Human leptospirosis: An emerging risk in Europe?

Comparative Immunology, Microbiology and Infectious Diseases 37 (2014) 77–83

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Human leptospirosis: An emerging risk in Europe? Julien Dupouey a , Benoît Faucher b , Sophie Edouard c , Hervé Richet a,c , Angeli Kodjo d , Michel Drancourt a,c , Bernard Davoust c,e,∗ a Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire La Timone, 264 rue Saint-Pierre, 13385 Marseille Cedex 05, France b Service des Maladies Infectieuses, CHU Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, 13015 Marseille, France c Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS UMR 7278 IRD 198 INSERM U1095 Aix-Marseille Université, Facultés de médecine et de pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France d Laboratoire des leptospires, Equipe PERS, VetAgro Sup, Campus Vétérinaire de Lyon, 1 Av Bourgelat, 69280 Marcy l’Etoile, France e Groupe de travail en épidémiologie animale du service de santé des armées, BP95 83800 Toulon Cedex 9, France

a r t i c l e

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Article history: Received 29 June 2013 Received in revised form 2 December 2013 Accepted 7 December 2013 Keywords: Leptospira interrogans Leptospirosis Rodents transmission Zoonoses Environmental exposure Epidemiology Europe

a b s t r a c t Leptospirosis has been reemerging in both developed and developing countries including Europe, where, this phenomenon has notably been associated with urban transmission. However, the comprehensive data that are needed to fully understand the ongoing epidemiological trends are lacking. In this article, we report surveillance data from throughout Europe, especially in France, to have an overview of this neglected disease in temperate countries. Our results underline the important role of wild rodents as reservoir of leptospirosis, and highlight the potential danger of a reemergence of this under-reported infectious disease in European cities, associated with the important expansion of the rat population in urban areas. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiological situation in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case notification in France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of rodents as a reservoir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ∗ Corresponding author at: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE), CNRS UMR 7278 IRD 198 INSERM U1095 Aix-Marseille Université, Facultés de médecine et de pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France. Tel.: +33 4 91 32 43 75. E-mail address: [email protected] (B. Davoust). 0147-9571/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cimid.2013.12.002

Leptospirosis, a disease caused by pathogenic spirochetes belonging to the Leptospira genus, represents a worldwide public health problem affecting both industrialized and developing countries. Annually, approximately 500,000 severe cases occur worldwide, with a mortality

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rate of 5–20% [1]. Human infection occurs via direct contact with the urine of infected animals or indirectly through interaction with a urine-contaminated environment. These bacteria can survive outside the host if conditions are favorable (i.e., a warm, wet climate) [1,2]. In Europe, the incidence of leptospirosis decreased during the second half of the last century. Moreover, autochthonous transmission reportedly disappeared in several territories, including France, leading to a decrease in disease awareness and prevention efforts [3]. However, the re-emergence of leptospirosis in industrialized countries, particularly in urban areas, was recently reported [4–6]. For example, this phenomenon was reported in Marseille, the main city in southeastern France [3]. Both field investigations and information from surveillance networks were needed to determine the actual ongoing trends and to enable the adoption of relevant policies to raise disease awareness. Overall, the comprehensive data necessary for assessing the dynamics of leptospirosis incidence in Europe are lacking. Specifically, the impact from increasing urban transmission and/or from the spread of sylvatic transmission to new territories remains undetermined. In this work, we collected data from across Europe’s national surveillance networks to evaluate the status of leptospirosis in European countries. We then focused on the epidemiological situation in France. These data highlight the involvement of rodents as reservoirs for urban and peri-urban leptospirosis and emphasizes the risk of reemergence of this under-diagnosed infectious disease in developed countries. 2. Epidemiological situation in Europe Literature review showed two types of surveillance methods: (i) an active surveillance, more sensitive but time-limited, complex and expensive, and (ii) a passive surveillance, corresponding to report of cases, mandatory or based on voluntary report, which is less expensive but not exhaustive. Therefore, obtaining homogeneous epidemiological data on leptospirosis from throughout Europe has proven challenging. First, all of the detection systems likely suffer from an under-reporting bias [7], which may vary over time. For instance, the high-profile death of a British Olympic rower from leptospirosis in 2010 raised awareness of the disease in the United Kingdom and led to a subsequent improvement in diagnosis and reporting [8]. Moreover, national survey systems were found to vary between European Union (EU) countries: whereas most countries benefited from comprehensive compulsory systems (Germany, United Kingdom, etc.), others relied on sentinel networks (as in Spain) or voluntary reporting (as in France) [9]. Our work relied on the following means of data collection: (i) requests for national numbers sent to each national reference center and/or health ministry in Europe; (ii) data from the European Centre for Disease Prevention and Control [9]; and (iii) a review of the available data found by searching “leptospirosis” and the name of each country in Promed, Google Scholar, and Pubmed. The World Health Organization (WHO) defined a suspected case of leptospirosis as a case that is compatible

