India’s performance in controlling Visceral Leishmaniasis as compared to Brazil over past three decades: findings from global burden of disease study

Visceral leishmaniasis (VL) is a neglected tropical disease which contributes to the mortality and morbidity significantly in India and Brazil. This study was planned to compare the trends of incidence, prevalence, death and disability-adjusted life years (DALY) of VL burden in India and Brazil from 1990 to 2019 using Global burden of disease study (GBD) data. The metrics are presented as age-standardized rates per 100,000 inhabitants with their respective uncertainty intervals (95% UI) and relative percentages of change. The decline in the Incidence rate is more in case of India (16.82 cases per 100,000 in 1990 to 0.60 cases in 2019) as compared to Brazil (3.12 cases per 100,000 in 1990 to 2.65 cases in 2019). The annualized rate of change in number of prevalent cases for India is − 0.95 (95% UI − 0.98 to − 0.91) whereas for Brazil it is − 0.06 (95% UI − 0.41 to 0.52). The annualized rate of change in number of DALY for India is − 0.94 (95% UI − 0.96 to − 0.92) whereas for Brazil it is − 0.09 (95% UI − 0.25 to 0.28). The annualized rate of change in number of deaths for India is − 0.93 (95% UI − 0.95 to − 0.92) whereas for Brazil it is increasing i.e. 0.04 (95% UI − 0.12 to 0.51). India achieves significant reduction in the age standardized incidence, prevalence, mortality and DALY of VL as compared to Brazil during the period of 1990 to 2019. A multi-centric study is required to assess bottleneck in the existing strategies of VLSCP in Brazil.


Introduction
Zoonoses are diseases and infections which are naturally transmitted between vertebrate animals and man & Anthroponoses are diseases transmissible from human to human. Visceral Leishmaniasis (VL) or Kala-azar is a zoonotic as well as anthroponotic disease (Hubálek 2003). VL is a neglected tropical disease which contributes to the mortality and morbidity significantly in India and Brazil (Sundar and Chakravarty 2012). In India, it is caused by parasite called Leishmania donovani and transmitted from one person to another by the bite of infected female sand fly known as Phlebotomus argentipes (Muniaraj 2014). The parasites can also be transmitted directly from person to person through the sharing of infected needles which is often the case with the HIV-VL co-infection. In the Americas, the etiological agent is the protozoan Leishmania infantum, which is transmitted through the bite of the phlebotomine Lutzomyia longipalpis, with dogs being its main urban reservoir (Lainson and Shaw 1978).
Annually 50,000 to 90,000 new cases of VL occur globally, among them only 25-45% reported to World Health Organization (WHO). According to the outbreak and mortality potential, VL remains one of the top parasitic diseases. Both India and Brazil have found their places in the list of ten countries which have reported more than 95% of new cases to WHO in 2018 (WHO factsheet 2020). According to the World Bank, India and Brazil belong to lower-middle income economies and upper-middle income economies respectively. In 2017, expenditure of India on health was 3.53% of the Gross Domestic Product, whereas Brazil's health expenditure in the same year was 9.45% (World Bank 2020). If we look at the state-wise scenario, Kala-azar is endemic in northern and eastern States of India namely Bihar, Jharkhand, Uttar Pradesh and West Bengal. 54 districts of these four states have attained endemic region status for kala-azar and few other districts have reported occasional cases as well. The latest estimated figure is 165.4 million population which is under the risk of developing kala-azar in these four states combined (MoHFW, GoI 2020). In the Americas, 12 countries have registered the presence of VL. 90% of these cases are reported in Brazil alone with the case fatality rate being around 7% (da Rocha et al 2018). Until 1990, only the Kala-azar affected and worst hit States used to carry out Kala-azar control activities in India. As the incidence of Kala-azar was soaring in parts of India, the GoI launched a centrally sponsored ''Kala-azar Control Program'' during 1991 (Kishore et al. 2006). In 2000, the program was further reviewed by an expert committee chaired by the director general of health services, and recommendation was made to incorporate the elimination of Kala-azar from India in the National Health Policy (Thakur et al. 2009) by renaming the same as ''National Kala-azar Elimination Programme''. As we shifted our focus to review the existing policies of Brazil, we acknowledged the launch of The Brazilian Visceral Leishmaniasis Surveillance and Control Programme (VLSCP) strategies in early 1990s. This strategy included a considerable number of public health measures like canine serological analysis followed by euthanasia of seropositive dogs, together with chemical control of the vector and diagnostic techniques, early diagnosis and treatment of human cases, and population awareness (da Rocha et al 2018). From the data, it is evident that both the countries (India and Brazil) had significant burden of kala-azar in early 1990s and they have given special emphasis on the control of kala-azar in their country. To the best of our knowledge there is no comparative study available that has assessed trends in the burden of Visceral Leishmaniasis and its control in India and Brazil.
Research question: What is the effect of Visceral Leishmaniasis control programmes in India and Brazil?
Hypothesis: Is there any difference in the effect of Visceral Leishmaniasis control programmes in India and Brazil.
Objective: This study was planned to compare the trends of Visceral Leishmaniasis burden and its control in India and Brazil over past three decades using Global burden of disease study data.

