Clinical features and therapeutic response in adult and pediatric patients with American tegumentary leishmaniasis in Rio de Janeiro

Clinical features and therapeutic response in adult and pediatric patients with American... Abstract Background American tegumentary leishmaniasis (ATL) is a neglected disease with wide territorial distribution. Knowledge is scarce in children and adolescents. This study aims to compare the clinical features and response to antimony treatment in pediatric and adult patients with cutaneous leishmaniasis. Methods A retrospective cohort study was performed with 659 patients who attended a reference centre in Rio de Janeiro, Brazil, from 2000 to 2015. The pediatric cohort consisted of 131 (20%) patients and the adult cohort consisted of 528 (80%) patients. Results The epidemiological profile, antimony therapeutic response and incidence of adverse events (AE) were different in the pediatric cohort compared with the adult cohort. Mucosal form was less frequent in the pediatric cohort (RR:0.49, p=0.011). Lesions in the head, neck and trunk were more frequent in the pediatric cohort (RR:1.49, p=0.043). The effectiveness of antimony treatment was superior in the pediatric cohort (88.3% vs 76.6%) with a shorter healing time (RR:0.49, p=0.009). Pediatric patients had lower proportions of moderate to severe AE compared with adults (RR:0.45, p=0.027). Clinical AE predominated in the adult cohort (RR:0.40, p=0.000) and laboratory AE in the pediatric cohort (RR:1.50, p=0.023). Conclusions This study adds to the body of knowledge on differences that exist between different age groups in ATL. American tegumentary leishmaniasis, cutaneous leishmaniasis, leishmaniasis, retrospective cohort study Introduction Cutaneous leishmaniasis (CL) has historically been a public health problem in different regions of the world. It is part of a complex of diseases with a wide clinical spectrum and epidemiological diversity. Nevertheless, it remains a neglected disease that primarily affects underserved populations, compromising their social interactions and productive capacity. In the New World, it is called American tegumentary leishmaniasis (ATL). Brazil is one of the countries with the highest incidence, with autochthonous cases registered in all states.1 In Brazil, three main species of Leishmania are involved in human disease: Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis. The most widespread species in Brazil is Leishmania (V.) braziliensis.2 In the state of Rio de Janeiro, L. (V.) braziliensis is almost exclusively responsible for CL cases, and its transmission is dependent on the adaptation of the vector to the domestic and peridomestic environment.3,Leishmania (V.) braziliensis circulating in Rio de Janeiro seems to be genetically homogeneous.4 Children and adults are different regarding biologic response and epidemiological dynamics of certain diseases. This appears to be the case with ATL. However, literature regarding age differences in ATL is as scarce as it is contradictory.5–8 Regional publications show variations in the incidence and prevalence of the disease in different age groups. Some Latin American countries show high proportions of ATL in children: 49.2% in Panama, 39.5% in El Salvador, 36.7% in Nicaragua and 31.9% in Costa Rica.1 In Brazil, there is a wide range in the proportion of children affected in different regions of the country. In Bahia, in the northeast region of Brazil, 11.5% of patients were children aged ≤5 y.7 In Maranhão, also in the Brazilian northeast region next to the Amazon Basin, 4.1% of patients were children aged ≤5 y, and the percentage of patients aged ≤15 y was 24.8%.6 In Amazonas (in the north of Brazil), children aged ≤14 y comprised 20.65% of patients.8 In endemic areas of CL in the Old World, this proportion also fluctuates.5,9 Several studies show that there are variations in lesion location, severity and response to treatment in children when compared with adults affected by ATL,8–11 while others do not demonstrate distinctions in clinical presentations among different age ranges.5 However, the literature is still limited. This study aims to compare the clinical characteristics and response to antimony treatment in pediatric and adult patients with ATL. Materials and methods Study design In this retrospective cohort study, we used data from patients with a diagnosis of ATL treated at the Laboratory of Clinical Research and Surveillance in Leishmaniasis (LapClinVigiLeish), Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz). LapClinVigiLeish is a reference centre for ATL for the Rio de Janeiro state; about 50% of all ATL cases occurring in the Rio de Janeiro state, and 90% in the Rio de Janeiro metropolitan area, are attended to at LapClinVigiLeish. All patients aged <60 y with a diagnosis of ATL confirmed by laboratory (parasitological and immunological) and clinical-epidemiological criteria who were treated with meglumine antimoniate at LapClinVigiLeish between 5 January 2000 and 30 December 2015 were eligible for the study. Exclusion criteria were being enlisted in the military, being pregnant, being a prisoner, having a serious uncontrolled comorbid disease, having a primary or a secondary immunodeficiency or having a severe psychiatric disorder other than anxiety or depressive episodes. The study was performed according to the ethical principles outlined in the Declaration of Helsinki and the guidelines from Brazilian National Health Council resolution 196/96 and 251/97 on research involving human subjects. Procedures Data were collected from retrospective chart review and maintained in a separate RedCap version 7.0.7 database (Vanderbilt University, Nashville, TN, USA). All patients completed at least one comprehensive clinical assessment at LapClinVigiLeish including a complete medical history, physical examination, a standard set of laboratory tests and ECG. We compared the first antimony treatment in patients aged <18 y (pediatric cohort) and patients aged 18–59 y (adult cohort) with ATL. The pediatric group was composed of children (aged <12 y) and adolescents (aged 12-18 y). Therapeutic success was assessed by the treating physicians and defined as epithelialization within 120 d after the start of treatment. Data from the patients were reviewed by two investigators to ascertain whether therapeutic success was achieved. In our analyses, we included sociodemographic characteristics, clinical manifestations, epidemiological variables, specific therapeutic response and outcomes. Data on adverse events (AE) were gathered from all medical and laboratory records and evaluated using a grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events (http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf.). Drug-related AE were recorded from the date of the first dose to 30 d after the last dose. The AE leading to drug interruption and the reasons for temporary or permanent discontinuation were collected. Outcomes The primary outcome of this study was to determine whether there is a difference in antimony therapeutic response between the pediatric and adult cohorts. Secondary outcomes were to evaluate whether there are discrepancies in AE between the pediatric and adult cohorts. AE were categorized by type (clinical, laboratory or ECG) and intensity (mild and moderate to severe). Statistical analysis A