Trial.

BACKGROUND: The treatment of cutaneous leishmaniasis (CL) caused by Leishmania braziliensis in Brazil with pentavalent antimony (Sbv) is associated with a high rate of failure, up to 45% of cases. In addition, Sbv can only administered parenterally and has important toxic effect. An effective, safe, and oral treatment for CL is required. METHODS: A randomized controlled clinical trial was conducted to compare the efficacy and safety of high-dosage oral fluconazole (6.5-8.0 mg/kg/d for 28 days) versus a standard Sbv protocol (20 mg/kg/d for 20 days) for the treatment of CL in Bahia, Brazil. RESULTS: A total of 53 subjects were included in the trial; 26 were treated with Sbv, and 27 with fluconazole. Intention-to-treat analysis showed initial cure rates (2 months after treatment) of 22.2% (6 of 27) in the fluconazole and 53.8% (14 of 26) in the Sbv group (P = .04). Six months after treatment, the final cure rate remained the same in both groups, without any relapses. The frequencies of adverse effects in the Sbv and fluconazole groups were similar, 34.6% versus 37% respectively. One patient treated with fluconazole discontinued treatment owing to malaise, headache, and moderate dizziness (Common Terminology Criteria for Adverse Events grade 2). CONCLUSIONS: Oral fluconazole at a dosage of 6.5-8 mg/kg/d for 28 days should not be considered an effective treatment for CL caused by L. braziliensisClinical Trials Registration. NCT01953744.

Intermediate monocytes contribute to pathologic immune response in Leishmania braziliensis infections.

Ulcer development in patients with cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is associated with high levels of tumor necrosis factor (TNF). We found that early after infection, before ulcer development, the frequency of CD16(+) (both intermediate [CD14(+)CD16(+)] and nonclassical [CD14(dim)CD16(+)]) monocytes was increased in the peripheral blood of patients with L. braziliensis, compared with uninfected controls. These results suggest that CD16(+) monocytes might promote disease. Also, we found that intermediate monocytes expressed CCR2 and that increased levels of CCL2 protein were present in lesions from patients, suggesting that intermediate monocytes are more likely than nonclassical monocytes to migrate to the lesion site. Finally, we found that the intermediate monocytes produced TNF. Our results show that intermediate monocytes are increased in frequency soon after infection; express CCR2, which would promote their migration into the lesions; and, owing to their production of TNF, can enhance the inflammatory response.

Treatment of Disseminated Leishmaniasis With Liposomal Amphotericin B.

BACKGROUND: Disseminated leishmaniasis (DL) is a severe and emerging form of American tegumentary leishmaniasis, associated primarily with infection by Leishmania brasiliensis. DL is defined by the presence of ≥10 mixed-type lesions such as inflammatory papules and ulcers, located in ≥2 body parts. Most patients have hundreds of lesions all over the body, and mucosal involvement is detected in up to 44% of cases. DL is a difficult to cure disease and pentavalent antimony (Sb(v)) is used as standard treatment, its highest dosage being 20 mg/kg/day, for 30 days. However, less than 25% of DL cases will be cured after standard therapy, and the majority of cases will require more than one course of Sb(v) for a cure. In this context, new therapies are needed that offer a higher cure rate and a better safety profile, with convenience in drug administration. METHODS: We have evaluated liposomal amphotericin B in 20 patients with DL in an open clinical trial. The total dose ranged from 17 to 37 mg/kg, used in 7 to 14 days of treatment. RESULTS: Cure rate at 3 months after therapy was 70%. One relapse was documented 4 months after treatment, producing a final cure rate of 65%. Although liposomal amphotericin B was considered well tolerated, mild adverse events were documented in 75% of the patients. CONCLUSIONS: Liposomal amphotericin B is an effective therapy for DL, with a higher final cure rate of 75% observed when used in a total dose above 30 mg/kg. CLINICAL TRIALS REGISTRATION: NCT02025491.

Pentavalent Antimony Associated with G-CSF in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) braziliensis.

Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, in recent decades has shown decreasing cure rates after treatment with meglumine antimoniate (MA). Granulocyte colony-stimulating factor (G-CSF) is a cytokine associated with epithelialization and healing processes. METHODS: This study compares the effectiveness of G-CSF associated with MA in the treatment of CL. A total of 32 patients aged between 18 and 50 years with CL confirmed for L. braziliensis were included in this study. G-CSF or placebo (0.9% saline) was applied by intralesional infiltration at four equidistant points on the edges of the largest ulcer on days 0 and 15 of treatment associated with intravenous MA. RESULTS: Males predominated in the G-CSF group (59%), while females predominated in the control group (53%). Injuries to the lower limbs predominated in both study groups. The cure rate in the G-CSF group was 65% and in the control group it was 47%, 90 days after initiation of therapy. CONCLUSIONS: Our data indicate that the association of G-CSF with MA is not superior to MA monotherapy. Although not significant, the potential benefit of this combination deserves further investigation. The use of higher doses or other routes of application of G-CSF in a greater number of patients should contribute to a definitive response.

Improved Treatment Outcome Following the Use of a Wound Dressings in Cutaneous Leishmaniasis Lesions.

Leishmaniasis, caused by Leishmania parasites, is a neglected tropical disease and Cutaneous Leishmaniasis (CL) is the most common form. Despite the associated toxicity and adverse effects, Meglumine antimoniate (MA) remains the first-choice treatment for CL in Brazil, pressing the need for the development of better alternatives. Bacterial NanoCellulose (BNC), a biocompatible nanomaterial, has unique properties regarding wound healing. In a previous study, we showed that use of topical BNC + systemic MA significantly increased the cure rate of CL patients, compared to treatment with MA alone. Herein, we performed a study comparing the combination of a wound dressing (BNC or placebo) plus systemic MA versus systemic MA alone, in CL caused by Leishmania braziliensis. We show that patients treated with the combination treatment (BNC or placebo) + MA showed improved cure rates and decreased need for rescue treatment, although differences compared to controls (systemic MA alone) were not significant. However, the overall time-to-cure was significantly lower in groups treated with the combination treatment (BNC+ systemic MA or placebo + systemic MA) in comparison to controls (MA alone), indicating that the use of a wound dressing improves CL treatment outcome. Assessment of the immune response in peripheral blood showed an overall downmodulation in the inflammatory landscape and a significant decrease in the production of IL-1a (p < 0.05) in patients treated with topical BNC + systemic MA. Our results show that the application of wound dressings to CL lesions can improve chemotherapy outcome in CL caused by L. braziliensis.

Case report: Cyclophosphamide pulse therapy for chronic recalcitrant erythema nodosum leprosum.

Chronic recalcitrant erythema nodosum leprosum (ENL) or type 2 reaction (T2R) is a severe condition found in approximately 50% of multibacillary leprosy subjects. T2R is associated with important morbidities and may lead to several disabilities, not only due to nerve damage but also due to the prolonged use of corticosteroids, thalidomide, or immunosuppressors. We describe here four leprosy patients with chronic recalcitrant ENL treated with cyclophosphamide pulse therapy. All subjects had been on prednisone and thalidomide therapy for at least 30 months but showed inflammatory activity when doses were reduced. Pulse therapy with 1.0 g of cyclophosphamide was used every 4-6 weeks for a minimum of three applications. After pulse therapy, all cases presented total or partial regression of symptoms, and we were able to taper thalidomide and prednisone doses, with better control of ENL, avoiding further hospital admissions and disabilities. No side effects were observed during or after infusion therapy. Cyclophosphamide pulse therapy may be useful and safe to control chronic recalcitrant ENL.

Clinical Profile and Diagnosis of Recurrent Cutaneous Leishmaniasis.

This case-control study compared the clinical profile, parasite load, polymerase chain reaction positivity, and response to therapy in patients with recurrent cutaneous leishmaniasis (RCL) with primary cutaneous leishmaniasis (CL). The RCL patients had milder diseases with lower parasite loads, a lower number of lesions, and more self-healing diseases than primary CL patients.

Cutaneous leishmaniasis treatment and therapeutic outcomes in special populations: A collaborative retrospective study.

