GIS-based risk mapping of cutaneous leishmaniasis: a survey in an endemic area of Central Iran

Cutaneous leishmaniasis (CL) is a vector-borne infectious disease that is affected by various environmental agents. The main objective of this study was to determine the spatial distribution of CL incidence by using Geographical Information System (GIS). This is a cross-sectional study that was conducted during 5 years from 2014 to 2018 in Isfahan, Iran. We used the required data on each leishmaniasis patient that were recorded from 44 counties of Isfahan in the databases and archive of the Provincial Health Centre. We used GIS for determining the incidence of CL in the high-risk foci. Moran index was used to identify high risk points (clustering in similar values) compared to the values of neighborhood points. Hot spot analysis was conducted by Getis-Ord-Gi. The highest incidence of the disease occurred in the age group of 18–64 years and 61.6% of patients were male. According to seasonal distribution, autumn (58.6%) had the highest frequency. Time trend of incidence showed that it had both decreasing and increasing, and there was a sudden upward trend of disease in 2018 except only two counties. The hot spots were involved the central areas of the Isfahan province slightly toward to the north and southeast of the province. Moran index showed that the differences for all points were not significant (p-value>0.05). Varzaneh (placed in southeast of Isfahan) was the hottest spot and had the worst position for leishmaniasis compared to all years and all cities.


Introduction
Leishmaniasis is a vector-borne infectious disease that is affected by various environmental agents, such as distribution of reservoir hosts and vectors of leishmaniasis. Among diseases spread by insects, leishmaniasis is endemic in 88 countries on four continents (16 developed countries and 72 developing countries) (Anker et al. 2000).
The disease can be presented in three basic clinical forms: cutaneous, mucocutaneous, or visceral leishmaniasis. Cutaneous leishmaniasis (CL) is known as one of the most important neglected tropical disease which has been reported form about 100 countries. Around 90% of CL have been reported form Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, Syria, Brazil, and Peru. Moreover, approved studies ranked Iran among top-ten courtiers accounting for the 70 to 75 of global CL cases. Iranian researches indicated that cutaneous form of leishmaniasis has been prevalent in 5000 people since 1941 to 2010 and has been transmitted in 17 provinces out of 31 provinces. It is also notable that Isfahan province is one of the most important focus of CL in Iran. Despite the new diagnosis and treatments of leishmaniasis, it is still considered a serious public health concern particularly in developing countries including Iran and has an economic burden on health resources (Rasti et al. 2018, Norouzinezhad et al. 2016, Jafari et al. 2020, Mandal et al. 2018, Glans et al. 2018.
Utilizing maps, spatial analysis, and regression techniques can aid modeling the subtle statistical relationship between variables. In fact, using this information in epidemiological studies can help public health policy makers in improving decision for control and prevention of disease (Golpayegani et al. 2018, Artun 2019, Ostad et al. 2016, Blachowski 2016. Leishmaniasis is a disease that occurs in different geographical regions with a different focal distribution, and Geographical Information System (GIS) is one of the most important and useful epidemiological tools for the determining geographical areas and populations at risk. In fact, it is an applicative software for the determining spatial distribution of disease quantitatively and qualitatively for managing health to control various diseases, such as CL, malaria, and HIV infection. A development of the GIS during the two last decades has provided more powerful and efficient tools to investigate spatial patterns needed to study infectious diseases (Ostad et al. 2016;Shirzadi et al. 2019;Alvar, et al. 2012).
The main objective of this study was to determine the spatial distribution of CL incidence in Isfahan province by using GIS software during 2014-2018. We hope this study increases awareness and helps planning the potential guide approaches to address this global health concern through this study.

Materials and methods
This is a cross-sectional study that was conducted during 5 years from 2014 to 2018 throughout a leishmaniasis endemic area of Central Iran.

Study area
Isfahan Province is one of the provinces of central Iran and consists of 44 counties. It has an area of 115,932 km 2 lying within the 31°43′ to 34°22′ N and 49°38′ to 55°31′ E with moderate and dry climates and is considered arid and semiarid regions of the Iran. This province has a population of approximately 4,629,312 inhabitants (Ramezankhani et al. 2017).

