11 Mar 2016: The PLOS Neglected Tropical Diseases Staff (2016) Correction: Epidemiology of Leptospirosis in Africa: A Systematic Review of a Neglected Zoonosis and a Paradigm for 'One Health' in Africa. doi: info:doi/10.1371/journal.pntd.0004552 View correction
Leptospirosis is an important but neglected bacterial zoonosis that has been largely overlooked in Africa. In this systematic review, we aimed to summarise and compare current knowledge of: (1) the geographic distribution, prevalence, incidence and diversity of acute human leptospirosis in Africa; and (2) the geographic distribution, host range, prevalence and diversity of Leptospira spp. infection in animal hosts in Africa.
Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we searched for studies that described (1) acute human leptospirosis and (2) pathogenic Leptospira spp. infection in animals. We performed a literature search using eight international and regional databases for English and non-English articles published between January 1930 to October 2014 that met out pre-defined inclusion criteria and strict case definitions.
Results and Discussion
We identified 97 studies that described acute human leptospirosis (n = 46) or animal Leptospira infection (n = 51) in 26 African countries. The prevalence of acute human leptospirosis ranged from 2 3% to 19 8% (n = 11) in hospital patients with febrile illness. Incidence estimates were largely restricted to the Indian Ocean islands (3 to 101 cases per 100,000 per year (n = 6)). Data from Tanzania indicate that human disease incidence is also high in mainland Africa (75 to 102 cases per 100,000 per year). Three major species (Leptospira borgpetersenii, L. interrogans and L. kirschneri) are predominant in reports from Africa and isolates from a diverse range of serogroups have been reported in human and animal infections. Cattle appear to be important hosts of a large number of Leptospira serogroups in Africa, but few data are available to allow comparison of Leptospira infection in linked human and animal populations. We advocate a ‘One Health’ approach to promote multidisciplinary research efforts to improve understanding of the animal to human transmission of leptospirosis on the African continent.
Leptospirosis is an important bacterial zoonosis that affects people and animals worldwide. It is common in tropical areas where people and animals live in close contact, but the disease has been widely neglected in Africa. In this study we aimed to demonstrate the extent of leptospirosis in Africa and describe the diversity of the causative agent Leptospira spp. in human and animal infections across the continent. Through a systematic literature review, we identified 97 studies from 26 African countries that described human disease or animal infection and met inclusion criteria. Leptospirosis was the cause of illness in 2 3% to 19 8% of hospital patients with a fever. Where population-level data were available, leptospirosis was estimated to affect 3 to 102 people per 100,000 every year. A variety of animal hosts of Leptospira spp. were identified. Cattle were reported as carriers of a variety of serological types of Leptospira spp. infection. The role of cattle and many other different animal hosts in human disease transmission remains unclear. Our review demonstrates that leptospirosis is a substantial cause of human illness in Africa, and we recommend integration of human and animal studies in the future to help us understand the epidemiology of leptospirosis on this continent.
Citation: Allan KJ, Biggs HM, Halliday JEB, Kazwala RR, Maro VP, Cleaveland S, et al. (2015) Epidemiology of Leptospirosis in Africa: A Systematic Review of a Neglected Zoonosis and a Paradigm for ‘One Health’ in Africa. PLoS Negl Trop Dis 9(9): e0003899. doi:10.1371/journal.pntd.0003899
Editor: Jakob Zinsstag, Swiss Tropical and Public Health Institute, SWITZERLAND
Received: December 23, 2015; Accepted: June 10, 2015; Published: September 14, 2015
Copyright: © 2015 Allan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: Data can be accessed through: http://dx.doi.org/10.5525/gla.researchdata.191.
Funding: This research was supported by the joint US National Institutes of Health (NIH:www.nih.gov) – National Science Foundation (NSF:www.nsf.gov) Ecology of Infectious Disease program (R01TW009237) and the RCUK, DFID and UK Biotechnology and Biological Sciences Research Council (BBSRC:www.bbsrc.ac.uk) (grant numbers BB/J010367/1, BB/L018926, BB/L017679, BB/L018845). KJA is supported by the Wellcome Trust (www.wellcome.ac.uk)(096400/Z/11/Z). RRK also received support from the Wellcome Trust under the Afrique One initiative (WT 087535MA). HMB received support from the NIH Interdisciplinary Research Training Program in AIDS (NIAID-AI007392). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Endemic zoonotic diseases affect impoverished and developing communities worldwide but are frequently overshadowed in public and clinician awareness by high profile infections such as malaria and HIV/AIDS [1, 2]. In Africa, zoonotic infections are both directly responsible for human illness and death and indirectly impact human well-being as a result of reduced livestock productivity and food security [3–5]. However, bacterial zoonoses including leptospirosis remain under-diagnosed and under-reported in Africa, and as a result are overlooked as public health priorities [1, 2, 6].
Leptospirosis is one of the most common and widespread zoonotic infections in the world and is recognised as a neglected disease by the World Health Organisation (WHO) . Human leptospirosis is caused by infection with pathogenic strains of Leptospira spp. bacteria [8, 9]. More than 250 pathogenic Leptospira serovars are known to exist worldwide, which are classified into 25 serogroups on the basis of their serological phenotype [10, 11]. Recent species determination by DNA homology has identified 13 pathogenic Leptospira spp., and seven of these (L. interrogans, L. borgpetersenii, L. santarosai, L. noguchii, L. weilli, L. kirschneri and L. alexanderi) are considered as the foremost agents of human and animal disease [10, 12]. Both serological and DNA-based classification systems are currently in use for clinical diagnosis and in understanding the pathogenesis and epidemiology of the disease [11, 13, 14].
A wide range of animals can carry pathogenic Leptospira bacteria and act as a source of infection [8, 11]. Leptospira serovars often demonstrate a degree of animal host preference and some common relationships between serovars and their hosts are reported [9, 15]. Following infection, the bacteria colonise the renal tubules and urogenital tract and are shed in the urine of infected animals. Animal species may be asymptomatic carriers of infection (maintenance hosts) or develop clinical disease (accidental hosts) depending on the infecting serovar [11, 16]. In food producing animals, cattle and pigs are relatively susceptible to clinical infection resulting in production losses including reduced milk yield, reproductive failure and abortions [16, 17].
In people, disease occurs through direct or indirect contact with infected urine from an animal host [8, 9, 15]. Good knowledge of Leptospira serovars circulating in local animal populations is important to determine sources and transmission routes for human infection . In the early stages, human leptospirosis manifests most commonly as a non-specific febrile illness that is hard to distinguish from other aetiologies of febrile disease particularly in tropical areas [11, 18, 19]. Infection can result in severe secondary sequelae including renal failure and pulmonary haemorrhagic syndrome, and a case fatality ratio of up to 50% has been reported in complicated cases [15, 19].
Leptospirosis is particularly common in the tropical areas where people and animals live in close contact, and warm and humid conditions favour environmental survival and transmission of the pathogen [8, 9]. In South-East Asia and South America, leptospirosis is recognised as an important cause of renal failure and febrile disease [18–22]. However, despite its global importance, large gaps persist in our knowledge of the burden and epidemiology of leptospirosis in Africa. Reports from the WHO Leptospirosis Epidemiology Reference Group (LERG) indicate that leptospirosis incidence may be high in Africa, but also highlight the lack of available data [7, 23]. Although reported seroprevalence data demonstrates widespread exposure to Leptospira spp. in humans and animals in Africa,  little is known about the extent of human disease or the epidemiology of Leptospira infection in different animal species in Africa.
To tackle these gaps in current understanding and awareness of human and animal Leptospira infection in Africa, we performed a systematic review of peer-reviewed and grey literature following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . Our aims were summarise and compare: (1) current knowledge of the geographic distribution, prevalence, incidence and diversity of acute human leptospirosis in Africa; and (2) the geographic distribution, host range, prevalence and diversity of Leptospira spp. infection in animal hosts in Africa.
A detailed protocol for this study can be found in the supplementary material (S1 File). Following the PRISMA guidelines and checklist (S1 Checklist) references for this review were identified through searches of eight international and regional databases (Table 1) using the search string ‘Leptospirosis’ OR ‘Leptospira’ and ‘Africa*’ for articles published between January 1930 and October 2014 inclusively. Additional articles for inclusion were identified by bibliography hand searches of relevant articles .
Study selection and criteria
Abstracts and titles were compiled in EndNote (Thomson Reuters, Philadelphia, PA, USA) and reviewed independently by two researchers (KJA, HMB) to determine whether each article met pre-determined abstract inclusion and exclusion criteria (S1 File). A third researcher (JEBH) served as a tiebreaker for any discordant decisions. Citations were included if they presented data on human or animal Leptospira spp. infection from any country within the United Nations (UN) definition of Africa . We excluded abstracts that did not refer to original human or animal leptospirosis research data, or did not describe naturally occurring cases of leptospirosis in human or animal populations. We included case reports but excluded reports of returned travellers because of potential uncertainty around the specific location where infection was acquired.
