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General review
Legionnaires’ disease in France Légionellose en France C. Campèse a,∗,1 , G. Descours b,2 , A. Lepoutre a,3 , L. Beraud b,4 , C. Maine a,5 , D. Che a,6 , S. Jarraud b,7 b
a Institut de veille sanitaire, 12, rue du Val-d’Osne, 94415 Saint-Maurice cedex, France Centre national de référence des légionelles, centre de Biologie Est, 59, boulevard Pinel, 69677 Bron, France
Received 15 December 2014; received in revised form 31 December 2014; accepted 29 January 2015 Available online 24 February 2015
Abstract The aim of this review was to describe the current knowledge of Legionnaires’ disease (LD) illustrated by the epidemiological situation in France in 2013. LD is a severe pneumonia commonly caused by Legionella pneumophila serogroup 1. The diagnosis is usually based on the urinary antigen test. This rapid method reduces the delay between clinical suspicion and initiation of an appropriate treatment. However, the availability of a clinical strain is important to improve knowledge of circulating bacteria, to document case clusters, and to identify the sources of contamination. The source of contamination is unknown in most cases. The main contamination sources generating aerosols are water network systems and cooling towers. Thanks to the strengthening of clinical and environmental monitoring and to several guidelines, no epidemic has been reported in France since 2006. Despite these efforts, the number of LD cases has not decreased in recent years. It is essential that applied research continue to better understand the spatial and temporal dynamics of the disease and its characteristics (impact of environmental factors, sources of exposure, strains, host, etc.). Fundamental knowledge has been greatly improved (pathogenesis, immune mechanisms, etc.). The results of this research should help define new strategies for the diagnosis, prevention, and control to decrease the number of LD cases diagnosed every year. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Legionnaires’ disease; Epidemiology; France
Résumé Cet article avait pour objectif d’effectuer une synthèse sur les connaissances actuelles de la légionellose illustrées par le bilan épidémiologique en France en 2013. La légionellose est une pneumopathie souvent sévère due en majorité aux bactéries Legionella pneumophila sérogroupe 1. Le diagnostic repose essentiellement sur la détection de l’antigène dans les urines, méthode permettant d’écourter le délai entre la suspicion clinique et la mise en route d’un traitement adapté. Cependant, la disponibilité d’une souche clinique est primordiale car elle permet d’améliorer les connaissances sur les bactéries, de documenter les cas groupés et de préciser les sources de contamination. Pour la majorité des cas, la source de contamination demeure inconnue. Les principales installations susceptibles d’être à l’origine des cas sont les réseaux d’eaux sanitaires et les
∗ 1 2 3 4 5 6 7
Corresponding author. E-mail address: [email protected] (C. Campèse). Christine Campese performed the analyses and wrote the article. Ghislaine Descours helped draft the article. Agnes Lepoutre proofread the article and provided additional data. Laetitia Beraud proofread the article and provided additional data. Catherine Maine collected the mandatory notification surveillance data. Didier Che helped draft the article. Sophie Jarraud wrote the microbiology sections and helped draft the article.
http://dx.doi.org/10.1016/j.medmal.2015.01.015 0399-077X/© 2015 Elsevier Masson SAS. All rights reserved.
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tours aéroréfrigérantes. Grâce au renforcement de la surveillance et à la diffusion de nombreuses règlementations visant l’amélioration des mesures de contrôles et de prévention, aucune épidémie n’a été identifiée en France depuis 2006. Malgré ces efforts, le nombre de cas de légionellose ne diminue pas ces dernières années. Pour mieux comprendre la dynamique temporospatiale de la légionellose et l’ensemble des déterminants de la maladie (impact des facteurs environnementaux, caractéristiques des sources d’exposition, des souches et de l’hôte. . .), il est essentiel que les recherches appliquées se poursuivent. Parallèlement, les connaissances fondamentales ont largement progressé. Ces recherches contribueront à terme à la définition de nouvelles stratégies de diagnostic, de contrôle et de prévention et à faire régresser le nombre de cas de légionellose diagnostiqués chaque année. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Légionellose ; Épidémiologie ; France
1. Introduction Legionella was first identified during a pneumonia epidemic in Philadelphia, in 1976 [1]. Knowledge of Legionella, its ecology, as well as on the determinants and risk factors of the disease has greatly increased since [2]. However, some uncertainties remain, particularly on the relationship between genotype and virulence, or on the host’s genetic factors. The number of Legionnaires’ disease (LD) cases has no longer been decreasing, in recent years in France, despite improved measures for the control and prevention of contamination sources. We reviewed the current knowledge, illustrated by the epidemiological data of LD cases in France, in 2013. 2. Global information on Legionella and Legionnaires’ disease Legionella are Gram-negative intracellular bacilli, the genus of which includes close to 60 species and 70 serogroups [3]. Nearly 30 species have been documented as pathogenic for humans and the main species responsible for most cases of LD in Europe and in the USA, is Legionella pneumophila; serogroup 1 (Lp1) is the most frequently identified (approximately 90% of cases) [4]. Legionella are hydrotelluric bacteria found in the natural aquatic environment. They can easily grow in artificial media if conditions are favorable. Water hardness or optimum pH, scale deposits, corrosion, and the presence of metallic residues such as iron or zinc could increase the survival and proliferation of bacteria [5]. The same is true for the presence of amoebae and microbial niches (biofilm) that protect bacteria against physical (heat shock) and chemical (chlorine, biocides) treatments. It is mainly from artificial reservoirs such as sanitary water networks or water-cooling towers (WCT) that Legionella, conveyed in the environment as aerosols, can diffuse in the environment and causes the disease among exposed persons [6]. Soil or compost can also be a source of contamination, especially in case of Legionella longbeachae LD more frequently reported in Australia and New Zealand. [7] Many sources of contamination have been documented: shower, spa, decorative fountain, nebulization device, and WCT. These devices were the source of most major LD outbreaks worldwide [8–12]. Investigations have documented the ability of Legionella to be spread in the atmosphere over long distances, more than 6 km around a
