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A comprehensive review of cutaneous leishmaniasis in kerman province, southeastern iran-narrative review article.

Background: Cutaneous leishmaniasis (CL) remains a serious public health concern in Kerman Province, eastern Iran. This study was aimed to conduct a comprehensive review and highlights various aspects of CL in the province of Kerman. Methods: This article mainly focuses on the studies published in the past 26 years on CL in the province. Current data for the present status were obtained through the provincial health system. Results: Bam was the most infected district (63.6%), followed by Kerman (24.7%) and other districts to a less extent. Leishmania tropica is the major causative agent (95.5%) of CL in Kerman province, however, L. major accounts for 4.5% of the total cases. Bam, Kerman and southern districts of Kerman province were purely anthroponotic CL (ACL), while Rafsanjan, Baft, and Sirjan showed both ACL and zoonotic CL (ZCL). In contrast, Orzoieh district was merely endemic to ZCL type. Phlebotomus sergenti was the main vector in ACL foci while Ph. papatasi was the major vector in the ZCL district of Orzoieh. Localized CL was the most prevalent form (80%) of the disease, while leishmaniasis recidivans was the most uncommon clinical manifestation (18.7%). Conclusion: Due to recent rises in CL disease both in regard of increases in incidence rate and expansion of the disease to new foci, and presence of various risk factors in the province, control measures and health strategies should have high priorities to help treat the existing cases and prevent the expansion of the disease to new areas.


Introduction
Leishmaniasis is among the ninth important infectious diseases in terms of mortality and morbidity (1). The incidence rate of CL is increasing and geographical distribution of the disease is expanding to new foci, due to the presence of various risk factors including population growth and dis-placement, urbanization, anthropogenic environmental modifications, human behaviors, drug resistance, and new agricultural practices (2)(3)(4)(5)(6)(7)(8)(9). The preliminary study on CL goes back to 1976 in Kerman Province, where Yaghoobi-Erashadi carried out a house-to-house survey and visited 820 individuals in high-risk areas in city of Kerman. He reported an active lesion of 7.8% and scar rate of 18.7%. However, the findings could not be generalized to the total population (10). During 1980-1981, Seyedi-Rashti and colleagues reported the trend of urban CL among 35,000 children in 77 elementary and 36 junior high schools in Kerman City. The overall prevalence rate of the active lesion was 0.8% and the scar rate was 4.4%. These authors reported more than 95% of indoor sand flies to be of Ph. sergenti species (11). Later on, in 1993 for the first time, Nadim and Aflatoonian reported ACL from the district of Bam where more dimensions of the disease have currently been elucidated (12). Cutaneous leishmaniasis epidemiology has been significantly changing with the occasional incidence fluctuation in Kerman province, owing to the presence of general and much more specific risk factors caused by recent, man-made precipitating determinants. At present, in light of the introduction of much more modern, refined, and sophisticated techniques, extensive and profound studies have been carried out in various aspects of the disease related to the causative agents, demographic characteristics, reservoirs, biological vectors, and control approaches. Several studies on vaccine efficacy (13)(14)(15), treatment modalities (16)(17) and implementation of control measures (12,(18)(19)(20) have been completed in high endemic areas of the province. The present study is aimed to review historically various aspects of CL in Kerman province, where all three species of the old world leishmaniasis coexist in complex foci in diverse epidemiological settings of Kerman province. Anthroponotic CL (ACL) was more common with a considerable public health impact in some parts of the province, in which human and Ph. sergenti were reservoir host and biological vectors, respectively (21)(22)(23)(24)(25). Zoonotic CL (ZCL) caused by L. major is present in lower incidence rate and coexisted with L. tropica in some foci (25)(26)(27). Rhombomys opimus gerbils were the principal reservoir and Ph. papatasi, the main sand fly vector (28). L. infantum is endemic in southwestern Orzoieh district in Kerman province and have been sporadically reported throughout the province, but not included in here.