power calculation of sample size was not performed because of the retrospective design of this study. We hypothesized that ATL in children and adolescents (pediatric cohort) was associated with a more severe disease and had a less successful treatment outcome compared with adults (adult cohort). Demographic and treatment differences between children, adolescents and adults were compared using Fisher’s exact tests or χ2 tests for categorical variables and t tests or Mann-Whitney U tests for continuous variables where appropriate. We verified the proportion of the genders and of the probable infection site (domestic/peridomestic and outdoor activities). We calculated the prevalence of clinical variables at the time of first clinical visit (type of lesion, number of cutaneous lesions, anatomical location, area of the largest lesion and evolution time until diagnosis) in both study groups estimating the prevalence ratio. The analysis of the therapeutic response (treatment effectiveness and healing time) and AE (presence, type and intensity of AE) was performed by estimating RR. All statistical tests were two-sided and a p-value of <0.05 was considered statistically significant for all comparisons. All analyses were performed in SPSS software version 20.0 (IBM Corp., Armonk, NY, USA). Results Table 1 shows gender, exposure, clinical form, anatomical location, type and number of cutaneous lesions, area of the largest cutaneous lesion and time until diagnosis in both cohorts. Table 1 Prevalence of clinical forms and epidemiological characteristics of American tegumentary leishmaniasis (ATL) patients collected at first visit, according to the cohorts groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) agross prevalence difference (proportional) bprevalence ratio cat 5% level dwork and travel exposure were considered outdoor activities eboth mucocutaneous and mucosal clinical forms fan ulcerated lesion was compared with the grouped forms: papule, infiltrated and verrucous plaque gthe presence of ≥2 lesions was considered multiple lesions hmain sites affected by cutaneous leishmaniasis in the anatomical location variable imultiple sites when skin lesions were present in ≥2 body sites divided into: head and neck, trunk, upper limbs and lower limbs jarea of the largest cutaneous lesion was calculated considering a circular area and the radius relative to the largest diameter of the lesion *significant p-value. Open in new tab Table 1 Prevalence of clinical forms and epidemiological characteristics of American tegumentary leishmaniasis (ATL) patients collected at first visit, according to the cohorts groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) agross prevalence difference (proportional) bprevalence ratio cat 5% level dwork and travel exposure were considered outdoor activities eboth mucocutaneous and mucosal clinical forms fan ulcerated lesion was compared with the grouped forms: papule, infiltrated and verrucous plaque gthe presence of ≥2 lesions was considered multiple lesions hmain sites affected by cutaneous leishmaniasis in the anatomical location variable imultiple sites when skin lesions were present in ≥2 body sites divided into: head and neck, trunk, upper limbs and lower limbs jarea of the largest cutaneous lesion was calculated considering a circular area and the radius relative to the largest diameter of the lesion *significant p-value. Open in new tab The male gender was predominant in both cohorts. The mean age in the pediatric cohort was 10.4 (SD ± 4.35) y and in the adult cohort it was 37.36 (SD ± 11.81) y. The probable site of infection was more frequent at the domestic/peridomestic area for both groups, but it predominated in the pediatric group (CI: 1.118 to 4.902, p=0.015). We did not find differences between the two groups on the lesion type (ulcerated or not), number of cutaneous lesions (multiple or single) or the area of the largest lesion. The mucocutaneous form was less frequent in the pediatric cohort (p=0.011). Lesions in the head, neck and trunk were more frequent in the pediatric cohort (RR:1.49, p=0.043). Table 2 shows the results of the AE and the effectiveness of antimony treatment. The effectiveness was superior in the pediatric cohort (88.3%) compared with the adult cohort (76.6%) with a shorter healing time (RR:0.49, p=0.009). Table 2 Therapeutic response and adverse events (AE) in patients with American tegumentary leishmaniasis (ATL), according to the cohort groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) aat the level of 5% bclinical healing was considered epithelialization in up to 120 d cmean (μ), median (md), SD (σ) dthe presence of AE encompassed any alteration or worsening of the condition, be it clinical, laboratory or ECG, during the treatment for ATL epresence of AE grouped in clinical, laboratory and ECG fthe intensity of AE were classified according to the grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events *significant p-value. Open in new tab Table 2 Therapeutic response and adverse events (AE) in patients with American tegumentary leishmaniasis (ATL), according to the cohort groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) aat the level of 5% bclinical healing was considered epithelialization in up to 120 d cmean (μ), median (md), SD (σ) dthe presence of AE encompassed any alteration or worsening of the condition, be it clinical, laboratory or ECG, during the treatment for ATL epresence of AE grouped in clinical, laboratory and ECG fthe intensity of AE were classified according to the grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events *significant p-value. Open in new tab There was no significant difference between cohorts concerning AE. When categorized by type (clinical, laboratory and ECG), clinical AE predominated in the adult cohort (RR:0.40, p=0.000) and laboratory AE in the pediatric cohort (RR:1.50, p=0.023). Pediatric patients had lower proportions of moderate to severe AE compared with adults (RR:0.45, p=0.027). Figure 1 shows that systemic, local, cutaneous, musculoskeletal, neurological, renal and hematological AE predominated in the adult cohort, as well as pancreatic enzyme elevations. Cardiovascular AE, as well as hepatic enzyme elevations and plasma glucose disturbances, were more frequent in the pediatric cohort. Figure 1 Open in new tabDownload slide Distribution of adverse events (AE) of patients with American tegumentary leishmaniasis (ATL) by organs and systems according to the cohorts. INI/Fiocruz, 2000–2015; a systemic AE include malaise, fever, chills, syncope and tremors; b gastrointestinal AE include nausea, vomiting, anorexia, dry mouth, constipation, pirose and abdominal pain; c neurological AE include herpes zoster, vertigo, headache and somnolence; d hepatic enzymes refer to changes in aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), alkaline phosphatase and gamma glutamyl transferase; e pancreatic enzymes refer to changes in lipase and amylase values; f glycemic AE refer to hypoglycemia and hyperglycemia. Figure 1 Open in new tabDownload slide Distribution of adverse events (AE) of patients with American tegumentary leishmaniasis (ATL) by organs and systems according to the cohorts. INI/Fiocruz, 2000–2015; a systemic AE include malaise, fever, chills, syncope and tremors; b gastrointestinal AE include nausea, vomiting, anorexia, dry