WCT [12,13]. The investigations also showed that the internationally demonstrated incubation period ranges between 2 and 10 days (median of 6 days) but may be exceptionally longer (up to 19 days) [9,14]. Infection by Legionella is influenced by several factors related to the bacterium (species, serogroup, or sequence type) and its ecology, but also related to environmental factors that determine the survival and spread of the bacterium in the environment. Thus, the incidence of LD was associated with weather conditions such as humidity, rainfall, and temperature [15,16]. Factors related to the host characteristics are also important. Monitoring data indicates a death rate of 10% and at least 70% of the patients have 1 or more risk factor such as advanced age, immunosuppression (particularly related to corticosteroid but also to anti-TNF therapy), diabetes, tobacco abuse, and chronic lung disease [17,18]. LD rarely occurs in individuals less than 20 years of age and is extremely rare in children. Human genetic factors have not really been studied but could also help to determine susceptibility to the disease. 2.1. Pathogenesis of Legionella The Legionella bacterium is considered as an opportunistic pathogen, man being only an accidental host. The cellular mechanisms involved in replication in the amoeba, Legionella’s preferential host, are similar to those observed in human cells, especially macrophages and epithelial cells. The type IV secretion system called Dot/Icm is essential for this replication allowing secretion into the host cell cytosol of more than 300 bacterial effectors that will allow the diversion of the usual endocytic pathway by inhibiting phagolysosomal fusion and creating a specialized replicative vacuole. In parallel, the impact of innate immunity in the clearance of the bacterium will be paramount in humans. Thus, 3 important bacterial factors, flagellin, Dot system/Icm, and lipopolysaccharide (LPS) are recognized by cellular receptors or receptors located within the host cell, which then triggers the production of pro-inflammatory cytokines having a central role in the anti-Legionella restrictive response. Very recently, the comparative analysis of genomes of various Legionella species with different ability to infect humans revealed great differences in gene content. Major species pathogenic for humans, Legionella pneumophila and L. longbeachae contain a set of genes that appear to increase
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their ability to infect mammalian cells. The key to success seems to be a better ability to subvert host functions to create a protective niche for intracellular replication through a specific set of secreted effectors out of the 300 available [19]. L. pneumophila serogroup 1 (Lp1) is responsible for most cases of LD, but some epidemiological data suggests that not all Lp1 have the same pathogenicity. The data analysis of 8 available Lp1 strain genomes revealed a highly conserved core genome of nearly 2,500 orthologous genes, and a great variety of accessory genome due to horizontal transfers among prokaryotes, but also among prokaryotes and eukaryotes, proving the interaction with amoebas; 6% to 11% of the genes are specific to each strain. Thus, more than 1,000 genes are not all present in the 8 genomes [20,21]. The analysis of genomic data suggests that the cluster of LPS Lp1 biosynthetic genes may explain, for a large part, the predominance of serogroup 1 in human infection [19]. 3. Diagnosis The diagnosis of LD is based on clinical and biological information. 3.1. Clinical symptoms There is no specific clinical or radiological sign for LD. The clinical presentation is progressive and can begin with asthenia, along with a mild fever that rises quickly to 39–40 ◦ C, and an initial non productive cough. This presentation may also include myalgia, headaches, and digestive disorders such as diarrhea, nausea, and vomiting. Neurological disorders such as confusion or delirium can also be observed. The infection may be complicated by respiratory failure, acute renal failure, and rhabdomyolysis. Extrapulmonary manifestations can be observed more rarely (heart, joint, etc.). The diagnosis relies on a radiologically confirmed pneumonia with alveolar or alveolarinterstitial syndrome, most often bilateral [22,23].
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Legionella by culture of lower respiratory tract samples is highly recommended for all LD cases. It can be made from sputum and any other type of lower respiratory tract samples (tracheal aspiration, bronchoalveolar lavage). The culture of Legionella is slow (3–10 days) and requires specific media but it can nevertheless be performed after 72 hours of antibiotic treatment, especially for the most severe cases of LD [27]. Co-culture techniques on amebic layer, taking into account the fact that the bacterium grows intracellularly, thus allowing in some cases to increase the sensitivity of culture by removing the contaminating oropharyngeal flora [28]. Isolating strains by phenotypic and genotypic methods allows documenting the cluster nature of cases and clarifying the potential sources of contamination (see below). PCR is performed most often on low respiratory tract samples and allows for a rapid diagnosis. Molecular techniques allow detecting all L. pneumophila serogroups and all other Legionella species. The accurate identification of L. pneumophila serogroup is currently only possible for Lp1 in specialized laboratories [29]. The sensitivity of PCR with low respiratory tract samples is 80 to 100% and its specificity is close to 100%. PCR performed on non-pulmonary samples (urine and serum) looks interesting but its sensitivity is too low to be used as a diagnostic method [30]. Blood tests give a late or retrospective diagnosis and should be limited to a specific use such as for the LD diagnosis of L. pneumophila serogroup 1 to 7 for the main kits on the market. The sera should be sent to the National Reference Center for Legionella (NHRC) for other serogroups and other species. The diagnosis of LD is confirmed only by proving a 4-fold increase in antibody titer between 2 samples, measured by indirect immunofluorescence (IIF). The antibodies may be detected 1 to 2 weeks after the onset of infection; the peak is reached 4 to 5 weeks later. However, this may vary considerably among patients and many cross-reactions have been reported with mycobacteria, leptospira, Chlamydia, Mycoplasma, Citrobacter, Campylobacter and Coxiella burnetii.
