INTRODUCTION Leishmaniasis, one of the most important parasitic disease transmitted by Phlebotominae vectors is wide- spread, and has different epidemiological and clinical fea- tures. The disease is endemic in more than 98 countries on four continents, and an estimated 700,000 to 1 million new cases and 20,000 to 30,000 deaths occur annually across the world 1–2 . Visceral leishmaniasis (VL) is one of the most important clinical form of leishmaniasis in humans as well as canines 2 . The causal agent of the disease belongs to the group of Leishmania donovani complex (Order Ki- netoplastida), which is transmitted by different species of female sandflies 2–5 . The disease can be fatal if left untreat- ed, and even with the availability of treatment, the mor- tality rate reported 6 varies from 10 to 20%. Leishmania infantum is the main causative agent of VL in humans and dogs in Mediterranean region 2 . Recently, L. tropica and L. major have been reported in some cases, as principal agents of VL in human 8–10 and domestic dogs 11–12 . Visceral leishmaniasis is endemic in several parts of Iran includ- ing Ardabil, East Azerbayjan, Fars, Bushehr, Kerman and Qom and North Khorasan provinces 12–13 . Though, it has been reported to exist in sporadic form in other areas of Iran 14–15 . The domestic and wild dogs are the most impor- tant reservoirs for VL in Iran 12–16 . Domestic dogs and wild canines such as foxes, jackals and wolves are infected with L. infantum, which seem to play an important role in the wild cycle of the disease in mountainous areas 14–17 . Determining the prevalence of canine VL (CVL) in endemic areas is necessary for controlling zoonotic vis- ceral leishmaniasis (ZVL) 17–18 . The prevalence of L. in- fantum infection varies from 2.6 to 26.6% in different parts of the world 17 . The clinical symptoms of CVL vary from asymptomatic forms to restricted and deadly infec- tion 16, 18 . Moreover, the incubation period lasts from sev- J Vector Borne Dis 55, September 2018, pp. 173–183 Review Article Geographic distribution and spatial analysis of Leishmania infantum infection in domestic and wild animal reservoir hosts of zoonotic visceral leishmaniasis in Iran: A systematic review M. Mohebali 1–2 , E. Moradi-Asl 3 & Y. Rassi 4 1 Department of Medical Parasitology and Mycology, School of Public Health, 2 Center for Research of Endemic Parasites of Iran, Tehran University of Medical Sciences, Tehran; 3 Department of Public Health, School of Public Health, Ardabil University of Medical Sciences, Ardabil; 4 Department of Medical Entomology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran ABSTRACT Visceral leishmaniasis (VL) is an important parasitic disease which is endemic in different parts of Iran; and domestic and wild canines are principal reservoir hosts of the disease. The objective of this study was to review the spatial distribution of canine VL (CVL) caused by Leishmania infantum in domestic and wild canines in different geographical areas of Iran. An extensive literature search was conducted in different international and national databases, including Cochrane, MEDLINE/PubMed, Scopus, Web of Science and Iran Medex to find articles with the words “visceral leishmaniasis in Iran” in their titles and “canine visceral leishmaniasis in Iran” or “feline visceral leishmaniasis in Iran” or “accidental reservoir hosts of visceral leishmaniasis in Iran” in their subtitles, irrespective of the type and duration of study. Screening of the irrelevant articles from total 36,342, yielded 61 eligible articles. More than 93% of the studies were carried out on domestic dogs (Canis familiaris, n = 57) and the remaining were on other carnivores such as wild canines including foxes (Vulpes vulpes, n = 4), jackals (C. aureus, n = 6) and wolves (C. lupus, n = 6); while studies on domestic cats (Felis catus, n = 3) as well as desert rodents (n = 2) were rare. The average rate of L. infantum infections reported among domestic dogs using direct agglutination test (DAT) in Iran was 12.5%. The highest prevalence rate (14%) was reported from the northwest regions of the country where VL is endemic. The review indicates that CVL is endemic in various parts of Iran and domestic dogs are the main and potential reservoir hosts of the disease. Other carnivores, such as domestic cats and some species of desert rodents (Cricetulus migratorius, Mesocricetus auratus and Meriones persicus) seem to be playing a role in the maintenance of transmission cycle of L. infantum in the endemic areas of the disease. Key words Domestic canines; Iran; reservoirs; visceral leishmaniasis [Downloaded free from http://www.jvbd.org on Friday, January 4, 2019, IP: 5.122.114.141]
