An investigation of the effects of environmental and ecologic factors on cutaneous leishmaniasis in the old world: a systematic review study

Objectives: Leishmaniasis is a neglected and widespread parasitic disease that can lead to serious health problems. The current review study aimed to synthesize the relationship between ecologic and environmental factors (e.g., weather conditions, climatology, temperature and topol-ogy) and the incidence of cutaneous leishmaniasis (CL) in the Old World. Content: A systematic review was conducted based on English, and Persian articles published from 2015 to 2020 in PubMed/Medline, Science Direct, Web of Science and Google Scholar. Keywords used to search articles were leishmaniasis, environmental factors, weather condition, soil, temperature, land cover, ecologic* and topogr*. All articles were selected and assessed for eligibility according to the titles or abstracts. The quality screening process of articles was carried out by two independent authors. The selected articles were checked according to the inclusion and exclusion criteria. Summary and outlook: 2015 2020 were and after evaluating the articles, 23 articles met the eligibility criteria; finally, 14 full-text articles were included in the systematic review. it can be concluded that designing an early warning system is necessary to predict the incidence of CL based on different weather conditions.


Introduction
Leishmaniasis is a serious public health problem in the world that is considered a re-emerging international vector-borne human disease [1,2]. Phlebotomine sandflies are the vectors of its parasite named Leishmania [1]. Leishmaniasis has two important types: cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). CL is one of the important, but mostly neglected, endemic tropical diseases in Iran [2,3].
According to the report published by the World Health Organization (WHO) in 2019, the annual incidence of leishmaniasis has been estimated to range from 700,000 to 1.2 million in the world [4,5]. It is estimated that the incidence of leishmaniasis is more than 12 million cases worldwide, and 1.5-2 million new cases are added to this rate annually, 75% of which are of cutaneous forms [6]. CL is hard to treat because no vaccine is yet available [3].
The majority of CL wounds have been observed on the hands (62.75%), head/neck (24.8%) and body (2.7%) [7]. A more prevalent symptom of CL is a single and self-healing cutaneous lesion that might proceed to a persistent, metastatic disease with granulomatous nodules affecting multiple secondary sites on the skin and resulting in delicate facial mucosa, which can sometimes diffuse throughout the cutaneous system. The basis for such diverse pathologies is multifactorial, ranging from parasite phylogeny to host immunocompetence and various environmental factors [8].
About 102 countries have reported leishmaniasis, and more than 90% of the total new cases of leishmaniasis have occurred in eight countries [7,9]. Based on the WHO report in 2019, over 95% of new CL cases in 2017 occurred in six countries including Afghanistan, Algeria, Brazil, Colombia, Iraq, the Syrian Arab Republic and Islamic Republic of Iran [4]. CL in the Old World was caused by Leishmania tropica (more common in the Mediterranean Basin, the Middle East, Pakistan and India) and Leishmania infantum (sporadically in the Middle East, South Russia and rural regions of Africa). Moreover, CL is heavily dependent on some demographic and socioeconomic factors such as poverty [3], male gender, rurality and childhood age [7,10].
Leishmaniasis is an important parasitic disease prevalent around the world with serious health effects related to weather conditions [11]. Spatial analyses in different studies have shown that environmental factors, such as weather conditions, are the most important factors playing a role in CL incidence [1,11,12]. According to a review study, CL incidence varies in different provinces of Iran from 1.8 to 37.9%. The geographic distribution of CL disease shows that CL cases mostly occur in the east, center and southern regions of Iran, and 62.6% of CL cases live in rural areas [7]. Thus, to prevent and control CL, effective and appropriate strategies need to be developed and the spatial pattern and detecting hotspots of CL should be carefully studied [1,11,12]. The epidemiology and morbidity of CL are related to weather conditions and other environmental factors that are related to the composition, distribution and behavior of sand flies as the main vector species [13]. CL vectors are mainly distributed in forests, soil lands, disturbed environments and dry farms [14][15][16]. Inconclusive findings have been observed in the results of numerous studies investigating the role of weather conditions on CL in different countries, especially in terms of relative humidity [17,18], rainfall [15,19] and lag of time in temperature and humidity [15,17]. Hence, this study aimed to assess the degree to which CL incidence was dependent on weather conditions and other environmental factors in the Old World.