3.2. Microbiological diagnosis Several methods are used. Screening for soluble Legionella antigens in urine is the fastest and most frequently used method (96% of LD diagnosis in France). The test becomes positive after 24 to 48 hours after the onset of clinical signs. The urinary excretion of antigens may persist from 3 to 4 weeks to several months despite an adequate antibiotic treatment [24]. The currently available tests most frequently detect Lp1 by immunochromatography with calorimetric or fluorescence revelation. The sensitivity of tests for Lp1 is 70–90%. This can be improved for some test (5%) if urine is first concentrated [25]. The sensitivity is decreased to 50% for nosocomial cases. This lower sensitivity was clearly associated with the characteristics of strains causing nosocomial cases [26]. The specificity is test-dependent but may reach 99% for the most effective ones. Pretreatment of urine by heating is recommended to avoid false-positive results. Culture is the gold standard and is mandatory to identify case clusters and identify the sources of contamination. Screening for
4. Treatment The antibiotic treatment is chosen according to the severity of LD and the underlying conditions. Macrolides (azithromycin preferentially) are recommended as monotherapy for mild presentations. Fluoroquinolone monotherapy or a macrolide and fluoroquinolone combination are recommended for severe presentations and/or immunosuppressed patients. Other families of antibiotics such as rifampicin may also be used. The duration of treatment is 8 to 14 days for non-severe presentations, can be extended to 21 days for severe presentations and/or immunocompromised patients [31]. Beta-lactams should not be proposed because they are not active given the intracellular location of Legionella. There is no scientific evidence to recommending antibiotic prophylaxis in case of exposure in community or hospital settings. However, in case of clustered nosocomial cases of LD, antibiotic prophylaxis can be considered depending on the
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Fig. 1. Trends in the number of cases and annual incidence rate of Legionnaires’ disease in France, 1988–2013. Évolution du nombre de cas et du taux annuel d’incidence de la légionellose en France, 1988–2013.
exposure to the source of contamination and on the level of immunosuppression of patients [32]. 5. Monitoring system The surveillance of LD in France relies on data collected by mandatory notification (French acronym DO). All LD cases diagnosed by clinicians and biologists must be notified to the regional health agencies (ARS) that validate the information, conduct an enquiry to identify risk exposures, look for other cases related to these exposures, and implement, when necessary, measures of control and prevention. ARS send the reports to the National Institute for Public Health Surveillance (InVS) in charge of epidemiological monitoring at a national level (www.invs.sante.fr). France participates in the European LD surveillance network (ELDSNet) related to travel associated cases, coordinated by the European Centre for Disease Prevention and Control (ECDC) [33] which notifies the cases of LD in patients having stayed in a tourist facility, in the 10 days before the onset of LD, whether the
journey is inside or outside the country where the case occurred. If these institutions are located in countries outside the European Union, the World Health Organization (WHO) informs the health authorities of the country. The NHRC (http://cnr-legionelles.univ-lyon1.fr) collects all clinical isolates of Legionella at the same time; this collection currently includes more than 5,000 isolates. These isolates have been routinely typed since 2008 by 3 methods for local (investigation of cases) and global (emergence of clones) molecular epidemiology: use of monoclonal antibodies (mAbs) analysis of macrorestriction profiles of total DNA by PFGE (pulsedfield gel electrophoresis), and amplification and sequencing (“Sequence Based Typing” [SBT]) of 7 selected genes that is the reference method in Europe [34]. These last 2 techniques have a discriminating power superior to 98% and 96% respectively. These 3 methods allow documenting cluster cases to specify the sources of contamination, and to carry out space and time monitoring of strains causing the cases of LD. It is possible to perform typing by SBT directly on pulmonary samples, if no strain was isolated [35,36].
Incidence rate / 100,000 individual 12 10
Male patients
8
Female patients 6 4 2 0 AGE =80
Fig. 2. Incidence rate of cases of Legionnaires’ disease notified in France by sex and age class in 2013. Taux d’incidence par sexe et par classe d’âge des cas de légionellose notifiés en France en 2013.
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Fig. 3. Mean annual standardized incidence rate of Legionnaires’ disease by region in France, 2013. Taux annuel moyen standardisé d’incidence de la légionellose par région en France métropolitaine, 2006–2009.
6. Control and prevention [37]
7. Epidemiological assessment in 2013
Control and prevention measures must target the potential sources of contamination by limiting or eliminating the risk. They must be implemented as early as possible when cases are identified to prevent new cases. Many guidelines have been issued, since the 90s, to limit the risk of LD. The measures concern water networks in healthcare facilities, spas, and old people’s homes. More recently, they have targeted institutions open to the public (recreation, tourism, etc.) with a regulation published in February 2010 mentioning the mandatory monitoring of water networks with a yearly screening for legionella. Furthermore, on cooling installations dispersing water into an air stream (wet cooling towers), new regulatory texts were published in December 2013. They recommend monitoring and periodic checks defined based on the results obtained. The High Council of Public Health published a new guideline on risks associated, with Legionella at the end of 2013 [37]. This guideline was intended primarily for ARS personnel (public health and environmental health), inspection services of classified installations and personnel directly involved the epidemiological and environmental investigations.
One thousand two hundred and sixty-two cases of LD were reported in France in 2013, and the incidence rate of notified LD cases in metropolitan France was 1.94 per 100,000 individuals (Fig. 1). This rate was similar to those of Italy, Spain, Denmark, and the Netherlands but higher than the European average that was 1.2 per 100,000 individuals in 2012. The number of cases reported in 2013 was slightly lower than in 2012 (1,298 cases). The median age was 65 years (range: 15 to 98 years) and male/female sex ratio was 2.5 (899 male and 363 female patients). The incidence increased with age and the highest incidence rates were observed in patients more than 80 years of age (7.1/100,000) (Fig. 2). Regarding risk factors, 74% of patients (931/1262) had at least 1 known risk factor, and smoking was the only risk factor reported in 29% of cases. The outcome of the disease was known for 93% of the patients (1,168/1,262) and the death rate was 12.2% (143 deaths). Patients who died were older (73 years versus 63 years, P < 0.001) and more often reported hospital exposure during the incubation period (21% vs. 11% P = 0.007) than
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survivors. The West-East geographical gradient in the incidence rate of notified LD cases was always significant and ranged from 0.4/105 inhabitants in Bretagne to 4.4/105 inhabitants in Alsace (Fig. 3). One thousand two hundred and forty-four of the 1,262 cases (98%) were confirmed cases and 1,222 cases were due to Lp1 (97%). A strain was isolated in 323 cases (25.6% of cases, against 23.7% in 2012). The clinical strain could be compared to isolated environmental strains of a place the patient had been to in 51 cases (16%), and among these, the genomic profiles of clinical and environmental strains were identical in 30 patients (59%). These 30 patients had stayed in 9 hospitals, 13 homes, 3 tourist facilities, and 5 other institutions; domestic water systems were the most likely source of contamination according to the results of environmental and microbiological investigations. Exposure to risk during 2 to 10 days before the first clinical signs was reported by 465 patients (37%). Among these, 86 patients (7% overall) had stayed in a hospital during the period of exposure and 42 (49%) were proven nosocomial cases (hospitalized throughout the assumed exposure period). Fiftynine patients (6%) had lived in an institution for elderly people and 6 patients (1%) had attended a spa. The primary source of exposure (239 patients = 19%) was a trip with a stay in a tourist facility for 145 patients (12% overall). The other reported exposures were attending public institutions, occupational exposure, or other types of exposure (spa, home, etc.). In 2013, 190 French tourist facilities were notified by the European Network ELDSNet, 13 of which had received at least 2 patients over a 2-year period, corresponding to a cluster according to the Eldsnet network case definition. The results of investigations carried out in 2013 for 11 of these 13 facilities revealed a level of legionella above the regulatory threshold in samples from the domestic water network for 6 (55%) of them. The ARS in cooperation with the regional InVS offices (French acronym Cires) conducted several investigations of cluster cases (defined by less than 10 cases) in 2013. These investigations of cases clustered in time and space did not allow identifying any common source of contamination.