Transcript
INTRODUCTION
Leishmaniasis, one of the most important parasitic disease transmitted by Phlebotominae vectors is wide-spread, and has different epidemiological and clinical fea-tures. The disease is endemic in more than 98 countries on four continents, and an estimated 700,000 to 1 million new cases and 20,000 to 30,000 deaths occur annually across the world1–2. Visceral leishmaniasis (VL) is one of the most important clinical form of leishmaniasis in humans as well as canines2. The causal agent of the disease belongs to the group of Leishmania donovani complex (Order Ki-netoplastida), which is transmitted by different species of female sandflies2–5. The disease can be fatal if left untreat-ed, and even with the availability of treatment, the mor-tality rate reported6 varies from 10 to 20%. Leishmania infantum is the main causative agent of VL in humans and dogs in Mediterranean region2. Recently, L. tropica and
L. major have been reported in some cases, as principal agents of VL in human8–10 and domestic dogs11–12. Visceral leishmaniasis is endemic in several parts of Iran includ-ing Ardabil, East Azerbayjan, Fars, Bushehr, Kerman and Qom and North Khorasan provinces12–13. Though, it has been reported to exist in sporadic form in other areas of Iran14–15. The domestic and wild dogs are the most impor-tant reservoirs for VL in Iran12–16. Domestic dogs and wild canines such as foxes, jackals and wolves are infected with L. infantum, which seem to play an important role in the wild cycle of the disease in mountainous areas14–17.
Determining the prevalence of canine VL (CVL) in endemic areas is necessary for controlling zoonotic vis-ceral leishmaniasis (ZVL)17–18. The prevalence of L. in-fantum infection varies from 2.6 to 26.6% in different parts of the world17. The clinical symptoms of CVL vary from asymptomatic forms to restricted and deadly infec-tion16, 18. Moreover, the incubation period lasts from sev-
J Vector Borne Dis 55, September 2018, pp. 173–183
Review Article
Geographic distribution and spatial analysis of Leishmania infantum infection in domestic and wild animal reservoir hosts of zoonotic visceral leishmaniasis in Iran: A systematic review
M. Mohebali1–2, E. Moradi-Asl3 & Y. Rassi4
1Department of Medical Parasitology and Mycology, School of Public Health, 2Center for Research of Endemic Parasites of Iran, Tehran University of Medical Sciences, Tehran; 3Department of Public Health, School of Public Health, Ardabil University of Medical Sciences, Ardabil; 4Department of Medical Entomology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
ABSTRACT
Visceral leishmaniasis (VL) is an important parasitic disease which is endemic in different parts of Iran; and domestic and wild canines are principal reservoir hosts of the disease. The objective of this study was to review the spatial distribution of canine VL (CVL) caused by Leishmania infantum in domestic and wild canines in different geographical areas of Iran. An extensive literature search was conducted in different international and national databases, including Cochrane, MEDLINE/PubMed, Scopus, Web of Science and Iran Medex to find articles with the words “visceral leishmaniasis in Iran” in their titles and “canine visceral leishmaniasis in Iran” or “feline visceral leishmaniasis in Iran” or “accidental reservoir hosts of visceral leishmaniasis in Iran” in their subtitles, irrespective of the type and duration of study. Screening of the irrelevant articles from total 36,342, yielded 61 eligible articles. More than 93% of the studies were carried out on domestic dogs (Canis familiaris, n = 57) and the remaining were on other carnivores such as wild canines including foxes (Vulpes vulpes, n = 4), jackals (C. aureus, n = 6) and wolves (C. lupus, n = 6); while studies on domestic cats (Felis catus, n = 3) as well as desert rodents (n = 2) were rare. The average rate of L. infantum infections reported among domestic dogs using direct agglutination test (DAT) in Iran was 12.5%. The highest prevalence rate (14%) was reported from the northwest regions of the country where VL is endemic. The review indicates that CVL is endemic in various parts of Iran and domestic dogs are the main and potential reservoir hosts of the disease. Other carnivores, such as domestic cats and some species of desert rodents (Cricetulus migratorius, Mesocricetus auratus and Meriones persicus) seem to be playing a role in the maintenance of transmission cycle of L. infantum in the endemic areas of the disease.
