Burden and Trends of Leishmaniasis over the Last One Decade across the Globe: Trend Analysis of WHO Regions

Introduction: In terms of the global burden of diseases, leishmaniasis is the third most serious and often fatally untreated tropical disease. The number of people suffering from leishmaniasis is estimated to be 12–15 million. Because of the comparatively underestimated reported number of cases, leishmaniasis is not seen as an immediate health issue in various regions by local and international health policymakers. Therefore, strong evidence is required for policymakers to make decisions. Therefore, we aimed to conduct secondary data analysis to assess the trends of Leishmaniasis over the last decade and understand the endemicity of different regions for Leishmaniasis across the world. Methods: We undertook a retrospective study with secondary data analysis of the WHO data from 2008 to 2018, publicly available, for cutaneous and visceral Leishmaniasis. The data for around 194 countries were included in the analysis and these countries were merged into different regions based on the WHO classification. We categorized all 94 countries into regions such as America, Europe, Africa, SouthEast Asia, the Eastern Mediterranean, and Western Pacific. Since the data were limited to the frequency of cases and there were no other variables, therefore, we were able to do the descriptive analysis. Results: Generally, the number of cutaneous Leishmaniasis cases has declined for all regions except for the Eastern Mediterranean region. A declining trend of imported cases of cutaneous Leishmaniasis was found for all regions mainly from 2015 to 2018. The cases of visceral leishmaniasis in the Eastern Mediterranean region, Africa, America, and Europe have remained stable. However, after remaining stagnant for about four years, the number of visceral leishmaniasis in South Asia showed a steep decline. Of the 194 countries, 76.39% are considered as endemic for cutaneous Leishmaniasis and 44.3% are considered as endemic for visceral Leishmaniasis. Conclusion: Though cases of Leishmaniasis have decreased over the past decade, regions need to make efforts to capture the true number of cases with an effective surveillance system. There appears to be a stable trend in most countries, although it is unclear whether that trend is due to regulation steps taken by various governments or to cases being underreported. Governments in various regions therefore need to make efforts to identify true cases and to take effective control steps.


INTRODUCTION
Leishmaniasis is a severe and frequently deadly neglected tropical disease related to undernourishment, population movement, inadequate housing, and a feeble immune system, which chiefly affects the poor (1,2). Leishmaniasis is the third most severe arthropod-borne disease in terms of the global burden of diseases (3). Due to its close association with poverty and the inadequate resources supplied in new instruments for diagnosis, treatment, and control, leishmaniasis is believed one of the "most neglected diseases" (4). Leishmaniasis is categorized into cutaneous, mucocutaneous, diffuse skin, and visceral types on the basis of clinical symptoms (5,6).
Leishmaniasis has three clinical forms: visceral (also known as kala-azar), cutaneous, and mucocutaneous (5,6). The most serious form of leishmaniasis is visceral and almost always fatal if untreated (5,6). The principal vectors of leishmaniasis are phlebotomine sand flies and there is a positive association between the geographic distribution of sand flies and the disease (7). Various types of leishmaniasis have been found in 89 countries, according to the World Health Organization, and over 350 million people are at risk. It is estimated that the number of individuals suffering from leishmaniasis is twelve to fifteen million. There are two million new cases of leishmaniasis per year, of which around half million are visceral leishmaniasis infected cases and one and half million are cutaneous Leishmaniasis infected cases (8). In 2015, more than 60% of the new cases of cutaneous leishmaniasis (CL) arose in six countries, including Afghanistan, Colombia, Brazil, and Iran, according to WHO records (9). In tropical and subtropical regions, they are more common (10). Cutaneous and visceral manifestations of the disease occur predominantly in fourteen Eastern Mediterranean countries (11). In several geographic regions, leishmaniasis has emerged or reemerged, which provokes global health and economic problems influencing humans, animals, and the natural world. (12). It is endemic in 98 countries with > 350 million susceptible people with around 700 000-1.2 million new cases, 600 000-1 million new cases of cutaneous disease additional every year, 50 000-90 000 new cases of visceral leishmaniasis additional per annum, and about 20 000-40 000 losses annually from the disease (9,13,14). In six countries, namely Sudan, India, Ethiopia, Nepal, Bangladesh, South Sudan, and Brazil, more than 90% of the yearly incidences of visceral Leishmaniasis occur (9,(14)(15)(16)(17). Eastern Africa is the second biggest visceral Leishmaniasis focus, adding to the global burden with 30,000-40,000 new cases each year after the Indian sub-continent (9,13). In 2015, close to 200,000 visceral Leishmaniasis cases were registered to the WHO (18); these figures are believed to reflect a major underestimate, especially in Africa. Leishmaniasis ranks second in mortality and seventh in loss of disability-adjusted life years among tropical diseases (3,19). Leishmaniasis is not seen by local and international health policymakers as an urgent health problem in different regions, likely due to the presumed non-serious nature of CL and the relatively underestimated number of cases registered (20,21). This reveals that strong evidence is required about the number of cases of Leishmaniasis for policymakers to make decisions. Such evidence can come from reliable sources such as WHO, however, the data from such sources need to be adequately analyzed to make evidence-based decisions. Therefore, we aimed to conduct secondary data analysis to understand the endemicity of different regions for Leishmaniasis across the world. Besides, we also purported to assess the trends of Leishmaniasis cases over the last decade.