has not significantly decreased. Furthermore, the sources of contamination for most cases were not identified or suspected. It is therefore important to improve the documentation of risk exposure to identify new potential sources of contamination (new air conditioning systems, humidifiers, home devices, etc.) by careful documenting, during history taking with the patient or their relatives, any exposure that may have caused the disease. Identifying the sources of contamination and investigating of case clusters should be facilitated by the increasing number of strains isolated from clinical samples. Furthermore, PCR diagnosis included in the criteria defining LD since 2010 should allow better identifying even rare cases of L. non-pneumophila LD, particularly in immunocompromised patients. The current data (more than 8,500 isolates) from 57 countries is available on the Public Health England website http:// bioinformatics.phe.org.uk/legionella/legionella sbt/php/sbt homepage.php reveals the predominance of 6 ST on more than 1,700 ST identified in human infections (ST1, ST23, ST47, ST62, ST42, ST37). In France, strains ST23, ST1, and ST47 cause 39% of diagnosed LD cases with an identified strain. Likewise, in the environment, some STs, and particularly ST1, are widely distributed but the reasons for this predominance are still unknown [40]. It is essential to carry on applied research to better understand the spatial and temporal dynamics of LD, and all its determinants (impact of environmental factors, characteristics of sources of exposure, of strains, and of host, etc.). Fundamental knowledge has greatly increased (pathophysiology, immune mechanisms, etc.). This research should help define new strategies for the diagnosis, control, prevention, and decrease the number of LD cases diagnosed each year. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments
8. Discussion–Conclusion The surveillance of LD in France has considerably improved since the late 1990s. The number of cases in 2013 confirmed a stable rate in the number of reported cases since 2008. The completeness of the reporting rate at the national level had improved significantly in 2010 and was estimated at 89% (10% in 1995, 33% in 1998); it seems satisfactory today [38]. The patient features remain identical in terms of age, sex, risk factors, and lethality, and in terms of exposure and microbiological characteristics (species and serogroup). The “West-East” geographic gradient incidence rate documented in 2006 is still present [39]. This gradient is probably influenced by several factors such as: weather factors that require further investigations; diagnostic variations; and the density of potential exposure sources and their characteristics. No epidemic (> 10 cases) has been identified since 2006 thanks to improved monitoring and issuing of many regulations. However, the number of cases diagnosed every year
We thank all partners in healthcare monitoring, clinicians, biologists, nurses, public health physicians, sanitary engineering engineers and technicians, as well as all local and regional partners, Cires and the CNR-Legionella team. All the epidemiological data is available on the InVS website: http://www.invs.sante.fr/Dossiers-thematiques/Maladiesinfectieuses/Infections-respiratoires/Legionellose/Donnees-desurveillance. References [1] Fraser DW, Tsai TR, Orenstein W, Parkin WE, Beecham HJ, Sharrar RG, et al. Legionnaires’ disease: description of an epidemic of pneumonia. N Engl J Med 1977;297(22):1189–97. [2] Che D, Campese C, Jarraud S. Legionella and legionnaires’ disease: what do we know? Pathol Biol (Paris) 2011;59(3):134–6. [3] Gomez-Valero L, Rusniok C, Buchrieser C. Legionella pneumophila: population genetics, phylogeny and genomics. Infect Genet Evol 2009;9(5):727–39.
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[23] Chidiac C, Che D, Pires-Cronenberger S, Jarraud S, Campese C, Bissery A, et al. Factors associated with hospital mortality in community-acquired legionellosis in France. Eur Respir J 2012;39(4):963–70. [24] Sopena N, Sabria M, Pedro-Botet ML, Reynaga E, Garcia-Nunez M, Dominguez J, et al. Factors related to persistence of Legionella urinary antigen excretion in patients with legionnaires’ disease. Eur J Clin Microbiol Infect Dis 2002;21(12):845–8. [25] Jarraud S, Descours G, Ginevra C, Lina G, Etienne J. Identification of legionella in clinical samples. Methods Mol Biol 2013;954:27–56. [26] Helbig JH, Uldum SA, Bernander S, Luck PC, Wewalka G, Abraham B, et al. Clinical utility of urinary antigen detection for diagnosis of community-acquired, travel-associated, and nosocomial legionnaires’ disease. J Clin Microbiol 2003;41(2):838–40. [27] Descours G, Cassier P, Forey F, Ginevra C, Etienne J, Lina G, et al. Evaluation of BMPA, MWY, GVPC and BCYE media for the isolation of Legionella species from respiratory samples. J Microbiol Methods 2014;98:119–21. [28] Descours G, Suet A, Ginevra C, Campese C, Slimani S, Ader F, et al. Contribution of amoebic coculture to recovery of Legionella isolates from respiratory samples: prospective analysis over a period of 32 months. J Clin Microbiol 2012;50(5):1725–6. [29] Merault N, Rusniok C, Jarraud S, Gomez-Valero L, Cazalet C, Marin M, et al. Specific real-time PCR for simultaneous detection and identification of Legionella pneumophila serogroup 1 in water and clinical samples. Appl Environ Microbiol 2011;77(5):1708–17. [30] Matsiota-Bernard P, Waser S, Vrioni G. Detection of Legionella pneumophila DNA in urine and serum samples from patients with pneumonia. Clin Microbiol Infect 2000;6(4):223–5. [31] Afssaps. Mise au point. Traitement antibiotique de la légionellose chez l’adulte. Saint Denis: Afssaps [mis à jour le 06/2011]. Accessed on 09/01/2013. URL: http://ansm.sante.fr/var/ansm site/storage/original/ application/5e0a0a6ce0725ba42387dc31a14551eb.pdf [32] Conseil supérieur d’hygiène publique de France section des maladies transmissibles. Avis relatif à la place de l’antibioprophylaxie dans la prévention des légionelloses nosocomiales. 