BACKGROUND: Treatment guidance for children and older adult patients affected by cutaneous leishmaniasis (CL) is unclear due to limited representation of these groups in clinical trials. METHODS: We conducted a collaborative retrospective study to describe the effectiveness and safety of antileishmanial treatments in children ≤ 10 and adults ≥ 60 years of age, treated between 2014 and 2018 in ten CL referral centers in Latin America. RESULTS: 2,037 clinical records were assessed for eligibility. Of them, the main reason for non-inclusion was lack of data on treatment follow-up and therapeutic response (182/242, 75% of children and 179/468, 38% of adults). Data on 1,325 eligible CL patients (736 children and 589 older adults) were analyzed. In both age groups, disease presentation was mild, with a median number of lesions of one (IQR: 1-2) and median lesion diameter of less than 3 cm. Less than 50% of the patients had data for two or more follow-up visits post-treatment (being only 28% in pediatric patients). Systemic antimonials were the most common monotherapy regimen in both age groups (590/736, 80.2% of children and 308/589, 52.3% of older adults) with overall cure rates of 54.6% (95% CI: 50.5-58.6%) and 68.2% (95% CI: 62.6-73.4%), respectively. Other treatments used include miltefosine, amphotericin B, intralesional antimonials, and pentamidine. Adverse reactions related to the main treatment were experienced in 11.9% (86/722) of children versus 38.4% (206/537) of older adults. Most adverse reactions were of mild intensity. CONCLUSION: Our findings support the need for greater availability and use of alternatives to systemic antimonials, particularly local therapies, and development of strategies to improve patient follow-up across the region, with special attention to pediatric populations.

Miltefosine and cutaneous leishmaniasis.

PURPOSE OF REVIEW: Miltefosine is a new oral treatment against leishmaniasis. The evidence about its use in New and Old World cutaneous leishmaniasis is presented and discussed. RECENT FINDINGS: Miltefosine is being tested with small clinical trials mainly in endemic cutaneous leishmaniasis regions of South America and Iran. Severe cutaneous leishmaniasis forms successfully treated with miltefosine are reported. SUMMARY: The use of miltefosine in cutaneous leishmaniasis has been addressed in a few clinical trials. An important advantage of this drug is its oral administration when compared with the standard parenteral drugs in the context of a large-scale use in the inner regions of the endemic countries. Miltefosine also shows activity in severe or refractory cases. However, this review points out the need for further investment on clinical research into cutaneous leishmaniasis treatment.

A pilot and open trial to evaluate topical Bacterial Cellulose bio-curatives in the treatment of cutaneous leishmaniasis caused by L. braziliensis.

The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high failure rate and long time to heal. Moreover, standard Sbv treatment cures only 50-60% of the cases. In this pilot clinical trial, we evaluated the topical use of bacterial cellulose (BC) bio-curatives + Sbv in the treatment of CL caused by L. braziliensis, in Bahia, Brazil. A total of 20 patients were randomized in two groups assigned to receive either parenteral Sbv alone or parenteral Sbv plus topically applied BC bio-curatives. CL patients treated with Sbv + topical BC bio-curatives had a significantly higher cure rate at 60 days post initiation of treatment compared to CL patients treated with Sbv alone (P=0.01). At day 90 post initiation of treatment, cure rate was similar in the two groups as was overall healing time. Adverse effects or local reactions to topical BC application were not observed. This pilot trial shows that the potential use of a combined therapy consisting of topical BC bio-curatives and parenteral Sbv in favoring healing of CL lesions caused by L. braziliensis, at an early time point.

Clinical criteria for Mucosal Leishmaniasis diagnosis in rural South America: A systematic literature review.

BACKGROUND: Mucosal Leishmaniasis (ML), a neglected tropical disease caused by Leishmania parasites, impairs the quality of life of under-resourced populations in South America. If not treated promptly, this disease progresses to facial deformities and death. The low sensitivity of microscopy results and the unavailability of other accurate tests hamper the diagnosis. As clinical criteria are readily available in any setting, these may be combined in a syndromic algorithm, which in turn can be used as a diagnostic tool. We explore potential clinical criteria for a syndromic diagnostic algorithm for ML in rural healthcare settings in South America. METHODOLOGY/PRINCIPAL FINDINGS: The protocol for this systematic review was pre-registered in PROSPERO with the number: CRD42017074148. In patients with ML, described in case series identified through a systematic retrieval process, we explored the cumulative ML detection rates of clinical criteria. Participants: all patients with active mucosal disease from an endemic area in South America. Any original, non-treatment study was eligible, and case reports were excluded. PUBMED, EMBASE, Web of Science, SCIELO, and LILACS databases were searched without restrictions. The risk of bias was assessed with the JBI checklist for case series. We included 10 full texts describing 192 ML patients. Male gender had the highest detection rate (88%), followed by ulcer of the nasal mucosa (77%), age >15 (69%), and symptom duration >4 months (63%). SIGNIFICANCE: Within this selection of patients, we found that the male gender, ulcer of the nasal mucosa, age >15, and symptom duration >4 months lead to the highest detection rates. However, higher detection comes -naturally- with a higher rate of false positives as well. As we only included ML patients, this could not be verified. Therefore, the criteria that we found to be most promising should be validated in a well-designed prospective study.

