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Factors associated with survival in patients with visceral leishmaniasis treated at a reference hospital in northern Minas Gerais - Brazil

ABSTRACT

Background:

Visceral leishmaniasis (VL) is a public health problem and is a relevant cause of death in developing countries. This study aimed to evaluate the 20-year survival and predictors of worse prognosis in patients with VL admitted to a reference hospital for the treatment of infectious diseases between 1995 and 2016 in northern Minas Gerais, an area of high endemicity for VL.

Methods:

This retrospective cohort study was conducted at a hospital in northern Minas Gerais, Brazil. All patients with VL were evaluated over a 20-year period. The medical records were thoroughly analyzed. Cox regression analysis was performed to estimate factors associated with the probability of survival.

Results:

The cohort included 972 individuals, mostly male children <10 years old, from urban areas who presented at admission with the classic triad of fever, hepatosplenomegaly, and skin pallor. The mean hemoglobin level was 7.53 mg/dl. The mean interval between symptom onset and hospital admission was 40 days. The instituted therapies ranged from pentavalent antimonates to amphotericin, or both. The probability of survival was reduced to 78% one year after symptom onset. Hemoglobin levels and age were strongly associated with the probability of survival.

Conclusions:

Regardless of the mechanism underlying the reduction in hemoglobin and the non-modifiable factors of age, early initiation of drug treatment is the most appropriate strategy for increasing survival in patients with VL, which challenges health systems to reduce the interval between the onset of symptoms and hospital admission.

Keywords:
Leishmaniasis; Visceral; Survival; Prognosis; Public Health

INTRODUCTION

Visceral leishmaniasis (VL) is an infectious parasitic disease affecting neglected populations. VL is caused by the protozoa of the Leishmania donovani complex, which includes three species with typical morphological variations. For example, the Leishmania donovani species is the most common in the Old World (mainly in India), and in America, the Leishmania (Leishmania) chagasi or Leishmania (Leishmania) infantum11. Lainson R. As espécies de Leishmania Neotropical: uma breve revisão histórica de sua descoberta, ecologia e taxonomia. Rev Pan-Amaz Saude [Internet]. Junho de 2010 [cited 17 de julho de 2022] ; 1(2): 13-32. Available at: Available at: http://scielo.iec.gov.br/scielo.php?script=sci_arttext&pid=S217662232010000200002&lng=en . Doi: http://dx.doi.org/10.5123/S2176-62232010000200002.
http://scielo.iec.gov.br/scielo.php?scri...
,22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91. are more common.

VL is the most severe form of leishmaniasis and causes a group of diseases with a broad clinical spectrum. These diseases are transmitted by infected female sand flies, i.e., it is a vector-borne disease. If not treated properly, VL is fatal in 95% of the cases33. Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
https://www.who.int/news-room/fact-sheet...
.

Clinically, VL commonly presents as prolonged fever, hepatosplenomegaly, and skin pallor. However, it can also result in weight loss and decreased appetite. From a laboratory point of view, pancytopenia is frequently detected with reduced hematimetric parameters, thus leading to anemia, leukopenia, and thrombocytopenia, which in turn favor the triggers coinfection and hemorrhagic events. Early diagnosis increases the likelihood of survival and is based on clinical, epidemiological, serological, and direct parasitological examination. Parasitological examination is the gold standard and is usually more expensive and more invasive22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.

3. Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
https://www.who.int/news-room/fact-sheet...
-44. Martins IML, Silva JS, Campos DKO, Oliveira RS, Silva PLN, Carvalho SFG, et al. Visceral leishmaniasis: historical series of hospitalized patients and correlation with climate in an endemic area in Minas Gerais, Brazil. Laboratório J Bras Patol Med [online]. 2021;57:e2702021. [Accessed 2021 December 28] Available from: https://doi.org/10.5935/1676-2444.20210045. Epub 2021 November 29. ISSN 1678-4774.
https://doi.org/10.5935/1676-2444.202100...
.

According to the World Health Organization (WHO)33. Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
https://www.who.int/news-room/fact-sheet...
, 90% of the cases reported in 2021 occurred in ten countries, Brazil, Ethiopia, Eritrea, India, Iraq, Kenya, Nepal, Somalia, South Sudan, and Sudan.

In 20 years, Brazil has reported more than 50.000 cases of VL, and the WHO estimates that there are an average of 70.000 new cases of VL annually, suggesting that the cases could be underdiagnosed and underreported55. Donato LE, Freitas LRS, Duarte EC, Romero GAS. Visceral leishmaniasis lethality in Brazil: an exploratory analysis of associated demographic and socioeconomic factors. Rev Soc Bras Med Trop. 2020;53:e20200007. Available from: https://doi.org/10.1590/0037-8682-0007-2020. PMID: 32935778; PMCID: PMC7491564.
https://doi.org/10.1590/0037-8682-0007-2...
. In Latin America, 70% of the cases occur in Brazil 33. Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
https://www.who.int/news-room/fact-sheet...
,66. Brasil, Ministério da Saúde. Leishmaniose Visceral - Casos confirmados notificados no Sistema de Informação de Agravos de Notificação - SINAN Brasil. January 2022. Available at: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinannet/cnv/leishvbr.def.
http://tabnet.datasus.gov.br/cgi/deftoht...
. Of the cases reported in Brazil, 43.5% occurred in children under 10 years of age, and the infection was most prevalent age group in the age group of 1-4 years (12.712 cases, 25.4%)66. Brasil, Ministério da Saúde. Leishmaniose Visceral - Casos confirmados notificados no Sistema de Informação de Agravos de Notificação - SINAN Brasil. January 2022. Available at: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinannet/cnv/leishvbr.def.
http://tabnet.datasus.gov.br/cgi/deftoht...
.

The Notifiable Diseases Information System (SINAN) showed an 85% increase in VL lethality from 1994 to 2004, increasing from 3.6% in 1994 to 6.7% in 2003, and to 8.4% in 200477. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica . Leishmaniose visceral grave: normas e condutas. Brasília: Editora do Ministério da Saúde, 2006. 60 p.. Between 2007 and 2020, based on the number of confirmed cases and deaths from VL, the lethality rate was estimated to be 6.82%. This decrease could be explained by the introduction of new therapeutic options and intensified strategies to combat the vector and control urban reservoirs66. Brasil, Ministério da Saúde. Leishmaniose Visceral - Casos confirmados notificados no Sistema de Informação de Agravos de Notificação - SINAN Brasil. January 2022. Available at: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinannet/cnv/leishvbr.def.
http://tabnet.datasus.gov.br/cgi/deftoht...

7. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica . Leishmaniose visceral grave: normas e condutas. Brasília: Editora do Ministério da Saúde, 2006. 60 p.

8. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Leishmaniose visceral: recomendações clínicas para redução da letalidade Brasília: Ministério da Saúde, 2011. 78 p.

9. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de vigilância e controle da leishmaniose visceral1. ed., 5. reimpr. - Brasília : Ministério da Saúde, 2014. 120 p.
-1010. Carvalho LS, das Graças Braga M, da Silva Costa DA, Simões TC, Lula MD, Silveira MR. Lethality among individuals infected with visceral leishmaniasis in Brazil: a retrospective study (2007-2018). Parasitol Res. 2022;121(2):725-36. Available from: https://doi.org/10.1007/s00436-022-07429-3. Epub 2022 Jan 11. PMID: 35013872.
https://doi.org/10.1007/s00436-022-07429...
.

Regarding the survival of patients with VL, several factors have been identified as predictors of reduced survival probability and can be categorized into clinical, sociodemographic, laboratory, and contextual variables.

In the clinical variables: comorbidities22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.,1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.

12. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...

13. Oliveira AM, López RVM, Dibo MR, Rodas LAC, Guirado MM, Chiaravalloti-Neto F. Dispersion ofLutzomyia longipalpisand expansion of visceral leishmaniasis in São Paulo State, Brazil: identification of associated factors through survival analysis. Parasit Vectors. 2018;11:503. Available from: https://doi.org/10.1186/s13071-018-3084-1
https://doi.org/10.1186/s13071-018-3084-...
-1414. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40., hemorrhagic sites22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.,1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.,1313. Oliveira AM, López RVM, Dibo MR, Rodas LAC, Guirado MM, Chiaravalloti-Neto F. Dispersion ofLutzomyia longipalpisand expansion of visceral leishmaniasis in São Paulo State, Brazil: identification of associated factors through survival analysis. Parasit Vectors. 2018;11:503. Available from: https://doi.org/10.1186/s13071-018-3084-1
https://doi.org/10.1186/s13071-018-3084-...
,1515. Luz JGG, Naves DB, Carvalho AG, Meira GA, Dias JVL, Fontes CJF. Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality. Rev Inst Med Trop São Paulo. 2018;60:e12:1-9., jaundice22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.,1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.-1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
severe malnutrition1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
, long-term illness1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
, concomitant bacterial infections1414. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40.,1515. Luz JGG, Naves DB, Carvalho AG, Meira GA, Dias JVL, Fontes CJF. Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality. Rev Inst Med Trop São Paulo. 2018;60:e12:1-9., vomiting1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43., edema1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43., splenomegaly1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.,1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
, pneumonia1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43., bleeding on admission1616. Ben Helel K, Ben Rejeb M, Habboul Z, Khattat N, Mejaouel H, Said-Latiri H, et al. Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. PLoS ONE 2017;12(12):e0189725. Available from: https://doi.org/10.1371/journal. pone.0189725: 1-9.
https://doi.org/10.1371/journal...
, delay between onset of symptoms and admission more than 15 days1616. Ben Helel K, Ben Rejeb M, Habboul Z, Khattat N, Mejaouel H, Said-Latiri H, et al. Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. PLoS ONE 2017;12(12):e0189725. Available from: https://doi.org/10.1371/journal. pone.0189725: 1-9.
https://doi.org/10.1371/journal...
, waiting time between onset of symptoms and treatment1717. Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17., and duration of treatment1717. Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17.. Jaundice, HIV coinfection, tuberculosis, edema, and bleeding were strongly associated with a negative prognosis in some studies (OR > 3)22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.,1111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.

12. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...

13. Oliveira AM, López RVM, Dibo MR, Rodas LAC, Guirado MM, Chiaravalloti-Neto F. Dispersion ofLutzomyia longipalpisand expansion of visceral leishmaniasis in São Paulo State, Brazil: identification of associated factors through survival analysis. Parasit Vectors. 2018;11:503. Available from: https://doi.org/10.1186/s13071-018-3084-1
https://doi.org/10.1186/s13071-018-3084-...

14. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40.

15. Luz JGG, Naves DB, Carvalho AG, Meira GA, Dias JVL, Fontes CJF. Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality. Rev Inst Med Trop São Paulo. 2018;60:e12:1-9.

16. Ben Helel K, Ben Rejeb M, Habboul Z, Khattat N, Mejaouel H, Said-Latiri H, et al. Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. PLoS ONE 2017;12(12):e0189725. Available from: https://doi.org/10.1371/journal. pone.0189725: 1-9.
https://doi.org/10.1371/journal...
-1717. Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17..

In the laboratory variables: elevated presence of some chemical mediators of immune response22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91., platelet count less than 50.000/mm31111. Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43., hemoglobin 6.5 mg/dl1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
, low total blood cell count, low platelets and high aspartate transaminase/alanine aminotransferase1414. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40., white blood cell count less than 4.000/mm3, and cytolysis1616. Ben Helel K, Ben Rejeb M, Habboul Z, Khattat N, Mejaouel H, Said-Latiri H, et al. Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. PLoS ONE 2017;12(12):e0189725. Available from: https://doi.org/10.1371/journal. pone.0189725: 1-9.
https://doi.org/10.1371/journal...
.

In the sociodemographic factors, age1717. Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17. presented as a heterogeneous aspect in the studies; specifically, age ≥60 years1212. Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
https://doi.org/10.1371/ journal.pntd.00...
or <12 months1414. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40.. Low education1818. Nunes BEBR, Leal TC, Paiva JPS, Silva LF, Carmo RF, Machado MF, et al. Social determinants of mortality due to visceral leishmaniasis in Brazil (2001-2015): an ecological study. Rev Soc Bras Med Trop . 2020;53:e20190262. was also a significant predictor.

The contextual variables included lack of garbage collection, unemployment rate, low per capita income and income inequality1818. Nunes BEBR, Leal TC, Paiva JPS, Silva LF, Carmo RF, Machado MF, et al. Social determinants of mortality due to visceral leishmaniasis in Brazil (2001-2015): an ecological study. Rev Soc Bras Med Trop . 2020;53:e20190262., district of residence1717. Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17. high and low average temperatures, and road construction1313. Oliveira AM, López RVM, Dibo MR, Rodas LAC, Guirado MM, Chiaravalloti-Neto F. Dispersion ofLutzomyia longipalpisand expansion of visceral leishmaniasis in São Paulo State, Brazil: identification of associated factors through survival analysis. Parasit Vectors. 2018;11:503. Available from: https://doi.org/10.1186/s13071-018-3084-1
https://doi.org/10.1186/s13071-018-3084-...
.