Overview of the study
This review was mainly focused on the studies published in the past 26 years on CL in the province of Kerman, southeast of Iran. For this purpose, a comprehensive literature review of local and international databases were conducted using Leishmania species, cutaneous leishmaniasis (CL), in Kerman, Iran. Since CL in Kerman province is a notifiable disease and its management is integrated in the primary health care (PHC) system, data in the status (2011-2013) were obtained through the provincial health system. Data for the present situation was not available for district of Rafsanjan. There was no comprehensive report on CL in Kerman province. In the current paper, various aspects of control strategies including prevention, control approaches, and case-management were considered, described and discussed. The experience gained in the course of sustained and prolonged ACL epidemic following the earthquake of 2003 in Bam is potentially important as well as practically in order to develop a control program and also in management of the disease, especially in CL endemic regions.

Kerman Province
Presently, Kerman is the largest province of Iran, with the population of 2.7 million, which consists one fourth of fruit trees of the country including pistachios in north and north-west, orchards of oranges and various crops in south, and palm trees with fruitful dates in Bam. The province covers an area of 181,714 km 2 and is located in the Southeastern part of the country. The province consists of 23 districts and the CL has historically been present in Bam and Kerman districts. In recent years, the disease has been expanded and spread to new foci throughout the province. The climate is extraordinarily variable, which makes it unique, depending upon the relief of the land. The climate in north and northwestern areas is fairly moderate and dry while in the south and southeast, the weather is warm and humid. The altitude var-ies between 300 m above sea level in Manujan district to about 2,600 m in Baft.

Diagnostic methods
Skin scrapings from the periphery of the lesions were obtained, smeared on glass slides, fixed with methanol, stained by Giemsa, and observed under a compound light microscope. The diagnosis was confirmed by direct examination of all cases and in many cases, cultured in NNN and / or RPMI1640 media.The identity of Leishmania species was determined by indirect fluorescent antibody test (IFAT) and/or enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies (mAb), conventional-PCR, nested -PCR or real-time PCR. In a few instances, inoculation of mice was used for biological confirmation of L.major or isoenzyme to identify Leishmania species and strains, respectively.

Prevention and control strategies
A combination of control approaches has been applied. ACL clinic has been established to coordinate various activities to control and treat ACL in Bam. These measures have included training teams of health personnel for health education, diagnosis of the cases, and identification of the causative agent, active and passive case-detection, treatment and implementation of control measures (16)(17)(18)(19)(20)29). Since CL is a notifiable disease in Kerman province, cases are found by passive case-detection through health surveillance system, exception being for Bam, where all CL cases are detected by both active and passive strategies.

Personal and environmental measures
Spraying insecticide residuals, application of insecticide-impregnated nets (19)(20), and personal protection measures are other control strategies, which have been used to diminish the extent of the CL epidemic, especially in Bam district. Various measures have been implemented to control the cases where the disease was endemic or epidemic, particularly in emerging foci such as Dehbakri and Nezambabad counties in Bam (30,31), Mohammadabad county in Jiroft (24) and in rural communities of Orzoieh district (6,26,32).
A face-to-face health education program has been conducted in a large scale for public and schoolchildren (33). Each individual referring to the CL clinic was given a stick repellent impregnated with diethyl toluamide (DEET) and the lesions were dressed. In addition, the installation of deltamethrin-impregnated screens and curtains has been assessed as a preventive measure against Ph. sergenti in Bam (19)(20). Improving housing conditions, land clearance around human dwellings, insecticide spraying in high-risk areas and removal of million tons of debris and rubbles were other measures for environmental management (34).

Treatment
Meglumine antimoniate (Glucantime) is the firstline treatment for CL, either systemically or intralesionally (35). National guideline for the treatment strategies of CL includes cryotherapy in combination with glucantime. Various modalities are used in endemic areas including CO 2 laser was also used to treat ACL patients; occasionally it was more effective in treating ACL than combined cryotherapy along with intralesional glucantime (17). For the treatment of leishmaniasis recidivans, glucantime along with allopurinol were used with a cure rate of over 90% (16). The prevention and treatment costs were significantly lower than the cases in other CL endemic countries (36,37).