18/03/2005. Accessed on 10/11/2014. URL: http://www.sante.gouv.fr/dossiers/cshpf/a mt 180305 legionellose prophy.pdf [33] Beaute J, Zucs P, de JB. Legionnaires disease in Europe, 2009–2010. Euro Surveill 2013;18(10):20417. [34] Luck C, Fry NK, Helbig JH, Jarraud S, Harrison TG. Typing methods for legionella. Methods Mol Biol 2013;954:119–48. [35] Mentasti M, Fry NK, Afshar B, Palepou-Foxley C, Naik FC, Harrison TG. Application of Legionella pneumophila-specific quantitative real-time PCR combined with direct amplification and sequence-based typing in the diagnosis and epidemiological investigation of Legionnaires’ disease. Eur J Clin Microbiol Infect Dis 2012;31(8):2017–28. [36] Ginevra C, Lopez M, Forey F, Reyrolle M, Meugnier H, Vandenesch F, et al. Evaluation of a nested-PCR-derived sequence-based typing method applied directly to respiratory samples from patients with Legionnaires’ disease. J Clin Microbiol 2009;47(4):981–7. [37] Ministère des affaires sociales et de la santé, Direction générale de la santé. DGS/EA4 no 2014-167 du 23 mai 2014 relative à la diffusion du guide du Haut Conseil de la santé publique (HCSP) pour l’investigation et l’aide à la gestion sur le risque lié aux légionelles. 23/05/2014. Accessed on 10/11/2014. URL: http://www.sante.gouv.fr/fichiers/ bo/2014/14-08/ste 20140008 0000 0103.pdf [38] Campese C, Jarraud S, Sommen C, Maine C, Che D. Legionnaires’ disease in France: sensitivity of the mandatory notification has improved over the last decade. Epidemiol Infect 2013;141(12):2644–9. [39] Campese C, Jarraud S, Maine C, Che D. La légionellose en France : augmentation du nombre de cas en 2010. Bull Epidedemiol Hebd 2011;29–30:325–7. [40] Cassier P, Campese C, Le Strat Y, Che D, Ginevra C, Etienne J, et al. Epidemiological characteristics associated with ST23 clones compared to ST1 and ST47 clones of Legionnaires’ disease cases in France. New microbes and new infections. À paraître en 2014. DOI: 10.1016/j.nmni.2014.10.006.
ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 45 (2015) 65–71
General review
Legionnaires’ disease in France Légionellose en France C. Campèse a,∗,1 , G. Descours b,2 , A. Lepoutre a,3 , L. Beraud b,4 , C. Maine a,5 , D. Che a,6 , S. Jarraud b,7 b
a Institut de veille sanitaire, 12, rue du Val-d’Osne, 94415 Saint-Maurice cedex, France Centre national de référence des légionelles, centre de Biologie Est, 59, boulevard Pinel, 69677 Bron, France
Received 15 December 2014; received in revised form 31 December 2014; accepted 29 January 2015 Available online 24 February 2015
Abstract The aim of this review was to describe the current knowledge of Legionnaires’ disease (LD) illustrated by the epidemiological situation in France in 2013. LD is a severe pneumonia commonly caused by Legionella pneumophila serogroup 1. The diagnosis is usually based on the urinary antigen test. This rapid method reduces the delay between clinical suspicion and initiation of an appropriate treatment. However, the availability of a clinical strain is important to improve knowledge of circulating bacteria, to document case clusters, and to identify the sources of contamination. The source of contamination is unknown in most cases. The main contamination sources generating aerosols are water network systems and cooling towers. Thanks to the strengthening of clinical and environmental monitoring and to several guidelines, no epidemic has been reported in France since 2006. Despite these efforts, the number of LD cases has not decreased in recent years. It is essential that applied research continue to better understand the spatial and temporal dynamics of the disease and its characteristics (impact of environmental factors, sources of exposure, strains, host, etc.). Fundamental knowledge has been greatly improved (pathogenesis, immune mechanisms, etc.). The results of this research should help define new strategies for the diagnosis, prevention, and control to decrease the number of LD cases diagnosed every year. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Legionnaires’ disease; Epidemiology; France
Résumé Cet article avait pour objectif d’effectuer une synthèse sur les connaissances actuelles de la légionellose illustrées par le bilan épidémiologique en France en 2013. La légionellose est une pneumopathie souvent sévère due en majorité aux bactéries Legionella pneumophila sérogroupe 1. Le diagnostic repose essentiellement sur la détection de l’antigène dans les urines, méthode permettant d’écourter le délai entre la suspicion clinique et la mise en route d’un traitement adapté. Cependant, la disponibilité d’une souche clinique est primordiale car elle permet d’améliorer les connaissances sur les bactéries, de documenter les cas groupés et de préciser les sources de contamination. Pour la majorité des cas, la source de contamination demeure inconnue. Les principales installations susceptibles d’être à l’origine des cas sont les réseaux d’eaux sanitaires et les
∗ 1 2 3 4 5 6 7
Corresponding author. E-mail address: [email protected] (C. Campèse). Christine Campese performed the analyses and wrote the article. Ghislaine Descours helped draft the article. Agnes Lepoutre proofread the article and provided additional data. Laetitia Beraud proofread the article and provided additional data. Catherine Maine collected the mandatory notification surveillance data. Didier Che helped draft the article. Sophie Jarraud wrote the microbiology sections and helped draft the article.
http://dx.doi.org/10.1016/j.medmal.2015.01.015 0399-077X/© 2015 Elsevier Masson SAS. All rights reserved.