Based on these covariates, the intervention measures can be more specific and given in a timely manner to optimize the disease prognosis.

This study aimed to evaluate the 20-year survival and predictors of worse prognosis in patients with VL admitted to a reference hospital for the treatment of infectious diseases between 1995 and 2016 in northern Minas Gerais, an area of high endemicity for VL.

METHODS

● Ethical considerations

Although the present study used secondary data to analyze mortality in individuals with VL, this work was referred to the Ethics Committee on Human Research (CEP/Unimontes) and received a favorable opinion for its development (Opinion 1.471.595).

● Study Design

A retrospective cohort study was conducted in patients diagnosed with VL and followed up using medical records, medical charts, and an internal transfer control system. The follow-up time was 24 months in this study. The study was conducted at the Clemente de Faria University Hospital - HUCF (which is a reference in Leishmaniases), located in the city of Montes Claros, northern Minas Gerais - Brazil, 421.7 km from the capital Belo Horizonte and has an estimated population of 417.478 people1919. Instituto Brasileiro de Geografia e Estatística (IBGE). Panorama cidades [Internet]. IBGE, 2021. [ cited 2022, junho 15]. Available at: Available at: https://cidades.ibge.gov.br/brasil/mg/montes-claros/panorama
https://cidades.ibge.gov.br/brasil/mg/mo...
. The hospital is part of the administrative unit of Montes Claros State University UNIMONTES and has 151 beds. It is a public service funded by the state and federal resources2020. Universidade Estadual de Montes Claros - UNIMONTES. Hospital Universitário Clemente de Faria [Internet]. Montes Claros; 2022 (cited may 2022). Available at: Available at: https://unimontes.br/unidades/hospital-universitario/
https://unimontes.br/unidades/hospital-u...
.

● Data Collection

Data for up to 20 years prior to the study were collected. Data from January 1, 1995, to December 31, 2016 was collected. For data collection, an instrument was developed by the researchers themselves based on variables known to correlate with VL: demographic, socioeconomic, and laboratory variables; origin; diagnostic tests; selected therapy; and clinical evolution.

All patients with VL hospitalized during the study period were investigated using a census. Data collection was carried out by professionals trained with the instrument terms and the data extracted from medical records. All data collection was supervised by a primary researcher.

Serological diagnosis was done using immunofluorescence and immunochromatographic methods or rapid tests, depending on availability. The tests followed the standardization of the Ezequiel Dias Foundation (FUNED), whose laboratory is a reference in the state of Minas Gerais (MG) for infectious and parasitic diseases,

● Survival data

Specifically, for the assessment of survival, the follow-up time was determined from the appearance of the first signs and symptoms reported by the patient until failure. In this study, the failure event was death due to VL, and cases of hospital discharge, transfer to another service, and even death for other reasons were censored.

● Statistical Analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 24.0). Initially, the independent variables were presented descriptively, and then bivariate analyses were carried out using the simple Cox regression model at a significance level of p ≤ 0.2 to determine the variables to be included in the multiple model (COX regression). Next, the Kaplan-Meier method was used to estimate the probability of survival at each time point, with and without stratification.

Log-rank and Breslow tests were used to evaluate the survival curves of the strata of categorical variables, age and treatment, respectively.

Pearson's correlation test was used because the residuals of the variables that remained in the final model followed a normal distribution (age in years and hemoglobin), resulting in a null correlation between these covariates and follow-up time. The proportionality assumption for the COX regression model used to estimate the effect of covariates on survival was met. The final multiple model comprised of the variables which were statistically significant (p < 0.05).

RESULTS

We identified 972 individuals (male to female ratio: 1.18:1; mean age: 12.9 ± 17.06 years) with confirmed VL diagnosis. Most individuals with VL were children from municipalities or districts in areas considered endemic for leishmaniasis (northern macro-regions and Jequitinhonha Valley of Minas Gerais State and southern macro-region of Bahia State). Approximately 20% of individuals resided in rural areas.

In more than 90% of the cases, these individuals presented with the classic triad of VL: fever, hepatosplenomegaly, and skin pallor. The diagnosis was often confirmed by serology, followed by clinical and/or parasitological tests. These individuals were treated with the standard first-line (e.g., pentavalent antimonate) and second-line medications, (e.g., amphotericin B), and in many cases (36.9%) both drugs were used for treatment when the treatment started with the first line but was replaced by the second line due to the adverse effects of the drug.

However, it is important to note that, from 2011 to 2014, there was experience of treating patients with VL treated with both drugs simultaneously, according to a multicenter study that included the hospital unit of this study and later documented by Romero et al. in 2017.2121. Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, et al. Eficácia e segurança dos tratamentos disponíveis para leishmaniose visceral no Brasil: um estudo multicêntrico, randomizado e aberto. PLoS Negl Trop Dis. 2017; 11(6):e0005706. Available from: https://doi.org/10.1371/journal.pntd.0005706
https://doi.org/10.1371/journal.pntd.000...
. However, there was no difference to the standard treatment plan, which is first treatment with glucantime and then amphotericin, or in specific cases, amphotericin was the first choice for eligible patients. During hospitalization, the mean hemoglobin was 7.53 mg/dL (Table 1).

TABLE 1:
Selected independent variables (demographic, clinical, biochemical and therapeutic) as predictors of survival probability in patients with visceral leishmaniasis admitted to HUCF between 1995 and 2016.

The time interval between symptom onset and hospital admission with VL diagnosis was 39.8 days (± 54.81), ranging from two days to two years. The mean hospital stay was 18.41 days (± 9.86), ranging from one to ninety days. Among the patient who were followed-up, 18 patients (approximately 2% of the cases)n died. Of these, 72.2% were male, 27.8% were up to two years old, 72.2% lived in urban areas, Montes Claros was the place of origin (22.2%), and 61.1% were treated with amphotericin. A portion of the patients were transferred to other services (1.6%), and the majority were discharged during outpatient follow-up (96.5%).

The Kaplan-Meier curve demonstrated that the probability of survival after one year of follow-up was 78% (Figure 1). The variable age in years was dichotomized into individuals <10 and >10 years to verify if there was a difference between the survival curves of younger and older individuals, but the log-rank test showed no statistical difference (probably due to sample fluctuation.