Materials and methods
A systematic review was conducted based on English and Persian articles published from 2015 to 2020 (23 March) in four databases including PubMed/Medline, Science Direct, Web of Science and Google Scholar. All the related articles were selected and assessed to find the eligible articles whose titles or abstracts addressed leishmaniasis or environmental factors related to leishmaniasis. The references of related articles were also searched and used in the review. The quality screening process of articles was carried out by two independent authors. The selected articles were checked in terms of inclusion and exclusion criteria.
Inclusion criteria: Epidemiological (ecological and crosssectional) studies assessing the associations between leishmaniasis and environmental factors (e.g., weather conditions, elevation, humidity, temperature, rainfall, soil cover, land cover, ecological factors and land topography) were included. All the articles that were published in six years (August 2015 to March 2020) in English and Persian languages about countries in the Old World, especially Eastern Mediterranean Region (EMRO) including Afghanistan, Turkey, Islamic Republic of Iran, Iraq, Syrian Arab Republic and Algeria were included in the study.
Exclusion criteria: The following studies were excluded from the review: therapeutic studies that evaluated the effect of heat, cold or other environmental factors in the treatment of leishmaniasis, the randomized clinical trials, studies that assessed the incidence of the disease in animals such as dogs, all studies that were published in the proceedings of symposiums or conferences, unpublished literature, studies with confusing results or incomprehensible analyses and studies exhibiting bias or inconsistencies in their findings.

Search strategy
After framing review questions regarding the effects of environmental factors on CL, relevant studies were searched and detected. Four databases, including PubMed/Medline, Google Scholar, Web of Science and Science Direct, were searched to find eligible articles. The keywords and search strategy included leishmaniasis, environmental factors, climate, weather condition, soil, temperature, land cover, ecologic* and topogr*.

Data extraction
After the full consideration of all databases based on the keywords, the proper records were entered into EndNote X8 (Thomson Reuters, New York, USA), and duplicate records were removed. Based on the conducted search, the titles and abstracts of the searched articles were reviewed and screened for eligibility. The full reviews of the related articles based on titles and abstracts were considered for the final selection. The data describing author, objective, study place, sample size, study type, environmental variables, statistical analysis and the main results were all extracted.

Quality assessment
The assessment of the quality of studies was carried out based on the STROBE checklist of observational studies. Each article was assessed independently by two authors, and then the data were extracted independently. Another author acted as an arbiter to resolve any disagreements. Then, the important bibliographical information and the main results of each article were extracted and summarized. The results and interpretation of the findings are presented in the results section and Table 1.

Results
The literature search and selection process are depicted in Figure 1. A total of 827 relevant articles and their references were initially searched in the four databases. After removing duplicates in the Endnote software, 362 articles remained for the screening process based on the titles and abstracts. During the screening process, 294 articles were removed by checking the titles and abstracts, and 68 articles were checked to be full-text articles. After evaluation, 45 full-text articles were removed, and 23 full-text articles met the eligibility criteria for the systematic review. Finally, after removing nine articles, 14 full-text articles were included in the systematic review (shown in Table 1) [1,6,9,11,12,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Based on the findings, the effects of environmental factors on the incidence of CL in the Old World are discussed below.