Articles classified as eligible for inclusion were retrieved in full text format and assessed against pre-defined case definitions (Table 2) of human acute leptospirosis and carrier animal status agreed upon by three authors (KJA, HMB, JEBH). Rigorous diagnostic criteria were specified in accordance with WHO and international reference laboratory guidelines (Table 2) [7, 11, 16]. Serological diagnostics were not included in the case definition for carrier animals because of the inability to differentiate between previous exposure and current infection status. We also excluded articles describing studies that used laboratory animal inoculations as a diagnostic test for leptospirosis because of concerns over the risk of false positive results as a consequence of pre-existing infection in experimental animal colonies, diagnostic sensitivity and cross-contamination . Full text articles were reviewed by two authors (KJA, HMB) and were excluded if they failed to meet case definitions, if results from the same cohort were presented more comprehensively in another eligible article, or if insufficient information was provided in the study methodology to determine whether the case definitions were met. Non-English language articles identified for full text review (n = 97) included French language articles translated by KJA with assistance from a native language speaker (n = 83); German language articles translated by a native language speaker (n = 7); Italian articles translated by a native language speaker (n = 4); Afrikaans (n = 2) and Dutch language articles (n = 1), which were translated using online translation software with support from a Dutch language speaker .
Data extraction and synthesis
Two reviewers (KJA, HMB) independently extracted pre-determined qualitative and quantitative data from each included article. Data on infection prevalence and incidence for comparable studies (i.e. similar study inclusion criteria and diagnostic methodologies) were compiled, and ranges were presented by study type (human studies), location or host species (animal studies) if three or more citations reporting comparable data were identified. Data on serological and genetic typing of leptospiral isolates from people and animals were compiled and summarised by country and by animal species. Additional data on serogroup and genetic species of reported serovars was obtained from the Leptospirosis Library, maintained by the Leptospirosis Reference Centre, Royal Tropical Institute (KIT), Netherlands .
Critical assessment of methodological quality and bias
The risk of bias in included studies such as selection or reporting bias was assessed following the Cochrane guidelines for systematic reviews of medical interventions . Full text study validity and methodological quality was assessed by comparison to pre-determined case definition criteria to control for heterogeneity in study design and diagnostic methodology (Table 2). Studies classified as high-risk for bias were not included in quantitative analysis of leptospirosis prevalence and incidence data.
Our searches yielded 681 unique articles from a total of 1201 abstracts identified by database searches. Data can be accessed through: http://dx.doi.org/10.5525/gla.researchdata.191. After abstract and full text review, 95 citations published between 1956 and 2014 were eligible for inclusion. Hand searches identified two additional articles that met inclusion criteria but were not identified in the original database search. Reasons for full-text exclusion are detailed in Fig 1. In total we included 97 articles that described human or animal studies conducted in 26 (44.8%) of 58 countries included in the UN macro-geographical definition of the African continent (Fig 2) . Major risks of bias identified in eligible studies were selection bias, attrition bias in studies that relied on paired serology (MAT) for confirmatory diagnosis, and reporting bias, as descriptions of diagnostic methodology and results were often incomplete.
Selection of eligible articles for study inclusion.
Acute human leptospirosis studies
Acute human leptospirosis was reported in 46 eligible studies from 18 African countries (Fig 2) [31–76]. South Africa was the most frequently represented country with a total of six articles [43, 47, 54, 57, 65, 71], followed by Egypt [45, 55, 56, 58, 59] and Kenya [31, 37–39, 42] with five included articles. Twenty-one articles described acute human leptospirosis in hospital or health centre-based cohort studies (Table 3). Five articles described data from passive population-based surveillance [35, 41, 64, 70, 73], and two articles described active case-finding in the setting of an outbreak of acute febrile illness [31, 72]. Non-specific febrile illness was the most common clinical criteria described for cohort or surveillance study inclusion. Jaundice was stated as a primary inclusion criterion in three hospital-based cohort studies [44, 61, 66]. Haemoglobinuria was stated as the only inclusion criterion in one study conducted in the Democratic Republic of the Congo (DRC) .
Diagnostic methodologies for human studies
The majority of studies (n = 41/46) used microscopic agglutination test (MAT) as a primary method to diagnose human cases of acute leptospirosis. IgM enzyme linked immunosorbent assay (ELISA) testing was the only diagnostic method used in three studies [31, 40, 63], but was more commonly used as part of a multi-faceted diagnostic approach (n = 6/46) [44, 45, 58, 64, 68, 73]. Fifteen (32 6%) of 46 eligible human studies demonstrated leptospirosis infection by blood culture in combination with serological diagnostics [34, 35, 37–39, 41, 44, 54–56, 58, 59, 64, 69], and nine (19 5%) studies also used PCR detection as well as culture and serology [34, 35, 41, 56, 58, 59, 64, 70, 73]. Genetic targets for diagnostic PCR assays included lbf1,[34, 35] lipL32 [34, 35], rrs [34, 35, 70], and ligA [58, 59]. No culture-independent genetic typing of Leptospira spp. was reported in any included human studies.
Human leptospirosis prevalence
Leptospirosis prevalence varied by study design and inclusion criteria (Table 3). In hospital-based prospective cohort studies in mainland Africa that enrolled patients with non-specific febrile illness and used MAT serology for diagnosis of acute leptospirosis with or without adjunct diagnostics, prevalence ranged from 2 3% to 19 8% (n = 11; number of patients: median = 166; range = 39–2441) [33, 36–39, 42, 44, 45, 55, 58, 68]. A hospital-based prospective cohort study of febrile patients in Mayotte that diagnosed acute leptospirosis by PCR and culture without serology reported a prevalence of 13 7% (number of patients = 2523) . In hospital-based cohort studies that used jaundice as the main study enrolment criterion, prevalence of acute leptospirosis ranged from 2 0% to 16 1% (n = 3; number of patients: median = 102; range = 99–392) [44–46]. Acute leptospirosis was also reported in one patient (2 3%) of 38 with haemoglobinuria , three patients (25 0%) of 12 involved in an outbreak of acute febrile disease in a pastoralist community in northern Kenya , and eight patients (9 8%) of 82 involved in an outbreak of acute pulmonary disease (pneumonia) in a mining camp in DRC .
Human leptospirosis incidence
Incidence estimates were calculated in five population-based surveillance studies [35, 41, 64, 70, 73] and two hospital-based prospective cohort studies [63, 74]. The only estimate of incidence from mainland Africa came from northern Tanzania, where regional incidence of 75 to 102 cases per 100,000 people per year was reported. This estimate was obtained by combining data on leptospirosis prevalence from hospital-based surveillance of febrile disease with multipliers derived from a population-based health-care utilisation survey . For the Indian Ocean islands, incidence estimates were available for the Seychelles where the average annual incidence was estimated as 60 to101 cases per 100,000 [63, 70]; Réunion where the average annual incidence reported in three studies using a variety of data sources ranged from 3 1 to 12 0 cases per 100,000 [41, 64, 73] and Mayotte, where the average annual incidence calculated from cases identified through four years of active hospital-based surveillance between 2007 and 2010 was reported as 25 cases per 100,000 .
Human case reports
Sixteen case reports describing acute leptospirosis in a total of 34 individuals were considered eligible for study inclusion. A wide range of clinical manifestations were reported including febrile illness, jaundice, meningitis, and acute respiratory distress syndrome. Case reports described confirmed or probable acute leptospirosis in patients in South Africa (n = 6) [43, 47, 54, 57, 65, 71], Gabon (n = 3) [48, 62, 76], Morocco (n = 3) [50, 52, 53], Algeria (n = 1) , Mali (n = 1) , Réunion (n = 1) , and Senegal (n = 1) . With the exception of Réunion and Senegal, case reports were the only eligible data on acute human leptospirosis from these countries.
Animal Leptospira infection studies
Naturally occurring Leptospira spp. infection in animal hosts was reported by 51 eligible citations describing studies performed in 17 African countries (Fig 2) [77–127]. South Africa [84, 100, 101, 104, 117, 120–122] and Zimbabwe [83, 93–99] were the most frequently represented countries with a total of eight included articles per country, followed by Tanzania with seven articles [106, 110–112, 114–116]. Wild animal surveys were most commonly described (n = 21/51) followed by strain typing of Leptospira spp. previously isolated from naturally infected animal hosts (n = 13/51), livestock disease outbreaks (n = 7/51) and abattoir surveys (n = 7/51). Four citations (n = 4/51) reported human leptospirosis outbreaks as the inciting cause for investigations into animal carrier status [86, 109, 117, 123].