with the clinical description and a presumptive laboratory diagnosis and a confirmed case as a suspect case with a confirmatory laboratory diagnosis (isolation of Leptospira from a clinical specimen, fourfold or greater increase in Leptospira agglutination titer between acute- and convalescent-phase serum specimens studied at the same laboratory, demonstration of Leptospira in tissue by direct immunofluorescence, Leptospira agglutination titer of ≥800 by Microscopic Agglutination Test (MAT) in one or more serum specimens, or detection of pathogenic Leptospira DNA (e.g., by PCR from a clinical specimen) [http://www. who.int/zoonoses/diseases/Leptospirosissurveillance.pdf]. In 2010, 588 confirmed leptospirosis cases were reported in 25 European countries. With an overall incidence of 0.13/100,000 inhabitants, leptospirosis remained a rare disease in EU countries (Fig. 1) [9]. Indeed, most risk factors associated with leptospirosis endemicity (tropical climate, flooding, poor sanitation) are not traditionally encountered in EU countries [10]. The highest leptospirosis notification rates were observed in Romania (0.84/100,000 inhabitants), Slovakia (0.50/100,000 inhabitants), Slovenia (0.44/100,000 inhabitants), Ireland (0.38/100,000 inhabitants), and Czech Republic (0.38/100,000 inhabitants) [9]. The overall incidence in Europe appeared to be stable in the last several years following a progressive decrease that occurred during the 2000s (Fig. 2) [7,9]. This overall trend masks marked differences between countries with asynchronous epidemiologic peaks (Table 1). Such variation between European countries in the timing of incidence peaks has been reported previously [12]. In addition to the cyclic variations in incidence that occur every few years, epidemic peaks may be associated with climatic events, such as flooding in the Czech Republic [13], or with exposure that occurs during social events such as marathons or other crowded recreational activities [14–17]. Leptospirosis had a seasonal trend, with majority of cases occurred between July and October (maximum incidence in August and September) [10]. The most frequently implicated serovar was Icterohemorrhagiae, although other serovars, such as Grippotyphosa or Pomona, were also involved [18]. However, in more than 10% of positive cases, the species could not be determined due to cross-reactivity in the microscopic agglutination test [11]. In Europe, overall risk factors have included male gender (M/F ratio: 4/1), adult age (15–64 years), and recreational or professional exposure to fresh water, as described for France [4,7,9,18]. Indeed, small epidemics were reported following the flooding of basements (in Denmark [personal communication of Statens Serum Institut of Denmark, 2012]); participation in outdoor sports, such as triathlons, following heavy rain (in Austria [14] and Germany [15]); rowing (United Kingdom [8]); bathing in rivers (France [16]); or fishing [18]. Consequently, high incidences were reported in late summer and fall throughout Europe [9,12,19]. Professional exposure notably involved cattle raising, farming [19,20], and working on the land [18]. In recent years, there have been increasing reports of urban or peri-urban transmission in developed countries, including Germany [4], Russia [7], and France [3]. The proliferation of rats has been implicated as a possible source of