Data collection
In this study, we used the required data on each leishmaniasis patient, i.e., age, gender, residence (urban, rural), season of disease outbreak, and ulcer zone, that were recorded from 44 counties of Isfahan province in the related databases and also in the archive of the Provincial Health Centre during a period of 2014-2018. In these past 5 years, leishmaniasis patients who were confirmed by a positive skin test and/or parasitological examination were identified in Isfahan province and subsequently were eligible for our study.
The annual incidence rate of CL was defined as follows: Annual incidence rate for each city = (total number of CL new cases per year / total population at risk) × 10000 Population census counts were estimated by statistical center of Iran for the period of 5 years (2014-2018).

Statistical and spatial analysis
We used GIS to determine the incidence of CL in the high-risk foci. Geographic latitude and longitude of the area were calculated and digital maps of Isfahan province were designed to show the distribution of CL.
After preparing the project file in Arc-Map software, the maps were extracted by ArcGIS version 10.2 (ESRI Inc., Redlands, CA, USA) software. Density maps were designed using Spatial Analyst, GeoStatistical Analyst, and appropriate models.
Moran index was used to identify high risk points (clustering in similar values) compared to the values of neighborhood points, ranging from −1 to +1. This index is the most useful index for measuring spatial correlation between points, events, and phenomena (Kavousi et al. 2020). In our study, 95% significance level (P<0.05) was considered. Hot spot analysis was conducted by Getis-OrdGi_ which provides a Z score value to indicate whether features with either high or low values cluster spatially (hot and cold spots) (Abedi-Astaneh et al. 2016).

Results
The incidence of CL during 5 years (2014)(2015)(2016)(2017)(2018) in the cities of Isfahan province has shown both upward and downward trends. It should be noted that 14 of 44 cities in Isfahan province have been excluded due to the absence of leishmaniasis patients or having only one patient per 10,000 populations (Table 1).
In our study, the range groups were included: 6 years or less, 7-17 years, 18-64 years, and 65 years or more. The highest incidence of the disease occurred in the age group of 18-64 years and the lowest occurred in the age group of 65 years and older. About 61.6% of patients were male (Table 2).
According to seasonal distribution of CL, autumn (58.56%) and summer (26.96%) had the highest frequency and spring (4.05%) and winter (10.41%) had the lowest frequency during the years of the study. The disease had a peak in autumn. Figure 1, which shows the distribution map of the incidence of cutaneous leishmaniasis in Isfahan cities from 2014 to 2018, indicates that the number of cities with the frequency of leishmaniasis has decreased during these 5 years, so that in      compared to other cities and has been considered a hyperendemic region of Isfahan province (Chart 1).  Varzaneh were considered hot spots and Chadegan as cold spot. Varzaneh was the hottest spot (at the level of 99%) and had the most unsuitable position in during 5 years and among all cities.  Table 3 shows the Moran index for each city at the optimal interval confidence, which has its highest value at the z-score peaks and the p-value was close to 0. In this study, the differences for all points were not significant (p-value>0.05), and therefore non-endemic cities were not affected by endemic areas.