Carrier animal species
Leptospira spp. infection was demonstrated in a wide range of animal hosts (S1 Table), including cattle (Bos spp.) [85, 87, 89–91, 93–102, 111, 114, 119, 121, 127]; pigs (Sus scrofa domestica) [78, 79, 84, 85, 100, 104, 106, 122]; goats (Capra aegagrus hircus) ; Rusa deer (Rusa timorensis) ; dogs (Canis lupis familiaris) [85, 113, 116]; cats (Felis catus) [85, 113, 116]; rodents including the African grass rat (Arvicanthus niloticus) [87, 88], African giant pouched rat (Cricetomys gambianus) [110, 112], lesser tufted-tailed rat (Eliurus minor) , fringe-tailed Gerbil (Gerbilliscus robustus) [77, 88], rusty-bellied brush-furred rat (Lophuromus sikapusi) , multimammate mouse (Mastomys sp.) [83, 87, 103, 115], house mouse (Mus musculus) [80, 81, 83, 85, 118, 120, 124], brown rat (Rattus norvegicus) [82, 85, 103, 108, 117, 118, 120, 124], black rat (Rattus rattus) [83, 85, 86, 92, 103, 118, 120, 124], South African pouched mouse (Saccostomys campestris) ; and a range of other free-living mammal species including shrews (Crocidura spp. and Suncus murinus) [86, 103, 115, 118]; mongoose (Herpestes ichneumon, Mungo mungo and Paracynictic selousi) [80, 105]; Egyptian fox (Vulpes vulpes niloticus) ; shrew tenrecs (Microgale cowani, Microgale dobsoni, Microgale longicaudata, Microgale majori, Microgale principula) ; streaked tenrecs (Hemicentetes nigriceps, Hemicentetes semispinosus) ; and various bat species (Chaerephon pusillus, Miniopterus gleni, Miniopterus goudoti, Miniopterus griffithsi, Miniopterus griveaudi, Miniopterus mahafaliensis, Miniopterus majori, Miniopterus soroculus, Mormopterus francoismoutoui, Mormopterus jugularis, Mytotis goudoti, Otomops madagascariensis, Rousettus obliviosus, Triaenops furculus, Triaenops menamena) [107, 125]. Studies demonstrating infection in cattle were most common (n = 20/51) followed by pigs (n = 8/51), black rats (n = 8/51), brown rats (n = 7/51) and house mice (n = 7/51).
Diagnostic methodologies for animal studies
Culture and isolation was the most common detection method for Leptospira infection in animal studies (n = 43/51). PCR assays were used to demonstrate Leptospira spp. infection in 13 (25 5%) out of 51 studies [85, 86, 92, 103, 105, 107, 115, 118, 120, 123–126]. In three studies, culture and PCR were used in combination to determine infection status [92, 115, 118]. As with human studies, a variety of genetic targets were used in PCR assays to detect pathogenic leptospiral DNA, including lipL32/hap1, [85, 86, 118], secY, , rrl , and rrs [107, 115, 120]. PCR was predominantly used to demonstrate Leptospira spp. infection in rodents and wild animal species. Only one study in Réunion also used PCR assays to demonstrate infection in domestic animals .
Prevalence in animal populations
Leptospira infection prevalence varied widely by target animal species and diagnostic methodology (S1 Table). Studies that used PCR diagnosis reported higher infection prevalence than studies that relied on Leptospira culture and isolation. Overall Leptospira infection prevalence reported in black rats tested by PCR ranged from 11 0% to 65 8% (n = 6; number of animals: median = 79, range = 33–141) [85, 86, 92, 103, 118, 124]. In two studies where black rats were tested by both PCR and culture, prevalence was higher by PCR (11 0%, n = 100; and 28.7%, n = 94) than by culture (4 0% and 3 2%) in Egypt , and Madagascar respectively . A similar relationship was observed in brown rats, house mice and Asian house shrews tested in Madagascar . Cattle and brown rats were the most common species tested by culture. Prevalence in brown rats ranged from 2 7% to 8 5% by culture (n = 3; number of animals: median = 256, range = 130–919) [82, 108, 117] but was considerably higher in three studies that used PCR to detect infection (10 0% to 4 7%; number of animals: median = 11, range = 10–96) [103, 118, 124]. In four abattoir-based surveillance studies of cattle from Egypt, Nigeria and Zimbabwe [87, 89, 93, 127], renal Leptospira spp. carrier status was detected by culture in 1 1% to 10 4% of sampled animals (number of animals: median = 480, range = 74–625), compared to 18 2% (number of animals = 77) in a single PCR-based study from Mayotte .
Serological typing of infecting leptospires in humans and animals
Serological typing of Leptospira spp. isolates from patients with acute leptospirosis was described in cohort studies conducted in the DRC , Egypt [55, 56], Ghana , Kenya [37–39] and Mayotte [34, 35], and in a case report from South Africa . Isolates belonging to 15 serogroups were reported (Table 4). Mini and Icterohaemorrhagiae were the most commonly reported serogroups. Isolates that were equally cross-reactive with representative serovars from more than one serogroup (Mini/Hebdomadis and Pyrogenes/Ballum) were reported by two studies in Mayotte [34, 35]. In animal studies, isolates belonging to 12 serogroups were reported from 33 articles. At least one animal host was identified within Africa for 11 (73 3%) out of the 15 human-infecting serogroups identified in this review (Table 4). However, only six of these serogroups were detected in human and animal populations from the same country. These were serogroup Autumnalis in Kenya [39, 88]; and serogroups Canicola [56, 92, 113], Grippotyphosa [56, 80, 81, 92], Icterohaemorrhagiae [55, 80, 92, 127], Pomona [55, 56, 127] and Pyrogenes [56, 92] in Egypt. Serogroups associated with human febrile illness were frequently isolated from multiple animal hosts. One of the most commonly reported serogroups isolated from patients in Africa, serogroup Icterohaemorrhagiae, was isolated from cattle, brown rats, Egyptian mongoose and an Egyptian fox. Cattle were identified as carrier hosts for the widest range of Leptospira serogroups (n = 9) but several other animal species, such as African grass rats and black rats were also identified as carrier hosts for multiple serogroups.
Genetic typing of leptospires in humans and animals
Leptospira spp. isolated from human patients with acute leptospirosis belonged to five pathogenic Leptospira species (Table 5). L. interrogans was the most widespread and common species reported in either human or animal studies in Africa. Multiple animal hosts were identified for L. interrogans as well as the other common species, L. borgpetersenii and L. kirschneri, from a variety of countries. The widest diversity in Leptospira spp. was reported from two Kenyan studies of acute human leptospirosis, where isolates belonging to five species were identified (L. borgpetersenii, L. interrogans, L. kirschneri, L. noguchii and L. santarosai) [38, 39]. However, L. noguchii and L. santarosai were not detected in any other studies. Four Leptospira species: L. borgpetersenii, L. borgpetersenii-like, L. interrogans and L. kirschneri; were identified in two human studies on Mayotte, as well as by a concurrent study of black rats performed during the same period [34, 35, 86]. Divergent Leptospira spp. described as L. borgpetersenii-like and L. borgpetersenii Group B were detected in human and animal studies respectively in Mayotte, and in a study of indigenous small mammals in Madagascar [34, 35, 86, 125]. Sequencing and alignment of the atypical isolates from rat kidneys in Mayotte  showed perfect identity with isolates derived from people .
This systematic review is the first to synthesize and compile data on the epidemiology of acute human leptospirosis and pathogenic Leptospira spp. infection in animals in Africa. Leptospirosis remains amongst the neglected tropical diseases and is frequently overlooked in research priorities for African countries . Yet, through this systematic review we have revealed a wealth of scientific evidence for acute human infection demonstrating that acute leptospirosis is an important cause of febrile illness in hospital patients across the African continent. Few studies providing population-level data on leptospirosis incidence in Africa were identified but available estimates indicate that the disease incidence is high in both island and mainland populations. In reports of human disease and animal infection, three predominant species, Leptospira borgpetersenii, L. interrogans and L. kirschneri, and a variety of Leptospira serogroups were diagnosed. Leptospira infection was reported in a wide range of domestic and wild animal species from across Africa but studies linking data on animal infections with studies of acute human disease were rare.
Acute leptospirosis was diagnosed in up to 19 8% of inpatients with non-specific febrile illness in hospital-based cohort studies conducted in several countries identified by this review. In sub-Saharan Africa, recent studies have highlighted that clinical over-diagnosis of malaria may conceal other aetiologies of febrile illness [20, 128]. Consistent with findings in other resource-limited tropical settings (e.g. South America [15, 129] and South-East Asia [130–132]), the evidence synthesised here demonstrates that acute leptospirosis infection is geographically widespread across the continent and should be considered as an important differential diagnosis for non-specific febrile illness in Africa.
Few estimates of leptospirosis incidence in Africa were identified by our review, revealing a key gap in research and surveillance outputs to date. The majority of incidence estimates identified came from the Indian Ocean islands where reports of annual incidence ranged from 3 1 to 101 cases per 100,000 people. In the African continent, the western Indian Ocean Islands appear to be the best-characterised region with regards to the human leptospirosis burden, possibly as a consequence of greater access to public health laboratories through French Territorial links . We identified only one report of annual leptospirosis incidence from mainland Africa. This estimate of 75 to 102 cases per 100,000 people  was calculated from Tanzanian hospital-based surveillance data and is consistent with the WHO leptospirosis burden epidemiology reference group (LERG) predicted median African incidence of 95 5 cases per 100,000 . At present, given the lack of population level data highlighted by LERG and by this review, estimates of the incidence of leptospirosis in Africa should be interpreted with care. However the data that are available from the continent indicate that the overall leptospirosis burden is likely to be high relative to other global regions. If the incidence figures identified by this review are close to the true burden of disease, up to 750,000 people in Africa will develop acute leptospirosis each year, representing a substantial disease burden that would far exceed current worldwide estimates (500,000 annual cases worldwide) .
