Visceral leishmaniasis in Brazil: scenarios and challenges for the surveillance and control

Adaptation of the vector and displacement of infected dogs to previously disease-free areas challenges visceral leishmaniasis (VL) control, and leads to geographic dispersion and occurrence in urban and peri-urban areas. Continuous VL control measures over time must be applied with a wide geographic reach, along with better diagnosis practices and timely treatment. The high case-fatality of human VL in areas of recent introduction and its growing association with HIV impose the need for an early diagnosis, treatment and the adoption of active search for human and canine cases incorporated into the routine of periodic home visits by health professionals. The increasing on public rejection of canine euthanasia as a control measure, the limitations of canine therapy with the current available drugs, and the controversies regarding available vaccines for canine protection are discussed. Good prospects on the insecticide-impregnated collars as an effective control measure are emphasized.

Spatial distribution and effects of land use and cover on cutaneous leishmaniasis vectors in the municipality of Paracambi, Rio de Janeiro, Brazil

ABSTRACT The municipality of Paracambi (Rio de Janeiro, Brazil) reports sporadic cases of American cutaneous leishmaniasis (ACL). Previous studies detected Nyssomyia intermedia (Diptera: Psychodidae) as the main vector in the region, but its spatial distribution and the presence of other vector species have not been evaluated. This study aims at filling this knowledge gap, by studying the ecology of sand flies, their spatiotemporal distribution, and correlation with land use/cover. Two campaigns of monthly sand fly collections using light traps and manual captures were conducted in 1992-1994 and 2001-2003. Females were dissected to detect natural Leishmania infections. The spatial distribution of sand flies was assessed using kernel density maps. Correlations with land use/cover were evaluated by extracting satellite imagery data around the capture points. A total of 17,232 sand flies from 13 species were captured. Medically important species included Ny. intermedia, Migonemyia migonei, Pintomyia fischeri and Ny. whitmani. No Leishmania-infected females were detected. Highest densities were detected in the peri-urban areas Cascata and Sabugo, and in rural areas São José and Mutirão. Ny. intermedia had statistically significant correlations with pasture and agricultural areas. Present results strengthened that Ny. intermedia and Mg. migonei are the main local ACL vectors. Correlations with land use evidence the association between ACL and anthropic environmental change.

Comparison of parasite load by qPCR and histopathological changes of inner and outer edge of ulcerated cutaneous lesions of cutaneous leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis (CL) is an infectious vector-borne disease caused by protozoa of the Leishmania genus that affects humans and animals. The distribution of parasites in the lesion is not uniform, and there are divergences in the literature about the choice of the better sampling site for diagnosis-inner or outer edge of the ulcerated skin lesion. In this context, determining the region of the lesion with the highest parasite density and, consequently, the appropriate site for collecting samples can define the success of the laboratory diagnosis. Hence, this study aims to comparatively evaluate the parasite load by qPCR, quantification of amastigotes forms in the direct exam, and the histopathological profile on the inner and outer edges of ulcerated CL lesions. METHODS: Samples from ulcerated skin lesions from 39 patients with confirmed CL were examined. We performed scraping of the ulcer inner edge (base) and outer edge (raised border) and lesion biopsy for imprint and histopathological examination. Slides smears were stained by Giemsa and observed in optical microscopy, the material contained on the smears was used to determine parasite load by quantitative real-time PCR (qPCR) with primers directed to the Leishmania (Viannia) minicircle kinetoplast DNA. The histopathological exam was performed to evaluate cell profile, tissue alterations and semi-quantitative assessment of amastigote forms in inner and outer edges. PRINCIPAL FINDINGS: Parasite loads were higher on the inner edge compared to the outer edge of the lesions, either by qPCR technique (P<0.001) and histopathological examination (P< 0.003). There was no significant difference in the parasite load between the imprint and scraping on the outer edge (P = 1.0000). CONCLUSION/SIGNIFICANCE: The results suggest that clinical specimens from the inner edge of the ulcerated CL lesions are the most suitable for both molecular diagnosis and direct parasitological examination.

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions.

INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern.

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions

Abstract INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern.