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Fig. 1. Leptospirosis incidence in Europe in 2010 (cases/100,000 inhabitants) [ND = presence of leptospirosis, but lack of comprehensive data] [9,11, personal communications].

transmission in France [3,21]. The presence of wild reservoirs for leptospirosis and their role in the increase of urban cases will be discussed later in this report. Although leptospirosis can be considered an emerging disease in travelers [22], these anecdotal imported cases

do not represent a significant public health problem [23]. A recent survey in Germany showed that 84% of leptospirosis cases were likely autochthonous [4]. Interestingly, travel to European countries may be implicated in as many as 33% of cases [24], especially if risky activities, such as adventure

0.7 0.6 0.5 0.4

Mainland France Marseille region

0.3 Europe 0.2 0.1 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Fig. 2. Evolution of leptospirosis incidence in mainland France, the Marseille region, and Europe, 2000–2011 [9,11, personal communications].

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Table 1 Incidence of leptospirosis in Europe, 2000–2010 (cases/100,000 inhabitant). Country

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Albania Austria Belarus Belgium Bosnia and Herzegovina Bulgaria Croatia Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Lithuania Luxembourg Malta Montenegro Netherlands Norway Poland Portugal Republic of Moldova Romania Russia Serbia Slovakia Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom

ND 0 ND 0.2 0.7 0.4 1.3 ND 0.1 0.1 0.3 0.1 0.4 0.1 0.1 0.9 0 0.2 0.1 1.4 0.6 0 0 0.2 0.2 0 0 0.4 ND 1.6 ND ND 0.8 0.2 0 0 0.1 0 ND 0.1

ND 0 ND 0.3 ND 0.3 3.1 ND 1 0.1 0.6 0.1 0.5 0.1 0.2 0.6 0 0.2 0.1 1.6 0.5 ND 0.5 ND 0.2 0 0 0.8 ND 1.4 ND ND 0.8 0.3 0.1 0 ND 0 ND 0.1

ND 0 ND 0.3 ND 0.3 1.9 ND 0.9 2.4 0.1 0.1 0.6 0.1 0.2 0.3 0 0.2 0.1 0.9 0.8 ND 0 ND 0.2 0 0 0.4 ND 1.5 ND ND 0.7 1 0.1 0 ND 0 ND 0.1

ND 0 ND 0.2 ND 0.3 0.9 0.3 0.2 0.1 0.1 0.1 0.5 0 0.4 0.3 0 0.2 0.1 0.4 0.4 ND 0.3 ND 0.1 0 0 0.7 ND 1.1 ND ND 0.3 0.4 0 0 ND 0 ND 0

0.4 0.1 ND 0.1 ND 0.4 1.8 0 0.2 0.3 0.6 0.1 0.4 0.1 0.3 0.3 0 0.3 0.1 0.6 0.2 ND 0.8 ND 0.2 0 0 0.5 ND ND ND 0.5 0.4 0.6 0 0 ND 0 ND 0.1

0.2 0.1 ND 0.2 ND 0.6 2.8 0 0.5 0.1 0.8 0.1 0.3 0.1 0.3 0.3 0 0.4 0.1 0.3 0.2 ND 0.7 ND 0.2 0 0 0.3 ND 2.1 ND 0.6 0.6 0.4 0.1 0 ND 0 ND 0.1

ND 0.1 ND 0.2 ND 0.26 0.9 0 0.18 0.09 0.45 0.1 0.3 0.06 0.14 0.27 0 0.43 0.04 0.22 0.1 0 0.25 ND 0.14 0 0.01 0.33 ND 1.79 ND 0.4 0.41 0.25 0 0.02 ND 0 ND 0.09