Our review has revealed three predominant Leptospira species and a considerable diversity in reported pathogenic Leptospira serogroups in people and animals across the continent. Animal hosts, including livestock and invasive and indigenous rodent species, were reported for the majority of species and serogroups detected in human cases. However, there was poor geographical overlap in serogroup reporting between human and animal studies. Based on the findings of this review, we suggest that the major animal hosts of human-infecting serovars may vary across Africa and that both livestock and rodents may play important roles in human disease transmission. Few data were identified that described Leptospira spp. diversity in human cases and animal populations from the same country, and few studies attempted to link data on acute human leptospirosis with evidence of Leptospira infection in local animal populations. Studies on the Indian Ocean Islands of Mayotte and Madagascar were the exception to this. Isolates with unusual patterns of genetic and serological diversity, recently reclassified as a new pathogenic species Leptospira mayottensis , were detected from both human and black rat infections, implicating the black rat as the source of these human infections [35, 86]. These studies demonstrate the value of integrated human and animal research to identify sources and transmission routes of human leptospirosis, which can in turn help prioritise investment in disease prevention and control efforts.
The data included in this review most likely represents only the tip of the leptospirosis iceberg in Africa. Underreporting of leptospirosis is thought to be substantial and an overall lack of awareness about the disease and poor accessibility of diagnostic facilities are likely to contribute to this underreporting in Africa populations [135–137]. Patterns in reporting characteristics such as over-representation of study areas with greater research infrastructure, logistical connections or prior knowledge of a disease burden may also have resulted in reporting bias, particularly in assessing the geographic distribution of reports. We observed patient selection bias in some human studies, which limited the usefulness of reported prevalence data from these sources. Methodological limitations identified in this review include the use of the broad geographical search term ‘Africa’ rather than individual country names in our initial database searches. This approach may have missed eligible citations that are not indexed to the term ‘Africa’ in our selected databases. Our inclusion criteria may have created a bias towards more recent citations because of diagnostic technological advancements since the early era of our search period. Marked heterogeneity in methods and reporting criteria for serological diagnostic data prevented the meaningful synthesis and analysis of data on the reactive serogroups in human studies. We chose to include non-English language articles to allow inclusion of articles published in the colonial era, or in local language journals. Wherever possible, a proficient language speaker, in partnership with a study author, performed article translation. However, it is possible that some eligible studies may have been overlooked due to translation limitations.
Addressing the neglect of leptospirosis in Africa will be a major challenging for the future of leptospirosis research. Systematic review studies such as this can help to raise awareness of the human health threat of leptospirosis in Africa among researchers and policy makers. For medical clinicians, the non-specific presenting signs of acute leptospirosis in patients poses a substantial diagnostic challenge in developing countries where laboratory capacity rarely exists to diagnose the infection [18–20]. Hence, increasing clinician awareness and the development of treatment guidelines for the management of febrile patients should be a priority in resource-limited settings . Integration of risk factor analysis in human cohort studies of febrile disease is also strongly advocated and would be a valuable next step in identifying groups at high risk of infection, and defining important animal to human transmission routes.
Knowledge of reservoir or carrier animal hosts is considered essential to understanding the epidemiology, transmission and control of leptospirosis in each setting [9, 11], yet our review has revealed that the linkages between Leptospira infections in people and animals are rarely addressed in the existing literature. Human and animal Leptospira infections are inextricably linked, and the multi-host epidemiology of leptospirosis means that there may be many potential sources of infection in a given setting. In the future, greater emphasis should be placed on performing multidisciplinary human and animal leptospirosis studies in the same geographical settings. Connecting investigations of animal reservoir populations with confirmed human cases would improve our understanding of the role that different animal species play in the transmission of pathogenic Leptospira serovars in a variety of geographic and environmental settings  . Using an integrated ‘One Health’ approach to explore the relationship between human and animal Leptospira infection in areas where human disease is identified would also provide invaluable evidence to quantify the direct and indirect impacts of leptospirosis on human and animal populations in Africa [140, 141].
Control measures to prevent human leptospirosis often focus on rodent hosts of the disease. However, this review reveals that livestock are also important hosts of Leptospira infection in Africa, and may play a more substantial role in human disease transmission than is widely recognised. The clinical and sub-clinical productivity impacts of Leptospira infection in domestic animal populations in Africa are poorly understood. Around the world, several Leptospira serovars are considered to be of economic importance and cause production losses in a variety of livestock farming species including cattle, sheep, goats and pigs [17, 100, 142, 143]. More than 300 million of the world’s poorest people live in Africa, and at least 60% of these are in some part dependent on livestock for their livelihood . Therefore, we consider that evaluating the impact of Leptospira infection on livestock health and productivity is also an important priority for prospective research in Africa. In the future, control of Leptospira infection in livestock species may have considerable scope to directly and indirectly improve human health and well-being in Africa, through reduced human leptospirosis transmission and increased productivity in livestock that subsistence farming communities [8, 142, 143, 145].
Finally, in 1967, the German leptospirosis researcher Kathe commented that ‘The world map of leptospirosis is, in fact, the world map of leptospirologists’ . This is particularly true with regards to Africa. With this systematic review, we have started to outline the map of African leptospirosis; it is now time to fill in the gaps.
S1 Checklist. PRISMA checklist.
S1 File. Study protocol: Epidemiology of Leptospirosis in Africa.
S1 Table. Summary of included animal studies reporting confirmed cases of animal Leptospira spp. infection in Africa, 1930–2014.
We gratefully acknowledge Megan von Isenburg (Duke University Medical Center Library and Archives) and Alastair Allan (University of Sheffield) for advice on database and search strategies, and Ferdinand von Götzen, Erika Abbondati and Julie Woodfield for translation assistance for foreign language articles. We are grateful to the anonymous reviewers of this study for their thorough and helpful review, which led to substantial improvements of the manuscript. Finally, we also acknowledge the Hubert-Yeargan Center for Global Health at Duke University and Kilimanjaro Christian Medical Centre for critical infrastructure support.
Conceived and designed the experiments: KJA HMB JEBH RRK VPM SC JAC. Performed the experiments: KJA HMB JEBH. Analyzed the data: KJA HMB JEBH SC JAC. Wrote the paper: KJA HMB JEBH RRK VPM SC JAC. Literature searches: KJA HMB. Translation of foreign language articles: KJA. Data synthesis: KJA HMB.
- 1. World Health Organization. The Control of Neglected Disease: a route to poverty alleviation. Geneva: 2006.
- 2. Maudlin I, Eisler MC, Welburn SC. Neglected and endemic zoonoses. Philos Trans R Soc Lond B Biol Sci. 2009;364(1530):2777–87. Epub 2009/08/19. doi: 10.1098/rstb.2009.0067. pmid:19687045
- 3. Schelling E, Grace D, Willingham AL III, Randolph T. Research approaches for improved pro-poor control of zoonoses. Food Nutr Bull. 2007;28(Supplement 2):345S–56S.
- 4. Perry B, Grace D. The impacts of livestock diseases and their control on growth and development processes that are pro-poor. Philos Trans R Soc Lond B Biol Sci. 2009;364(1530):2643–55. doi: 10.1098/rstb.2009.0097. pmid:19687035
- 5. Halliday J, Daborn C, Auty H, Mtema Z, Lembo T, Barend M, et al. Bringing together emerging and endemic zoonoses surveillance: shared challenges and a common solution. Philos Trans R Soc Lond B Biol Sci. 2012;367(1604):2872–80. doi: 10.1098/rstb.2011.0362. pmid:22966142
- 6. Molyneux D, Hallaj Z, Keusch GT, McManus DP, Ngowi H, Cleaveland S, et al. Zoonoses and marginalised infectious diseases of poverty: Where do we stand. Parasit Vectors. 2011;4:106–12. doi: 10.1186/1756-3305-4-106. pmid:21672216
- 7. World Health Organization. Report of the Second Meeting of the Leptospirosis Burden Epidermiology Reference Group. Geneva: World Health Organization, 2011.