mouth, constipation, pirose and abdominal pain; c neurological AE include herpes zoster, vertigo, headache and somnolence; d hepatic enzymes refer to changes in aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), alkaline phosphatase and gamma glutamyl transferase; e pancreatic enzymes refer to changes in lipase and amylase values; f glycemic AE refer to hypoglycemia and hyperglycemia. Discussion In our study, antimony therapeutic response and incidence of AE were different in the two cohorts. Contrary to our expectations, the effectiveness of antimony treatment was superior in the pediatric group, with a shorter healing time. Studies suggest differences in the therapeutic outcome of antimoniate between age groups10,12 and some of them report lower effectiveness in pediatric ATL.13 Parasitic genetic variance, patient biological differences and drug pharmacokinetics may influence therapeutic response. We did not find any variable that could explain this difference. Although we did not include typing of the parasites, unpublished results show that 98% of the parasites isolated in our centre are L. (V.) braziliensis. Although we are the main reference centre for leishmaniasis in Rio de Janeiro, we do not manage all the infections in the state. This is a limitation of our study. One of the most discussed topics in leishmaniasis is antimoniate treatment toxicity. The controversy between effectiveness and safety has become one of the main discussions in scientific publications. Some investigators point out that, as it is a disease with low lethality, safety is an element that overcomes effectiveness. Among those are advocates of low dose,12 intermittent14 or intralesional antimony treatment.15 Economic studies of cost-effectiveness, cost-benefit and cost reduction have been conducted to solve this issue and influence decision-making.16 There were no differences in our study between the two groups regarding total AE. Nevertheless, we observed clinical AE predominating in adults and laboratory AE in the pediatric group. The proportion of moderate to severe AE was significantly higher in the adult cohort. It is notable that the metabolism of the drug or its clearance is different across age groups.13 The mucocutaneous presentation was more frequent in the adult cohort. This form of presentation is often considered secondary to a previous infection and, thus, is to be expected as age advances.17 We did not find differences between the two groups on lesion type (ulcerated or not), the number of cutaneous lesions (multiple or single) or their area. It is possible that the higher proportions of lesions observed in the head, neck and trunk of children are caused more by body exposition in tropical climates.5,18 Some studies report differences between adults and children with respect to clinical features of ATL.19 Immunological, biological and age-specific factors may have an influence on this behavior.20–23 Nevertheless, there are contradictions regarding the location and severity of lesions. Some studies report greater severity in children.9,10 Although there is little evidence to support the role of immunity in the severity of clinical forms of leishmaniasis, some data suggest that herd immunity and the level of endemicity may play an important role.17 Males predominated in both the pediatric and adult cohorts. Studies performed in Brazil and Latin America show similar results.24–26 Gender distribution is balanced in endemic countries of the Old World, possibly as a consequence of disease urbanization leading to a more homogeneous transmission pattern.5,9 However, recent studies in Latin America reveal similar rates of infection in both men and women.27 Disparities may be influenced by less access for women to public healthcare services and by cultural behaviors.28 The pediatric cohort constituted 20% of the subjects. Studies in Brazil report similar or slightly higher percentages.6,8,29 There are regions, however, with smaller proportions.30 Human leishmaniasis displays epidemiological distinctions according to the participation of humans in transmission cycles. The sylvatic cycle is characterized by indistinct human infection as a result of accidental exposition to sylvatic reservoirs and vectors. In recent decades, there has been a dissemination of leishmaniasis in the outskirts of cities.3 These areas are close to endemic forests, with an increased risk of transmission in all age groups.7,26 On the other hand, as a rule, the occupational cycle affects adults and is associated with labor activities such as road construction, logging and agriculture in areas where the parasite is present. The exception to this rule is illegal child labor.8 Vector adaptation to the environment and herd immunity could influence the epidemiological particularities and disease transmission.17 Certain characteristics of our socioeconomic reality may favor the expansion of endemic areas, creating significant ATL foci.10,18,24 Neglected diseases, such as ATL, contribute to maintaining social inequality. Although there are groups dedicated to the subject, it does not receive proper scrutiny, perhaps because it primarily affects the disadvantaged, and accurate advocacy in promoting policies that improve health equity do not exist. The adult population is the subject of most studies. These investigations frequently overlook childhood and adolescence infection. Conclusion The epidemiological profile, antimony therapeutic response and incidence of AE were different in the pediatric and adult cohorts. Further studies on ATL focused on these age groups could clarify these issues. An interesting issue for further investigation is the role of children and adolescents in the spread of endemics in the periphery of Brazilian cities. This study adds to the body of knowledge on the differences that exist between different age groups in ATL. Authors’ contributions SJBP and MIFP (group leaders): study planning and design, study implementation, analysis and interpretation of data, review, major contributions to writing, reading and approving the final version of the paper. TCRS: study implementation, analysis and interpretation of data, major contributions to writing, reading and approving the final version of the paper. LFAO, MRL, MNS, MMS, CMVR, ACCM and AOS: major contributions to writing, reading and approving the final version of the paper. Acknowledgements We thank Maria F. Madeira, Aline F. Silva, Eliame Mouta-Confort and Luciana C Miranda for laboratory support. Funding None. Competing interests None declared. Ethical approval This study was approved by the Ethical Committee of INI, Fiocruz, under registry number CAAE: 54541316.9.0000.5262. References 1. Pan-American Health Organization , World Health Organization . Plan of action to strengthen the surveillance and control of leishmaniasis in the Americas 2017–2022 2017 . http://iris.paho.org/xmlui/bitstream/handle/123456789/34147/PlanactionLeish20172022-eng.pdf?sequence=5&isAllowed=y [accessed 10 January 2018] 2. Saúde Ministério da . Secretaria de Vigilância em Saúde, Departamento de Vigilância das Doenças Transmissíveis. Manual de vigilância da leishmaniose tegumentar . Brasília : Editora Ministério da Saúde , 2017 . Google Preview WorldCat COPAC 3. Marzochi MCA , Marzochi KBF . Tegumentary and visceral leishmaniases in Brazil: Emerging anthropozoonosis and