Emergence of macrolide-resistantBordetella pertussisin France, 2024: out of China

Emergence of macrolide-resistant Bordetella pertussis in France, 2024: out of China | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Emergence of macrolide-resistant Bordetella pertussis in France, 2024: out of China Valérie Bouchez , Noémie Lefrancq , Julie Toubiana , Carla Rodrigues , View ORCID Profile Sylvain Brisse doi: https://doi.org/10.1101/2025.03.15.25324024 Valérie Bouchez 1 Institut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens , Paris, France 2 National Reference Center for Whooping Cough and Other Bordetella Infections, Institut Pasteur , Paris, France 3 European Reference Laboratory for Diphtheria and Whooping Cough, Institut Pasteur , Paris, France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Noémie Lefrancq 4 Eidgenössische Technische Hochschule (ETH) , Zürich, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julie Toubiana 1 Institut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens , Paris, France 2 National Reference Center for Whooping Cough and Other Bordetella Infections, Institut Pasteur , Paris, France 3 European Reference Laboratory for Diphtheria and Whooping Cough, Institut Pasteur , Paris, France 5 Department of General Pediatrics and Pediatric Infectious Diseases, Hôpital Necker-Enfants Malades, APHP, Université Paris Cité , Paris, France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Carla Rodrigues 1 Institut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens , Paris, France 2 National Reference Center for Whooping Cough and Other Bordetella Infections, Institut Pasteur , Paris, France 3 European Reference Laboratory for Diphtheria and Whooping Cough, Institut Pasteur , Paris, France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sylvain Brisse 1 Institut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens , Paris, France 2 National Reference Center for Whooping Cough and Other Bordetella Infections, Institut Pasteur , Paris, France 3 European Reference Laboratory for Diphtheria and Whooping Cough, Institut Pasteur , Paris, France Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sylvain Brisse For correspondence: sylvain.brisse{at}pasteur.fr Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Objectives Pertussis is a highly contagious, potentially fatal vaccine-preventable respiratory disease, primarily caused by Bordetella pertussis ( Bp ). Macrolides constitute the first-line treatment for pertussis, reducing bacterial carriage and transmission. Despite consistent surveillance, only one resistant isolate had ever been reported in France before 2024 (in 2011). Here, we report 14 macrolide-resistant Bp (MRBP) cases, collected in France between February and November 2024, during the largest whooping cough outbreak of the last 20 years. We aimed to investigate whether these MRBP arose from macrolide-susceptible Bp (MSBP) in France or were instead imported. Methods Illumina sequencing was performed for all French isolates from 2024 and in addition, long-read sequencing was performed for the MRBP isolates. We compared the 14 MRBP genomic sequences with 1,571 macrolide-susceptible cultivated B. pertussis isolates collected in France (1993-2024, including 331 from 2024), the MRBP isolate from 2011, and 824 Bp collected in China (2018-2024), including 596 MRBP (75.2%). Results Phylogenetic analysis based on whole-genome single nucleotide polymorphisms revealed that the French MRBP belong to three separate branches nested within the diversity of MRBP isolates from China, suggesting three independent introductions into France. Two of these branches comprised more than one isolate, detected across several French administrative regions, indicating forward transmission and spatial dissemination. The MRBP isolates from France and China belonged to a single clade of the ptxP 3 lineage corresponding to the previous genotype denomination MT28. Conclusion The rise of MRBP in France is driven by importation followed by local dissemination. This exceptional emergence is concerning, given the high expected fitness of PRN-negative ptxP3 MRBP isolates in acellular vaccination countries. Besides vaccination, effective control of MRBP will require enhanced surveillance, strict adherence to transmission control guidelines, and prudent use of macrolides to avoid selective pressure favouring MRBP. Introduction Pertussis is a highly contagious vaccine-preventable respiratory disease, primarily caused by Bordetella pertussis ( Bp ), that can be lethal in young infants. In 2024, an intense resurgence of pertussis occurred in Europe and elsewhere ( 1 ), after circulating at very low levels since 2020. In France, an increase in the incidence of pertussis was reported ( 1 , 2 ). Macrolides constitute the first-line treatment for pertussis, reducing bacterial carriage and transmission. Of major public health concern, macrolide-resistant Bp (MRBP) isolates have been reported in China since 2011, now reaching > 90% in some settings ( 4 – 7 ) . Elsewhere, only sporadic MRBP cases have been reported up