ND 0.11 ND 0.08 ND 0.21 ND 0 0.23 0.15 0.15 0.04 0.52 0.2 0.12 0.31 ND 0.51 0.08 0.09 0.18 0 0.25 ND 0.23 ND 0.02 0.36 ND 1.37 ND ND 0.32 0.35 ND 0.01 ND ND ND 0.13

ND 0.13 ND 0.05 ND 0.12 ND 0 0.16 0.15 0.15 0.15 0.55 0.08 0.11 0.15 ND 0.66 0.07 0.13 0.06 0 0.49 ND 0.23 ND 0.01 0.14 ND 0.93 ND ND 0.43 0.3 ND 0.07 ND ND ND 0.12

ND 0.11 ND 0.07 ND 0.15 ND 0 0.31 0.04 0.08 0.23 0.32 0.11 0.28 0.09 ND 0.56 0.06 0.22 0.15 0 0.73 ND 0.15 ND 0.01 0.3 ND 0.59 ND ND 0.3 0.1 ND 0.04 ND ND ND 0.09

ND 0.11 ND 0.08 ND 0.15 ND 0 0.38 0.11 0.08 0 0.06 0.09 0.21 0.09 ND 0.38 0.03 0.09 0.15 0 0.24 ND 0.18 ND 0.01 0.27 ND 0.84 ND ND 0.5 0.44 ND 0.04 ND ND ND 0.07

ND = absence of official data [7,9, 11, personal communications].

and water sports or seasonal exposed agricultural activities, were performed [20]. As diagnosis remains difficult due to clinical findings that range broadly from isolated fever to multi-organ failure, delayed diagnosis is partially responsible for occasional deaths due to the disease [25]. For instance, 18 fatal cases were reported in England and Wales between 1988 and 2006 [8]. 3. Case notification in France In France, leptospirosis cases are reported on a voluntary basis to the National Reference Center (Pasteur Institute, Paris). The National Reference Center works with most companies that perform diagnosis confirmation tests [11]. However, some cases may remain undetected depending on the awareness and motivation of local physicians. France reports one of the highest endemicity levels in Europe, but these numbers are mostly derived from the French overseas territories [11]; between 500 and 1000 cases occur each year in the territories administered by France, mostly overseas (West Indies, Polynesia, La Réunion, French Guiana, New Caledonia). The incidence in

these regions is from 10 to 100 times higher than in mainland France, varying from 5 cases per 100,000 in French Guiana to more than 1000 cases per 100,000 inhabitants in Futuna, with regular reports of small and medium outbreaks [26]. The overall incidence appeared stable over the last decade following a slow decline over the course of the 20th century [12] (Fig. 2). This decrease was interrupted by a few increases in incidence, which all resolved within a few years. Even excluding overseas cases, mainland France exhibits one of the five highest reported incidences of leptospirosis in Europe (0.37/100,000 inhabitants in 2011, representing 230 cases). It tends to be a seasonal disease, with more than half of the cases occurring between August and October [11]. Leptospira of the serovar Icterohemorrhagiae is the most frequently encountered (36% of 230 serology in 2011), with rats and wild rodents being the preferred host [1,28], while the incidence of serovar Grippotyphosa infection increased from 9.4 in 2010 to 21% in 2011 [11]. In France, leptospirosis is considered a workrelated disease. Indeed, the recognized risk factors include working in sewers, waterways, and fish farming [1,9,29],

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Fig. 3. Global leptospirosis incidence in France, 2006–2010 (cases/100,000 inhabitants) [11].