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tours aéroréfrigérantes. Grâce au renforcement de la surveillance et à la diffusion de nombreuses règlementations visant l’amélioration des mesures de contrôles et de prévention, aucune épidémie n’a été identifiée en France depuis 2006. Malgré ces efforts, le nombre de cas de légionellose ne diminue pas ces dernières années. Pour mieux comprendre la dynamique temporospatiale de la légionellose et l’ensemble des déterminants de la maladie (impact des facteurs environnementaux, caractéristiques des sources d’exposition, des souches et de l’hôte. . .), il est essentiel que les recherches appliquées se poursuivent. Parallèlement, les connaissances fondamentales ont largement progressé. Ces recherches contribueront à terme à la définition de nouvelles stratégies de diagnostic, de contrôle et de prévention et à faire régresser le nombre de cas de légionellose diagnostiqués chaque année. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Légionellose ; Épidémiologie ; France
1. Introduction Legionella was first identified during a pneumonia epidemic in Philadelphia, in 1976 [1]. Knowledge of Legionella, its ecology, as well as on the determinants and risk factors of the disease has greatly increased since [2]. However, some uncertainties remain, particularly on the relationship between genotype and virulence, or on the host’s genetic factors. The number of Legionnaires’ disease (LD) cases has no longer been decreasing, in recent years in France, despite improved measures for the control and prevention of contamination sources. We reviewed the current knowledge, illustrated by the epidemiological data of LD cases in France, in 2013. 2. Global information on Legionella and Legionnaires’ disease Legionella are Gram-negative intracellular bacilli, the genus of which includes close to 60 species and 70 serogroups [3]. Nearly 30 species have been documented as pathogenic for humans and the main species responsible for most cases of LD in Europe and in the USA, is Legionella pneumophila; serogroup 1 (Lp1) is the most frequently identified (approximately 90% of cases) [4]. Legionella are hydrotelluric bacteria found in the natural aquatic environment. They can easily grow in artificial media if conditions are favorable. Water hardness or optimum pH, scale deposits, corrosion, and the presence of metallic residues such as iron or zinc could increase the survival and proliferation of bacteria [5]. The same is true for the presence of amoebae and microbial niches (biofilm) that protect bacteria against physical (heat shock) and chemical (chlorine, biocides) treatments. It is mainly from artificial reservoirs such as sanitary water networks or water-cooling towers (WCT) that Legionella, conveyed in the environment as aerosols, can diffuse in the environment and causes the disease among exposed persons [6]. Soil or compost can also be a source of contamination, especially in case of Legionella longbeachae LD more frequently reported in Australia and New Zealand. [7] Many sources of contamination have been documented: shower, spa, decorative fountain, nebulization device, and WCT. These devices were the source of most major LD outbreaks worldwide [8–12]. Investigations have documented the ability of Legionella to be spread in the atmosphere over long distances, more than 6 km around a
WCT [12,13]. The investigations also showed that the internationally demonstrated incubation period ranges between 2 and 10 days (median of 6 days) but may be exceptionally longer (up to 19 days) [9,14]. Infection by Legionella is influenced by several factors related to the bacterium (species, serogroup, or sequence type) and its ecology, but also related to environmental factors that determine the survival and spread of the bacterium in the environment. Thus, the incidence of LD was associated with weather conditions such as humidity, rainfall, and temperature [15,16]. Factors related to the host characteristics are also important. Monitoring data indicates a death rate of 10% and at least 70% of the patients have 1 or more risk factor such as advanced age, immunosuppression (particularly related to corticosteroid but also to anti-TNF therapy), diabetes, tobacco abuse, and chronic lung disease [17,18]. LD rarely occurs in individuals less than 20 years of age and is extremely rare in children. Human genetic factors have not really been studied but could also help to determine susceptibility to the disease. 2.1. Pathogenesis of Legionella The Legionella bacterium is considered as an opportunistic pathogen, man being only an accidental host. The cellular mechanisms involved in replication in the amoeba, Legionella’s preferential host, are similar to those observed in human cells, especially macrophages and epithelial cells. The type IV secretion system called Dot/Icm is essential for this replication allowing secretion into the host cell cytosol of more than 300 bacterial effectors that will allow the diversion of the usual endocytic pathway by inhibiting phagolysosomal fusion and creating a specialized replicative vacuole. In parallel, the impact of innate immunity in the clearance of the bacterium will be paramount in humans. Thus, 3 important bacterial factors, flagellin, Dot system/Icm, and lipopolysaccharide (LPS) are recognized by cellular receptors or receptors located within the host cell, which then triggers the production of pro-inflammatory cytokines having a central role in the anti-Legionella restrictive response. Very recently, the comparative analysis of genomes of various Legionella species with different ability to infect humans revealed great differences in gene content. Major species pathogenic for humans, Legionella pneumophila and L. longbeachae contain a set of genes that appear to increase
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their ability to infect mammalian cells. The key to success seems to be a better ability to subvert host functions to create a protective niche for intracellular replication through a specific set of secreted effectors out of the 300 available [19]. L. pneumophila serogroup 1 (Lp1) is responsible for most cases of LD, but some epidemiological data suggests that not all Lp1 have the same pathogenicity. The data analysis of 8 available Lp1 strain genomes revealed a highly conserved core genome of nearly 2,500 orthologous genes, and a great variety of accessory genome due to horizontal transfers among prokaryotes, but also among prokaryotes and eukaryotes, proving the interaction with amoebas; 6% to 11% of the genes are specific to each strain. Thus, more than 1,000 genes are not all present in the 8 genomes [20,21]. The analysis of genomic data suggests that the cluster of LPS Lp1 biosynthetic genes may explain, for a large part, the predominance of serogroup 1 in human infection [19]. 3. Diagnosis The diagnosis of LD is based on clinical and biological information. 3.1. Clinical symptoms There is no specific clinical or radiological sign for LD. The clinical presentation is progressive and can begin with asthenia, along with a mild fever that rises quickly to 39–40 ◦ C, and an initial non productive cough. This presentation may also include myalgia, headaches, and digestive disorders such as diarrhea, nausea, and vomiting. Neurological disorders such as confusion or delirium can also be observed. The infection may be complicated by respiratory failure, acute renal failure, and rhabdomyolysis. Extrapulmonary manifestations can be observed more rarely (heart, joint, etc.). The diagnosis relies on a radiologically confirmed pneumonia with alveolar or alveolarinterstitial syndrome, most often bilateral [22,23].