FIGURE 1:
Survival function for Visceral Leishmaniasis among patients treated at HUCF between 1995 and 2016.

Another aspect highlighted was the difference in the therapeutic plans. The difference in survival between the treatments adopted based on the Breslow test was borderline (p = 0.054); however, it was not possible to rule out the possibility of differences in survival probability between treatments (Figure 2).

FIGURE 2:
Survival of Visceral Leishmaniasis according to treatment among patients treated at HUCF between 1995 and 2016.

The independent variables that remained in the final model were hemoglobin and age (Table 2). Using the multiple Cox regression model, it is possible to observe that an increase of 1 (one) unit in hemoglobin dosage reduced the hazard ratio for death by 44.7%, keeping the other variables (i.e. age) constant. Increasing patients life expectancy by one year increased the hazard ratio for death by 3%, keeping the other variables constant.

TABLE 2:
COX regression model with proportional hazards for survival analysis of patients with visceral leishmaniasis seen at HUCF 1995 and 2016.

DISCUSSION

This study of 972 individuals showed that the factors associated with survival in this study were age and hemoglobin

Yeshaw et al22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91., in a retrospective cohort of 586 individuals showed that the factors associated with an increased incidence of mortality in patients with VL, included comorbidities, nosebleeds, treatment toxicity, jaundice, and being bedridden at admission. Based on the findings of the present study it can be suggested that nosebleeds might contribute to reduced hemoglobin and impact prognosis, as well as treatment toxicity, leading to a change in the therapeutic approach.

Based on this, Costa et al2222. Costa CHN, Werneck GL, Costa DL, Holanda TA, Aguiar GB, Carvalho AS. Is severe visceral leishmaniasis a systemic inflammatory response syndrome? - A case control study. Rev Soc Bras Med Trop . 2010; 43(4):386-92. had proposed bleeding and anemia as negative prognostic factors. The biological plausibility of bleeding and anemia in VL cases is correlated with increased levels of pro-inflammatory cytokines: IL-8, IL-1β, IL-10, and IFN-γ, which are also exacerbated in cases of bacterial coinfection. According to Moulik2323. Moulik S, Karmakar J, Joshi S, Dube A, Mandal C, Chatterjee M. Status of IL-4 and IL-10 driven markers in experimental models of Visceral Leishmaniasis. Parasite Immunol. 2021;43(1):e12783. Available from: https://doi.org/10.1111/pim.12783. Epub 2020 Aug 27. PMID: 32734677.
https://doi.org/10.1111/pim.12783...
, there is a positive correlation between the parasite load in VL and elevated levels of IL-10 in animal models. This suggests that this mechanism could be triggered by Leishmania chagasi for its survival in the body. However, the parasite-host interaction that sustains VL is still limited.

Another study2424. Tadesse D, Abdissa A, Mekonnen M, Belay T, Hailu A. Antibody and cytokine levels in visceral leishmaniasis patients with varied parasitemia before, during, and after treatment in patients admitted to Arba Minch General Hospital, southern Ethiopia. PLoS Negl Trop Dis . 2021;15(8):e0009632. Available from: https://doi.org/10.1371/journal.pntd.0009632. PMID: 34351903; PMCID: PMC8370634.
https://doi.org/10.1371/journal.pntd.000...
corroborated these findings and demonstrated elevated levels of IL-10, IFN-γ, and TGF-β1 before the institution of treatment. The observed increase in serum IL-10 levels decreased remarkably within one week of treatment initiation. In addition, hematimetric parameters such as hemoglobin, leukocytes and platelets were restored to normal levels after the treatment was implemented. They findings further suggested the adoption of clinically associated IL-10 measurements as a criterion for curing the infection.

It is important to highlight the work of Morimoto2525. Morimoto A, Uchida K, Chambers JK, Sato K, Hong J, Sanjoba C, et al. Hemophagocytosis induced by Leishmania donovani infection is beneficial to parasite survival within macrophages. PLoS Negl Trop Dis . 2019;13(11):e0007816. https://doi.org/10.1371/journal.pntd.0007816. PMID: 31738750; PMCID: PMC6886864.
https://doi.org/10.1371/journal.pntd.000...
who demonstrated that in animal models he observed the hemophagocytic activity of macrophages infected with Leishmania parasites in animal models, the study showed the benefits of this procedure, that is, inducing the infected macrophage to perform phagocytosis of red blood cells for its survival

Thus, two possible mechanisms can explain the reduction of hemoglobin: bleeding favored by pro-inflammatory cytokines, and hemophagocytosis induced by the parasite.

Pinho et al2626. Pinho FA, Vendrame CMV, Maciel BLL, Silva LDS, Miyashiro SI, Jerônimo SMB, et al. Association between Insulin-Like Growth Factor-I Levels and the Disease Progression and Anemia in Visceral Leishmaniasis. Am J Trop Med Hyg. 2019;100(4):808-15. Available from: https://doi.org/10.4269/ajtmh.17-0982. PMID: 30761980; PMCID: PMC6447109.
https://doi.org/10.4269/ajtmh.17-0982...
observed a positive association between low expression of insulin-like growth factor-1 (IGF-1) and lower hemoglobin levels in patients with severe VL, suggesting a pathogenic mechanism different from that related to cytokine production and hemophagocytosis.

Henn et al2727. Henn GAL, Ramos Júnior AN, Colares JKB, Mendes LP, Silveira JGC, Lima AAF, et al. Is Visceral Leishmaniasis the same in HIV-coinfected adults? Braz J Infect Dis. 2018;22(2):92-8. Available from: https://doi.org/10.1016/j.bjid.2018.03.001. Epub 2018 Mar 27. PMID: 29601790.
https://doi.org/10.1016/j.bjid.2018.03.0...
investigated the laboratory characteristics of patients with VL coinfected with HIV, and measured the hematimetric parameters. That study showed lower levels of hemoglobin, lymphocyte count, and liver enzymes, and higher platelet and eosinophil counts in patients with VL coinfected with HIV when compared to patients with only VL. This increased the mortality outcome in those patients.

Mulaw et al2828. Mulaw T, Tariku A, Tsegaye AT, Abebe Z. Effect of iron-folic acid supplementation on change of hemoglobin among visceral Leishmaniasis patients in northwest Ethiopia: a retrospective follow up study. BMC Hematol. 2018;18:29. Available from: https://doi.org/10.1186/s12878-018-0123-2. PMID: 30258634; PMCID: PMC6151065.
https://doi.org/10.1186/s12878-018-0123-...
proposed that iron and folic acid supplementation increased hemoglobin levels in patients with VL; however, this procedure favored the parasite. Parasite replication increases when trace elements are absorbed by amastigotes. The high affinity of protozoans for iron ions favors its survival and reproduction in intracellular environments.