possibilities for their control . Cad Saude Publica 1994 ; 10 ( Suppl 2 ): 359 – 375 . WorldCat 4. Baptista C , Schubach AO , Madeira MF et al. Leishmania (Viannia) braziliensis genotypes identified in lesions of patients with atypical or typical manifestations of tegumentary leishmaniasis: Evaluation by two molecular markers . Exp Parasitol 2009 ; 121 ( 4 ): 317 – 322 . WorldCat 5. Layegh P , Moghiman T , Hoseini SAA . Children and cutaneous leishmaniasis: a clinical report and review . J Infect Dev Ctries 2013 ; 7 ( 8 ): 614 – 617 . WorldCat 6. Martins lM , Rebelo JMM , Santos MCF et al. Ecoepidemiologia da leishmaniose tegumentar no município de Buriticupu, Amazônia do Maranhão, Brasil, 1996 a 1998 . Cad Saude Publica 2004 ; 20 ( 3 ): 735 – 743 . WorldCat 7. Ampuero J , Macêdo V , Marsden P . Características clínicas da leishmaniose tegumentar em crianças de 0 a 5 anos em uma área endêmica de Leishmania (Viannia) braziliensis . Rev Soc Bras Med Trop 2006 ; 39 : 22 – 26 . WorldCat 8. Guerra JAO , Barbosa MGV , Loureiro ACSP et al. Leishmaniose tegumentar Americana em crianças: Aspectos epidemiológicos de casos atendidos em Manaus, Amazonas, Brasil . Cad Saude Publica 2007 ; 23 ( 9 ): 2215 – 2223 . WorldCat 9. Aksoy M , Doni N , Ozkul HU et al. Pediatric cutaneous leishmaniasis in an endemic region in Turkey: a retrospective analysis of 8786 cases during 1998-2014 . PLoS Negl Trop Dis 2016 ; 1 : 11 . WorldCat 10. Palacios R , Osorio IE , Grajalew IF et al. Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimoniate for cutaneous leishmaniasis due to Leishmania Vianna species . Am J Trop Med Hyg 2001 ; 64 ( 3–4 ): 187 – 193 . WorldCat 11. Delgado O , Silva S , Coraspe V et al. American cutaneous leishmaniasis in children and adolescents from Northcentral Venezuela . Trop Biomed 2008 ; 25 ( 3 ): 178 – 183 . WorldCat 12. Saheki MN , Lyra MR , Bedoya-Pacheco SJ et al. Low versus high dose of antimony for American cutaneous leishmaniasis: A randomized controlled blind non-inferiority trial in Rio de Janeiro, Brazil . PLoS One 2017 ; 12 ( 5 ):e0178592. WorldCat 13. Layegh P , Pezeshkpoor F , Soruri AH et al. Efficacy of cryotherapy versus intralesional meglumine antimoniate (glucantime) for treatment of cutaneous leishmaniasis in children . Am J Trop Med Hyg 2009 ; 80 : 172 – 175 . WorldCat 14. Vasconcellos ECF , Schubach AO , Valete-Rosalino CM et al. American Tegumentary Leishmaniasis in older adults: 44 cases treated with an intermittent low-dose antimonial schedule in Rio de Janeiro, Brazil . J Am Geriatr Soc 2010 ; 58 ( 3 ): 614 – 620 . WorldCat 15. Silva RE , Junior AT , Senna MRC et al. Intralesional meglumine antimoniate for the treatment of localised cutaneous leishmaniasis: A retrospective review of a Brazilian referral Centre . Mem Inst Oswaldo Cruz 2016 ; 111 ( 8 ): 512 – 516 . WorldCat 16. Berger BA , Cossio A , Saravia NG et al. Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis . PLOS Negl Trop Dis 2017 ; 11 ( 4 ):e0005459. WorldCat 17. Bedoya-Pacheco SJ , Araujo-Melo MH , Valete-Rosalino CM et al. Endemic tegumentar leishmaniasis in Brazil: Correlation between level of endemicity and number of cases of mucosal disease . Am J Trop Med Hyg 2011 ; 84 ( 6 ): 901 – 905 . WorldCat 18. Ampuero J , Urdaneta M , Macedo VO . Factores de riesgo Para la transmisión de leishmaniasis cutánea en niños de 0 a 5 años en un área endémica de Leishmania (Viannia) braziliensis . Cad Saude Publica 2005 ; 21 : 161 – 170 . WorldCat 19. Bustamante MCFS , Pereira MJS , Schubach AO et al. Epidemiological profile of cutaneous leishmaniasis in an endemic region in the state of Rio de Janeiro, Brazil . Rev Bras Parasitol 2009 ; 18 ( 3 ): 34 – 40 . WorldCat 20. Mendez S , Reckling SK , Piccirillo CA . Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity . J Exp Med 2004 ; 200 ( 2 ): 201 – 210 . WorldCat 21. Perez-Franco JE , Cruz-Barrera MI , Robayo ML et al. Clinical and parasitological features of patients with American cutaneous leishmaniasis that did not respond to treatment with meglumine antimoniate . PLOS Negl Trop Dis 2016 ; 10 ( 5 ):e0004739. WorldCat 22. Peterson A , Townsend C , Lindsay P et al. Influences of climate change on the potential distribution of Lutzomyia longipalpis. (Psychodidae: Phlebotominae) . Int J Parasitol 2017 ; 47 ( 10–11 ): 667 – 674 . WorldCat 23. Mendonça MG , de Brito ME , Rodrigues EH et al. Persistence of leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: Is there a sterile cure? J Infect Dis 2004 ; 189 ( 6 ): 1018 – 1023 . WorldCat 24. Nassif PW , Castilho-Peres M , Rosa APZ et al. Clinical, laboratory, and therapeutic characteristics of American tegumentary leishmaniasis in the 15th state health division, Northwest Paraná state, southern Brazil . Rev Soc Bras Med Trop 2016 ; 49 ( 5 ): 593 – 601 . WorldCat 25. Vita GF , Costa Pereira MAV , Ferreira I et al. Status of the american tegumentary leishmaniasis in the state of Rio de Janeiro, Brazil, from 2004 to 2013 . Rev Inst Med Trop Sao Paulo 2016 ; 58 : 71 . WorldCat 26. Weigle KA , Santrich C , Martinez F et al. Epidemiology of cutaneous leishmaniasis in Colombia:Environmental and behavioral risk factors for infection, clinical manifestations, and pathogenicity . J Infect Dis 1993 ; 168 : 709 – 714 . WorldCat 27. Velez ID , Hendrickx E , Robledo SM , del Pilar Agudelo S . Gender and cutaneous leishmaniasis in Colombia . Cad Saude Publica. 2001 ; 17 : 171 – 180 . WorldCat 28. Okwor I , Uzonna J . Social and economic burden of human leishmaniasis . Am J Trop Med Hyg 2016 ; 94 ( 3 ): 489 – 493 . WorldCat 29. Castro EA , Soccol VT , Membrive N et al. Estudo das características epidemiológicas e clínicas de 332 casos de leishmaniose tegumentar notificados na região norte do Estado do Paraná de 1993 a 1998 . Rev Soc Bras Med Trop 2002 ; 35 ( 5 ): 445 – 452 . WorldCat 30. Monteiro WM , Neitzke HC , Lonardoni MVC et al. Distribuição geográfica e características epidemiológicas da leishmaniose tegumentar Americana em áreas de colonização antiga do Estado do Paraná, Sul do Brasil . Cad Saude Publica 2008 ; 24 ( 6 ): 1291 – 1303 . WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Transactions of The Royal Society of Tropical Medicine and Hygiene Oxford University Press

Clinical features and therapeutic response in adult and pediatric patients with American tegumentary leishmaniasis in Rio de Janeiro

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Abstract