MATERIALS AND METHODS
We undertook a retrospective study with secondary data analysis of the publicly available data for cutaneous and visceral Leishmaniasis. Primarily recent data of WHO was used that was available from 2008 to 2018 for visceral and cutaneous leishmaniasis. The data sheets of WHO had cases that were categorized into crude cases of cutaneous and visceral Leishmaniasis that were prevalent in different countries. Further, data were also available for imported cases of visceral and cutaneous leishmaniasis. Apart from this, we also approached the data sheets to assess the endemicity of various countries for visceral and cutaneous leishmaniasis. The data for around 94 countries were included in the analysis and these countries were merged into different regions based on the WHO classification. We categorized all 94 countries into regions such as America, Europe, Africa, South-East Asia, the Eastern Mediterranean, and Western Pacific. Since data for only one country were available in the Western Pacific region, therefore, we merged this with South-East Asia. After cleaning the data, we matched each country with its respective region and calculated the total number of cases after merging the data from different files. All countries with missing data were not included in the analysis and thus were not assigned respective regions. We imported the files into statistical software and analyzed the data by running frequencies. Since the data were limited to the frequency of cases and there were no other variables, therefore, we were able to do the descriptive analysis. We assessed the trends of cases of visceral and cutaneous leishmaniasis over the last ten years. However, the data were available for imported cases for the last six years. For the study of the data obtained, SPSS software was used, and findings were drawn up in the form of graphs. Since the data were publicly available, no ethical approval was required.

DISCUSSION
To understand the endemicity of various regions of Leishmaniasis worldwide and to measure trends in cases of Leishmaniasis over the last decade, we aimed to perform secondary data analysis. Overall, our findings revealed that the number of cutaneous Leishmaniasis cases has declined for all regions except for the Eastern Mediterranean region. These findings might be due to the true augmentation of cases in the Eastern Mediterranean region over many years or this might be due to an improved reporting system. This is because multiple countries have established surveillance systems in the region to improve the reporting mechanism of Leishmaniasis. Likewise, we found a declining trend of imported cases of cutaneous Leishmaniasis for all regions mainly from 2015 to 2018. However, there were relatively higher cases in the Eastern Mediterranean region. These findings can be collectively explained by numerous reasons such as underreporting of the cases or true decline in the number of cases due to effective interventions taken by the respective government of the regions. In contrast to these findings, the cases for visceral Leishmaniasis have remained stable for the Eastern Mediterranean region, Africa, America, and Europe. However, the number of visceral Leishmaniases has shown a steep decline in South Asia after being remained stagnant for around four years. The existing literature reveals that generally, Leishmaniasis is on the wane in South-East Asian countries, however, there are few countries in the region with a higher number of cases. Further, findings revealed that imported cases were higher in the Eastern Mediterranean regions in initial years followed by a rapid decline in 2015 and stable frequency then onwards. Since we did not explore the reasons for such a pattern in our study due to limited data, these patterns could be seasonal or migratory or even the lifestyle of the people living in a particular country. For example, the existing evidence demonstrates that people living in the highlands are heavily exposed to sandflies due to sleeping outside the house in the farm and camp. The explanation may be because visceral leishmaniasis epidemics are often related to migration and the introduction of non-immune individuals into areas with current transmission cycles, and most migrants live outside the home. However, future research is required to understand the underlying reasons that could explain such patterns. In addition, a unique pattern of leishmaniasis cases in the Eastern Mediterranean region can be explained by several factors (11). Most of them rely on human activities, such as changes in the climate, relocation of non-immune communities, or the construction of agro-industrial projects, military activities, urbanization, etc. Further, environmental modifications, such as dam building, may alter soil and vegetation temperature and humidity, which may result in changes in the composition and density of sandfly species, as well as changes in the rodent species populations (22). The advent of new colonies with nonimmune populations promotes the production of leishmaniasis. The rise of leishmaniasis in the regions might also result from the disruption of control methods previously used, such as insecticide spraying or early detection and treatment of positive cases. Surprisingly, the data shows a stable number of cases in the African region, which might be due to the underreporting of cases. There is no proper surveillance system in the region that could trace and detect cases on time (23). Further, the rural to urban migration and infrastructure in most African countries do not coincide with the number of cases (24). The existing literature on African countries demonstrates the need to develop strong surveillance and monitoring system to detect and report the true number of cases. In contrast, there is a rapid decline in the number of visceral leishmaniasis cases in the South-East Asia region that reflects the underlying efforts of the governments in the region (25). For example, in the past, attempts such as mobilization of resources, surveillance systems to diagnose and report cases, and active case detection have been enforced to reduce the number of cases over time (25). However, the sustainability of such achievement will depend on the availability of funds, political will, concentrated analysis, and strict oversight over the years.

STRENGTHS AND LIMITATIONS
One of the biggest strengths of this analysis was that it was a regional level analysis that provides an overview of the number of cases of Leishmaniasis across the world. Second, we were able to see the trends for the last ten years that could provide useful insights to researchers and policymakers for evidence-based decisions. However, findings need to be interpreted with caution due to the inherent limitations of the study. For example, the data were not available for all countries in the regions. Second, data were not available for sociodemographic and geographic factors of the region to identify the factors and explore reasons for different trends of the cases in the regions.

CONCLUSION
Although the cases of Leishmaniasis have declined over the last decade, regions need to put efforts to capture the true number of cases with a proper surveillance system. It seems that there is a stable trend in most regions, but it is ambiguous whether such a trend is due to control measures taken by different governments or due to underreporting of the cases. Therefore, governments of different regions need to make efforts to correctly identify the cases and take appropriate control measures. Long-term and short-term strategic plans need to be developed by the regions to address this neglected disease across the world.