- 8. Hartskeerl R, Collares-Pereira M, Ellis W. Emergence, control and re-emerging leptospirosis: dynamics of infection in the changing world. Clin Microbiol Infect. 2011;17(4):494–501. doi: 10.1111/j.1469-0691.2011.03474.x. pmid:21414083
- 9. Adler B, de la Pena Moctezuma A. Leptospira and leptospirosis. Vet Microbiol. 2010;140(3–4):287–96. Epub 2009/04/07. doi: 10.1016/j.vetmic.2009.03.012. pmid:19345023
- 10. Cerqueira GM, Picardeau M. A century of Leptospira strain typing. Infect Genet Evol. 2009;9(5):760–8. doi: 10.1016/j.meegid.2009.06.009. pmid:19540362
- 11. Levett PN. Leptospirosis. Clin Microbiol Rev. 2001;14(2):296–326. pmid:11292640 doi: 10.1128/cmr.14.2.296-326.2001
- 12. Evangelista KV, Coburn J. Leptospira as an emerging pathogen: a review of its biology, pathogenesis and host immune responses. Future Microbiol. 2010;5(9):1413–25. Epub 2010/09/24. doi: 10.2217/fmb.10.102. pmid:20860485
- 13. Ko AI, Goarant C, Picardeau M. Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nature Rev Microbiol. 2009;7(10):736–47. doi: 10.1038/nrmicro2208
- 14. Ahmed A, Thaipadungpanit J, Boonsilp S, Wuthiekanun V, Nalam K, Spratt BG, et al. Comparison of two multilocus sequence based genotyping schemes for leptospira species. PLoS Negl Trop Dis. 2011;5(11):e1374. doi: 10.1371/journal.pntd.0001374. pmid:22087342
- 15. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003;3(12):757–71. pmid:14652202 doi: 10.1016/s1473-3099(03)00830-2
- 16. Faine S. Leptospira and leptospirosis: CRC Press Inc.; 1994.
- 17. Ellis WA. Leptospirosis as a cause of reproductive failure. Vet Clin North Am Food Anim Pract. 1994;10(3):463–78. pmid:7728630
- 18. Cruz LS, Vargas R, Lopes AA. Leptospirosis: a worldwide resurgent zoonosis and important cause of acute renal failure and death in developing nations. Ethn Dis. 2009;19(1 Suppl 1):37–41. Epub 2009/06/02.
- 19. McBride AJ, Athanazio DA, Reis MG, Ko AI. Leptospirosis. Curr Opin Infect Dis. 2005;18(5):376–86. Epub 2005/09/09. pmid:16148523 doi: 10.1097/01.qco.0000178824.05715.2c
- 20. Crump JA, Morrissey AB, Nicholson WL, Massung RF, Stoddard RA, Galloway RL, et al. Etiology of severe non-malaria febrile illness in northern Tanzania: a prospective cohort study. PLoS Negl Trop Dis. 2013;7(7):e2324. doi: 10.1371/journal.pntd.0002324. pmid:23875053
- 21. Acestor N, Cooksey R, Newton PN, Menard D, Guerin PJ, Nakagawa J, et al. Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review—terra incognita impairing treatment policies. PLoS One. 2012;7(9):e44269. Epub 2012/09/13. doi: 10.1371/journal.pone.0044269. pmid:22970193
- 22. Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Pérès A, Paris DH, Phetsouvanh R, et al. Causes of non-malarial fever in Laos: a prospective study. The Lancet Global Health. 2013;1(1):e46–e54. pmid:24748368 doi: 10.1016/s2214-109x(13)70008-1
- 23. Abela-Ridder B, Sikkema R, Hartskeerl RA. Estimating the burden of human leptospirosis. Int J Antimicrob Agents. 2010;36(Suppl. 1):S5–S7. doi: 10.1016/j.ijantimicag.2010.06.012. pmid:20688484
- 24. de Vries SG, Visser BJ, Nagel IM, Goris MG, Hartskeerl RA, Grobusch MP. Leptospirosis in Sub-Saharan Africa: a systematic review. Int J Infect Dis. 2014;28c:47–64. Epub 2014/09/10. doi: 10.1016/j.ijid.2014.06.013
- 25. Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. BMJ. 2009;339:336–39. doi: 10.1136/bmj.b2535
- 26. Hopewell S, Clarke M, Lefebvre C, Scherer R. Handsearching versus electronic searching to identify reports of randomized trials. The Cochrane database of systematic reviews. 2007;(2):Mr000001. Epub 2007/04/20. doi: 10.1002/14651858.mr000001
- 27. United Nations Statistics Division. Composition of macro geographical (continental) regions, geographical sub-regions, and selected economic and other groupings [Website]. 2012 [cited 2014 3rd February]. http://unstats.un.org/unsd/methods/m49/m49regin.htm.
- 28. Google Translate. http://www.translate.google.co.uk Mountain View, California, USA [cited 2013 3rd June]. http://translate.google.com.
- 29. Royal Tropical Institute (KIT). Leptospira library Amsterdam: KIT Biomedical Research; 2014 [cited 2014 3rd February]. http://www.kit.nl/NET/Leptospirsosis/LeptospiraLibrary/Strains/AlphabeticListBySerovar.
- 30. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions: Wiley Online Library; 2008.
- 31. Ari MD, Guracha A, Fadeel MA, Njuguna C, Njenga MK, Kalani R, et al. Challenges of Establishing the Correct Diagnosis of Outbreaks of Acute Febrile Illnesses in Africa: The Case of a Likely Brucella Outbreak among Nomadic Pastoralists, Northeast Kenya, March-July 2005. Am J Trop Med Hyg. 2011;85(5):909–12. PubMed doi: 10.4269/ajtmh.2011.11-0030. pmid:22049048
- 32. Aubry P, Bordahandy R, Ferah T, Mailloux M, Thomas J. [An anademy of ictero-hemorrhagic leptospirosis in a military group in Algeria (author's translation)]. Bull Soc Pathol Exot Filiales. 1975;68(4):370–6. Epub 1975/07/01. pmid:1243751
- 33. Biggs HM, Bui DM, Galloway RL, Stoddard RA, Shadomy SV, Morrissey AB, et al. Leptospirosis among hospitalized febrile patients in northern Tanzania. Am J Trop Med Hyg. 2011;85(2):275–81. Epub 2011/08/05. doi: 10.4269/ajtmh.2011.11-0176. pmid:21813847
- 34. Bourhy P, Collet L, Clement S, Huerre M, Ave P, Giry C, et al. Isolation and characterization of new Leptospira genotypes from patients in mayotte (Indian Ocean). PLoS Negl Trop Dis. 2010;4(6):e724. doi: 10.1371/journal.pntd.0000724. pmid:20582311
- 35. Bourhy P, Collet L, Lernout T, Zinini F, Hartskeerl RA, Linden Hvd, et al. Human leptospira isolates circulating in Mayotte (Indian Ocean) have unique serological and molecular features. J Clin Microbiol. 2012;50(2):307–11. doi: 10.1128/JCM.05931-11. pmid:22162544
- 36. Collares-Pereira M, Gomes AC, Prassad M, Vaz RG, Ferrinho P, Stanek G, et al. Preliminary survey of Leptospirosis and Lyme disease amongst febrile patients attending community hospital ambulatory care in Maputo, Mozambique. Cent Afr J Med. 1997;43(8):234–8. Epub 1997/08/01. pmid:9431763
- 37. de Geus A, Kranendonk O, Bohlander HJ. Clinical leptospirosis in Kwale District, Coast Province, Kenya. East Afr Med J. 1969;46(9):491–6. Epub 1969/09/01. pmid:5363300
- 38. de Geus A, Wolff JW, Timmer VE. Clinical leptospirosis in Kenya (2): A field study in Nyanza Province. East Afr Med J. 1977;54(3):125–32. Epub 1977/03/01. pmid:885096
- 39. de Geus A, Wolff JW, Timmer VE. Clinical leptospirosis in Kenya (1): a clinical study in Kwale District, Coast Province. East Afr Med J. 1977;54(3):115–24. Epub 1977/03/01. pmid:885095
- 40. Delacollette C, Taelman H, Wery M. An etiologic study of hemoglobinuria and blackwater fever in the Kivu Mountains, Zaire. Ann Soc Belg Med Trop 1995;75(1):51–63. pmid:7794063
- 41. Desvars A, Jego S, Chiroleu F, Bourhy P, Cardinale E, Michault A. Seasonality of human leptospirosis in Reunion Island (Indian Ocean) and its association with meteorological data. PLoS One. 2011;(May):e20377. doi: 10.1371/journal.pone.0020377. pmid:21655257
- 42. Forrester AT, Kranendonk O, Turner LH, Wolff JW, Bohlander HJ. Serological evidence of human leptospirosis in Kenya. East Afr Med J. 1969;46(9):497–506. Epub 1969/09/01. pmid:5363301
- 43. Gear J, Wolstenholme B, Jackson A, Chesler E, Brueckner RM. Leptospirosis in South Africa: The occurrence of cases of leptospiral meningo-encephalitis on the witwatersrand. S Afr Med J. 1958;32(4):94–100. pmid:13506751
- 44. Hogerzeil HV, De Geus A, Terpstra WJ, Korver H, Ligthart GS. Leptospirosis in rural Ghana: Part 2. Current leptospirosis. Trop Geogr Med. 1986;38(4):408–14. Epub 1986/12/01. pmid:3810845
- 45. Ismail TF, Wasfy MO, Abdul-Rahman B, Murray CK, Hospenthal DR, Abdel-Fadeel M, et al. Retrospective serosurvey of leptospirosis among patients with acute febrile illness and hepatitis in Egypt. Am J Trop Med Hyg. 2006;75(6):1085–89. Epub 2006/12/19. pmid:17172371
- 46. Kinebuchi H, Afoakwa SN. Leptospirosis in Ghana. Ghana Med J. 1973;12(2):190–93. Epub 1973/06/01. pmid:4805646
- 47. Klopper JF. [Leptospirosis—a discussion of 4 cases]. S Afr Med J. 1969;43(37):1138–40. Epub 1969/09/13. pmid:5353782
- 48. Koko J, Moussavou A, Orima C, Seilhan C, Lemba-Abaka A, Damas S. Leptospirosis in children in Libreville: first case report, a difficult diagnosis. Bull Soc Pathol Exot. 2001;94(5):394–96. pmid:11889939
- 49. Kolochine-Erber B, Brygoo ER. Investigation of the leptospiroses on Madagascar. Bull Soc Pathol Exot. 1956;49(4):686–98.