Key words Domestic canines; Iran; reservoirs; visceral leishmaniasis
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J Vector Borne Dis 55, September 2018174
eral months to several years, depending on the virulence of the parasite and host genetic characteristics19. Differ-ent serological and molecular methods are used to detect L. infantum in humans and reservoirs19–20. The easiest and most cost-effective detection method in this regard is direct agglutination test (DAT) which has high sensi-tivity and specificity and is widely used in developing countries19–20. Domestic dogs are most important reser-voirs of the disease, which might not show any symp-toms for a long time and relative resistance to antileish-manial treatments can easily distribute VL in different regions17, 20–21.
Therefore, one of the best ways of preventing infec-tion to humans is rapid identification and control of the reservoir population, including infected domestic dogs and wild canines17. Hence, determining the disease status in animal reservoirs and their control can play a significant role in preventing VL spread to humans19, 22. Given the plethora of studies conducted on domestic and wildlife reservoirs in different areas of Iran, it is necessary to es-timate the prevalence of L. infantum infections in differ-ent reservoirs in endemic and non-endemic areas of Iran. This study was an attempt to review the earlier studies of VL caused by L. infantum carried out on animal reservoir hosts using different methods in Iran.
Study designThis study systematically searched all the earlier pub-
lished studies, reports and documentations related to VL that used parasitological (microscopy and culture), sero-logical (DAT) and molecular methods for its identifica-tion/diagnosis. International databases such as Cochrane, MEDLINE/PubMed, Google Scholar, Science Direct, Scopus, Web of Science, Veterinary information net-work, VetMed Resource, Zoological Records, Biological Abstracts, CAB Abstracts as well Iran’s databases (for Persian articles) including Iran Medex, Scientific Infor-mation Database (SID ) and Magiran were searched with no time limitation. The results were qualitatively summa-rized in order to find out any precise information relating to the purpose of the study.
Quality assessment and data extractionInitially, all the article titles were entered into a ref-
erence manager software, namely End Note. After dele-tion of the duplicate cases, they were assorted for initial screening. In the first stage, these article titles were re-viewed. Afterward, all the articles that were irrelevant to the objectives of the study were removed from the prima-ry databank. Next, two persons scrutinized the titles and abstracts; and the articles that were selected by both the
Fig. 1: Flow chart demonstrating database search, screening and selection of studies.
persons were finalized for subsequent analysis (Fig. 1).
Search methodologyThe following words and phrases were used in or-
der to search the articles: “visceral leishmaniasis in Iran” in the titles and “canine visceral leishmaniasis in Iran” or “feline visceral leishmaniasis” or “acciden-tal reservoir hosts of visceral leishmaniasis in Iran” in subtitles. Other key words included visceral leishmani-asis, kala-azar, canine visceral leishmaniasis, leishmani-asis in domestic and wild canine, leishmaniasis in dogs, foxes, wolves, jackals, and rodents, L. infantum in dogs and canines.
Analyzed methods All the studies were in the form of a M.Sc., or Ph.D.
theses and research projects, whose results had been pub-lished as research articles in prestigious journals. All of the compiled articles in this review study had met the rules of publishing a scientific article in the journals. The exclu-sion criteria consisted of the absence of the issue number and approval letter by the university. Data were summa-rized based on individual provinces, endemic and non-endemic areas, as well as two groups of wild and domestic reservoirs. The prevalence of the CVL disease, based on the years and different regions at the provincial level, was developed using the Arc GIS 10.4.1 software, and dis-tribution maps were generated based on the type of res-ervoirs (Fig. 2). SPSS ver. 23 and quantitative statistical
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175Mohebali et al: Distribution and spatial analysis of L. infantum infection in Iran
Fig. 3: Frequency of studies carried out on CVL in Iran (1982–2017).