Results
Bam was the most widely infected district (63.6%), followed by Kerman City (24.7%), and other districts were sporadically affected ( Table 1). The most prevalent form of CL in Kerman province was ACL caused by L. tropica, which was mainly endemic in Bam, although the sporadic cases of L. major have already been reported in rural areas (Table 2) (25,38,39 ). Two different isoenzyme of L. tropica (39); MON-39 (77.8%) and MON-55 (22.2%) have been previously reported. After the earthquake in Bam, the epidemics of ACL occurred in the city and rural areas of Bam, where the cases significantly increased, steadily from 2003 (1% incidence) to 2.5% in the peak epidemic in 2006 (three years after the earthquake) (40-41). A similar pattern of incidence risk was observed among opium addicts and non-opium addicts in seven years follow-up examinations in Bam (42). The epidemics of ACL occurred in two counties within Bam district; Dehbakri (31) and Nezamabad (30), and Mohammadabad County (24) in Jiroft after the earthquake. The current data indicated ( Table 2) that CL in Kerman district was predominantly of ACL type (97%), although L .major was reported to a less extent (3%). Similarly, the majority of the cases occurred in southern districts was ACL. In three districts of Rafsanjan, Baft, and Sirjan ZCL caused by L .major and ACL caused by L. tropica co-exist (25,43). The type of CL in Orzoieh district was purely L. major (6,26,27,32), as indicated in Table 2.
In line with the CL cases in the province, Ph. sergenti was the major biological vector (range; 80.3%-94%) in city of Bam (21)(22) and the predominant phlebotomine species was Ph. papatasi in Orzoieh (27) and Rafsanjan districts (44) ( Table 3). Methods for discriminating the sand fly vectors were microscopy for the city of Bam (19,21) and Bahreman County in Rafsanjan (44) , while microscopy (26) and PCR based method for Orzoieh (27) and real-time PCR coupled with high resolu-tion melting curve for Dehbakri County in Bam (22). The anatomical location of lesions significantly varied in ACL patients compared to ZCL cases. The majority of lesions were single and located on face (60%), followed by hands, legs, and other parts (40%) before the earthquake in Bam. On the other hand, the location of lesions was significantly changed to hands, legs (70%), face, and other locations after the earthquake in Bam (25,40,41,45). When the anatomical location of the lesions was considered in ACL endemic districts such as Kerman or other southern districts, females were more significantly infected than the corresponding males. The reason for such a difference has not been well described. In ZCL endemic foci, extremities were more significantly infected (6,26,32). In the province, ACL cases reported from all age groups throughout the year, although children in colder seasons contracted the disease more frequently than older individuals did. However, in ZCL areas of Rafsanjan, Orzoieh, Sirjan, or Baft, extremities (hands and legs) were more commonly and equally involved in children of both sex (6,25,26,35 ).   The duration of ACL cases was frequently around 8 to 10 months, but for uncommon clinical presentation, it might last for a few years (46).CL may evolve into several clinical forms; localized CL (LCL) is the most prevalent form for 95% of the cases (unpublished data). The first sign of infection is a small erythema, which develops to a papule after a variable prepatent period at the site of sand fly bite. Then, the papule progresses into nodule, ulcer, recovery stage, and eventually leave a permanent depressed scar as the characteristic of LCL (unpublished data). The duration of lupoid lesion varies from 2 to 8 years and diameter of the lesion was 1-5 cm with yellowish-brown appearance with papules around or in the scar. Most of the lesions (95%) were on the face and more frequent in males than females (Fig. 1). However, a few cases of other clinical presentations (<2%) including sporotrichoid, erysipeloid, zosteriform, or eczematoid lesions were seen (unpublished data).

Conclusion
The present rise in the number of cases along with unprecedented epidemics and emergences strongly suggests that health authorities should consider CL as an important public health problem with variable morbidity impacts. A comprehensive surveillance, C C including active and passive case-finding approaches, along with the prompt detection of causative agent, and immediate treatment of the patients should receive high priority. Furthermore, due to the presence of various risk factors including non-immune individuals, anthropogenic ecological disturbances, population growth and displacement, industrial development, occurrence of man-made and natural disasters and drug resistance, it is crucial to plan future control strategies and public health measures to help treat active lesions to prevent the expansion of the disease to new areas.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.