The time between the onset of symptoms and treatment is a significant variable that determines the prognosis of the affected individuals44. Martins IML, Silva JS, Campos DKO, Oliveira RS, Silva PLN, Carvalho SFG, et al. Visceral leishmaniasis: historical series of hospitalized patients and correlation with climate in an endemic area in Minas Gerais, Brazil. Laboratório J Bras Patol Med [online]. 2021;57:e2702021. [Accessed 2021 December 28] Available from: https://doi.org/10.5935/1676-2444.20210045. Epub 2021 November 29. ISSN 1678-4774.
https://doi.org/10.5935/1676-2444.202100...
. Although this interval in this study was approximately 30 days on average, there were cases that remained for more than a year without proper diagnosis and necessary therapeutic intervention, suggesting a failure of the health system.

World Health Organization - OMS33. Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
https://www.who.int/news-room/fact-sheet...
presented clear information that confirms the Kaplan-Meier curve of this study; a longer follow-up time indicates a significant reduction in the probability of survival. Therefore, early detection and development of drug therapies are important.

This issue presents a challenge to health systems in developing countries. Training of health professionals, epidemiological surveillance, enhancement of human development, environmental management, and rational use of insecticides are strategies that can impact the health of neglected populations in relation to VL.

In this study, the difference in the Kaplan-Meier curve between the treatments adopted was borderline (p = 0.054), and it is not prudent to rule out the difference in the probability of survival between the therapeutic strategies or to consider them identical.

It is important to point out that there could have been a selection bias in this sample that influenced the Kaplan-Meier curve in terms of treatment-related survival. The most severely ill patients from the clinical and laboratory perspectives were selected for the amphotericin regimen, as recommended by the Brazilian Ministry of Health88. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Leishmaniose visceral: recomendações clínicas para redução da letalidade Brasília: Ministério da Saúde, 2011. 78 p.. Thus, there was a greater propensity for death, which could have generated an association between this treatment and a lower chance of survival.

In a study by Yeshaw22. Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91. The drug toxicity in patients was shown to be a negative predictor of survival, with a death risk of 5.87 (95% CI 3.30-10.44) in relation to those who did not present adverse reaction. Anti-leishmania drugs in general have significant toxicity depending on the dose and condition of the individual. Arrhythmias and pancreatitis are possible manifestations in individuals undergoing anti-leishmania treatment99. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de vigilância e controle da leishmaniose visceral1. ed., 5. reimpr. - Brasília : Ministério da Saúde, 2014. 120 p..

Bulté2929. Bulté D, Van Bockstal L, Dirkx L, Van den Kerkhof M, De Trez C, Timmermans JP, et al. Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition. PLoS Negl Trop Dis . 2021;15(7):e0009622. Available from: https://doi.org/10.1371/journal.pntd.0009622. PMID: 34292975; PMCID: PMC8330912.
https://doi.org/10.1371/journal.pntd.000...
described an increase in the infectivity of a strain of Leishmania infantum due to resistance to miltefosine, highlighting a possible therapeutic failure resulting from treatment of this parasite variant. Oliveira3030. Oliveira VVG, Aranda de Souza MA, Cavalcanti RRM, de Oliveira Cardoso MV, Leite ACL, da Silva Junior VA, et al. Study of in vitro biological activity of thiazoles on Leishmania (Leishmania) infantum. J Glob Antimicrob Resist. 2020;22:414-21. Available from: https://doi.org/10.1016/j.jgar.2020.02.028. Epub 2020 Mar 9. PMID: 32165288.
https://doi.org/10.1016/j.jgar.2020.02.0...
proposed the use of thiazolic derivatives as alternative treatments for VL. That in vitro study showed promising results, with lower toxicity to mammalian cells and evident leishmanicidal activity.

Currently, the recommended treatment regimen for patients with VL in Europe, the Americas, and the Mediterranean is liposomal amphotericin B at 20-21 mg/kg without HIV coinfection3131. Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63(12):e202-e264. Available from: https://doi.org/10.1093/cid/ciw670. Epub 2016 Nov 14. PMID: 27941151.
https://doi.org/10.1093/cid/ciw670...

32. Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol. 2006;61:223-74. Available from: https://doi.org/10.1016/S0065-308X(05)61006-8. PMID: 16735166.
https://doi.org/10.1016/S0065-308X(05)61...

33. Bern C, Adler-Moore J, Berenguer J, Boelaert M, den Boer M, Davidson RN, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis . 2006;43(7):917-24. Available from: https://doi.org/10.1086/507530. Epub 2006 Aug 28. PMID: 16941377.
https://doi.org/10.1086/507530...
-3434. Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis . 2004;38(3):377-83. Available from: https://doi.org/10.1086/380971. Epub 2004 Jan 13. PMID: 14727208.
https://doi.org/10.1086/380971...
. However, until the time of this study, as per the protocols of the Brazilian Ministry of Health, pentavalent antimoniate formulations was the first-line of treatment99. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de vigilância e controle da leishmaniose visceral1. ed., 5. reimpr. - Brasília : Ministério da Saúde, 2014. 120 p.. Cost is a limiting factor; however, through donations and public policies, liposomal amphotericin B may be adopted as a first option88. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Leishmaniose visceral: recomendações clínicas para redução da letalidade Brasília: Ministério da Saúde, 2011. 78 p.,99. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de vigilância e controle da leishmaniose visceral1. ed., 5. reimpr. - Brasília : Ministério da Saúde, 2014. 120 p.,3535. Maia-Elkhoury ANS, Sierra Romero GA, O B Valadas SY, L Sousa-Gomes M, Lauletta Lindoso JA, Cupolillo E, et al. Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity? PLoS Negl Trop Dis . 2019;13(12):e0007841. Available from: https://doi.org/10.1371/journal.pntd.0007841. PMID: 31856199; PMCID: PMC6922316.
https://doi.org/10.1371/journal.pntd.000...
. Other therapeutic strategies have been investigated in other studies3636. Van Griensven J, Diro E. Visceral Leishmaniasis: Recent Advances in Diagnostics and Treatment Regimens. Infect Dis Clin North Am. 2019;33(1):79-99. Available from: https://doi.org/10.1016/j.idc.2018.10.005. PMID: 30712769.
https://doi.org/10.1016/j.idc.2018.10.00...
,3737. Rezaei R, Hazrati Tappeh K, Seyyedi S, Mikaili P. The Anti-leishmanial Efficacy of Artemisia dracunculus Ethanolic Extract in Vitro and Its Effects on IFN-γ and IL-4 Response. Iran J Parasitol. 2017;12(3):398-407. PMID: 28979350; PMCID: PMC5623920..