Abstract Background American tegumentary leishmaniasis (ATL) is a neglected disease with wide territorial distribution. Knowledge is scarce in children and adolescents. This study aims to compare the clinical features and response to antimony treatment in pediatric and adult patients with cutaneous leishmaniasis. Methods A retrospective cohort study was performed with 659 patients who attended a reference centre in Rio de Janeiro, Brazil, from 2000 to 2015. The pediatric cohort consisted of 131 (20%) patients and the adult cohort consisted of 528 (80%) patients. Results The epidemiological profile, antimony therapeutic response and incidence of adverse events (AE) were different in the pediatric cohort compared with the adult cohort. Mucosal form was less frequent in the pediatric cohort (RR:0.49, p=0.011). Lesions in the head, neck and trunk were more frequent in the pediatric cohort (RR:1.49, p=0.043). The effectiveness of antimony treatment was superior in the pediatric cohort (88.3% vs 76.6%) with a shorter healing time (RR:0.49, p=0.009). Pediatric patients had lower proportions of moderate to severe AE compared with adults (RR:0.45, p=0.027). Clinical AE predominated in the adult cohort (RR:0.40, p=0.000) and laboratory AE in the pediatric cohort (RR:1.50, p=0.023). Conclusions This study adds to the body of knowledge on differences that exist between different age groups in ATL. American tegumentary leishmaniasis, cutaneous leishmaniasis, leishmaniasis, retrospective cohort study Introduction Cutaneous leishmaniasis (CL) has historically been a public health problem in different regions of the world. It is part of a complex of diseases with a wide clinical spectrum and epidemiological diversity. Nevertheless, it remains a neglected disease that primarily affects underserved populations, compromising their social interactions and productive capacity. In the New World, it is called American tegumentary leishmaniasis (ATL). Brazil is one of the countries with the highest incidence, with autochthonous cases registered in all states.1 In Brazil, three main species of Leishmania are involved in human disease: Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis. The most widespread species in Brazil is Leishmania (V.) braziliensis.2 In the state of Rio de Janeiro, L. (V.) braziliensis is almost exclusively responsible for CL cases, and its transmission is dependent on the adaptation of the vector to the domestic and peridomestic environment.3,Leishmania (V.) braziliensis circulating in Rio de Janeiro seems to be genetically homogeneous.4 Children and adults are different regarding biologic response and epidemiological dynamics of certain diseases. This appears to be the case with ATL. However, literature regarding age differences in ATL is as scarce as it is contradictory.5–8 Regional publications show variations in the incidence and prevalence of the disease in different age groups. Some Latin American countries show high proportions of ATL in children: 49.2% in Panama, 39.5% in El Salvador, 36.7% in Nicaragua and 31.9% in Costa Rica.1 In Brazil, there is a wide range in the proportion of children affected in different regions of the country. In Bahia, in the northeast region of Brazil, 11.5% of patients were children aged ≤5 y.7 In Maranhão, also in the Brazilian northeast region next to the Amazon Basin, 4.1% of patients were children aged ≤5 y, and the percentage of patients aged ≤15 y was 24.8%.6 In Amazonas (in the north of Brazil), children aged ≤14 y comprised 20.65% of patients.8 In endemic areas of CL in the Old World, this proportion also fluctuates.5,9 Several studies show that there are variations in lesion location, severity and response to treatment in children when compared with adults affected by ATL,8–11 while others do not demonstrate distinctions in clinical presentations among different age ranges.5 However, the literature is still limited. This study aims to compare the clinical characteristics and response to antimony treatment in pediatric and adult patients with ATL. Materials and methods Study design In this retrospective cohort study, we used data from patients with a diagnosis of ATL treated at the Laboratory of Clinical Research and Surveillance in Leishmaniasis (LapClinVigiLeish), Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz). LapClinVigiLeish is a reference centre for ATL for the Rio de Janeiro state; about 50% of all ATL cases occurring in the Rio de Janeiro state, and 90% in the Rio de Janeiro metropolitan area, are attended to at LapClinVigiLeish. All patients aged <60 y with a diagnosis of ATL confirmed by laboratory (parasitological and immunological) and clinical-epidemiological criteria who were treated with meglumine antimoniate at LapClinVigiLeish between 5 January 2000 and 30 December 2015 were eligible for the study. Exclusion criteria were being enlisted in the military, being pregnant, being a prisoner, having a serious uncontrolled comorbid disease, having a primary or a secondary immunodeficiency or having a severe psychiatric disorder other than anxiety or depressive episodes. The study was performed according to the ethical principles outlined in the Declaration of Helsinki and the guidelines from Brazilian National Health Council resolution 196/96 and 251/97 on research involving human subjects. Procedures Data were collected from retrospective chart review and maintained in a separate RedCap version 7.0.7 database (Vanderbilt University, Nashville, TN, USA). All patients completed at least one comprehensive clinical assessment at LapClinVigiLeish including a complete medical history, physical examination, a standard set of laboratory tests and ECG. We compared the first antimony treatment in patients aged <18 y (pediatric cohort) and patients aged 18–59 y (adult cohort) with ATL. The pediatric group was composed of children (aged <12 y) and adolescents (aged 12-18 y). Therapeutic success was assessed by the treating physicians and defined as epithelialization within 120 d after the start of treatment. Data from the patients were reviewed by two investigators to ascertain whether therapeutic success was achieved. In our analyses, we included sociodemographic characteristics, clinical manifestations, epidemiological variables, specific therapeutic response and outcomes. Data on adverse events (AE) were gathered from all medical and laboratory records and evaluated using a grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events (http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf.). Drug-related AE were recorded from the date of the first dose to 30 d after the last dose. The AE leading to drug interruption and the reasons for temporary or permanent discontinuation were collected. Outcomes The primary outcome of this study was to determine whether there is a difference in antimony therapeutic response between the pediatric and adult cohorts. Secondary outcomes were to evaluate whether there are discrepancies in AE between the pediatric and adult cohorts. AE were categorized by type (clinical, laboratory or ECG) and intensity (mild and moderate to severe). Statistical analysis A power calculation of sample size was not performed because of the retrospective design of this study. We hypothesized that ATL in children and adolescents (pediatric cohort) was associated with a more severe disease and had a less successful treatment outcome compared with adults (adult cohort). Demographic and treatment differences between children, adolescents and adults were compared using Fisher’s exact tests or χ2 tests for categorical variables and t tests or Mann-Whitney U tests for continuous variables where appropriate. We verified the proportion of the genders and of the probable infection site (domestic/peridomestic and outdoor activities). We calculated the prevalence of clinical variables at the time of first clinical visit (type of lesion, number of cutaneous lesions, anatomical location, area of the largest lesion and evolution time until diagnosis) in both study groups estimating the prevalence ratio. The analysis of the therapeutic response (treatment effectiveness and healing time) and AE (presence, type and intensity of AE) was performed by estimating RR. All statistical tests were two-sided and a p-value of <0.05 was considered statistically