Leishmaniose visceral: cenários epidemiológicos e desafios / Visceral leishmaniasis: epidemiological scenarios and challenges

Um retrospecto histórico e epidemiológico da leishmaniose visceral (LV) no mundo e no Brasil e possíveis cenários dependentes de condicionantes ambientais, biológicos e sociais ressalta estratégias de vigilância e controle, enfatizando: associação de procedimentos com continuidade; conquistas e controvérsias em diagnóstico, tratamento, vacinação e uso de coleira com deltametrina, no cão; e ineficácia da terapêutica canina com as drogas disponíveis, mas boas perspectivas da vacina, na proteção individual, e da coleira impregnada, no controle coletivo. Considera a situação epidemiológica potencializada pela galopante urbanização da LV e sua dispersão geográfica, salientando desafios de controle por deslocamento do vetor e do cão infectado a novas áreas através do transporte rodoviário e ferroviário, e conflitos de rejeição à eutanásia canina. Alerta sobre a alta letalidade da LV humana em áreas de instalação recente e por associação crescente com HIV, impondo diagnóstico e tratamento precoces, para evitar agravamento clínico e óbitos, e adoção da busca ativa de casos humanos e caninos incorporada à rotina das visitações domiciliares periódicas da Estratégia Saúde da Família, para detecção de febre prolongada e outros sinais de LV e o encaminhamento a unidades de Saúde. Admite que a introdução do cão infectado em áreas indenes continuará um grande desafio.

A historical and epidemiological retrospect of visceral leishmaniasis (VL) in the world and in Brazil, and possible scenarios dependent of environmental, biological and social conditions stands out strategies of surveillance and control, emphasizing the association of procedures with continuity; conquests and controversies in diagnosis, treatment, vaccination and use of deltametrin collar in the dog; and ineffectiveness of canine therapy with available drugs, but good vaccine prospects, in individual protection, and impregnated collar, in collective control. It considers the epidemiological situation potentiated by the galloping urbanization of VL and its geographical dispersion, highlighting control challenges by moving the vector and the infected dog to new areas through road and rail transport, and conflicts of rejection to canine euthanasia. Alert on the high lethality of human LV in areas of recent installation and by increasing association with HIV, imposing early diagnosis and treatment, to avoid clinical worsening and death, and adoption of the active search of human and canine cases incorporated into the routine of the periodic home visits of the Family Health Strategy to detect prolonged fever and other signs of LV and referral to health units. Introducing the infected dog into free transmission areas will remain a major challenge.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

BACKGROUND: American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES: To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS: Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS: Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS: Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013)

BACKGROUND American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. OBJECTIVES To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. METHODS Data were recovered from records of all ATL patients diagnosed during that period. FINDINGS Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. MAIN CONCLUSIONS Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Low versus high dose of antimony for American cutaneous leishmaniasis: A randomized controlled blind non-inferiority trial in Rio de Janeiro, Brazil.

BACKGROUND: Although high dose of antimony is the mainstay for treatment of American cutaneous leishmaniasis (ACL), ongoing major concerns remain over its toxicity. Whether or not low dose antimony regimens provide non-inferior effectiveness and lower toxicity has long been a question of dispute. METHODS: A single-blind, non-inferiority, randomized controlled trial was conducted comparing high dose with low dose of antimony in subjects with ACL treated at a referral center in Rio de Janeiro, an endemic area of Leishmania (Viannia) braziliensis transmission. The primary outcome was clinical cure at 360 days of follow-up in the modified-intention-to-treat (mITT) and per-protocol (PP) populations. Non-inferiority margin was 15%. Secondary objectives included occurrence of epithelialization, adverse events and drug discontinuations. This study was registered in ClinicalTrials.gov: NCT01301924. RESULTS: Overall, 72 patients were randomly assigned to one of the two treatment arms during October 2008 to July 2014. In mITT, clinical cure was observed in 77.8% of subjects in the low dose antimony group and 94.4% in the high dose antimony group after one series of treatment (risk difference 16.7%; 90% CI, 3.7-29.7). The results were confirmed in PP analysis, with 77.8% of subjects with clinical cure in the low dose antimony group and 97.1% in the high dose antimony group (risk difference 19.4%; 90% CI, 7.1-31.7). The upper limit of the confidence interval exceeded the 15% threshold and was also above zero supporting the hypothesis that low dose is inferior to high dose of antimony after one series of treatment. Nevertheless, more major adverse events, a greater number of adverse events and major adverse events per subject, and more drug discontinuations were observed in the high dose antimony group (all p<0.05). Interestingly, of all the subjects who were originally allocated to the low dose antimony group and were followed up after clinical failure, 85.7% achieved cure after a further treatment with local therapy or low dose of antimony. CONCLUSIONS: Compared with high dose, low dose of antimony was inferior at the pre-specified margin after one series of treatment of ACL, but was associated with a significantly lower toxicity. While high dose of antimony should remain the standard treatment for ACL, low dose antimony treatment might be preferred when toxicity is a primary concern.