The demographic profile of patients with VL is recurrent in the scientific literature: males, young (especially children under 10 years of age), living in urban areas44. Martins IML, Silva JS, Campos DKO, Oliveira RS, Silva PLN, Carvalho SFG, et al. Visceral leishmaniasis: historical series of hospitalized patients and correlation with climate in an endemic area in Minas Gerais, Brazil. Laboratório J Bras Patol Med [online]. 2021;57:e2702021. [Accessed 2021 December 28] Available from: https://doi.org/10.5935/1676-2444.20210045. Epub 2021 November 29. ISSN 1678-4774.
https://doi.org/10.5935/1676-2444.202100...
. Contrary to existing literature, in this study, increasing age (3%) was associated with an increased probability of death.

The Pan-American Health Organization points out that VL affects extreme age groups such as children under five years and adults over 50 years (the most vulnerable groups)3838. Organização Pan-Americana da Saúde (OPAS), Organização Mundial da Saúde (OMS). Cooperação Técnica entre o Ministério da Saúde e a Organização Pan-Americana da Saúde - Leishmaniose Visceral. 2022. Available from: https://www.paho.org/pt/topicos/leishmaniose.
https://www.paho.org/pt/topicos/leishman...
. In a study by Carvalho et al1010. Carvalho LS, das Graças Braga M, da Silva Costa DA, Simões TC, Lula MD, Silveira MR. Lethality among individuals infected with visceral leishmaniasis in Brazil: a retrospective study (2007-2018). Parasitol Res. 2022;121(2):725-36. Available from: https://doi.org/10.1007/s00436-022-07429-3. Epub 2022 Jan 11. PMID: 35013872.
https://doi.org/10.1007/s00436-022-07429...
the highest probability of death was observed in older age groups; which is consistent with the finidngs presented in another study3939. Oliveira JM de, Fernandes AC, Dorval MEC, Alves TP, Fernandes TD, Oshiro ET, et al. Mortalidade por leishmaniose visceral: aspectos clínicos e laboratoriais. Rev Soc Bras Med Trop [Internet]. 2010; 43(2):188-93. Available from: https://doi.org/10.1590/S0037-86822010000200016.
https://doi.org/10.1590/S0037-8682201000...
. In contrast, in the study by Salih et al1414. Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40. the condition of an infant or child was associated with a higher probability of death (p = 0.02).

A study on premature mortality in patients with VL showed that children <5 years of age were diagnosed earlier than those in other age groups, and their survival was also lower than that in other age groups3535. Maia-Elkhoury ANS, Sierra Romero GA, O B Valadas SY, L Sousa-Gomes M, Lauletta Lindoso JA, Cupolillo E, et al. Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity? PLoS Negl Trop Dis . 2019;13(12):e0007841. Available from: https://doi.org/10.1371/journal.pntd.0007841. PMID: 31856199; PMCID: PMC6922316.
https://doi.org/10.1371/journal.pntd.000...
.

This discrepancy between findings can be explained by sample fluctuation and the confounding factor of age in relation to comorbidities, since the individual with advancing age are more likely to have comorbidities. In this study, the proportion of individuals in younger age groups was higher (more than 65% were less than 10 years old).

Thus, regardless of the underlying mechanism affecting the hemoglobin levels or age factor of patients with VL, early initiation of the recommended drug therapy is the best alternative for the survival in these individuals.

This study has several limitations. The study uses secondary data (such as medical records) that were not generated for research purposes, and because it is a teaching hospital, there are academic issues and turnover of staff members involved in care. Hence, the results should be considered with caution. Further, VL case notification forms were not used, which could increase the number of variables and produce a more robust analysis, although under-reporting is a problem, as it does not occur frequently in health services, and this becomes a point of attention in the context of this study4141. Maia-Elkhoury ANS, Carmo EH, Sousa-Gomes ML, Mota E. Análise dos registros de leishmaniose visceral pelo método de captura-recaptura. Rev Saúde Pública [Internet]. 2007;41(6):931-7. Available from: https://doi.org/10.1590/S0034-89102007000600007
https://doi.org/10.1590/S0034-8910200700...
. However, the findings presented in this study can hep in future purposefully designed studies conducted to verify the impact of hemoglobin and age on the survival of patients with VL.

ACKNOWLEDGMENTS

We express our sincere thanks to the management of the Hospital Universitário Clemente Faria - HUCF, who allowed the work to be carried out in detail, to the entire team of the medical and statistical archive service, to the personnel of the information technology service, without you it would be impossible to carry out this work.