- 50. Lahsen AO, Rachidi T, Sodqi M, Abada R, Marhoum KE. [Facial palsy associated with leptospirosis]. Med Mal Infect. 2010;40(12):716–17. Epub 2010/07/08. doi: 10.1016/j.medmal.2010.04.010. pmid:20605692
- 51. Mailloux CH, Mailloux M, Giraudeau P, Gilot Y, Saint-Andre P. [First case of confirmed leptospirosis in Mali]. Bull Soc Pathol Exot Filiales. 1974;67(5):498–503. Epub 1974/09/01. pmid:4142867
- 52. Mailloux M. Leptospiroses in Morocco: New data [Engl. sum.]. Bull Soc Pathol Exot. 1967;58(5):841–47.
- 53. Mailloux M. [Simultaneous cases of leptospirosis in a family in Morocco]. Bull Soc Pathol Exot Filiales. 1971;64(1):42–5. Epub 1971/01/01. pmid:5109177
- 54. Maze SS, Kirsch RE. Leptospirosis Experience at Groote Schuur Hospital South Africa 1969–1979. S Afr Med J. 1981;59(2):33–6. pmid:7455830
- 55. Murray CK, Gray MR, Mende K, Parker TM, Samir A, Rahman BA, et al. Use of patient-specific Leptospira isolates in the diagnosis of leptospirosis employing microscopic agglutination testing (MAT). Trans R Soc Trop Med Hyg. 2011;105(4):209–13. Epub 2011/02/22. doi: 10.1016/j.trstmh.2010.12.004. pmid:21334705
- 56. Murray CK, Pimentel G, Parker T, Beckius ML, Samir A, Rhman BA, et al. Antimicrobial Susceptibilities of Clinical Human Isolates of Leptospira from Egypt. Am J Trop Med Hyg. 2008;79(6, Suppl. S):78.
- 57. Newman RC, Cohen HL. Weil's disease in Cape Town. A case report. S Afr Med J. 1962;36(41):851–3.
- 58. Parker TM, Ismail T, Fadeel MA, Maksoud MA, Morcos M, Newire E, et al. Laboratory-based surveillance for acute febrile illness in Egypt: A focus on leptospirosis. Am J Trop Med Hyg. 2006;75(5, Suppl. S):18.
- 59. Parker TM, Murray CK, Richards AL, Samir A, Ismail T, Fadeel MA, et al. Concurrent infections in acute febrile illness patients in Egypt. Am J Trop Med Hyg. 2007;77(2):390–92. Epub 2007/08/11. pmid:17690420
- 60. Payet M, Pene P, Dorolle CL, Bonnardot R, Bernou JC, Rahmi R. Hyos leptospirosis in Dakar [Engl. summ.]. Bull Soc Pathol Exot. 1965;58(1):54–9.
- 61. Payet M, Pene P, Sankale M, Bayet R, Bonnardot R, Bernou JC, et al. [Leptospirosis in Dakar]. Bull Soc Pathol Exot Filiales. 1966;59(2):207–17. Epub 1966/03/01. pmid:6012836
- 62. Perret JL, Moussavou-Kombila JB, Duong TH, Berthonneau JP, Nguemby-Mbina C. [First clinical and serological description of leptospirosis in Gabon]. Bull Soc Pathol Exot. 1994;87(3):181–82. Epub 1994/01/01. pmid:7827519
- 63. Pinn TG. Leptospirosis in the Seychelles. Med J Aust. 1992;156(3):163–67. pmid:1545718
- 64. Renault P, Boidin E, D'Ortenzio E, Balleydier E, Daniel B, Filleul L. Surveillance épidémiologique de la leptospirose à la Réunion, 2004–2008: possible impact de l'épidémie de chikungunya sur la létalité de la leptospirose. Bull Soc Pathol Exot. 2011;104(2):148–52. doi: 10.1007/s13149-010-0114-4. pmid:21174236
- 65. Samson RI, Pillay TS. Leptospirosis in Cape Town. S Afr Med J. 1966;40(41):1010–11. Epub 1966/11/12. pmid:5955088
- 66. Sankalé M, Sow AM, Ruscher H, Sarrat H. [Leptospirosis in the hospital environment in Dakar (results of a new survey)]. Bull Soc Med Afr Noire Lang Fr. 1973;18(2):227–35. Epub 1973/01/01. pmid:4779788
- 67. Silverie R, Monnier M, Lataste-Dorolle C. Leptospirosis in Madagascar. Human, bovine and porcine leptospiroses of the southern region. Bull Soc Pathol Exot. 1968;61:346–59.
- 68. Tagoe JA, Puplampu N, Odoom SC, Abdul-Rahman B, Habashy EE, Pimentel B, et al. Serosurvey of Leptospirosis among Patients with Acute Febrile Illness in Accra. Am J Trop Med Hyg. 2010;83(5, Suppl. S):306.
- 69. Van Riel J, Szpajshendler L, Van Riel M. Clinical, bacteriological and epidemiological study of a new focus of leptospirosis in the Belgian Congo. Bull Soc Pathol Exot Filiales. 1956;49(1):118–43. pmid:13329785
- 70. Yersin C, Bovet P, Merien F, Wong T, Panowsky J, Perolat P. Human leptospirosis in the Seychelles (Indian Ocean): a population-based study. Am J Trop Med Hyg. 1998;59(6):933–40. Epub 1999/01/14. pmid:9886203 doi: 10.1093/ije/28.3.583
- 71. Zaltzman M, Kallenbach JM, Goss GD, Lewis M, Zwi S, Gear JHS. Adult Respiratory Distress Syndrome in Leptospira-Canicola Infection. BMJ. 1981;283(6290):519–20. pmid:6790049 doi: 10.1136/bmj.283.6290.519
- 72. Bertherat E, Mueller MJ, Shako JC, Picardeau M. Discovery of a leptospirosis cluster amidst a pneumonic plague outbreak in a miners' camp in the Democratic Republic of the Congo. International journal of environmental research and public health. 2014;11(2):1824–33. Epub 2014/02/12. doi: 10.3390/ijerph110201824. pmid:24514425
- 73. Pages F, Polycarpe D, Dehecq JS, Picardeau M, Caillere N, Jaffar-Bandjee MC, et al. Human leptospirosis on Reunion Island: past and current burden. International journal of environmental research and public health. 2014;11(1):968–82. doi: 10.3390/ijerph110100968. pmid:24434593
- 74. Biggs HM, Hertz JT, Munishi OM, Galloway RL, Marks F, Saganda W, et al. Estimating leptospirosis incidence using hospital-based surveillance and a population-based health care utilization survey in Tanzania. PLoS Negl Trop Dis. 2013;7(12):e2589. Epub 2013/12/18. doi: 10.1371/journal.pntd.0002589. pmid:24340122
- 75. Legris T, Jaffar-Bandjee MC, Favre O, Lefrancois N, Genin R, Ragot C, et al. Ameboma: an unusual cause of gastrointestinal bleeding during severe leptospirosis. BMC Infect Dis. 2014;14(1):299–305. doi: 10.1186/1471-2334-14-299
- 76. Magne MC, Ondounda M, Mbethe LG, Mounguengui D, Nzenze JR. [Leptospirosis in Libreville (Gabon): four cases]. Medecine et sante tropicales. 2013;23(3):347–50. Epub 2013/10/08. doi: 10.1684/mst.2013.0228. pmid:24095884
- 77. Ball MG. Animal hosts of leptospires in Kenya and Uganda. Am J Trop Med Hyg. 1966;15(4):523–30. Epub 1966/07/01. pmid:4957422
- 78. Bakoss P. Leptospira tunis, a new serotype of the tarassovi group. Arch Inst Pasteur Tunis. 1969;46:17–23.
- 79. Bakoss P, Chadli A. The pig, reservoir of Leptospira mitis in Tunisia. Arch Inst Pasteur Tunis. 1965;42(1):85–91.
- 80. Barsoum IS, Moch RW, Botros BA, Kaiser MN. Leptospires isolated from wild mammals in Egypt. Trop Geogr Med. 1973;25(4):362–64. Epub 1973/12/01. pmid:4786650
- 81. Brownlow WJ, Dedeaux JD. Leptospirosis in animals of upper [southern] Egypt. Am J Trop Med Hyg. 1964;13(2):311–18.