Weather conditions
Weather patterns can provide a favorable condition for the propagation and transmission of leishmaniasis in endemic areas [11]. CL incidence was higher in areas with daily rainfalls, maximum/minimum temperature and humidity, and these environmental factors occurred mostly in hyperendemic areas of CL compared to the lowendemic ones. The substantial climatic variability in 2010-2014 in Khuzestan Province, Iran, was mentioned as the main reason for the change in the epidemiology and transmission of CL [11]. In another study, Nikonahad et al. [28] revealed a significant association between environmental/meteorological variables and CL incidence by the SARIMA models. Their results indicated that more robust preventive programs are needed in earthquake-prone areas and inceptisol soil type than needed in other areas [28]. The temperature at a lag of five months and relative humidity are the effective environmental factors in the occurrence of CL cases, and the effect of temperature seems to enhance in higher humidifies [17]. Besides, according to the Ordinary Least Square (OLS) model in Ramezankhani et al.'s study, temperature and humidity were the most important environmental factors of CL incidence. Moreover, it was observed that whereas temperature had direct effects on CL incidence, humidity exerted inverse effects [18]. Similar results were also reported by Ghatee et al. [21] and Chavy et al. [26]. In another study, Sharafi et al. reported that the amount of evaporation, the number of sunny days, the rate of wind velocity and temperature had direct effects on the incidence of CL [29].

Temperature
Because of an increase in the temperature at the end of the 21st century, the projection model predicted a 15% rise in the annual number of hospital admissions due to CL compared to 2000 [22]. The effect of high temperature on the incidence of CL was approved in Nikonahad et al.'s study [28]. In another study, Faraj and Lake showed that the most important factor behind CL incidence during summer and the beginning of autumn was the temperature, and an increase in temperature could raise the number of inflicted cases after two-to-four months [27]. Similarly, a strong, significant correlation was reported in Nikonahad et al.'s study between the increase in CL incidence and the monthly temperature (r=0.77; p-value=0.01) [28]. They showed that the number of days per month with a temperature of more than 30°C had a strong correlation with the increase in CL incidence (r=0.81; p-value=0.01) [28]. Moreover, the survival of adult sandflies in temperatures lower than 15°C was not reported [31]. The direct effect of temperature was also reported in studies by Ramezankhani et al. [18] and Adegboye et al. in Afghanistan [30], and Ghatee et al. [21] and Artun in Turkey [23]. Moreover, monthly cases were associated with the mean monthly temperature at a lag of five months (r=0.576) and with a monthly accumulated evaporation lag of five months (r=0.513) [17].

Rainfall and humidity
In Nikunahd et al.'s study, no significant relationship was found between the annual mean rainfall and CL incidence (p-value = 0.56) [28]. Another study in Saudi Arabia proved the effect of rainfall on CL transmission in the lowlands; hence, it can be argued that rainfall in elevated areas can increase the number of CL cases [27]. Besides, Selmane et al.'s study showed that there was a significant correlation between monthly CL cases and the monthly mean of relative humidity at a lag of zero month (r=0.560) and a lag of 12 months (r=0.582) [17]. In another study, however, the effect of humidity was found to be inverse [18].