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Legionella by culture of lower respiratory tract samples is highly recommended for all LD cases. It can be made from sputum and any other type of lower respiratory tract samples (tracheal aspiration, bronchoalveolar lavage). The culture of Legionella is slow (3–10 days) and requires specific media but it can nevertheless be performed after 72 hours of antibiotic treatment, especially for the most severe cases of LD [27]. Co-culture techniques on amebic layer, taking into account the fact that the bacterium grows intracellularly, thus allowing in some cases to increase the sensitivity of culture by removing the contaminating oropharyngeal flora [28]. Isolating strains by phenotypic and genotypic methods allows documenting the cluster nature of cases and clarifying the potential sources of contamination (see below). PCR is performed most often on low respiratory tract samples and allows for a rapid diagnosis. Molecular techniques allow detecting all L. pneumophila serogroups and all other Legionella species. The accurate identification of L. pneumophila serogroup is currently only possible for Lp1 in specialized laboratories [29]. The sensitivity of PCR with low respiratory tract samples is 80 to 100% and its specificity is close to 100%. PCR performed on non-pulmonary samples (urine and serum) looks interesting but its sensitivity is too low to be used as a diagnostic method [30]. Blood tests give a late or retrospective diagnosis and should be limited to a specific use such as for the LD diagnosis of L. pneumophila serogroup 1 to 7 for the main kits on the market. The sera should be sent to the National Reference Center for Legionella (NHRC) for other serogroups and other species. The diagnosis of LD is confirmed only by proving a 4-fold increase in antibody titer between 2 samples, measured by indirect immunofluorescence (IIF). The antibodies may be detected 1 to 2 weeks after the onset of infection; the peak is reached 4 to 5 weeks later. However, this may vary considerably among patients and many cross-reactions have been reported with mycobacteria, leptospira, Chlamydia, Mycoplasma, Citrobacter, Campylobacter and Coxiella burnetii.
3.2. Microbiological diagnosis Several methods are used. Screening for soluble Legionella antigens in urine is the fastest and most frequently used method (96% of LD diagnosis in France). The test becomes positive after 24 to 48 hours after the onset of clinical signs. The urinary excretion of antigens may persist from 3 to 4 weeks to several months despite an adequate antibiotic treatment [24]. The currently available tests most frequently detect Lp1 by immunochromatography with calorimetric or fluorescence revelation. The sensitivity of tests for Lp1 is 70–90%. This can be improved for some test (5%) if urine is first concentrated [25]. The sensitivity is decreased to 50% for nosocomial cases. This lower sensitivity was clearly associated with the characteristics of strains causing nosocomial cases [26]. The specificity is test-dependent but may reach 99% for the most effective ones. Pretreatment of urine by heating is recommended to avoid false-positive results. Culture is the gold standard and is mandatory to identify case clusters and identify the sources of contamination. Screening for
4. Treatment The antibiotic treatment is chosen according to the severity of LD and the underlying conditions. Macrolides (azithromycin preferentially) are recommended as monotherapy for mild presentations. Fluoroquinolone monotherapy or a macrolide and fluoroquinolone combination are recommended for severe presentations and/or immunosuppressed patients. Other families of antibiotics such as rifampicin may also be used. The duration of treatment is 8 to 14 days for non-severe presentations, can be extended to 21 days for severe presentations and/or immunocompromised patients [31]. Beta-lactams should not be proposed because they are not active given the intracellular location of Legionella. There is no scientific evidence to recommending antibiotic prophylaxis in case of exposure in community or hospital settings. However, in case of clustered nosocomial cases of LD, antibiotic prophylaxis can be considered depending on the
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Fig. 1. Trends in the number of cases and annual incidence rate of Legionnaires’ disease in France, 1988–2013. Évolution du nombre de cas et du taux annuel d’incidence de la légionellose en France, 1988–2013.
exposure to the source of contamination and on the level of immunosuppression of patients [32]. 5. Monitoring system The surveillance of LD in France relies on data collected by mandatory notification (French acronym DO). All LD cases diagnosed by clinicians and biologists must be notified to the regional health agencies (ARS) that validate the information, conduct an enquiry to identify risk exposures, look for other cases related to these exposures, and implement, when necessary, measures of control and prevention. ARS send the reports to the National Institute for Public Health Surveillance (InVS) in charge of epidemiological monitoring at a national level (www.invs.sante.fr). France participates in the European LD surveillance network (ELDSNet) related to travel associated cases, coordinated by the European Centre for Disease Prevention and Control (ECDC) [33] which notifies the cases of LD in patients having stayed in a tourist facility, in the 10 days before the onset of LD, whether the
journey is inside or outside the country where the case occurred. If these institutions are located in countries outside the European Union, the World Health Organization (WHO) informs the health authorities of the country. The NHRC (http://cnr-legionelles.univ-lyon1.fr) collects all clinical isolates of Legionella at the same time; this collection currently includes more than 5,000 isolates. These isolates have been routinely typed since 2008 by 3 methods for local (investigation of cases) and global (emergence of clones) molecular epidemiology: use of monoclonal antibodies (mAbs) analysis of macrorestriction profiles of total DNA by PFGE (pulsedfield gel electrophoresis), and amplification and sequencing (“Sequence Based Typing” [SBT]) of 7 selected genes that is the reference method in Europe [34]. These last 2 techniques have a discriminating power superior to 98% and 96% respectively. These 3 methods allow documenting cluster cases to specify the sources of contamination, and to carry out space and time monitoring of strains causing the cases of LD. It is possible to perform typing by SBT directly on pulmonary samples, if no strain was isolated [35,36].
Incidence rate / 100,000 individual 12 10
Male patients
8
Female patients 6 4 2 0 AGE =80
Fig. 2. Incidence rate of cases of Legionnaires’ disease notified in France by sex and age class in 2013. Taux d’incidence par sexe et par classe d’âge des cas de légionellose notifiés en France en 2013.
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Fig. 3. Mean annual standardized incidence rate of Legionnaires’ disease by region in France, 2013. Taux annuel moyen standardisé d’incidence de la légionellose par région en France métropolitaine, 2006–2009.
