Version May 2024
INTRODUCTION — Leishmaniasis consists of a complex of vector-borne diseases caused by more than 20 species of the protozoan genus Leishmania and is transmitted by sand fly vectors (table 1) [1,2]. Clinical manifestations range from cutaneous ulcers to systemic multiorgan disease. Visceral leishmaniasis (VL) is caused primarily by the two related species Leishmania donovani and Leishmania infantum (synonym Leishmania chagasi).
Issues related to epidemiology and control are discussed here. Issues related to clinical manifestations, diagnosis, and treatment are discussed separately. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Visceral leishmaniasis: Treatment".)
EPIDEMIOLOGY — The epidemiology and ecology of VL in a particular region are determined by characteristics of the parasite species, sand fly species, and mammalian reservoir host(s) (figure 1). In all major endemic areas, asymptomatic infections (measured by seroconversion and/or leishmanin skin testing) outnumber clinically manifest disease [3-6]. Seroconversion reflects newly acquired infection but may precede onset of clinical VL by months [4,5].
Close to 12,000 incident cases of VL were reported to the World Health Organization (WHO) in 2021 [7,8]; these figures are thought to represent a substantial underestimate, especially in Africa. Among tropical diseases, leishmaniasis ranks second in mortality and seventh in loss of disability-adjusted life years (DALYs) [9,10]. Leishmaniasis is considered one of the "most neglected diseases" given its strong association with poverty and the limited resources invested in new tools for diagnosis, treatment, and control [11,12].
The best measure of protective immunity is the leishmanin skin test (LST), which reflects durable but probably not permanent cell-mediated immunity. No standardized leishmanin antigen is available, but efforts are underway to develop such a reagent, with a focus on its potential use as an outcome measure in vaccine trials [13]. In observational studies, individuals with positive LST have more than 95 percent reduced risk of VL compared with those with negative LST, and the age-related rise in positive LST prevalence in a community parallels the age-related decrease in disease risk [6,14-16]. A parallel fall in the average age of VL patients may be observed as an epidemic matures [17]. Factors that increase the likelihood an individual will progress from leishmanial infection to clinical VL include poor nutritional status, age <5 years (for L. infantum infection), HIV coinfection, and host immunogenetic factors [15,18-22].
Species
L. donovani — Visceral leishmaniasis due to L. donovani occurs in South Asia (India, Bangladesh, and Nepal) and East Africa (Sudan, South Sudan, Ethiopia, Eritrea, Kenya, Uganda, and Somalia). Clinical disease due to L. donovani can affect individuals of all ages, although, in regions with sustained endemic transmission, the incidence may fall with increasing age because of a high rate of acquired immunity in adults [1,14].
In both the Indian subcontinent and East Africa, VL tends to occur in epidemic cycles; the incidence rises over a period of 2 to 5 years, peaks, and then falls, only to rise again after a 5- to 20-year period of low incidence [23,24]. In 2014, India and Bangladesh together reported approximately 10,000 VL cases, while Sudan, South Sudan, and Ethiopia together reported more than 14,000 cases [23]. The true case load was likely substantially higher.
In northeastern India, southeastern Nepal, and Bangladesh, efforts to eliminate VL (particularly L. donovani transmission) as a public health problem have been underway since 2005. Areas of emphasis have included improving timeliness and effectiveness of diagnosis and treatment as well as vector control through residual household insecticide application. In this area of transmission, humans are the only proven reservoir host [1,25-27]. Diagnosis with rapid tests and treatment with single dose liposomal amphotericin B 10 mg/kg at primary health care facilities in endemic areas have been crucial in decreasing the human infection reservoir [28]. Criteria for validation of elimination as a public health problem include maintenance of VL incidence below 1 per 10,000 population at the subdistrict (Bangladesh), block (India) or district (Nepal) level for at least 3 years, and documentation of all components of the elimination program, including sustained sensitive surveillance [29]. The incidence of VL has fallen markedly between 2005 and 2022 in all three countries [23,28,30-33]. In October 2023, Bangladesh received official validation of elimination of VL as a public health problem from the WHO; incidence has been below the elimination threshold since 2017 [34]. In Nepal, the incidence threshold has been reached, but in recent years VL cases are being reported from hilly districts not previously considered endemic, where control efforts had not been instituted and diagnosis and treatment are less accessible, presenting challenges to the elimination program [35]. Climate change is widely hypothesized to play a role. In India, only one block reported incidence above 1 per 10,000 in 2022 [36]. Efforts are underway to develop practical methods to sustain adequate surveillance in the face of very low incidence [37-39].