Discussion
The results of this review study showed that environmental factors, such as weather conditions and global warming, which lead to the deterioration of the eco-systems, were the most important risk factors for the spreading of CL in the Old World 5. Therefore, weather conditions can act as a non-negligible factor for the fluctuation of leishmaniasis in different countries and regions. According to our results, environmental factors, including weather conditions, temperature, rainfall, precipitation and humidity, can heavily influence the incidence of CL. Temperature is the most important environmental factor that is positively correlated with CL incidence with a lag of 2-5 months.  [15,19,27,[36][37][38][39], and the morbidity of the disease starts in March and reaches its peak in July. However, different models and scenarios have demonstrated that the incidence of CL can increase depending on weather conditions in the future years 22. Based on our findings, the effect of rainfall on CL cases is inconclusive. For example, Faraj's study reported that rainfall played a role in CL transmission in the lowlands with a lag of 1-3 months [19]. But, in Roger et al.'s study [15], an inverse correlation was observed between the number of annual infections and rainfall (r=−0.71) with a two-month lag and with the number of days and rainfall >50 mm with lags of 4 and 7 months [15]. Nevertheless, Roger et al.'s study showed that a decrease in rainfall was related to a rise in cases after two months [15]. However, the variability of the effects of climate factors may have different impacts on the occurrence of CL depending on the various Leishmania species [11].
The effects of environmental factors on the occurrence of zoonotic cutaneous leishmaniasis (ZCL) were similar to CL incidence in many studies. Yet, the maximum temperature of the warmest quarter, the rainfall in the driest month, the daily average temperature and daily rainfall were the factors affecting the abundance of leishmaniasis vector in the Old World [40]. Moreover, rodent density, average temperature, cumulative rainfall and average relative humidity with different time lags were effective environmental factors having impacts on the ecological condition of Phlebotomus sandflies [41,42] followed by humidity and precipitation [43]. Another study in Morocco showed a relationship between ZCL incidence and the proportion of rural population [44]. Likewise, other studies reported the co-infection of CL and VL among people and animals as well as negative correlations among normalized difference vegetation index (NDVI) and human density and canine cases [43,45,46]. Thus, it can be concluded that leishmaniasis is climate-sensitive, and changes in temperature, rainfall and humidity factors impact its epidemiology because of their effects on population size, distribution and the survival of sandflies [4,20].
Seid et al.'s study in 2014 in Ethiopia showed that geographical surface, slope, elevation and annual rainfall were the predictors of CL incidence with an overall prediction accuracy of 90.4% [3]. Besides, statistical models including only the temperature and precipitation variables and land-use predictors have demonstrated that such weather-related factors can explain 80% of the variance in the disease patterns whereas land-use factors can only explain 20% of the variance [47]. In Seid et al.'s study, the annual rainfall was the most important, effective climatology variable of CL incidence [3].
Hence, it can be argued that environmental factors had the highest contribution to the distribution of leishmaniasis in the Old World. These factors significantly affected the potential distribution of the main reservoir species [48]. Furthermore, information regarding weather conditions is necessary for the prediction of CL and variation of CL incidence in addition to the data of surveillance systems [17]. However, it can be predicted that because of future weather conditions as a result of the human modification of ecosystems, the incidence of CL will have increased by 35% up to 50% by 2050 [47]. Therefore, weather conditions, especially temperature and rainfall, should be considered in each region for modeling, disease monitoring and the management of CL incidence in each region. Moreover, GIS modeling methods are useful to facilitate the implementation of evidence-based, integrated disease-control activities.
Nevertheless, this study has some limitations regarding the assessment of relevant studies. Since the majority of CL cases in the Old World were restricted to the arid and semiarid areas of the north, the near east, the Middle East and Central Asia, a high proportion of included studies in this review were from Iran. Also, given the high number of studies focusing on CL, we restricted our results to a narrow time period. Therefore, other review studies with a wider range of studies are suggested for future reviews.

Conclusion
The results of this review study revealed that environmental and ecological factors considerably influenced the incidence of CL in the Old World. The local environmental factors, such as weather conditions, temperature and rainfall, can play a key role in the seasonal cycle of CL in a way that most CL cases in the Old World occurred in arid and semiarid areas. Therefore, the change and sequence of local temperature and other environmental factors can change the number of vectors; the number of CL cases can also fluctuate after biological processes in the incubation period. Although dry and warm weather occurring after a rainy season may increase the number of CL cases, wet and cold weather can decrease vector density and lead to a decline in the occurrence of CL during subsequent dry seasons. Finally, it seems that it is impossible to provide a unified strategy for controlling CL incidence in different countries. Thus, apart from educating people to prevent new cases on the one hand and the screening and treatment of patients in endemic areas as a reservoir of the disease on the other, it will be also helpful to consider weather conditions and other environmental factors in control programs. Moreover, according to our results regarding the effect of weather conditions on CL, it seems essential to design an early warning system to predict the incidence of CL based on variations in weather conditions. Full text excluded (n= 9)

Screening
Records screened by reading abstract (n= 174) -- Figure 1: Flow diagram of the study selection for the review process.
Research funding: This study was funded by the Qom University of Medical Sciences (Grant number 96898). Authors Contribution: All authors share similar contributions to the conception or design of the study, the interpretation of the collected data, and the final approval of the article.