6. Control and prevention [37]
7. Epidemiological assessment in 2013
Control and prevention measures must target the potential sources of contamination by limiting or eliminating the risk. They must be implemented as early as possible when cases are identified to prevent new cases. Many guidelines have been issued, since the 90s, to limit the risk of LD. The measures concern water networks in healthcare facilities, spas, and old people’s homes. More recently, they have targeted institutions open to the public (recreation, tourism, etc.) with a regulation published in February 2010 mentioning the mandatory monitoring of water networks with a yearly screening for legionella. Furthermore, on cooling installations dispersing water into an air stream (wet cooling towers), new regulatory texts were published in December 2013. They recommend monitoring and periodic checks defined based on the results obtained. The High Council of Public Health published a new guideline on risks associated, with Legionella at the end of 2013 [37]. This guideline was intended primarily for ARS personnel (public health and environmental health), inspection services of classified installations and personnel directly involved the epidemiological and environmental investigations.
One thousand two hundred and sixty-two cases of LD were reported in France in 2013, and the incidence rate of notified LD cases in metropolitan France was 1.94 per 100,000 individuals (Fig. 1). This rate was similar to those of Italy, Spain, Denmark, and the Netherlands but higher than the European average that was 1.2 per 100,000 individuals in 2012. The number of cases reported in 2013 was slightly lower than in 2012 (1,298 cases). The median age was 65 years (range: 15 to 98 years) and male/female sex ratio was 2.5 (899 male and 363 female patients). The incidence increased with age and the highest incidence rates were observed in patients more than 80 years of age (7.1/100,000) (Fig. 2). Regarding risk factors, 74% of patients (931/1262) had at least 1 known risk factor, and smoking was the only risk factor reported in 29% of cases. The outcome of the disease was known for 93% of the patients (1,168/1,262) and the death rate was 12.2% (143 deaths). Patients who died were older (73 years versus 63 years, P < 0.001) and more often reported hospital exposure during the incubation period (21% vs. 11% P = 0.007) than
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survivors. The West-East geographical gradient in the incidence rate of notified LD cases was always significant and ranged from 0.4/105 inhabitants in Bretagne to 4.4/105 inhabitants in Alsace (Fig. 3). One thousand two hundred and forty-four of the 1,262 cases (98%) were confirmed cases and 1,222 cases were due to Lp1 (97%). A strain was isolated in 323 cases (25.6% of cases, against 23.7% in 2012). The clinical strain could be compared to isolated environmental strains of a place the patient had been to in 51 cases (16%), and among these, the genomic profiles of clinical and environmental strains were identical in 30 patients (59%). These 30 patients had stayed in 9 hospitals, 13 homes, 3 tourist facilities, and 5 other institutions; domestic water systems were the most likely source of contamination according to the results of environmental and microbiological investigations. Exposure to risk during 2 to 10 days before the first clinical signs was reported by 465 patients (37%). Among these, 86 patients (7% overall) had stayed in a hospital during the period of exposure and 42 (49%) were proven nosocomial cases (hospitalized throughout the assumed exposure period). Fiftynine patients (6%) had lived in an institution for elderly people and 6 patients (1%) had attended a spa. The primary source of exposure (239 patients = 19%) was a trip with a stay in a tourist facility for 145 patients (12% overall). The other reported exposures were attending public institutions, occupational exposure, or other types of exposure (spa, home, etc.). In 2013, 190 French tourist facilities were notified by the European Network ELDSNet, 13 of which had received at least 2 patients over a 2-year period, corresponding to a cluster according to the Eldsnet network case definition. The results of investigations carried out in 2013 for 11 of these 13 facilities revealed a level of legionella above the regulatory threshold in samples from the domestic water network for 6 (55%) of them. The ARS in cooperation with the regional InVS offices (French acronym Cires) conducted several investigations of cluster cases (defined by less than 10 cases) in 2013. These investigations of cases clustered in time and space did not allow identifying any common source of contamination.
has not significantly decreased. Furthermore, the sources of contamination for most cases were not identified or suspected. It is therefore important to improve the documentation of risk exposure to identify new potential sources of contamination (new air conditioning systems, humidifiers, home devices, etc.) by careful documenting, during history taking with the patient or their relatives, any exposure that may have caused the disease. Identifying the sources of contamination and investigating of case clusters should be facilitated by the increasing number of strains isolated from clinical samples. Furthermore, PCR diagnosis included in the criteria defining LD since 2010 should allow better identifying even rare cases of L. non-pneumophila LD, particularly in immunocompromised patients. The current data (more than 8,500 isolates) from 57 countries is available on the Public Health England website http:// bioinformatics.phe.org.uk/legionella/legionella sbt/php/sbt homepage.php reveals the predominance of 6 ST on more than 1,700 ST identified in human infections (ST1, ST23, ST47, ST62, ST42, ST37). In France, strains ST23, ST1, and ST47 cause 39% of diagnosed LD cases with an identified strain. Likewise, in the environment, some STs, and particularly ST1, are widely distributed but the reasons for this predominance are still unknown [40]. It is essential to carry on applied research to better understand the spatial and temporal dynamics of LD, and all its determinants (impact of environmental factors, characteristics of sources of exposure, of strains, and of host, etc.). Fundamental knowledge has greatly increased (pathophysiology, immune mechanisms, etc.). This research should help define new strategies for the diagnosis, control, prevention, and decrease the number of LD cases diagnosed each year. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments
8. Discussion–Conclusion The surveillance of LD in France has considerably improved since the late 1990s. The number of cases in 2013 confirmed a stable rate in the number of reported cases since 2008. The completeness of the reporting rate at the national level had improved significantly in 2010 and was estimated at 89% (10% in 1995, 33% in 1998); it seems satisfactory today [38]. The patient features remain identical in terms of age, sex, risk factors, and lethality, and in terms of exposure and microbiological characteristics (species and serogroup). The “West-East” geographic gradient incidence rate documented in 2006 is still present [39]. This gradient is probably influenced by several factors such as: weather factors that require further investigations; diagnostic variations; and the density of potential exposure sources and their characteristics. No epidemic (> 10 cases) has been identified since 2006 thanks to improved monitoring and issuing of many regulations. However, the number of cases diagnosed every year
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