In East Africa, transmission of L. donovani consists of both anthroponotic and zoonotic components. In Sudan, sylvatic rodents and domestic dogs may act as reservoirs; however, large human VL outbreaks in villages and refugee settings are thought to reflect predominantly anthroponotic transmission [17,40-44]. With the marked decline in the number of VL cases in the Indian subcontinent, East Africa is now the region with the highest caseload globally [45]. There are now calls for a more concerted effort to control VL in East Africa, building on the lessons of the elimination programs in the Indian subcontinent [46,47].
L. infantum — VL due to L. infantum (synonym L. chagasi) occurs in the Mediterranean (including Spain, France, and Greece), the Middle East, Afghanistan, Iran, Pakistan, and Brazil. In addition, sporadic cases have been reported in Central Asia, China, Mexico, and Central and Latin America outside of Brazil [2,25].
In 2021, the highest L. infantum VL case load was reported from Brazil with 1492 cases [23]. Aside from Yemen where both L. donovani and L. infantum have been reported [48], all other L. infantum–endemic countries reported fewer than 100 human cases in 2021 [8].
Children <10 years and immunosuppressed adults have a higher risk of clinical disease due to L. infantum than immunocompetent adults [49-51]. The predominance of pediatric L. infantum cases may be related to several factors including lower parasite virulence than L. donovani, the immature innate immune response, lack of prior exposure and acquired immunity, and higher rates of malnutrition among children than adults [6,18,52]. The lower incidence of L. infantum among adults in endemic areas may be due in part to prior exposure resulting in cell-mediated immunity [6,14,53,54].
In one study including 200 United States soldiers deployed to Iraq between 2002 and 2011, 19.5 percent had at least one test positive for probable asymptomatic L. infantum infection (1 percent by polymerase chain reaction, 5 percent by serology, and 14 percent by interferon-gamma release assays) [55]. In another study of United States soldiers deployed to Iraq or Afghanistan from 2001 to 2016, 25 symptomatic cases of VL due to L. infantum were reported [56].
L. infantum is zoonotic, with infected domestic and feral dogs forming the primary reservoir in most geographic locations (figure 2) [1,2,25]. However, multiple other mammalian species, including foxes, raccoon-dogs, and jackals, can be infected with L. infantum, and a large outbreak in a suburb of Madrid was fueled by infection in hares [2,57-59]. Because of the zoonotic reservoirs, L. infantum transmission can be maintained in the absence of human VL cases.
Transmission — VL sand fly vectors include more than 10 species of the genus Phlebotomus (in the Old World) and Lutzomyia longipalpis (in the New World) [1,2]. The female sand fly is hematophagous; both sexes take sugar meals from plant sources. Important sand fly characteristics that vary by species include breeding sites, peak feeding times, population seasonality, preferred blood meal sources, aggregation, and resting behavior [2,60].
Leishmaniasis can also be transmitted via intravenous drug use, blood transfusion, organ transplantation, congenital infection, and laboratory accidents [61-66]. These modes of transmission are rare.
CONTROL — Control of VL is based on two major approaches: vector control to decrease sand fly bites among humans and management of infected humans and animals to decrease the infection reservoir.
Vector control — Sand flies have a relatively limited flight range, and, in areas where transmission is predominantly sylvatic, it may be possible to establish vegetation-free buffer zones around human dwellings [67,68]. In the major domestic transmission foci, interventions tend to focus on barrier methods such as bed nets and screens and insecticide application on surfaces where the flies rest. Thorough understanding of vector behavior is essential to design effective control strategies [67]. Vector control modalities include indoor residual insecticide spraying (IRS), insecticide-treated nets (ITNs), and other applications of insecticides or repellents to decrease sand fly biting.
●In areas where sand flies rest inside human dwellings, IRS every six months may be an effective intervention, although it is costly due to the infrastructure, equipment, and training required. Effective supervision is required to ensure the appropriate use of materials and to prevent diversion for agricultural applications. IRS conducted for malaria eradication in the Indian subcontinent during the 1950s and 1960s nearly eliminated VL, though a major resurgence occurred within a decade following the end of the program [69,70]. Major efforts have been made to evaluate and improve IRS programs in the Indian subcontinent [71,72]. The effectiveness of the Indian IRS program is still a matter of debate, in part because the vector appears to be more exophilic than previously thought [73,74]. (See "Malaria: Epidemiology, prevention, and control", section on 'Indoor residual spraying'.)