significant for all comparisons. All analyses were performed in SPSS software version 20.0 (IBM Corp., Armonk, NY, USA). Results Table 1 shows gender, exposure, clinical form, anatomical location, type and number of cutaneous lesions, area of the largest cutaneous lesion and time until diagnosis in both cohorts. Table 1 Prevalence of clinical forms and epidemiological characteristics of American tegumentary leishmaniasis (ATL) patients collected at first visit, according to the cohorts groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) agross prevalence difference (proportional) bprevalence ratio cat 5% level dwork and travel exposure were considered outdoor activities eboth mucocutaneous and mucosal clinical forms fan ulcerated lesion was compared with the grouped forms: papule, infiltrated and verrucous plaque gthe presence of ≥2 lesions was considered multiple lesions hmain sites affected by cutaneous leishmaniasis in the anatomical location variable imultiple sites when skin lesions were present in ≥2 body sites divided into: head and neck, trunk, upper limbs and lower limbs jarea of the largest cutaneous lesion was calculated considering a circular area and the radius relative to the largest diameter of the lesion *significant p-value. Open in new tab Table 1 Prevalence of clinical forms and epidemiological characteristics of American tegumentary leishmaniasis (ATL) patients collected at first visit, according to the cohorts groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) Cohort groups Variables Pediatric cohort Adult cohort Total, n (%) PD (%)a PRb 95% CI p-valuec Gender Female 49 (37.4) 187 (35.4) 236 (35.8) 0.014 (6.8) 1.07 0.751 to 1.525 0.699 Male 82 (62.6) 341 (64.6) 423 (64.2) Exposure Domestic/peridomestic 124 (94.7) 452 (86.8) 575 (88.2) 0.123 (57.2) 2.34 1.118 to 4.902 0.015* Outdoor activitiesd 7 (5.3) 69 (13.2) 76 (11.7) Clinical form Mucocutaneouse 12 (9.2) 100 (18.9) 112 (17.0) −0.11 (−50.7) 0.49 0.275 to 0.880 0.011* Cutaneous 119 (90.8) 428 (81.1) 547 (83) Type of cutaneous lesionf Ulcerated 107 (89.9) 378 (88.7) 485 (89.0) 0.016 (7.4) 1.10 0.607 to 2.002 0.775 Other 12 (10.1) 48 (11.3) 60 (11.0) Number of cutaneous lesionsg Multiple 33 (27.7) 159 (37.4) 192 (35.3) −0.073 (−29.7) 0.70 0.471 to 1.048 0.081 Single 86 (72.3) 266 (62.6) 352 (64.7) Anatomical locationh Head, neck and trunk 40 (33.6) 98 (23.0) 138 (25.3) 0.095 (32.9) 1.49 1.023 to 2.178 0.043* Limbs 79 (66.4) 328 (77.0) 407 (74.7) Number of anatomical locationsi Multiple sites 15 (12.6) 73 (17.1) 88 (16.1) −0.057 (−25.1) 0.75 0.436 to 1.284 0.295 Single site 104 (87.4) 353 (82.9) 457 (83.9) Area of the largest cutaneous lesion, (cm2)j ≥3 90 (84.9) 327 (87.4) 417 (86.9) −0.038 (−15.1) 0.85 0.499 to 1.445 0.537 <3 16 (15.1) 47 (12.6) 63 (13.1) Time until diagnosis, mo ≥2 94 (72.9) 391 (77.4) 485 (76.5) −0.041 (−17.5) 0.83 0.560 to 1.215 0.332 <2 35 (27.1) 114 (22.6) 149 (23.5) agross prevalence difference (proportional) bprevalence ratio cat 5% level dwork and travel exposure were considered outdoor activities eboth mucocutaneous and mucosal clinical forms fan ulcerated lesion was compared with the grouped forms: papule, infiltrated and verrucous plaque gthe presence of ≥2 lesions was considered multiple lesions hmain sites affected by cutaneous leishmaniasis in the anatomical location variable imultiple sites when skin lesions were present in ≥2 body sites divided into: head and neck, trunk, upper limbs and lower limbs jarea of the largest cutaneous lesion was calculated considering a circular area and the radius relative to the largest diameter of the lesion *significant p-value. Open in new tab The male gender was predominant in both cohorts. The mean age in the pediatric cohort was 10.4 (SD ± 4.35) y and in the adult cohort it was 37.36 (SD ± 11.81) y. The probable site of infection was more frequent at the domestic/peridomestic area for both groups, but it predominated in the pediatric group (CI: 1.118 to 4.902, p=0.015). We did not find differences between the two groups on the lesion type (ulcerated or not), number of cutaneous lesions (multiple or single) or the area of the largest lesion. The mucocutaneous form was less frequent in the pediatric cohort (p=0.011). Lesions in the head, neck and trunk were more frequent in the pediatric cohort (RR:1.49, p=0.043). Table 2 shows the results of the AE and the effectiveness of antimony treatment. The effectiveness was superior in the pediatric cohort (88.3%) compared with the adult cohort (76.6%) with a shorter healing time (RR:0.49, p=0.009). Table 2 Therapeutic response and adverse events (AE) in patients with American tegumentary leishmaniasis (ATL), according to the cohort groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) aat the level of 5% bclinical healing was considered epithelialization in up to 120 d cmean (μ), median (md), SD (σ) dthe presence of AE encompassed any alteration or worsening of the condition, be it clinical, laboratory or ECG, during the treatment for ATL epresence of AE grouped in clinical, laboratory and ECG fthe intensity of AE were classified according to the grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events *significant p-value. Open in new tab Table 2 Therapeutic response and adverse events (AE) in patients with American tegumentary leishmaniasis (ATL), according to the cohort groups. INI/Fiocruz, 2000–2015 Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) Cohort groups Variables Pediatric cohort Adult cohort Total RR 95% CI p-valuea Clinical outcomeb Therapeutic failure, first treatment 12 (11.7) 93 (23.4) 105 (21.0) 0.49 0.293 to 0.841 0.009* Therapeutic success, first treatment 91 (88.3) 305 (76.6) 396 (79.0) Healing time, moc μ=3.26 md=2.0 σ=2.84 μ=3.85 md=3.0 σ=7.14 AEd AE 60 (49.6) 289 (59.0) 349 (57.1) 0.74 0.537 to 1.015 0.065 Absence of AE 61 (50.4) 201 (41.0) 262 (42.9) Type of AEe Clinical 28 (23.1) 240 (49.2) 268 (44.0) 0.40 0.276 to 0.569 0.000* Laboratory 38 (31.4) 103 (21.1) 141 (23.1) 1.50 1.073 to 2.099 0.023* ECG 20 (16.5) 58 (11.9) 78 (12.8) 1.34 0.877 to 2.052 0.176 Intensity of AEf Moderate to severe 14 (23.3) 110 (38.3) 124 (35.7) 0.45 0.320 to 0.924 0.027* Mild 46 (76.7) 177 (61.7) 223 (64.3) aat the level of 5% bclinical healing was considered epithelialization in up to 120 d cmean (μ), median (md), SD (σ) dthe presence of AE encompassed any alteration or worsening of the condition, be it clinical, laboratory or ECG, during the treatment for ATL epresence of AE grouped in clinical, laboratory and ECG fthe intensity of AE were classified according to the grading scale adapted from the Division of AIDS Table for Grading of Severity of Adult and Pediatric Adverse Events *significant p-value. Open in new tab There was no significant difference between cohorts concerning AE. When categorized by type (clinical, laboratory and ECG), clinical AE predominated in the adult cohort (RR:0.40, p=0.000) and laboratory AE in the pediatric cohort (RR:1.50, p=0.023). Pediatric patients had lower proportions of moderate to severe AE compared with adults (RR:0.45, p=0.027). Figure 1 shows that systemic, local, cutaneous, musculoskeletal, neurological, renal and hematological AE predominated in the adult cohort, as well as pancreatic enzyme elevations. Cardiovascular AE, as well as hepatic enzyme elevations and plasma glucose disturbances, were more frequent in the pediatric