Material and methods
The GBD study offers a powerful resource to understand the changing health challenges facing people across the world in the twenty-first century. Led by the Institute for Health Metrics and Evaluation (IHME), the GBD study is the most comprehensive worldwide observational epidemiological study to date. By tracking progress within and between countries GBD provides an important tool to inform clinicians, researchers, and policy makers, promote accountability, and improve lives worldwide.
Over the past two decades, the IHME has developed a methodology to quantify the burden of diseases, injuries, and risk factors for informing health program and policymaking. GBD regularly provides comparable estimates of the key indicators of disease burden assessment, including the incidence prevalence, mortality and DALYs rate of Visceral Leishmaniasis. The present study utilized the GBD (2019) database to systematically summarize, analyze and compare the Incidence, Prevalence, mortality and DALYs of Visceral Leishmaniasis and its changes since 2019 for India and Brazil.

Data sources
GBD (2019) estimated each epidemiological quantity of interest-incidence, prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and disabilityadjusted life-years (DALYs)-for 23 age groups; males, females, and both sexes combined; and 204 countries and territories that were grouped into 21 regions and seven super-regions (GBD 2019 Diseases and Injuries Collaborators 2020). Total of 59 different data sources has been used to model the cause of death and 62 different data sources to model both cause of death and disability estimates for Visceral Leishmaniasis in India. The key sources of data to model the cause of death due to Visceral Leishmaniasis in India included Medical certification of cause of deaths of the country and of various states, India vital statistics report, WHO Global Health Observatory reported cases, other surveys on cause of death and published scientific articles (GBD 2019 Diseases and Injuries Collaborators 2020).
Total of 68 different data sources has been used to model the cause of death and 70 different data sources to model both cause of death and disability estimates for Visceral Leishmaniasis in Brazil. The key sources of data to model the cause of death due to Visceral Leishmaniasis in Brazil included Brazil Information system for notifiable disease for various years, Brazil mortality information system, Brazil WHO Leishmaniasis country profile, WHO Global Health Observatory reported cases, other surveys on cause of death and published scientific articles (GBD 2019 Diseases and Injuries Collaborators 2020).
Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model (CODEm) and spatiotemporal Gaussian process regression. A detailed description of CODEm is reported elsewhere Foreman et al. 2012;Murray et al. 2012Murray et al. , 2014. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution (GBD 2019 Diseases and Injuries Collaborators 2020).
We have included only a special category of Leishmaniasis in our paper, i.e., Visceral Leishmaniasis. Data sources for the incidence rate, prevalence, Death and DALYs of Visceral Leishmaniasis was extracted from an online tool produced by the IHME which is publicly available called the GHDx (Global Health Data Exchange) query tool (http://ghdx.healthdata.org/gbd-results-tool) (Global Burden of Disease Collaborative Network 2020) Percentage change and annualized rate of change of the estimates is reported.

Results
Overall there is decrease in the Incidence rate of Visceral Leishmaniasis for both India and Brazil, however the decline is more in case of India (16.82 cases per 100,000 in 1990 to 0.60 cases in 2019) as compared to Brazil (3.12 cases per 100,000 in 1990 to 2.65 cases in 2019) ( Table 1). The overall percentage decrease in Incidence rate per 100,000 from 1990 to 2019 in case of India and Brazil is 2703.33%and 17.74% respectively. The total number of incident cases due to Visceral Leishmaniasis in India declined from 174,821 cases in 1990 to 8145 cases in 2019; and for Brazil, it decreased slightly from 5275 cases in 1990 to 4983 cases in 2019. The annualized rate of change in number of incident cases for India is -0.95 There is decrease in the death rate of Visceral Leishmaniasis for both India and Brazil, However the decline is more in case of India (1.97 deaths per 100,000 in 1990 to 0.09 deaths in 2019) as compared to Brazil (0.63 deaths per 100,000 in 1990 to 0.51 deaths in 2019). The overall percentage decrease in death rate per 100,000 from 1990 to 2019 in case of India and Brazil is 2088.89% and 23.53% respectively. The total number of death due to Visceral Leishmaniasis in India declined from 18,068 deaths in 1990 to 1206 deaths in 2019; whereas in Brazil it increased from 992 deaths in 1990 to 1035 deaths in 2019. The annualized rate of change in number of deaths for India is -0.93 (95% UI -0.95 to -0.92) whereas for Brazil it is increasing i.e. 0.04 (95% UI -0.12 to 0.51) ( Table 1).
Age Standardized Incidence rates in India continuously fall from 1990 (16.81cases per 100,000) to 2000 (2.34 cases per 100,000), after that it increased till 2005 (4.34 cases per 100,000) and then gradually show declining trends till 2019 (0.60 cases per 100,000). In case of Brazil, incidence rates show a constant trend with slight variation and reached to 2.65 cases in 2019 from 3.12 in 1990 (Fig. 1).
A similar trend as seen in case of age-standardized mortality rates have been observed for age standardized DALY rate for both India and Brazil. Age Standardized DALY rates in India continuously fall from 1990 (124.1 DALY per 100,000) to 2001 (19.83 DALY per 100,000), after that it increased till 2007 (42.44 DALY per 100,000) and then gradually show declining trends till 2019 (5.88 DALY per 100,000). In case of Brazil, a slight variation in DALY rates over the years has been seen and it reached to 33.63 in 2019 from 41.55 in 1990 (Fig. 4).
In India as well as Brazil, age standardized incidence, prevalence, mortality and DALY rates of Visceral Leishmaniasis is reported higher in males vis-à-vis females for all years i.e. 1990 to 2019. India has reduced gender based gap in the age standardized incidence, prevalence, mortality and DALY rates since past one decade and maintained approximately equal rates in males as well as females since past six years, whereas Brazil has not able to reduce gender based gap in the age standardized incidence, prevalence, mortality and DALY rates since past three decades (Fig. 5). In India as well as Brazil, higher incidence, prevalence, mortality and DALY rates of Visceral Leishmaniasis is reported in the age groups (\ 1 year, 1 to 4 years, 5-9 years and 10-14 years) as compared to the age groups of 15 years and above (Fig. 6).