to now, including one case in France in 2011 ( 8 ). In China, MRBP isolates belong to two main phylogenetic clades called ptxP1 and ptxP3, which are marked by a mutation in the promoter of the pertussis toxin ( ptx P) gene cluster ( 4 , 6 ). Whereas ptxP1 MRBP isolates emerged around 2010 in China, ptxP3 MRBP emerged around 2016 and became predominant in some areas, such as Shanghai ( 6 , 9 , 10 ). This shift in ptxP genotype prevalence that was observed since 2019 in China might be associated with changes in pertussis vaccines in the country, which occurred approximately since 1995 from whole cell vaccines (wP) to acellular vaccines (aP) ( 11 ). ptxP3 isolates, particularly those that have lost the expression of the vaccine antigen pertactin (PRN), were previously inferred to have a much higher fitness, and thus to spread more rapidly, in aP-using countries ( 12 ). Here, we report 14 MRBP isolates from France collected between February and November 2024. Through genome-wide phylogenetic comparisons, we investigated whether the MRBPs arose from macrolide-susceptible Bp (MSBP) in France or were imported from abroad. We discuss possible reasons for their successful dissemination in France in light of their genomic features. Methods Bp isolates were collected through the Reseau Microbiologique de la Coqueluche (REMICOQ) network, which comprises laboratories from the Reseau National de la Coqueluche (RENACOQ) paediatric hospital-based surveillance network and additional collaborative hospital and outpatient laboratories ( 1 ). Culture was attempted at the French National Reference Center for Whooping Cough (NRC). Microbiological identification and characterisation were performed as previously described ( 1 , 13 ). Antibiotic susceptibility testing was performed by disk diffusion for ampicillin, cephalexin, streptomycin, trimethoprim-sulfamethoxazole, erythromycin, azithromycin, clarithromycin and spiramycin as previously described ( 1 ) and macrolide resistance was confirmed by E-test. In cases where macrolide resistance was confirmed, an extended panel of antibiotics was tested by disk diffusion, including piperacillin-tazobactam, ceftazidime, ceftriaxone, imipenem, doxycycline, amikacin, tobramycin, and tetracycline. We sequenced all Bp isolates from France in 2024 (see Supplementary appendix) and compared the genomic sequences of the 14 MRBP isolates with (i) 1,572 Bp collected in France (1993-2024, including the MRBP isolate from 2011 and 331 MSBP isolates sequenced in 2024), and (ii) 824 Bp collected in China in two large studies with publicly available genomic data (2018-2024; NCBI BioProjects PRJNA908268 and PRJNA1071282), including 596 MRBP (75.2%) ( 4 , 6 ). Phylogenetic analysis was performed using whole-genome single nucleotide polymorphisms (SNP) as previously described ( 12 ). Briefly, the SNP-based alignment was used to reconstruct the phylogenetic relationships of the isolates, using IQ-tree v2.3.6 and a GTR+F substitution model. The figures were generated using ggtree v3.2. Additionally, Nanopore sequencing was performed on the 14 French MRBP to define the number of mutated copies of the 23S rRNA gene (see Supplementary appendix). Finally, in response to the emergence of MRBP in France, we adapted a qPCR assay ( 14 ) to detect MRBP directly from respiratory samples (see Supplementary Appendix, protocol posted on protocols.io ( 14 )). Using this method, we screened the 534 pertussis-toxin positive samples (as defined by a positive qPCR for pertussis toxin gene ptxA ) collected in 2024. Results Out of 345 Bp isolates collected across France in 2024, 14 MRBP were identified. These were collected from 4 infants under 12 months of age, 5 children aged 1 to 6 years, and 5 adults ranging from 18 to 79 years old. Of the 9 documented cases, 2 required hospitalisation, including one newborn admitted to intensive care. The 14 isolates produced pertussis toxin (PT), filamentous haemagglutinin (FHA) and the fimbriae of serotype FIM2. Whereas one isolate was PRN-positive (see branch I3, Figure 1B ), the 13 others were PRN-negative (branches I1 and I2). This contrasted with the macrolide-susceptible Bp (MSBP) isolates collected over the study period, which all produced PRN except one. The 14 MRBP isolates carried the A2047G mutation in the 3 copies of the 23S rRNA gene, consistent with their antimicrobial resistance phenotype. Based on antigen genes ( 15 ), the 14 MRBP isolates belonged to the same genotype, Bp-agST4, and were characterised by a ptxP3 promoter. Differently, among MSBP isolates from 2024, 18 were characterised by a ptxP1 promoter and 11 or these displayed a new allele for fim3 ( fim3-26, characterised by a synonymous mutation C87T, also observed in fim3 -4, and an additional non-synonymous mutation leading to amino-acid substitution V165D). Download figure Open in new tab Figure 1. Phylogenetic diversity and geographic dissemination of macrolide-resistant Bordetella pertussis, France 2024. The tree was constructed based on whole genome SNPs using method described in Lefrancq et al . Panel A presents the tree obtained