Standardization of intralesional meglumine antimoniate treatment for cutaneous leishmaniasis.

INTRODUCTION:: Intralesional treatment for cutaneous leishmaniasis has been applied for over 30 years at the Oswaldo Cruz Foundation, Rio de Janeiro, with good therapeutic results and without relevant systemic toxicity. METHODS: Meglumine antimoniate was injected subcutaneously, using a long medium-caliber needle (for example, 30mm × 0.8mm); patients received 1-3 injections, with 15-day intervals. RESULTS: The technique is described in detail sufficient to enable replication. CONCLUSIONS:: The treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate is a simple, effective, and safe technique, which may be used in basic healthcare settings.

Standardization of intralesional meglumine antimoniate treatment for cutaneous leishmaniasis

Abstract INTRODUCTION: Intralesional treatment for cutaneous leishmaniasis has been applied for over 30 years at the Oswaldo Cruz Foundation, Rio de Janeiro, with good therapeutic results and without relevant systemic toxicity. METHODS Meglumine antimoniate was injected subcutaneously, using a long medium-caliber needle (for example, 30mm × 0.8mm); patients received 1-3 injections, with 15-day intervals. RESULTS The technique is described in detail sufficient to enable replication. CONCLUSIONS: The treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate is a simple, effective, and safe technique, which may be used in basic healthcare settings.

Visceral leishmaniasis in Rio de Janeiro, Brazil: eco-epidemiological aspects and control.

From 1977 (index case) to 2006, 87 cases of visceral leishmaniasis were confirmed in the municipality of Rio de Janeiro, Brazil, in periurban areas on the continental and coastal slopes of the Pedra Branca massif and the continental slopes of the Gericinó massif. The majority (65.5%) of the patients were more than five years old, predominantly males (61.5%), but without any difference between the sexes below the age of 14 years. The overall fatality rate was 10.4%. Two cases of visceral leishmaniasis/human immunodeficiency virus coinfection were detected. Leishmania chagasi was isolated from human and canine cases. The associations between the presence of phlebotomines and human and canine migrations, disorderly occupation involving degradation of environmental preservation areas and poor socioeconomic conditions may have created a favorable setting for the establishment and propagation of the disease. Close epidemiological surveillance associated with traditional control measures and others (active case researches, land clearing and health education), reduced the incidence of human cases from 2.8 per 100,000 inhabitants in 1981 to less than 0.01 per 100,000 since 1997. The canine infection rates decreased from 4.6% in 1984 to 1.6% in 2008. Lutzomyia longipalpis was not detected in some locations where human and canine cases occurred. In the years 2007 and 2008, no new human cases were reported, but there is a persistent and worrisome residual canine seroprevalence.

Visceral leishmaniasis in Rio de Janeiro, Brazil: eco-epidemiological aspects and control / Leishmaniose visceral no Rio de Janeiro, Brasil: aspectos eco-epidemiológicos e controle

From 1977 (index case) to 2006, 87 cases of visceral leishmaniasis were confirmed in the municipality of Rio de Janeiro, Brazil, in periurban areas on the continental and coastal slopes of the Pedra Branca massif and the continental slopes of the Gericinó massif. The majority (65.5 percent) of the patients were more than five years old, predominantly males (61.5 percent), but without any difference between the sexes below the age of 14 years. The overall fatality rate was 10.4 percent. Two cases of visceral leishmaniasis/human immunodeficiency virus coinfection were detected. Leishmania chagasi was isolated from human and canine cases. The associations between the presence of phlebotomines and human and canine migrations, disorderly occupation involving degradation of environmental preservation areas and poor socioeconomic conditions may have created a favorable setting for the establishment and propagation of the disease. Close epidemiological surveillance associated with traditional control measures and others (active case researches, land clearing and health education), reduced the incidence of human cases from 2.8 per 100,000 inhabitants in 1981 to less than 0.01 per 100,000 since 1997. The canine infection rates decreased from 4.6 percent in 1984 to 1.6 percent in 2008. Lutzomyia longipalpis was not detected in some locations where human and canine cases occurred. In the years 2007 and 2008, no new human cases were reported, but there is a persistent and worrisome residual canine seroprevalence.