Fig. 2: Distribution and prevalence rate of CVL in provinces of Iran (1982–2017).
tests, such as chi-square analysis and correlation analysis were used in order to investigate the status of CVL among different reservoirs as well as the relationship between age and gender. Moreover, all the diagnostic methods (molec-ular, serological and parasitological) were used in order to analyze the infection of the reservoirs.
Out of all the databases searched from 1982 to 2017, only 61 articles/studies were found eligible for inclusion in this systematic review. These studies were carried out in 20 of the 31 provinces, and >38% of them were conducted in northwest of Iran (Ardabil province). The highest num-ber of studies, i.e. 10 and 9 were conducted in 2011 and 2013, respectively (Fig. 3). The first study was conducted in 1982 in Mazandaran province (non-endemic area of VL) and the latest study was reported from Kerman prov-ince (endemic area) in 2017 (Table 1).
In these studies, a total of 24,884 animals were exam-ined, of which 94.23% were the owned pets and stray dogs and the remainders were other wild animals. Of all the dogs investigated, 90% were pets and sheep dogs and 10% of those were stray dogs. The infection rate with Leishma-nia parasites was 14.18% in the domestic dogs and 6.35% in wild canines (Table 2).
In total, 1434 cases of wildlife as reservoir hosts for VL have been investigated, in which the highest number of examined animals were rodents (48%) and the low-est were wolves (~3%) (Fig. 4). Analysis of L. infantum infection frequency in dogs according to different re-gions of the country shows that it was distributed mainly in 20 provinces of Iran, viz. Alborz, Ardabil, Bushehr, East Azarbaijan, Razavi Khorasan, Chaharmahal and Fig. 4: The percentage share of wildlife reservoirs in terms of CVL
in Iran (1982–2017).
Fig. 5: Geographical distribution of L. infantum infections in dogs, Iran 1982–2017.
Bakhtiari, Isfahan, Fars, Qom, Golestan, Hamadan, Ker-man, Khuzestan, Kohgiluyeh and Boyer-Ahmad, Lores-tan, Mazandaran, North Khorasan, Semnan, Sistan and Baluchestan and Tehran (Fig. 5).
Infection with L. infantum in domestic cats (by DAT method) was reported from three provinces of Iran,
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J Vector Borne Dis 55, September 2018176 Ta
ble
1. T
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s
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8234
617
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9330
345
14.8
214
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NP
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ebal
i et a
l24
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hehr
2001
613
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P 6
.76
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NP
1.95
Gav
gani
et a
l21
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abil
2002
199
43N
P21
.65
NP
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6Sa
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2003
458
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l26A
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0426
810
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P39
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l27A
rdab
il20
0430
323
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7.6
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6.93
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2004
328
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lane
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2006
223
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56Ze
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2005
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2006
196
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26.3
331
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0721
029
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2007
206
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0712
655
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2008
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[Downloaded free from http://www.jvbd.org on Friday, January 4, 2019, IP: 5.122.114.141]
177
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24.5
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1611
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rdab
il20
1611
820
NP
15.8
NP
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rasa
n20
1684
11N
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2017
6010
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16.7
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Tabl
e 1.
(con
td...
)Mohebali et al: Distribution and spatial analysis of L. infantum infection in Iran
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J Vector Borne Dis 55, September 2018178
namely Ardabil, East Azarbaijan, and Kerman, with the infection rates of 24.27, 23 and 6.70%, respectively66, 76, 91. Fox infection was reported from four provinces of Iran—North Khorasan, Ardabil, East Azerbaijan and Bush-ehr. The mean infection rate reported (using serological and parasitological methods) was 20.5, 10.71, 5.2 and 15.55%, respectively in these provinces (Fig. 6). The infection in jackals (identified via serological methods) was reported from six provinces namely, East Azerbaijan (20%), Ardabil (23%), Mazandaran (5.5%), North Kho-rasan (11.66%), Chahar Mahal and Bakhtiari (5.26%) and Bushehr (15%). The infection rate was 7.70% in Ardabil province using parasitological method. Infection with L. infantum in rodents was only reported from northwest of Iran (Ardabil and East Azerbaijan provinces) (Fig. 5). Among the five species of rodents investigated, infection share/frequency was highest for Meriones persicus (69%) and lowest for Mesocricetus auratus (0.5%). The infec-tion rate reported for Meriones persicus by using parasi-tological methods was 14.7%, for Cricetulus migratorius it was 7.2%, and for Mesocricetus auratus it was 75%; while no reports were observed for Mus musculus and Rattus norvegicus.