- 82. Chadli A, Bakoss P. Enquete sur la leptospirose en Tunisie. Arch Inst Pasteur Tunis. 1965;42(1):45–58.
- 83. Dalu JM, Feresu SB. Domestic rodents as reservoirs of pathogenic Leptospira on two city of Harare farms: Preliminary results of bacteriological and serological studies. Belg J Zool. 1997;127(Suppl.):105–12.
- 84. de Lange JF, Gummow B, Turner GV, Redman AR. The isolation of Leptospira interrogans serovar pomona and related serological findings associated with a mixed farming unit in the Transvaal. Onderstepoort J Vet Res. 1987;54(2):119–21. Epub 1987/06/01. pmid:3627726
- 85. Desvars A, Naze F, Benneveau A, Cardinale E, Michault A. Endemicity of leptospirosis in domestic and wild animal species from Reunion Island (Indian Ocean). Epidemiol Infect. 2013;1(1):1–12. doi: 10.1017/s0950268812002075
- 86. Desvars A, Naze F, Vourc'h G, Cardinale E, Picardeau M, Michault A, et al. Similarities in Leptospira serogroup and species distribution in animals and humans in the Indian Ocean island of Mayotte. Am J Trop Med Hyg. 2012;87(1):134–40. doi: 10.4269/ajtmh.2012.12-0102. pmid:22764304
- 87. Diallo AA, Dennis SM. Bacteriological survey of leptospirosis in Zaria, Nigeria. Trop Geogr Med. 1982;34(1):29–34. Epub 1982/03/01. pmid:7043824
- 88. Dikken H, Timmer VE, Njenga R. Three new leptospiral serovars from Kenya. Trop Geogr Med. 1981;33(4):343–6. Epub 1981/12/01. pmid:7342381
- 89. Ezeh AO, Ellis WA, Kmety E, Adesiyun AA, Addo PB. Bacteriological examination of bovine kidneys for leptospires in Plateau State, Nigeria. Rev Sci Tech. 1989;8(4):1005–8.
- 90. Ezeh AO, Kmety E, Ellis WA, Addo PB, Adesiyun AA. Characterisation of leptospires isolated from cattle and man in Plateau State, Nigeria. Rev Sci Tech. 1989;8(4):1009–20.
- 91. Ezeh AO, Kmety E, Ellis WA, Addo PB, Adesiyun AA. A new leptospiral serovar in the Pyrogenes serogroup isolated in Nigeria. Rev Sci Tech. 1990;9(4):1195–96. Epub 1990/12/01. pmid:2132712
- 92. Felt SA, Wasfy MO, El-Tras WF, Samir A, Rahaman BA, Boshra M, et al. Cross-species surveillance of Leptospira in domestic and peri-domestic animals in Mahalla City, Gharbeya Governorate, Egypt. Am J Trop Med Hyg. 2011;84(3):420–25. Epub 2011/03/03. doi: 10.4269/ajtmh.2011.10-0393. pmid:21363980
- 93. Feresu SB. Isolation of Leptospira interrogans from kidneys of Zimbabwe beef cattle. Vet Rec. 1992;130(20):446–48. Epub 1992/05/16. pmid:1621343 doi: 10.1136/vr.130.20.446
- 94. Feresu SB, Bolin CA, van de Kemp H, Korver H. Identification of a serogroup bataviae Leptospira strain isolated from an ox in Zimbabwe. Zentralbl Bakteriol. 1999;289(1):19–29. Epub 1999/03/30. pmid:10096163 doi: 10.1016/s0934-8840(99)80118-2
- 95. Feresu SB, Bolin CA, Korver H. A new leptospiral serovar in the Icterohaemorrhagiae serogroup isolated from an ox in Zimbabwe. Int J Syst Bacteriol. 1993;43(1):179–82. pmid:8427806 doi: 10.1099/00207713-43-1-179
- 96. Feresu SB, Bolin CA, Korver H. A new leptospiral serovar, ngavi, in the Tarassovi serogroup isolated from Zimbabwe oxen. Int J Syst Bacteriol. 1998;48(1):207–13. Epub 1998/05/02. doi: 10.1099/00207713-48-1-207
- 97. Feresu SB, Bolin CA, Korver H, Kemp Hvd. Identification of leptospires of the Pomona and Grippotyphosa serogroups isolated from cattle in Zimbabwe. Res Vet Sci. 1995;59(1):92–4. pmid:8525094 doi: 10.1016/0034-5288(95)90038-1
- 98. Feresu SB, Bolin CA, Korver H, Terpstra WJ. Classification of leptospires of the pyrogenes serogroup isolated from cattle in Zimbabwe by cross-agglutinin absorption and restriction fragment length polymorphism analysis. Int J Syst Bacteriol. 1994;44(3):541–46. Epub 1994/07/01. pmid:7915129 doi: 10.1099/00207713-44-3-541
- 99. Feresu SB, Korver H, Riquelme N, Baranton G, Bolin CA. Two new leptospiral serovars in the Hebdomadis serogroup isolated from Zimbabwe cattle. Int J Syst Bacteriol. 1996;46(3):694–98. Epub 1996/07/01. pmid:8782678 doi: 10.1099/00207713-46-3-694
- 100. Gummow B, Myburgh JG, Thompson PN, van der Lugt JJ, Spencer BT. Three case studies involving Leptospira interrogans serovar pomona infection in mixed farming units. J S Afr Vet Assoc. 1999;70(1):29–34. Epub 2000/06/16. pmid:10855820 doi: 10.4102/jsava.v70i1.747
- 101. Herr S, Riley AE, Neser JA, Roux D, De Lange JD. Leptospira Interrogans Ssp Pomona Associated with Abortion in Cattle Isolation Methods and Laboratory Animal Histo Pathology. Onderstepoort J Vet Res. 1982;49(1):57–62. pmid:7122066
- 102. Herr S, Winnen GM. First isolation of Leptospira interrogans serovar pomona from cattle in Botswana. J S Afr Vet Assoc. 1983;54(2):83–4. pmid:6631909
- 103. Houemenou G, Ahmed A, Libois R, Hartskeerl RA. Leptospira spp. Prevalence in Small Mammal Populations in Cotonou, Benin. ISRN Epidemiology. 2013. doi: 10.5402/2013/502638
- 104. Hunter P, van der Vyver FH, Selmer-Olsen A, Henton MM, Herr S, de Lange JF. Leptospirosis as a cause of "white spot" kidneys in South African pig abattoirs. Onderstepoort J Vet Res. 1987;54(1):59–62. Epub 1987/03/01. pmid:3587928
- 105. Jobbins S, Sanderson C, Alexander K. Leptospira interrogans at the Human-Wildlife Interface in Northern Botswana: A Newly Identified Public Health Threat. Zoonoses Public Health. 2013 doi: 10.111/zph.12052. Epub 14 May 2013.
- 106. Kessy MJ, Machang'u RS, Swai ES. A microbiological and serological study of leptospirosis among pigs in the Morogoro municipality, Tanzania. Trop Anim Health Prod. 2010;42(3):523–30. Epub 2009/09/19. doi: 10.1007/s11250-009-9455-z. pmid:19763865
- 107. Lagadec E, Gomard Y, Guernier V, Dietrich M, Pascalis H, Temmam S, et al. Pathogenic Leptospira spp. in Bats, Madagascar and Union of the Comoros. Emerg Infect Dis. 2012;18(10):1696–97. doi: 10.3201/eid1810.111898. pmid:23017768
- 108. Lazuga K, Bonnefous S. Contribution to the study of leptospirosis in rats in the city of Tunis [English and German summ.]. Arch Inst Pasteur Tunis. 1962;39(1):49–63.
- 109. Le Bras J, Guyer B, Sulzer C, Mailloux M. [Anademic focus of leptospirosis at Fondem (U.R. of Cameroon)]. Bull Soc Pathol Exot Filiales. 1977;70(6):569–83. Epub 1977/11/01. pmid:615682
- 110. Machang'u R, Mgode G, Asenga J, Mhamphi G, Hartskeerl R, Goris M, et al. Characterisation of Leptospira isolates from captive giant African pouched rats, Cricetomys gambianus. ACIAR Monograph Series. 2002;96:40–2. doi: 10.1016/j.femsim.2004.02.002
- 111. Machang'u RS, Mgode G, Mpanduji D. Leptospirosis in animals and humans in selected areas of Tanzania. Belg J Zool. 1997;127(Suppl.1):97–104.