REFERENCES

  • 1
    Lainson R. As espécies de Leishmania Neotropical: uma breve revisão histórica de sua descoberta, ecologia e taxonomia. Rev Pan-Amaz Saude [Internet]. Junho de 2010 [cited 17 de julho de 2022] ; 1(2): 13-32. Available at: Available at: http://scielo.iec.gov.br/scielo.php?script=sci_arttext&pid=S217662232010000200002&lng=en Doi: http://dx.doi.org/10.5123/S2176-62232010000200002.
    » https://doi.org/10.5123/S2176-62232010000200002» http://scielo.iec.gov.br/scielo.php?script=sci_arttext&pid=S217662232010000200002&lng=en
  • 2
    Yeshaw Y, Tsegaye AT, Nigatu SG. Incidence of Mortality and Its Predictors Among Adult Visceral Leishmaniasis Patients at the University of Gondar Hospital: A Retrospective Cohort Study. Infect Drug Resist. 2020;24(13):881-91.
  • 3
    Organização Mundial de Saúde (OMS). Leishmaniose [Internet]. Site da OMS: janeiro de 2022. Available at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
    » https://www.who.int/news-room/fact-sheets/detail/leishmaniasis
  • 4
    Martins IML, Silva JS, Campos DKO, Oliveira RS, Silva PLN, Carvalho SFG, et al. Visceral leishmaniasis: historical series of hospitalized patients and correlation with climate in an endemic area in Minas Gerais, Brazil. Laboratório J Bras Patol Med [online]. 2021;57:e2702021. [Accessed 2021 December 28] Available from: https://doi.org/10.5935/1676-2444.20210045. Epub 2021 November 29. ISSN 1678-4774.
    » https://doi.org/10.5935/1676-2444.20210045
  • 5
    Donato LE, Freitas LRS, Duarte EC, Romero GAS. Visceral leishmaniasis lethality in Brazil: an exploratory analysis of associated demographic and socioeconomic factors. Rev Soc Bras Med Trop. 2020;53:e20200007. Available from: https://doi.org/10.1590/0037-8682-0007-2020. PMID: 32935778; PMCID: PMC7491564.
    » https://doi.org/10.1590/0037-8682-0007-2020
  • 6
    Brasil, Ministério da Saúde. Leishmaniose Visceral - Casos confirmados notificados no Sistema de Informação de Agravos de Notificação - SINAN Brasil. January 2022. Available at: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinannet/cnv/leishvbr.def
    » http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sinannet/cnv/leishvbr.def
  • 7
    Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Departamento de Vigilância Epidemiológica . Leishmaniose visceral grave: normas e condutas. Brasília: Editora do Ministério da Saúde, 2006. 60 p.
  • 8
    Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Leishmaniose visceral: recomendações clínicas para redução da letalidade Brasília: Ministério da Saúde, 2011. 78 p.
  • 9
    Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de vigilância e controle da leishmaniose visceral1. ed., 5. reimpr. - Brasília : Ministério da Saúde, 2014. 120 p.
  • 10
    Carvalho LS, das Graças Braga M, da Silva Costa DA, Simões TC, Lula MD, Silveira MR. Lethality among individuals infected with visceral leishmaniasis in Brazil: a retrospective study (2007-2018). Parasitol Res. 2022;121(2):725-36. Available from: https://doi.org/10.1007/s00436-022-07429-3. Epub 2022 Jan 11. PMID: 35013872.
    » https://doi.org/10.1007/s00436-022-07429-3
  • 11
    Oliveira-Sena IV, Werneck GL. Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study. Journal of Infection and Public Health. 2020; (13):538-43.
  • 12
    Abongomera C, van Henten S, Vogt F, Buyze J, Verdonck K, van Griensven J. Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis. PLoS Negl Trop Dis. 2020; 14(5): e0008319. Available from: https://doi.org/10.1371/ journal.pntd.0008319
    » https://doi.org/10.1371/ journal.pntd.0008319
  • 13
    Oliveira AM, López RVM, Dibo MR, Rodas LAC, Guirado MM, Chiaravalloti-Neto F. Dispersion ofLutzomyia longipalpisand expansion of visceral leishmaniasis in São Paulo State, Brazil: identification of associated factors through survival analysis. Parasit Vectors. 2018;11:503. Available from: https://doi.org/10.1186/s13071-018-3084-1
    » https://doi.org/10.1186/s13071-018-3084-1
  • 14
    Salih OA, Nail AM, Modawe GA, Swar MO, Ahmed MH, Khalil A, et al. Risk factors of inpatients mortality of visceral leishmaniasis, Khartoum state, Sudan. J Global Infect Dis. 2020;12:135-40.
  • 15
    Luz JGG, Naves DB, Carvalho AG, Meira GA, Dias JVL, Fontes CJF. Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality. Rev Inst Med Trop São Paulo. 2018;60:e12:1-9.
  • 16
    Ben Helel K, Ben Rejeb M, Habboul Z, Khattat N, Mejaouel H, Said-Latiri H, et al. Risk factors for mortality of children with zoonotic visceral leishmaniasis in Central Tunisia. PLoS ONE 2017;12(12):e0189725. Available from: https://doi.org/10.1371/journal. pone.0189725: 1-9.
    » https://doi.org/10.1371/journal
  • 17
    Jervis S, Chapman LA, Dwivedi S, Karthick M, Das A, Le Rutte EA, et al. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors. 2017;10(1):1-17.
  • 18
    Nunes BEBR, Leal TC, Paiva JPS, Silva LF, Carmo RF, Machado MF, et al. Social determinants of mortality due to visceral leishmaniasis in Brazil (2001-2015): an ecological study. Rev Soc Bras Med Trop . 2020;53:e20190262.
  • 19
    Instituto Brasileiro de Geografia e Estatística (IBGE). Panorama cidades [Internet]. IBGE, 2021. [ cited 2022, junho 15]. Available at: Available at: https://cidades.ibge.gov.br/brasil/mg/montes-claros/panorama
    » https://cidades.ibge.gov.br/brasil/mg/montes-claros/panorama
  • 20
    Universidade Estadual de Montes Claros - UNIMONTES. Hospital Universitário Clemente de Faria [Internet]. Montes Claros; 2022 (cited may 2022). Available at: Available at: https://unimontes.br/unidades/hospital-universitario/
    » https://unimontes.br/unidades/hospital-universitario/
  • 21
    Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, et al. Eficácia e segurança dos tratamentos disponíveis para leishmaniose visceral no Brasil: um estudo multicêntrico, randomizado e aberto. PLoS Negl Trop Dis. 2017; 11(6):e0005706. Available from: https://doi.org/10.1371/journal.pntd.0005706
    » https://doi.org/10.1371/journal.pntd.0005706
  • 22
    Costa CHN, Werneck GL, Costa DL, Holanda TA, Aguiar GB, Carvalho AS. Is severe visceral leishmaniasis a systemic inflammatory response syndrome? - A case control study. Rev Soc Bras Med Trop . 2010; 43(4):386-92.
  • 23