Of the all domestic and wild reservoirs that were studied, L. infantum parasite was reported in 12.33% hosts using the molecular, serological and parasitological methods. The major diagnostic methods used in these studies included DAT (12.5%), ELISA (6.1%), PCR (1.7%), DIPESTIC rK39 (0.8%), IFA (0.1%) and parasi-tology (0.5 %).
The infection rate of L. infantum in different res-ervoirs examined by serological and parasitological methods was 23% for cats, 12.52% for domestic dogs, 11.33% for rodents, 10.2% for wolves, 9.9% for foxes and 6.36% for jackals. Other than L. infantum parasite, L. tropica and L. donovani were also isolated from the reservoirs. Leishmania tropica has been isolated from
dogs in the northwest, center, and northeast of Iran; from the jackals in northeastern Iran, and from foxes and wolves in northwest of Iran while L. donovani has been only reported in desert rodents in northwestern of Iran by using both serological and parasitological methods.
Among endemic areas, the highest infection rate was reported from the Ardabil province (24%) and the low-est infection rate was reported from Bushehr province (9%), using all diagnostic methods. In non-endemic ar-eas, the highest and lowest infection rates were report-ed from Golestan (32%) and Hamadan (4%) provinces, respectively. According to the included studies, the in-fection rate in CVL reservoirs varied from 6 to 24% in endemic areas and from 4 to 32% in non-endemic areas of Iran.
Each year, >20,000 to 30,000 human deaths occur from VL in the world7. The dogs and wild canines consti-tute the most important reservoirs for L. infantum in the old and new worlds14, 17, 37. Determining the prevalence and rate of infection in different reservoirs can help in controlling ZVL18. Various studies have shown that in the past decade, L. infantum was the most predominant Leish-mania species for both VL and CVL in different parts of Iran14, 24. It has been reported that dogs and wild canines in-cluding jackals, foxes and wolves are frequently infected with L. infantum in Iran13, 17, 20, 77.
Over the past 35 yr, about 61 studies have been car-ried out on domestic and wildlife reservoirs in different regions of Iran, especially endemic areas, all those point to the indispensable role of reservoirs in epidemiological as-pects of VL. The first study in non-endemic areas of Iran was conducted in 1982 in Mazandaran province22 where the reported infection rate was 3%, while the most recent one was conducted in Sistan and Baluchestan province in 2014, with the reported infection rate of 15.4%, indicat-ing the variability of the infection rate in different parts of the country.
Among the endemic regions of Iran, the first study was conducted in 1993 in Ardabil province23, where the infection rate was 14.8% by serological method. The most recent study was conducted in 2016, in the same province, and infection rate in dogs was found to be 32.6%, which represents an increase of reservoirs in this province74. The comparison of the results of the infection prevalence in reservoirs, in both endemic and non-endemic regions shows that the percentage of reservoir infection is high in both the regions. Findings pertaining to the prevalence of VL in humans also show that >50% of human cases occur in the endemic areas of the northwest of Iran, which is consistent with the prevalence of reservoirs infection in
Table 2. Prevalence of VL infections caused by L. infantum in different animal reservoir hosts in Iran (1982–2017)
migratorius, Mesocricetus auratus and Meriones persicus)
12.45309824884Total
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Fig. 6: Distribution of L. infantum infections among the studied animals, Iran 1982–2017—(a) Fox; (b) Cats; (c) Rodents; and (d) Jackals.