Discussion
Leishmaniasis is one of the zoonotic diseases and it is one of the most important epidemiological diseases in Isfahan that requires effective control measures. This study is a survey of the spatial distribution of CL and the effect of environmental factors on the incidence of this disease during 5 years (2014)(2015)(2016)(2017)(2018) in Isfahan province. Studies conducted using GIS can provide a clear picture of the spatial prevalence of diseases for health policy makers (Dehghani et al. 2019).
In our study, only 9 cities from 44 cities were endemic for leishmaniasis (33 cities had only 0 to 16 leishmaniasis cases in per 10,000 populations and were in white status according to the color scheme). The trend of CL during 5 years was both decreasing and increasing in all cities, but in 2018, it suddenly had an upward trend and a high increase in some cities, especially in Varzaneh (placed in southeast of Isfahan). This issue (increasing decreasing trend) is consistent with other studies in Iran. In a study by Hatami et al. that was conducted in the cities covered by Shiraz University of Medical Sciences in 2018, it was shown that the 10-year trend of leishmaniasis has had both a downward and an upward trend (Hatami et al. 2018). It seems that this trend is generally sinusoidal, and control of the reservoirs, such as rodent control and preventive measures such as mosquito nets, netting, and use of insect repellents, can cause to reduce the leishmaniasis transmission. In 2018, we had the highest number of leishmaniasis cases (compared to previous years) and this indicates the impact of another major factor that may be highly dependent on environmental changes. For example, in Varzaneh, the situation of leishmaniasis is dependent on the situation of Gavkhoni swamp, which requires improving the water and environmental conditions of this city more than before.
The age group of 18-64 years was the most vulnerable age group of leishmaniasis in this study. In other studies, the highest incidence of leishmaniasis was reported in the age group of children (under 10 years) (Nawaz et al. 2010;Rahim et al. 2003). However, another study conducted by Hamzavi et al. showed the most leishmaniasis cases between the ages of 20 and 29 (Hamzavi et al. 2009).
According to these studies and the results of our study, it can be concluded that although more bites occur in children, in Isfahan province, most cases occur in young to middle-aged people. This may be due to the localization of transmission agents in different areas, which has made this age group, who spend most of their time outside the home, more vulnerable. However, the preventive measures should continue to be considered for children and adolescents up to middle age.
Men also had the most cases, which here is the same as the previous reason because of spending most of their time outdoors. The number of men and women with leishmaniasis were equal in community-based studies, while the health center-based studies showed the higher number of men (van Henten et al. 2019;Abedi-Astaneh et al. 2016;Nejati et al. 2014).
In our study, the seasonal distribution showed that the peak of the disease was in autumn and the lowest frequency was in spring. The results were consistent with the main results of other studies. It also consistent with the leishmaniasis incubation period because the most mosquito bites occur every year from early September to early November (Hatami et al. 2018;Khajehdalluei et al. 2014;Mandal et al. 2018).
Distribution of disease in 5 years of our study showed that the number of cities involved with leishmaniasis has been decreased (from 9 cities to 4 cities). Therefore, it can be said that preventive and control measures of leishmaniasis and also raising awareness, attitude, and improving people's performance has been effective and has caused the cleansing of some cities. Despite of this decrease, unfortunately, some cities even had the highest record in the incidence of leishmaniasis, especially in 2018, such as Varzaneh, which was also considered a hyperendemic region. The high prevalence of leishmaniasis in Varzaneh can be dependent on the environmental and natural conditions of this region and the planting of arches as the main culprit. The study that assessed the effects of environmental factors on leishmaniasis transmission indicated that climate change and environmental variables will affect the distribution of leishmaniasis by the effect of temperature on parasite development and vector competence, by the effect on the range and abundance of the sandfly species, and affect the amount of human contact with the transmission cycles (Ready 2008).
In hotspot analysis, we found that hot spots covered the central areas of the Isfahan province and slightly inclined to the north and southeast of the province, which is mostly due to the presence of barren lands, swamps, and constructions that may provide a suitable place for mosquitoes and rodents. In 2018, Varzaneh was the hottest spot and had the worst position for leishmaniasis compared to all years and all cities. A spatial modeling of cutaneous leishmaniasis in Iran, illustrated a variety of factors including latitude and longitude, temperature, humidity, soil and control programs, and training as contributing factors to be included in leishmaniasis hot spots (Holakouie-Naieni et al. 2017). Despite the positive correlation, Moran's I index showed negative values mean the leishmaniasis foci were surrounded by nonsimilar regions. Therefore, the high incidence points had no effect on nonendemic points, which may be due to reduced migration within the province even to neighboring cities. Data availability Data and materials can be made available upon request.

Declarations
Ethics statement This study obtained ethical permission from the Ethical Committee, Research Deputy, IsfahanUniversity of Medical Sciences (Approval Number: 292106).
Consent to participate All authors have consent of participate in research.
Consent to publish All authors have consent of publish the research.