    Moulik S, Karmakar J, Joshi S, Dube A, Mandal C, Chatterjee M. Status of IL-4 and IL-10 driven markers in experimental models of Visceral Leishmaniasis. Parasite Immunol. 2021;43(1):e12783. Available from: https://doi.org/10.1111/pim.12783. Epub 2020 Aug 27. PMID: 32734677.
    » https://doi.org/10.1111/pim.12783
  • 24
    Tadesse D, Abdissa A, Mekonnen M, Belay T, Hailu A. Antibody and cytokine levels in visceral leishmaniasis patients with varied parasitemia before, during, and after treatment in patients admitted to Arba Minch General Hospital, southern Ethiopia. PLoS Negl Trop Dis . 2021;15(8):e0009632. Available from: https://doi.org/10.1371/journal.pntd.0009632. PMID: 34351903; PMCID: PMC8370634.
    » https://doi.org/10.1371/journal.pntd.0009632
  • 25
    Morimoto A, Uchida K, Chambers JK, Sato K, Hong J, Sanjoba C, et al. Hemophagocytosis induced by Leishmania donovani infection is beneficial to parasite survival within macrophages. PLoS Negl Trop Dis . 2019;13(11):e0007816. https://doi.org/10.1371/journal.pntd.0007816. PMID: 31738750; PMCID: PMC6886864.
    » https://doi.org/10.1371/journal.pntd.0007816
  • 26
    Pinho FA, Vendrame CMV, Maciel BLL, Silva LDS, Miyashiro SI, Jerônimo SMB, et al. Association between Insulin-Like Growth Factor-I Levels and the Disease Progression and Anemia in Visceral Leishmaniasis. Am J Trop Med Hyg. 2019;100(4):808-15. Available from: https://doi.org/10.4269/ajtmh.17-0982. PMID: 30761980; PMCID: PMC6447109.
    » https://doi.org/10.4269/ajtmh.17-0982
  • 27
    Henn GAL, Ramos Júnior AN, Colares JKB, Mendes LP, Silveira JGC, Lima AAF, et al. Is Visceral Leishmaniasis the same in HIV-coinfected adults? Braz J Infect Dis. 2018;22(2):92-8. Available from: https://doi.org/10.1016/j.bjid.2018.03.001. Epub 2018 Mar 27. PMID: 29601790.
    » https://doi.org/10.1016/j.bjid.2018.03.001
  • 28
    Mulaw T, Tariku A, Tsegaye AT, Abebe Z. Effect of iron-folic acid supplementation on change of hemoglobin among visceral Leishmaniasis patients in northwest Ethiopia: a retrospective follow up study. BMC Hematol. 2018;18:29. Available from: https://doi.org/10.1186/s12878-018-0123-2. PMID: 30258634; PMCID: PMC6151065.
    » https://doi.org/10.1186/s12878-018-0123-2
  • 29
    Bulté D, Van Bockstal L, Dirkx L, Van den Kerkhof M, De Trez C, Timmermans JP, et al. Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition. PLoS Negl Trop Dis . 2021;15(7):e0009622. Available from: https://doi.org/10.1371/journal.pntd.0009622. PMID: 34292975; PMCID: PMC8330912.
    » https://doi.org/10.1371/journal.pntd.0009622
  • 30
    Oliveira VVG, Aranda de Souza MA, Cavalcanti RRM, de Oliveira Cardoso MV, Leite ACL, da Silva Junior VA, et al. Study of in vitro biological activity of thiazoles on Leishmania (Leishmania) infantum. J Glob Antimicrob Resist. 2020;22:414-21. Available from: https://doi.org/10.1016/j.jgar.2020.02.028. Epub 2020 Mar 9. PMID: 32165288.
    » https://doi.org/10.1016/j.jgar.2020.02.028
  • 31
    Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, et al. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63(12):e202-e264. Available from: https://doi.org/10.1093/cid/ciw670. Epub 2016 Nov 14. PMID: 27941151.
    » https://doi.org/10.1093/cid/ciw670
  • 32
    Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol. 2006;61:223-74. Available from: https://doi.org/10.1016/S0065-308X(05)61006-8. PMID: 16735166.
    » https://doi.org/10.1016/S0065-308X(05)61006-8
  • 33
    Bern C, Adler-Moore J, Berenguer J, Boelaert M, den Boer M, Davidson RN, et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis . 2006;43(7):917-24. Available from: https://doi.org/10.1086/507530. Epub 2006 Aug 28. PMID: 16941377.
    » https://doi.org/10.1086/507530
  • 34
    Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis . 2004;38(3):377-83. Available from: https://doi.org/10.1086/380971. Epub 2004 Jan 13. PMID: 14727208.
    » https://doi.org/10.1086/380971
  • 35
    Maia-Elkhoury ANS, Sierra Romero GA, O B Valadas SY, L Sousa-Gomes M, Lauletta Lindoso JA, Cupolillo E, et al. Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity? PLoS Negl Trop Dis . 2019;13(12):e0007841. Available from: https://doi.org/10.1371/journal.pntd.0007841. PMID: 31856199; PMCID: PMC6922316.
    » https://doi.org/10.1371/journal.pntd.0007841
  • 36
    Van Griensven J, Diro E. Visceral Leishmaniasis: Recent Advances in Diagnostics and Treatment Regimens. Infect Dis Clin North Am. 2019;33(1):79-99. Available from: https://doi.org/10.1016/j.idc.2018.10.005. PMID: 30712769.
    » https://doi.org/10.1016/j.idc.2018.10.005
  • 37
    Rezaei R, Hazrati Tappeh K, Seyyedi S, Mikaili P. The Anti-leishmanial Efficacy of Artemisia dracunculus Ethanolic Extract in Vitro and Its Effects on IFN-γ and IL-4 Response. Iran J Parasitol. 2017;12(3):398-407. PMID: 28979350; PMCID: PMC5623920.
  • 38
    Organização Pan-Americana da Saúde (OPAS), Organização Mundial da Saúde (OMS). Cooperação Técnica entre o Ministério da Saúde e a Organização Pan-Americana da Saúde - Leishmaniose Visceral. 2022. Available from: https://www.paho.org/pt/topicos/leishmaniose
    » https://www.paho.org/pt/topicos/leishmaniose
  • 39
    Oliveira JM de, Fernandes AC, Dorval MEC, Alves TP, Fernandes TD, Oshiro ET, et al. Mortalidade por leishmaniose visceral: aspectos clínicos e laboratoriais. Rev Soc Bras Med Trop [Internet]. 2010; 43(2):188-93. Available from: https://doi.org/10.1590/S0037-86822010000200016.
    » https://doi.org/10.1590/S0037-86822010000200016
  • 40
    World Health Organization (WHO). Vitamin and Mineral Nutrition Information System. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Geneve: World Health Organization; 2011. (WHO/NMH/ NHD/MNM/11.1). http://www.who.int/vmnis/indicators/ haemoglobin.pdf
    » http://www.who.int/vmnis/indicators/ haemoglobin.pdf
  • 41
    Maia-Elkhoury ANS, Carmo EH, Sousa-Gomes ML, Mota E. Análise dos registros de leishmaniose visceral pelo método de captura-recaptura. Rev Saúde Pública [Internet]. 2007;41(6):931-7. Available from: https://doi.org/10.1590/S0034-89102007000600007
    » https://doi.org/10.1590/S0034-89102007000600007
  • Financial Support: The work was carried out with the authors' own resources, without formal financial support from any development agency.

Publication Dates

  • Publication in this collection
    23 Feb 2024
  • Date of issue
    2024

History

  • Received
    07 Apr 2023
  • Accepted
    08 Dec 2023
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