Mohebali et al: Distribution and spatial analysis of L. infantum infection in Iran
(a) (c)
(b) (d)
northwest of Iran13–14, 78–80.The prevalence rate of CVL in Iran is higher in en-
demic areas than in non-endemic ones and varies from 4–32%. In northeastern Brazil81, the infection rate of CVL was reported to be 3.95–5.31% in 2014; and in north Spain it was reported to be 28% by PCR method6. Among vari-ous reservoirs in Iran, domestic dogs and jackals showed the highest rate of infection with L. infantum implying that dogs and jackals are respectively their main domestic and wild reservoir in Iran. Leishmania infantum was isolated from Cricetulus migratorius and Mesocricetus auratus, Two species of parasites, i.e. L. infantum and L. donovani were isolated and reported from the Meriones persicus. These results indicate that rodents should be considered in devising strategies for epidemiological control of VL
in Iran. In a study conducted in Brazil, three parasites namely, L. donovani complex, L. mexicana complex and L. braziliensis were isolated and reported using molecular method81–82. In other areas, like Italy, Saudi Arabia and Venezuela, where human VL is active, natural infection of black rats with L. infantum and L. donovani and their role in preserving the disease has been reported in many studies83–85.
So far, three species of Leishmania parasites have been isolated and reported from wild and domestic res-ervoirs in Iran, 98% of which constitute/include L. infan-tum and L. tropica while L. donovani is rarely reported. This result shows that L. infantum is the main agent of CVL in Iran. In a WHO report also, L. infantum has been introduced as the main cause of Mediterranean VL in hu-
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mans and reservoirs 2, 16. Leishmania parasites have also been isolated from domestic and wildlife reservoirs in other parts of the world. For instance, in Mexico, three species of parasites including L. mexicana (20.63%), L. infantum (6%) and L. braziliensis (7.52%) were isolated from the blood serum of dogs by ELISA method86. The frequency of L. infantum infections in Mexico was less than that reported in Iran. In Spain, 28% of the studied animals were found to be infected with L. infantum by us-ing PCR method. The infection rate was found to be 29% in foxes, 25% in wild cats, 50% in weasels, 30% in sages and 26% in gravels87. As in Madrid, the L. infantum was isolated from 22.9% rabbits under investigation by rK39 method88. These results indicate that L. infantum infection has a wide distribution in domestic and wild reservoirs in most of the regions of Iran.
The first study in Iran was conducted on cats in 2010 in Fars and East Azerbaijan provinces and L. infantum was isolated from cats by molecular and parasitological meth-ods89. In Sao Paulo and Rio de Janeiro, Brazil L. infan-tum/chagasi was reported in domestic and wild cats5, 90. In an another study, high seroprevalence rates have been reported in domestic cats (Felis catus) based on detection of anti-L. infantum antibodies, indicating that infected cats might play a potential role in the maintenance of L. infantum in the endemic areas of ZVL91. This finding sug-gests that cats could play an important role in preserving VL in natural environments.
CONCLUSION
The review indicates that CVL is endemic in various parts of Iran and domestic dogs are the main and potential reservoir hosts of the disease. Other carnivores, such as domestic cats and some species of desert rodents (Cri-cetulus migratorius, Mesocricetus auratus and Meriones persicus) seem to be playing a role in the maintenance of transmission cycle of L. infantum in the endemic areas of the disease. High infection rates of CVL among domestic dogs compared to other canines pose a potential transmis-sion of the disease to humans. The status of other reservoir hosts, including domestic cats as well as domestic and wild rodents particularly in endemic areas could be help-ful in controlling the expansion of the disease. Moreover, the status estimation of sandflies that feed on the blood from these infected reservoir—Hosts is also necessary to prevent the disease transmission. Due to the increas-ing trend of CVL in Iran, it is strongly recommended that comprehensive plans should be implemented in order to prevent and control this disease, especially in endemic areas.
Conflict of interest: None.
ACKNOWLEDGEMENTS
This study was approved and financially supported by the Tehran University of Medical Sciences (Project Nos: 96-01-160-34180; 94-02-27-29919; and 97-01-160-37931).
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Correspondence to: Dr E. Moradi-Asl, Department of Public Health, School of Public Health, Ardabil University of Medical Sciences, Ardabil, Iran.