Discussion
We have compared the trends of kala-azar burden in India and Brazil from 1990 to 2019 using Global burden of disease study data.
The 4 A's named as accessibility, affordability, availability and awareness remained the key characteristics where India did sound progress in case of Kala-azar control strategies and execution over the past three decades. During the study period 1990-2019, comprehensive public health measures and strategies like integrated vector management (IVM) and effective as well as efficient interventions like Indoor residual spray, personal prophylaxis, micro-environmental management, etc., were found to contribute largely to the continuous decline in the incidence, prevalence and mortality due to VL. Apart from that, the introduction of rapid diagnosis test kits for the prompt diagnosis of VL even in areas with limited transportation facilities could be considered as the major milestone in fighting the disease. Inclusion of relatively safe oral drugs like Miltefosine for the treatment of VL helped to keep the infection in control. The provision of incentives to VL patients as well as peripheral health workers like ASHA raised the awareness and thus contributed to the decline in new cases in a significant manner. New initiatives like ''Kala-azar Mitra (Friend)' were started in which past treated patients act as a communicator for providing information to the health facilities or health worker regarding new Kala-azar resembling patient (MoHFW, GoI 2015). Various Non-Governmental Organizations like CARE India, Kala-azar Medical Research Centre etc. also specifically working on prevention and control of VL in the endemic zone, which helped in substantial reduction in the burden of VL in India.

Control of Visceral Leishmaniasis in Brazil
In this study constant trend with slight variation has been reported in the age standardized incidence rates of VL which changes from 3.12 cases per 100,000 in 1990 to 2.65 cases in 2019. Similar trend were reported in age standardized prevalence rates of VL which changes from 0.78 cases per 100,000 in 1990 to 0.66 cases in 2019. In urban areas of Brazil, VL primarily transmitted from domestic dogs to people by phlebotomine sand flies (Dye 1996), to eradicate disease in these areas the basis reproduction number (R 0 ) of L. infantum in the dog population should be decreased to \ 1. The vectorial capacity of sand fly depends on various entomological parameters such as bite rate in dogs, the life expectancy, vector density and the extrinsic incubation period (Werneck 2014). Brazil has revised VL control strategy in early 1990s and launched The Brazilian Visceral Leishmaniasis Surveillance and Control Programme (VLSCP). The substantially poor impact and penetration of interventions were quite eminent due to the low sensitivity of the diagnostic tests, the long delay between diagnosis and culling, and the low acceptance of culling by dog owners. Different studies have concluded that the treatment of infected dogs cannot be an effective long-term strategy as relapses are quite frequent in such cases, and same dogs become infectious again within a short period of time (Alvar et al. 1994). A recent study conducted by Werneck et al. recommended the modification of the existing delivery of interventions according to the different transmission scenarios, along with the existing strategies of VL control program, while preferably targeting the areas at highest risk. They also emphasized on collective and efficient efforts to solve operational barriers to the adequate implementation of preventive measures . A relevant quasi-experimental study conducted by da Rocha et al. on effectiveness of VLSCP pointed out several limitations in the strategies adopted by the VLSCP in the sense that the control interventions were not successful enough in interrupting L. infantum transmission, especially in urban areas (da Rocha et al. 2018).

Conclusion
Visceral Leishmaniasis is a public health problem in India as well as in Brazil. Both the countries have revised their strategies in early 1990s to control VL. India achieves significant reduction in the age standardized incidence, prevalence, mortality and DALY of VL as compared to Brazil during the period of 1990 to 2019. A multi-centric study is required to assess bottleneck in the existing strategies of VLSCP in Brazil. India's experience can be utilized for the further reduction in the burden of VL in Brazil.
Funding None.
Availability of data and material Data is publicly available on http://ghdx.healthdata.org/gbd-results-tool and free to use.
Code availability None.

Declarations
Conflict of interest All authors declare that they have no conflict of interest.