- 112. Machang'u RS, Mgode GF, Assenga J, Mhamphi G, Weetjens B, Cox C, et al. Serological and molecular characterization of leptospira serovar Kenya from captive African giant pouched rats (Cricetomys gambianus) from Morogoro Tanzania. FEMS Immunol Med Microbiol. 2004;41(2):117–21. pmid:15145455 doi: 10.1016/j.femsim.2004.02.002
- 113. Maronpot RR, Barsoum IS, Ezzat E. Canine leptospirosis in Cairo. J Infect Dis. 1971;123:548–50. pmid:5165538 doi: 10.1093/infdis/123.5.548
- 114. Mgode GF, Machang'u RS, Goris MG, Engelbert M, Sondij S, Hartskeerl RA. New Leptospira serovar Sokoine of serogroup Icterohaemorrhagiae from cattle in Tanzania. Int J Syst Evol Microbiol. 2006;56(3):593–7. doi: 10.1099/ijs.0.63278-0
- 115. Mgode GF, Mhamphi G, Katakweba A, Paemelaere E, Willekens N, Leirs H, et al. PCR detection of Leptospira DNA in rodents and insectivores from Tanzania. Belg J Zool. 2005;135:17–9.
- 116. Mugarula DR. Canine leptospirosis in Tabora township [Tanzania]. Bull Anim Health Prod Afr. 1984;32(1):99–101.
- 117. Rademan J, Steytler JG, Wright N. First isolations of Leptospirae in Cape Town. S Afr Med J. 1964;38(30):694–96.
- 118. Rahelinirina S, Leon A, Harstskeerl RA, Sertour N, Ahmed A, Raharimanana C, et al. First isolation and direct evidence for the existence of large small-mammal reservoirs of Leptospira sp. in Madagascar. PLoS One. 2010;5(11):e14111. Epub 2010/12/03. doi: 10.1371/journal.pone.0014111. pmid:21124843
- 119. Tabel H, Losos G. Report on an outbreak of bovine leptospirosis in Kenya due to Leptospira grippotyphosa. Bull Anim Health Prod Afr. 1979;27(1):61–4.
- 120. Taylor PJ, Arntzen L, Hayter M, Iles M, Frean J, Belmain S. Understanding and managing sanitary risks due to rodent zoonoses in an African city: beyond the Boston Model. Integr Zool. 2008;3(1):38–50. Epub 2008/03/01. doi: 10.1111/j.1749-4877.2008.00072.x. pmid:21396050
- 121. Te Brugge LA, Dreyer T. Leptospira-Interrogans Serovar Hardjo Associated with Bovine Abortion in South Africa. Onderstepoort J Vet Res. 1985;52(1):51–2. pmid:4011157
- 122. Van Rensburg WJJ. Isolation of Leptospira-Canicola in Pigs and Dogs in South Africa. J S Afr Vet Assoc. 1973;44(4):435–36. pmid:4794501
- 123. Zimmermann S, ter Meulen A, Calvet E, Koivogui L, Sylla O, Goris M, et al. Seroprevalence and reservoirs of leptospirosis in Conakry (Guinea). Int J Antimicrob Agents. 2007;29(Suppl. 2):S49. doi: 10.1016/s0924-8579(07)70159-0
- 124. Halliday JE, Knobel DL, Allan KJ, Bronsvoort BMdC, Handel I, Agwanda B, et al. Urban leptospirosis in Africa: a cross-sectional survey of Leptospira infection in rodents in the Kibera urban settlement, Nairobi, Kenya. Am J Trop Med Hyg. 2013;89(6):1095–102. doi: 10.4269/ajtmh.13-0415. pmid:24080637
- 125. Dietrich M, Wilkinson DA, Soarimalala V, Goodman SM, Dellagi K, Tortosa P. Diversification of an emerging pathogen in a biodiversity hotspot: Leptospira in endemic small mammals of Madagascar. Mol Ecol. 2014;23(11):2783–96. doi: 10.1111/mec.12777. pmid:24784171
- 126. Nimo Paintsil SC, Fichet-Calvet E, Mohareb E, Morales M, Bonney JH, Obiri-Danso K, et al. Rodent species and their correlation with human seropositivity for zoonotic infections in Ghana. Am J Trop Med Hyg. 2013;89 (Suppl 1):422.
- 127. Hatem ME, Ata NS, Abdou AM, Ibrahim ES, Bakry MA, Samir A. Surveillance of bovine leptospirosis: isolation and serodiagnosis. Global Veterinaria. 2014;13(1):127–32.
- 128. Reyburn H, Mbatia R, Drakely C, Carneiro I, Mwakasungula E, Mwerinde O, et al. Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: a prospective study. BMJ. 2004;329(7476). doi: 10.1136/bmj.38251.658229.55
- 129. Manock SR, Jacobsen KH, de Bravo NB, Russell KL, Negrete M, Olson JG, et al. Etiology of acute undifferentiated febrile illness in the Amazon basin of Ecuador. Am J Trop Med Hyg. 2009;81(1):146–51. Epub 2009/06/27. pmid:19556580
- 130. Suttinont C, Losuwanaluk K, Niwatayakul K, Hoontrakul S, Intaranongpai W, Silpasakorn S, et al. Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study. Ann Trop Med Parasitol. 2006;100(4):363–70. Epub 2006/06/10. pmid:16762116 doi: 10.1179/136485906x112158
- 131. Gasem MH, Wagenaar JF, Goris MG, Adi MS, Isbandrio BB, Hartskeerl RA, et al. Murine typhus and leptospirosis as causes of acute undifferentiated fever, Indonesia. Emerg Infect Dis. 2009;15(6):975–77. Epub 2009/06/16. doi: 10.3201/eid1506.081405. pmid:19523308
- 132. Kendall EA, LaRocque RC, Bui DM, Galloway R, Ari MD, Goswami D, et al. Leptospirosis as a cause of fever in urban Bangladesh. Am J Trop Med Hyg. 2010;82(6):1127–30. Epub 2010/06/04. doi: 10.4269/ajtmh.2010.09-0574. pmid:20519612
- 133. Desvars A, Michault A, Bourhy P. Leptospirosis in the western Indian Ocean islands: what is known so far? Vet Res. 2013;44(1). doi: 10.1186/1297-9716-44-80
- 134. Bourhy P, Collet L, Brisse S, Picardeau M. Leptospira mayottensis sp. nov., a pathogenic Leptospira species isolated from humans. Int J Syst Evol Microbiol. 2014; Epub 2014/09/25. doi: 10.1099/ijs.0.066597-0
- 135. Soors W, Dkhimi F, Criel B. Lack of access to health care for African indigents: a social exclusion perspective. International journal for equity in health. 2013;12:91. Epub 2013/11/19. doi: 10.1186/1475-9276-12-91. pmid:24238000
- 136. Rutherford ME, Mulholland K, Hill PC. How access to health care relates to under five mortality in subSaharan Africa: systematic review. Trop Med Int Health. 2010;15(5):508–19. doi: 10.1111/j.1365-3156.2010.02497.x. pmid:20345556
- 137. Petti CA, Polage CR, Quinn TC, Ronald AR, Sande MA. Laboratory medicine in Africa: a barrier to effective health care. Clin Infect Dis. 2006;42(3):377–82. Epub 2006/01/05. pmid:16392084 doi: 10.1086/499363
- 138. Crump JA, Gove S, Parry CM. Management of adolescents and adults with febrile illness in resource limited areas. BMJ. 2011;343:d4847. Epub August 8. doi: 10.1136/bmj.d4847. pmid:21824901
- 139. Cleaveland S, Borner M, Gislason M. Ecology and conservation: contributions to One Health. Revue Scientifique et Techique (International Office of Epizootics). 2014;33(2):615–27.
- 140. Mazet JAK, Clifford DL, Coppolillo PB, Deolalikar AB, Erickson JD, Kazwala RR. A "One Health" approach to address emerging zoonoses: The HALI project in Tanzania. PLoS Med. 2009;6(12):e1000190. doi: 10.1371/journal.pmed.1000190. pmid:20016689
- 141. Zinsstag J, Schelling E, Waltner-Toews D, Tanner M. From “one medicine” to “one health” and systemic approaches to health and well-being. Prev Vet Med. 2011;101(3–4):148–56. doi: 10.1016/j.prevetmed.2010.07.003. pmid:20832879
- 142. O'Doherty E, Sayers R, L OG, Shalloo L. Effect of exposure to Neospora caninum, Salmonella, and Leptospira interrogans serovar Hardjo on the economic performance of Irish dairy herds. J Dairy Sci. 2015;98(4):2789–800. Epub 2015/02/24. doi: 10.3168/jds.2014-8168. pmid:25704967
- 143. Cortizo P, Loureiro AP, Martins G, do Rodrigues PR, Faria BP, Lilenbaum W, et al. Risk factors to incidental leptospirosis and its role on the reproduction of ewes and goats of Espirito Santo state, Brazil. Trop Anim Health Prod. 2015;47(1):231–5. Epub 2014/10/03. doi: 10.1007/s11250-014-0684-4. pmid:25274622
- 144. Grace D, Mutua F, Ochungo P, Kruska R, Jones K, Brierley L, et al. Mapping of poverty and likely zoonoses hotspots. International Livestock Research Institute, 2012.
- 145. Halliday JEB, Allan KJ, Ekwem D, Cleaveland S, Kazwala RR, Crump JA. Endemic zoonoses in the tropics: a public health problem hiding in plain sight. Vet Rec. 2015;176(9):220–25. doi: 10.1136/vr.h798. pmid:25722334