cohort. Figure 1 Open in new tabDownload slide Distribution of adverse events (AE) of patients with American tegumentary leishmaniasis (ATL) by organs and systems according to the cohorts. INI/Fiocruz, 2000–2015; a systemic AE include malaise, fever, chills, syncope and tremors; b gastrointestinal AE include nausea, vomiting, anorexia, dry mouth, constipation, pirose and abdominal pain; c neurological AE include herpes zoster, vertigo, headache and somnolence; d hepatic enzymes refer to changes in aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), alkaline phosphatase and gamma glutamyl transferase; e pancreatic enzymes refer to changes in lipase and amylase values; f glycemic AE refer to hypoglycemia and hyperglycemia. Figure 1 Open in new tabDownload slide Distribution of adverse events (AE) of patients with American tegumentary leishmaniasis (ATL) by organs and systems according to the cohorts. INI/Fiocruz, 2000–2015; a systemic AE include malaise, fever, chills, syncope and tremors; b gastrointestinal AE include nausea, vomiting, anorexia, dry mouth, constipation, pirose and abdominal pain; c neurological AE include herpes zoster, vertigo, headache and somnolence; d hepatic enzymes refer to changes in aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), alkaline phosphatase and gamma glutamyl transferase; e pancreatic enzymes refer to changes in lipase and amylase values; f glycemic AE refer to hypoglycemia and hyperglycemia. Discussion In our study, antimony therapeutic response and incidence of AE were different in the two cohorts. Contrary to our expectations, the effectiveness of antimony treatment was superior in the pediatric group, with a shorter healing time. Studies suggest differences in the therapeutic outcome of antimoniate between age groups10,12 and some of them report lower effectiveness in pediatric ATL.13 Parasitic genetic variance, patient biological differences and drug pharmacokinetics may influence therapeutic response. We did not find any variable that could explain this difference. Although we did not include typing of the parasites, unpublished results show that 98% of the parasites isolated in our centre are L. (V.) braziliensis. Although we are the main reference centre for leishmaniasis in Rio de Janeiro, we do not manage all the infections in the state. This is a limitation of our study. One of the most discussed topics in leishmaniasis is antimoniate treatment toxicity. The controversy between effectiveness and safety has become one of the main discussions in scientific publications. Some investigators point out that, as it is a disease with low lethality, safety is an element that overcomes effectiveness. Among those are advocates of low dose,12 intermittent14 or intralesional antimony treatment.15 Economic studies of cost-effectiveness, cost-benefit and cost reduction have been conducted to solve this issue and influence decision-making.16 There were no differences in our study between the two groups regarding total AE. Nevertheless, we observed clinical AE predominating in adults and laboratory AE in the pediatric group. The proportion of moderate to severe AE was significantly higher in the adult cohort. It is notable that the metabolism of the drug or its clearance is different across age groups.13 The mucocutaneous presentation was more frequent in the adult cohort. This form of presentation is often considered secondary to a previous infection and, thus, is to be expected as age advances.17 We did not find differences between the two groups on lesion type (ulcerated or not), the number of cutaneous lesions (multiple or single) or their area. It is possible that the higher proportions of lesions observed in the head, neck and trunk of children are caused more by body exposition in tropical climates.5,18 Some studies report differences between adults and children with respect to clinical features of ATL.19 Immunological, biological and age-specific factors may have an influence on this behavior.20–23 Nevertheless, there are contradictions regarding the location and severity of lesions. Some studies report greater severity in children.9,10 Although there is little evidence to support the role of immunity in the severity of clinical forms of leishmaniasis, some data suggest that herd immunity and the level of endemicity may play an important role.17 Males predominated in both the pediatric and adult cohorts. Studies performed in Brazil and Latin America show similar results.24–26 Gender distribution is balanced in endemic countries of the Old World, possibly as a consequence of disease urbanization leading to a more homogeneous transmission pattern.5,9 However, recent studies in Latin America reveal similar rates of infection in both men and women.27 Disparities may be influenced by less access for women to public healthcare services and by cultural behaviors.28 The pediatric cohort constituted 20% of the subjects. Studies in Brazil report similar or slightly higher percentages.6,8,29 There are regions, however, with smaller proportions.30 Human leishmaniasis displays epidemiological distinctions according to the participation of humans in transmission cycles. The sylvatic cycle is characterized by indistinct human infection as a result of accidental exposition to sylvatic reservoirs and vectors. In recent decades, there has been a dissemination of leishmaniasis in the outskirts of cities.3 These areas are close to endemic forests, with an increased risk of transmission in all age groups.7,26 On the other hand, as a rule, the occupational cycle affects adults and is associated with labor activities such as road construction, logging and agriculture in areas where the parasite is present. The exception to this rule is illegal child labor.8 Vector adaptation to the environment and herd immunity could influence the epidemiological particularities and disease transmission.17 Certain characteristics of our socioeconomic reality may favor the expansion of endemic areas, creating significant ATL foci.10,18,24 Neglected diseases, such as ATL, contribute to maintaining social inequality. Although there are groups dedicated to the subject, it does not receive proper scrutiny, perhaps because it primarily affects the disadvantaged, and accurate advocacy in promoting policies that improve health equity do not exist. The adult population is the subject of most studies. These investigations frequently overlook childhood and adolescence infection. Conclusion The epidemiological profile, antimony therapeutic response and incidence of AE were different in the pediatric and adult cohorts. Further studies on ATL focused on these age groups could clarify these issues. An interesting issue for further investigation is the role of children and adolescents in the spread of endemics in the periphery of Brazilian cities. This study adds to the body of knowledge on the differences that exist between different age groups in ATL. Authors’ contributions SJBP and MIFP (group leaders): study planning and design, study implementation, analysis and interpretation of data, review, major contributions to writing, reading and approving the final version of the paper. TCRS: study implementation, analysis and interpretation of data, major contributions to writing, reading and approving the final version of the paper. LFAO, MRL, MNS, MMS, CMVR, ACCM and AOS: major