Entre 1977 (caso índice) e 2006 foram confirmados 87 casos de leishmaniose visceral no Município do Rio de Janeiro, oriundos de áreas peri-urbanas das vertentes continentais e litorâneas do Maciço da Pedra Branca e das vertentes continentais do Maciço do Gericinó. A maioria (65,5 por cento) dos pacientes tinha mais de 5 anos de idade, prevalecendo o sexo masculino (61,5 por cento), sem diferença de freqüência entre os sexos até os 14 anos. A letalidade foi de 10,4 por cento. Houve dois casos de co-infecção por leishmaniose visceral/vírus da imunodeficiência. Leishmania chagasi foi isolada de casos humanos e caninos. Presença de flebotomíneos associada a migrações humanas e caninas, ocupação desordenada degradando áreas de preservação ambiental e baixas condições socioeconômicas podem ter criado o contexto propício à instalação e à propagação da endemia. Vigilância epidemiológica estreita com as medidas tradicionais de controle e outras - busca ativa de pacientes, limpeza de terrenos e educação em saúde -, reduziram a incidência de casos humanos de 2,8 por 100 mil habitantes em 1981 para menos de 0,01 por 100 mil a partir de 1997. As taxas de infecção canina decresceram de 4,6 por cento em 1984 para 1,6 por cento em 2008. Lutzomyia longipalpis não foi detectada em algumas localidades onde ocorreram casos humanos e caninos. Em 2007 e 2008, nenhum novo caso da doença humana foi notificado, mas permanece uma preocupante prevalência sorológica residual canina.

Comparative study of amplification systems in immunoenzyme assays for the diagnosis of American tegumentary leishmaniasis.

We compared the accuracy and reliability of three amplification systems for enzyme immunoassays in the detection of specific IgG antibodies for the diagnosis of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis in patients from an endemic area in Rio de Janeiro, Brazil. Partially soluble antigens obtained from the promastigote forms of L. (V.) braziliensis were used. For development of the reaction, two chromogens, 1,2-orthophenylenediamine (OPD) and 3,3',5,5'-tetramethylbenzidine (TMB), and a fluorogen, 4-methylumbelliferylphosphate (MUP), were tested. The performance of each system was compared using the following parameters: accuracy, intraclass correlation coefficient (ICC), and area under the receiver operating characteristic (ROC) curve. Sensitivity was the same (97.4%) for all systems. The reliability was excellent (ICC = 98.6, 98.7, and 99.1%) and specificity was 93.7, 95.8, and 97.4% for OPD, MUP, and TMB, respectively, showing no statistical significance. Despite the absence of differences in the performance of the three systems, the use of TMB is suggested because of its operational advantages, such as low cost compared with fluorogens, easy manipulation, greater stability, and lower toxicity.

Retrospective study of 151 patients with cutaneous leishmaniasis treated with meglumine antimoniate

Descrição de uma série retrospectiva de 151 casos de leishmaniose cutânea atendidos entre 1967 e 1982. Destes, 139 (92%) pacientes apresentavam lesões ativas e foram tratados com antimoniato de meglumina diariamente: 81 adultos receberam uma ampola de 5ml e 58 crianças receberam 1 a 5ml. Quarenta e cinco (32,4%) pacientes receberam tratamento antimonial contínuo durante 25 a 116 dias e 94 (67,6%) receberam tratamento intermitente com 2 a 5 séries de antimoniato de meglumina, cada uma delas com duração de 10 a 25 dias e cujos intervalos de descanso entre as séries variaram de 10 a 60 dias. A dose de antimônio, calculada retrospectivamente em 66 (47,5%) casos, variou entre 3,9 e 28,7mg Sb5+/kg/dia. Desses pacientes, 35 receberam >10mg e 31 receberam <10mg Sb5+/kg/dia. Não houve diferença significativa no tempo de cicatrização entre adultos e crianças, entre esquemas intermitentes e ininterrupto, nem entre doses altas e baixas. Entretanto, o tempo de cicatrização nas pernas e pés (67,5 dias) foi superior ao encontrado em outras localizações (48,7 dias) (p < 0,001). Cinqüenta e um pacientes foram reavaliados entre cinco e 14 anos após o tratamento e mantinham-se clinicamente curados. Essa série originou ensaios clínicos prospectivos utilizando doses baixas de antimônio no Rio de Janeiro.