and immunization is recommended only for these exposed workers [11]. In addition to its association with certain professions, leptospirosis has traditionally been considered an occupational disease found in rural areas or imported from tropical endemic areas [12]. In fact, in the last ten years [11], the frequent implication of water activities, such as canoeing, bathing, or fishing in fresh water, in the contraction of leptospirosis has resulted in a growing association of the disease with recreational freshwater exposure rather than with professional activities [27]. Skin lesions, contact with wild rodents, and rural residence are indeed correlated with leptospirosis [2,12,27]. This epidemiological evolution highlights the success of a program designed to reduce professional exposure in France through immunization and specific prevention of transmission but also demonstrates the need for increased prevention efforts among water-sport participants and their medical practitioners [27]. The incidence of leptospirosis in the Marseille region began increasing a few years ago (Figs. 2 and 3), with some annual variability (0.12 cases in 2001–2003 to 0.22 cases per 100,000 population in 2011), compared to an absence of reported cases from 1985 to 1995 [3]. A rising urban/periurban transmission rate was thought to contribute to this re-emergence, specifically in Marseille, where the illness was associated with the proliferation of rats, the accumulation of garbage, and rainfall [3].

Thus, to understand the risks of human transmission in the cities of developed countries, information on the precise status of leptospirosis specifically within the city rodent population appears to be essential. 4. Role of rodents as a reservoir The nearly 300 Leptospira serovars have different significances in human pathology, with the most virulent serogroup being Icterohemorrhagiae. In general, each serovar has adapted to a certain mammalian host. Rodents represent the main reservoir, but several mammal species act as hosts, including dogs, pigs, and cattle [1]. Among the most important Leptospira serogroups involved in human disease, Icterohemorrhagiae (approximately 35% of cases) uses Rattus rats for its reservoir, Grippotyphosa (20% of cases) is found mostly in voles and other small rodents, and Australis (10% of cases) uses hedgehogs as its main host [30]. One of the known risk factors for the emergence of leptospirosis in humans is a prevalence of leptospirosis in the rodent population in close proximity to humans [31]. Rodents are generally regarded as one of the most important transmission sources of leptospirosis; Rattus norvegicus is the predominant urban-dwelling rat found in close proximity to humans [32]. Rats are known reservoirs of Icterohemorrhagiae and persistently excrete leptospires in their urine throughout life [21]. A quantifiable link between the prevalence of leptospirosis in rodent populations and

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human infection has never been established. However, rodent leptospirosis could be regarded as an indicator and a risk factor for human leptospirosis. Contact with stagnant water poses a significant infection risk for humans. In France, five clustered cases of leptospirosis were diagnosed in the Rochefort area in June 2001 among teenagers who had swum in a canal. An environmental investigation revealed the presence of rodents (R. norvegicus, Ondatra zibethicus, Myocastor coypus) excreting leptospires near the bathing area. The overall rate of seropositivity in rodents for all antigens considered was 30.8%, with Icterohemorrhagiae being the predominant serogroup (23.1%) [16]. In 649 rodents trapped in five regions of France between 2001 and 2003, the seroprevalence for leptospirosis was in the range of 20–53%, depending on the bacterial species detected. Hap1 PCR demonstrated a significant difference between the different reservoir species for renal carriage: muskrats and rats are more efficient maintenance hosts than coypu, but all of them infect water [28]. In another survey, rats (R. norvegicus) trapped in 2006 in Toulon harbor in southeastern France were tested for the presence of Leptospira spp. DNA in kidney tissue using specific real-time PCR. Ten of fifty-two (19.2%) rats were found to be positive, and 9/10 (17%) of these animals tested positive for Leptospira interrogans [21]. In Italy, 5 out of 11 brown rats (R. norvegicus) trapped in Rome along the accessible right bank of the Tiber river exhibited positivity for Leptospira by PCR. This survey indicates a high rate of leptospiral infection in the brown rats living in the most ancient urban area of Rome [33]. In July 2007, a suspected leptospirosis outbreak was recognized in Germany among strawberry harvesters from Eastern Europe. Contact between hand lesions and contaminated water or soil and infected voles was the most likely source of the outbreak. The unusually warm winter of 2006–2007 supported the growth of the vole population and contributed to the resurgence of leptospirosis in Germany. Leptospires of the serogroup Grippotyphosa were isolated from the kidneys of 7 of 11 (64%) voles [20]. Another animal reservoir implicated in leptospirosis is the coypu (Myocastor coypus) [34]. Coypu were introduced in many European countries at the end of 19th century and have colonized a major portion of the continent, particularly in France [35]. Recently, Vein et al. reported a significant circulation of leptospires in coypu populations in two wetlands in eastern France, with a significant prevalence of kidney carriage (up to 12.1% of 133 coypus); thus, coypu can be considered a real reservoir for leptospirosis [36]. In Marseille, a veterinary investigation found similar results in coypus living in an important and highly utilized city park [data not published]. These findings underscore the potentially significant role for coypus in the maintenance, circulation, and transmission of leptospirosis to humans. 5. Conclusion Our survey did not confirm that leptospirosis is a re-emerging disease in Europe, as was feared [2,7]. The incidence of leptospirosis proved to be stable, with an overall incidence of 0.13/100,000 inhabitants in Europe in 2010. These numbers must, however, be considered cautiously,