The Influence of Infection by Different Leishmania (Viannia) braziliensis Isolates on the Pathogenesis of Disseminated Leishmaniasis.

Disseminated Leishmaniasis (DL) is an emerging and severe form of Leishmania (Viannia) braziliensis infection defined by the presence of 10 and up to more than 1,000 skin lesions. The mechanisms underlying parasite dissemination remain unknown. Genotypic differences among species of L. braziliensis have been associated with different clinical forms of disease. The present work compared the function of monocytes obtained from patients with cutaneous leishmaniasis (CL) and DL in response to infection with L. braziliensis isolates of both these two clinical forms of disease. Mononuclear cells obtained from DL and CL patients were infected with different L. braziliensis isolates, and numbers of infected cells, parasite load, respiratory burst, TLR2 and TLR4 expression and cytokine production were evaluated. DL isolates infected more monocytes, induced greater respiratory burst, and more cytokine production compared to isolates from CL patients regardless of the origin of monocytes (DL or CL). However, greater parasite multiplication and higher TLR2 and TLR4 expression were seen in monocytes from DL patients compared to CL following infection with DL isolates. Our results indicate the participation of both parasite genotype and host factors in the pathogenesis of DL.

Cellular infiltrate in cutaneous leishmaniasis lesions and therapeutic outcome.

BACKGROUND: The treatment of cutaneous leishmaniasis is a challenge. A better understanding of the in situ mechanisms involved in the evolution and cure of the disease is essential for the development of new therapies. OBJECTIVE: Correlate histopathological and immunological characteristics of cutaneous leishmaniasis lesions with clinical outcome after different treatment regimens. METHODS: The authors analyzed cellular infiltration and immunohistochemistry staining for CD4, CD8 and IL-17 in biopsy samples from 33 patients with cutaneous leishmaniasis before treatment. All patients were recruited in a randomized clinical trial at Corte de Pedra (Bahia-Brazil) and assigned to receive Glucantime®, Glucantime® + Oral Tamoxifen or Glucantime® + Topical Tamoxifen. Patients were followed for 2 to 6 months to define disease outcome. RESULTS: A similar expression of CD4, CD8 and IL-17 was observed in lesion samples regardless of clinical outcome. In general, a higher amount of CD8 cells were observed compared with CD4 cells. An important observation was that all patients whose cellular infiltrate did not contain plasma cells were cured after treatment. STUDY LIMITATIONS: Isolated quantification of TCD8 and IL-17 using immunohistochemistry is insufficient to analyze the role of these molecules in the immunopathogenesis of cutaneous leishmaniasis. In addition, the expansion of the immunohistochemistry panel would allow a more complete analysis of the immune response in situ. CONCLUSIONS: The absence of plasma cells in cutaneous leishmaniasis lesions was related to a favorable therapeutic outcome.

High Anti-Leishmania IgG Antibody Levels Are Associated With Severity of Mucosal Leishmaniasis.

Background: Mucosal leishmaniasis (ML), the most inflammatory form of tegumentary leishmaniasis, is predominantly caused by Leishmania braziliensis. The disease is characterized by the development of lesions, mainly in the nasal mucosa. An exacerbated inflammatory response has been associated with the presence of destructive and disfiguring lesions, with stages of severity ranging from small nodulations to the complete destruction of the nasal pyramid architecture. As Leishmania is an intracellular parasite, most immunological studies have emphasized the cell-mediated immune response, while relatively few studies aimed to investigate the role antibodies in protection against, or the pathology of ML. Methods: Patients with a confirmed diagnosis of ML were classified according to clinical staging criteria. Serum levels of Leishmania-specific IgG, IgG1 and IgG2 antibodies were determined by ELISA before and after treatment with antimony or antimony plus pentoxifylline. Results: Patients in stages IV and V produced higher concentrations of IgG and IgG1 antibodies when compared to those in stage I and II. Significant reductions were seen in the concentrations of IgG and IgG2 antibodies in most patients who responded well to treatment. Conclusions: Our data demonstrate an association between IgG antibody titers and the severity of mucosal disease. The observed reduction in antibody production after successful treatment in most patients preliminarily indicates that these tests can be used to aid in the assessment of therapeutic response.