●Insecticide-treated bed nets may be effective in regions such as South Asia, where the peak period of vector activity is late in the evening [75-77]. However, a cluster-randomized trial of insecticide-treated nets failed to demonstrate a significant decrease in clinical VL and VL infection in sites in India and Nepal [78], and decreases in indoor vector density were smaller than anticipated [79]. Reasons for this failure are poorly understood but may be related to acquired insecticide resistance and changes in vector behavior (eg, from indoor to outdoor biting and resting) in response to insecticide pressure from poorly implemented indoor residual spray programs [74]. Long-lasting insecticide-treated nets appear to maintain efficacy based on standard laboratory bioassays for at least two years under field conditions in South Asia [80]. Limitations include the importance of regular use and that those at highest risk for VL are the least likely to obtain the materials successfully.
●Treated dog collars are a promising tool for vector control in areas of zoonotic VL [81].
Use of insect repellent and insecticide-treated clothing is advisable for travelers [82] but, in general, is not a practical routine intervention for residents of endemic areas. (See "Prevention of arthropod and insect bites: Repellents and other measures".)
Reservoir hosts — Rapid diagnosis and effective treatment of anthroponotic VL helps decrease the human reservoir of infection [83]. Patients with post-kala-azar dermal leishmaniasis (PKDL) are an especially important reservoir of infection for a number of reasons; PKDL can persist for years, PKDL treatment requires a prolonged course of therapy, and such patients are less likely to seek care than those with kala-azar [84-86]. Both VL and PKDL patients were shown to be infective to sand flies in xenodiagnosis studies conducted during the 1920s and 1930s [87,88]. More recent studies confirm the infectivity of PKDL patients [89,90]. Timely, improved detection, diagnosis, and treatment of PKDL will be essential to maintaining improved control of VL in India, Bangladesh, and Nepal [37].
Programs focusing on reduction of canine reservoirs to decrease zoonotic VL transmission have not proved highly effective. This may be due to inadequate diagnostic sensitivity to identify infectious dogs, delay between diagnosis and culling, and the finding that most of the sand fly infections derive from a small percentage of highly infectious dogs (superspreaders) [91,92]. Manipulations of animal populations may have unexpected consequences depending on host density and role (as infection reservoir, blood meal source for sand flies, and/or nonsusceptible host) [2,87,93].
SUMMARY
●Species – Visceral leishmaniasis (VL) is caused primarily by the two related species Leishmania donovani and Leishmania infantum (synonym Leishmania chagasi). (See 'Introduction' above and 'Species' above.)
•L. donovani – VL due to L. donovani occurs in South Asia (India, Bangladesh, and Nepal) and the Horn of Africa (Sudan, Ethiopia, Kenya, and Somalia). Clinical disease due to L. donovani affects all ages, including otherwise healthy adults. In the Indian subcontinent, L. donovani transmission is anthroponotic; humans are the only proven reservoir host. In East Africa, both anthroponotic and zoonotic L. donovani transmission occur. (See 'L. donovani' above.)
•L. infantum – VL due to L. infantum (synonym L. chagasi) occurs in the Mediterranean, the Middle East, Afghanistan, Iran, Pakistan, and Brazil. In addition, sporadic cases have been reported in Central Asia, China, Mexico, and Central and Latin America outside of Brazil. In general, clinical disease due to L. infantum is more likely to occur in children <10 years and immunosuppressed adults. L. infantum transmission is zoonotic; the major reservoir for L. infantum infection is the domestic dog. (See 'L. infantum' above.)
●Transmission – VL sand fly vectors include more than 10 species of the genus Phlebotomus (in the Old World) and Lutzomyia longipalpis (in the New World). VL can also be transmitted via intravenous drug use, blood transfusion, organ transplantation, congenital infection, and laboratory accidents; these modes of transmission are rare. (See 'Transmission' above.)
●Prevention and control - Control of VL is based on two major approaches: vector control to decrease sand fly bites among humans and management of infected humans and animals to decrease the infection reservoir. (See 'Control' above.)
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