as they may represent only the most easily identifiable cases; leptospirosis infection may remain asymptomatic or induce symptoms not specific enough to facilitate proper diagnosis of the disease [1]. Icterohemorrhagiae remains the predominant serovar, but numerous other serovars may also be involved. The high prevalence of leptospirosis observed in veterinary investigations throughout Europe supports this hypothesis. However, our survey highlights the potential for local epidemics to occur in Europe following climatic triggers or recreational exposure. It also highlights the potential for leptospirosis to spread to new territories either through the reappearance of sylvatic transmission in rural territories or through urbanization. Such spread into urban areas was also reported in other industrialized countries, such as Japan and the USA [6,37], and may involve the proliferation of rodents as well as the urbanization of previously wild animals, such as coypu. The expansion of the rat surface population in urban areas such as Marseille could be considered a key factor in the possible re-emergence of leptospirosis. In addition to confirming the persistence of the disease in Europe, our findings stress the need for maintained vigilance among physicians and for protracted prevention policies throughout Europe. Moreover, the leptospirosis burden in Europe might increase in the coming years due to several factors: (i) alterations in climate (current global warming or heavy rainfalls with flooding), (ii) the increasing population of urban rodents in European cities in close contact with human beings and with associated high leptospirosis carriage rates, (iii) human population growth and subsequent urbanization of affected rural territories, and (iv) the increase in intercontinental travels. Based on these facts, we hypothesize that leptospirosis will be a growing public health problem in Europe, particularly in urban settings [10,38,39]. To improve prevention and increase early diagnosis of this potentially fatal disease, information should be provided to both medical practitioners and to the public to increase awareness. Finally, the sources of infection in any human leptospirosis case should be traced to enable adequate eradication of the source or, at minimum, to reduce exposure by alerting public health authorities and the affected population. References [1] Levett PN. Leptospirosis. Clinical Microbiology Reviews 2001;14(2):296–326. [2] Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, et al. Peru-United States Leptospirosis Consortium: leptospirosis: a zoonotic disease of global importance. Lancet Infectious Diseases 2003;3(12):757–71. [3] Socolovschi C, Angelakis E, Renvoisé A, Fournier PE, Marié JL, Davoust B, et al. Strikes, flooding, rats, and leptospirosis in Marseille, France. International Journal of Infectious Diseases 2011;15:e710–5. [4] Jansen A, Schöneberg I, Frank C, Alpers K, Schneider T, Stark K. Leptospirosis in Germany, 1962–2003. Emerging Infectious Diseases 2005;11(7):1048–54. [5] Meites E, Jay MT, Deresinski S, Shieh WJ, Zaki SR, Tompkins L, et al. Reemerging leptospirosis, California. Emerging Infectious Diseases 2004;10(3):406–12. [6] Koizumi N, Muto M, Tanikawa T, Mizutani H, Sohmura Y, Hayashi E, et al. Human leptospirosis cases and the prevalence of rats harbouring Leptospira interrogans in urban areas of Tokyo, Japan. Journal of Medical Microbiology 2009;58:1227–30.

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