Anti-Leishmania IgG is a marker of disseminated leishmaniasis caused by Leishmania braziliensis.

BACKGROUND: In this study, we determined the accuracy of anti-Leishmania IgG and IgG subclasses to distinguish clinical forms of American tegumentary leishmaniasis (ATL) and and determined the relationship between antibodies levels with cytokine production and severity of ATL. METHODS: Participants were 40 patients with cutaneous leishmaniasis (CL), 20 patients with mucosal leishmaniasis (ML), 20 patients with disseminated leishmaniasis (DL), and 20 individuals with subclinical Leishmania braziliensis infection (SC). Diagnosis was performed by DNA of L. braziliensis or IFN-γ production in SC. IgG and subclasses of IgG to soluble Leishmania antigen and cytokine levels in supernatants of mononuclear cells were detected by ELISA. RESULTS: IgG was detected in 95%, 95%, and 100% of patients with CL, ML, and DL, respectively. Higher levels of anti-Leishmania IgG and IgG2 were seen in DL compared to CL, ML, and SC. ROC analysis confirmed the ability of IgG to distinguish DL from the other clinical forms. A direct correlation was observed between IgG titers and levels of IFN-γ and CXCL10 in CL and DL, and IgG2 antibodies were correlated with the number of lesions in DL. CONCLUSIONS: High anti-Leishmania IgG and IgG2 levels are characteristic of DL, and while IgG was correlated with pro-inflammatory cytokines, IgG2 was direct correlated with the number of lesions.

Association of miltefosine with granulocyte and macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis in the Amazon region: A randomized and controlled trial.

OBJECTIVES: To compare topical granulocyte and macrophage colony-stimulating factor (GM-CSF) and miltefosine (G + M) versus placebo and miltefosine (P + M) or parenteral meglumine antimoniate (MA) in the treatment of 150 patients with cutaneous leishmaniasis (CL) caused by Leishmania guyanensis in the Amazon. DESIGN: A randomized and double-blinded clinical trial. RESULTS: At 90 days after the initiation of therapy, the cure rates were 66%, 58%, and 52% for the groups P + M, G + M, and MA, respectively (p > 0.05). Cure rates at 180 days did not differ. Healing time was similar in the 3 groups, but faster in the MA group as compared to the G + M group (p = 0.04). Mild and transitory systemic adverse events were frequent in all groups (above 85%). Nausea (85%) and vomiting (39%) predominated in the miltefosine groups and arthralgia (51%) and myalgia (48%) in the MA group. One patient (group MA) stopped treatment after presenting with fever, exanthema, and severe arthralgia. CONCLUSIONS: Miltefosine did not present a higher cure rate than MA, and the association of GM-CSF did not improve the therapeutic response. Nevertheless, because of its less toxicity, easier administration, and a similar cure rate when compared with MA, miltefosine should remain as one of the main drugs for treating CL due to L. guyanensis. (Clinicaltrials.gov Identifier NCT03023111).

Diabetes Modifies the Clinic Presentation of Cutaneous Leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by 1 or multiple well-limited ulcerated lesions. Diabetes mellitus (DM) impairs neutrophil and monocyte function, and there is a report of vegetative lesions in a patient with both diseases in Morocco. Here we evaluate the influence of DM on clinical manifestations, immune response, and in the treatment of CL. METHODS: The participants were 36 DM patients with CL and 36 patients with CL without DM, matched by age and gender. The diagnosis of CL was performed by documentation of DNA of L. braziliensis by polymerase chain reaction in the lesion biopsy and histopathologic findings. All patients were treated with Glucantime (Sanofi-Aventis) 20 mg/kg of weight per day for 20 days. RESULTS: There was no difference in the majority of the clinical variables between the groups, and the cure rate in patients with CL and DM (67%) was similar to that observed in CL patients (56%; P ˃ .05). The most important finding was the documentation that 36% of the patients with DM and CL had atypical cutaneous lesions characterized by large superficial ulcers without defined borders. High levels of interferon-γ, tumor necrosis facor, and interleukin-1ß were detected in the supernatants of mononuclear cells stimulated with Leishmania antigen in patients with DM and atypical CL. Moreover, while cure was observed in only 33% of the patients with DM and atypical CL lesions, it was observed in 85% of patients with typical lesions (P < .05). CONCLUSIONS: DM modifies the clinical presentation of CL, enhances pro-inflammatory cytokine production, and impairs response to antimony therapy.