contributions to writing, reading and approving the final version of the paper. Acknowledgements We thank Maria F. Madeira, Aline F. Silva, Eliame Mouta-Confort and Luciana C Miranda for laboratory support. Funding None. Competing interests None declared. Ethical approval This study was approved by the Ethical Committee of INI, Fiocruz, under registry number CAAE: 54541316.9.0000.5262. References 1. Pan-American Health Organization , World Health Organization . Plan of action to strengthen the surveillance and control of leishmaniasis in the Americas 2017–2022 2017 . http://iris.paho.org/xmlui/bitstream/handle/123456789/34147/PlanactionLeish20172022-eng.pdf?sequence=5&isAllowed=y [accessed 10 January 2018] 2. Saúde Ministério da . Secretaria de Vigilância em Saúde, Departamento de Vigilância das Doenças Transmissíveis. Manual de vigilância da leishmaniose tegumentar . Brasília : Editora Ministério da Saúde , 2017 . Google Preview WorldCat COPAC 3. Marzochi MCA , Marzochi KBF . Tegumentary and visceral leishmaniases in Brazil: Emerging anthropozoonosis and possibilities for their control . Cad Saude Publica 1994 ; 10 ( Suppl 2 ): 359 – 375 . WorldCat 4. Baptista C , Schubach AO , Madeira MF et al. Leishmania (Viannia) braziliensis genotypes identified in lesions of patients with atypical or typical manifestations of tegumentary leishmaniasis: Evaluation by two molecular markers . Exp Parasitol 2009 ; 121 ( 4 ): 317 – 322 . WorldCat 5. Layegh P , Moghiman T , Hoseini SAA . Children and cutaneous leishmaniasis: a clinical report and review . J Infect Dev Ctries 2013 ; 7 ( 8 ): 614 – 617 . WorldCat 6. Martins lM , Rebelo JMM , Santos MCF et al. Ecoepidemiologia da leishmaniose tegumentar no município de Buriticupu, Amazônia do Maranhão, Brasil, 1996 a 1998 . Cad Saude Publica 2004 ; 20 ( 3 ): 735 – 743 . WorldCat 7. Ampuero J , Macêdo V , Marsden P . Características clínicas da leishmaniose tegumentar em crianças de 0 a 5 anos em uma área endêmica de Leishmania (Viannia) braziliensis . Rev Soc Bras Med Trop 2006 ; 39 : 22 – 26 . WorldCat 8. Guerra JAO , Barbosa MGV , Loureiro ACSP et al. Leishmaniose tegumentar Americana em crianças: Aspectos epidemiológicos de casos atendidos em Manaus, Amazonas, Brasil . Cad Saude Publica 2007 ; 23 ( 9 ): 2215 – 2223 . WorldCat 9. Aksoy M , Doni N , Ozkul HU et al. Pediatric cutaneous leishmaniasis in an endemic region in Turkey: a retrospective analysis of 8786 cases during 1998-2014 . PLoS Negl Trop Dis 2016 ; 1 : 11 . WorldCat 10. Palacios R , Osorio IE , Grajalew IF et al. Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimoniate for cutaneous leishmaniasis due to Leishmania Vianna species . Am J Trop Med Hyg 2001 ; 64 ( 3–4 ): 187 – 193 . WorldCat 11. Delgado O , Silva S , Coraspe V et al. American cutaneous leishmaniasis in children and adolescents from Northcentral Venezuela . Trop Biomed 2008 ; 25 ( 3 ): 178 – 183 . WorldCat 12. Saheki MN , Lyra MR , Bedoya-Pacheco SJ et al. Low versus high dose of antimony for American cutaneous leishmaniasis: A randomized controlled blind non-inferiority trial in Rio de Janeiro, Brazil . PLoS One 2017 ; 12 ( 5 ):e0178592. WorldCat 13. Layegh P , Pezeshkpoor F , Soruri AH et al. Efficacy of cryotherapy versus intralesional meglumine antimoniate (glucantime) for treatment of cutaneous leishmaniasis in children . Am J Trop Med Hyg 2009 ; 80 : 172 – 175 . WorldCat 14. Vasconcellos ECF , Schubach AO , Valete-Rosalino CM et al. American Tegumentary Leishmaniasis in older adults: 44 cases treated with an intermittent low-dose antimonial schedule in Rio de Janeiro, Brazil . J Am Geriatr Soc 2010 ; 58 ( 3 ): 614 – 620 . WorldCat 15. Silva RE , Junior AT , Senna MRC et al. Intralesional meglumine antimoniate for the treatment of localised cutaneous leishmaniasis: A retrospective review of a Brazilian referral Centre . Mem Inst Oswaldo Cruz 2016 ; 111 ( 8 ): 512 – 516 . WorldCat 16. Berger BA , Cossio A , Saravia NG et al. Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis . PLOS Negl Trop Dis 2017 ; 11 ( 4 ):e0005459. WorldCat 17. Bedoya-Pacheco SJ , Araujo-Melo MH , Valete-Rosalino CM et al. Endemic tegumentar leishmaniasis in Brazil: Correlation between level of endemicity and number of cases of mucosal disease . Am J Trop Med Hyg 2011 ; 84 ( 6 ): 901 – 905 . WorldCat 18. Ampuero J , Urdaneta M , Macedo VO . Factores de riesgo Para la transmisión de leishmaniasis cutánea en niños de 0 a 5 años en un área endémica de Leishmania (Viannia) braziliensis . Cad Saude Publica 2005 ; 21 : 161 – 170 . WorldCat 19. Bustamante MCFS , Pereira MJS , Schubach AO et al. Epidemiological profile of cutaneous leishmaniasis in an endemic region in the state of Rio de Janeiro, Brazil . Rev Bras Parasitol 2009 ; 18 ( 3 ): 34 – 40 . WorldCat 20. Mendez S , Reckling SK , Piccirillo CA . Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity . J Exp Med 2004 ; 200 ( 2 ): 201 – 210 . WorldCat 21. Perez-Franco JE , Cruz-Barrera MI , Robayo ML et al. Clinical and parasitological features of patients with American cutaneous leishmaniasis that did not respond to treatment with meglumine antimoniate . PLOS Negl Trop Dis 2016 ; 10 ( 5 ):e0004739. WorldCat 22. Peterson A , Townsend C , Lindsay P et al. Influences of climate change on the potential distribution of Lutzomyia longipalpis. (Psychodidae: Phlebotominae) . Int J Parasitol 2017 ; 47 ( 10–11 ): 667 – 674 . WorldCat 23. Mendonça MG , de Brito ME , Rodrigues EH et al. Persistence of leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: Is there a sterile cure? J Infect Dis 2004 ; 189 ( 6 ): 1018 – 1023 . WorldCat 24. Nassif PW , Castilho-Peres M , Rosa APZ et al. Clinical, laboratory, and therapeutic characteristics of American tegumentary leishmaniasis in the 15th state health division, Northwest Paraná state, southern Brazil . Rev Soc Bras Med Trop 2016 ; 49 ( 5 ): 593 – 601 . WorldCat 25. Vita GF , Costa Pereira MAV , Ferreira I et al. Status of the american tegumentary leishmaniasis in the state of Rio de Janeiro, Brazil, from 2004 to 2013 . Rev Inst Med Trop Sao Paulo 2016 ; 58 : 71 . WorldCat 26. Weigle KA , Santrich C , Martinez F et al. Epidemiology of cutaneous leishmaniasis in Colombia:Environmental and behavioral risk factors for infection, clinical manifestations, and pathogenicity . J Infect Dis 1993 ; 168 : 709 – 714 . WorldCat 27. Velez ID , Hendrickx E , Robledo SM , del Pilar Agudelo S . Gender and cutaneous leishmaniasis in Colombia . Cad Saude Publica. 2001 ; 17 : 171 – 180 . WorldCat 28. Okwor I , Uzonna J . Social and economic burden of human leishmaniasis . Am J Trop Med Hyg 2016 ; 94 ( 3 ): 489 – 493 . WorldCat 29. Castro EA , Soccol VT , Membrive N et al. Estudo das características epidemiológicas e clínicas de 332 casos de leishmaniose tegumentar notificados na região norte do Estado do Paraná de 1993 a 1998 . Rev Soc Bras Med Trop 2002 ; 35 ( 5 ): 445 – 452 . WorldCat 30. Monteiro WM , Neitzke HC , Lonardoni MVC et al. Distribuição geográfica e características epidemiológicas da leishmaniose tegumentar Americana em áreas de colonização antiga do Estado do Paraná, Sul do Brasil . Cad Saude Publica 2008 ; 24 ( 6 ): 1291 – 1303 . WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Transactions of The Royal Society of Tropical Medicine and HygieneOxford University Press

Published: May 12, 14

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