from the whole dataset: tree leaves are red for MRBP, (allele 13, i.e. , 23S rRNA A2047G mutation) or green for MSBP (allele 1); 2 isolates with a single mutated copy of the 23S rRNA gene are colored in orange. Landmark mutation ptxP3 is indicated at corresponding node with a black triangle. The columns indicate the country of origin (France: dark blue; China: light blue); years of collection (from 1975 to 2024), ptxP and fim3 alleles (light purple for allele 1, darker purple for alleles fim3 -2 and ptxP3 , light grey for other or undefined alleles). The scales indicate the number of SNPs per genome. Panel B focuses on the emerging ptxP3 -MRBP clade (349 isolates). Evolved SNPs shared by this clade at the black star location are detailed in the Supplementary Appendix, Table S2; the 23S rRNA mutation is indicated by a red star; a pertactin-inactivating mutation by a lightning symbol. The pertactin-negative subclade was introduced twice into France. The three introductions of MRBP into France are labelled as I1, I2 and I3 and highlighted by light grey horizontal bars (see Table S3 for details). Panel C presents the detailed trees of the three introductions of MRBP into France, and their geographic origins, as indicated in the map colored according to French administrative regions: orange for ‘Grand Est’ (GES), purple for ‘Ile de France’ (IDF), green for ‘Auvergne Rhône Alpes’ (ARA) and salmon for ‘Nouvelle Aquitaine’ (NAQ). Circles at branch tips are colored according to country (light blue: China; darker blue: France). The tree can be interactively visualized in Microreact ( https://microreact.org/project/5mvNLVqAoPoT2V6y2kUPFw-bp-cnr-china-all ). Phylogenetic analysis based on whole-genome single nucleotide polymorphisms ( Figure 1 ) revealed that the 14 MRBP belong, together with isolates from China, to a cluster of 349 MRBP isolates ( Figure 1B ; the ptxP3 -MRBP clade). However, they fall into three separate branches nested within the diversity of isolates from China, indicating three independent introductions of MRBP into France. Two of these branches comprised more than one isolate (branches I2 and I1, with 11 and 2 isolates, respectively; table S2), detected across several French administrative regions, suggesting forward transmission and spatial dissemination ( Figure 1C ). Eight mutations were found in isolates of the ptxP3 -MRBP clade and may have occurred in a common ancestor preceding this lineage’s expansion (see black star in Figure 1 ; Table 1 ). The first corresponds to the A2047G mutation within the 23S rRNA gene. Two others are observed within the prn gene (C531T, leading to allele 150) and within a putative toxin gene (T198M in gene BP1251). Two other non-synonymous SNPs are located in genes involved in regulatory functions: V67L in BP0983 coding for a transcriptional regulator controlling mexAB-oprM operon ( 16 ) and A165V in BP1924 coding for a TetR/AcrR transcriptional regulator. A further non-synonymous mutation (leading to L213P) is located in gene BP2754 coding for a penicillin-binding protein. The two remaining mutations were localised in hypothetical or miscellaneous proteins. View this table: View inline View popup Download powerpoint Table 1. Specific non-synonymous mutations observed in the ptxP3 -MRBP clade Regarding the screening of respiratory samples using the in-house qPCR protocol ( 17 ), out of 248 eligible samples based on ptxA qPCR Ct value, 3 (1.2%) were classified as MRBP. Culture attempts for these 3 samples were unsuccessful. Overall, combining isolates and respiratory samples, MRBP accounted for 2.8% (17/593) of the French 2024 tests. Discussion After four years (2020-2023) with low-level circulation of Bp , a large epidemic of whooping cough occurred in 2024 in France and other countries ( 1 ). Whereas a resurgence was expected, the emergence of MRBP was not. Only one MRBP isolate had been previously reported in France, in 2011 ( 18 ). Differently, in China, the first MRBP isolates were reported in 2011 in Shandong province, and increased in frequency in subsequent years, reaching more than 90% in some areas such as Shanghai ( 3 , 6 , 9 , 10 ). Whereas the first MRBP reported from China were characterised by a ptxP1 and fhaB3 genotype, those identified since 2016 are mostly of the ptxP3 and fhaB1 genotype ( 4 , 5 , 7 , 10 ), and before 2024 the expansion of this particularly fast-emerging MRBP genotype was documented exclusively in China. In France, most circulating MSBP isolates since the introduction of vaccination are ptxP3 and fhaB1 ( 1 , 12 , 13 , 19 ). The only MRBP isolate from France collected before 2024 (in 2011) was of genotype ptxP21 and fhaB1 . The emergence of ptxP3 and fhaB1 MRBP isolates in France in 2024 thus raised the question of their origin: have they been introduced in the country from China or elsewhere, or are they due to a local evolution from MSBP isolates in France? While our data suggest three direct introductions from China to France, cryptic transmission through intermediary unsampled countries cannot be excluded. More globally representative sampling and genomic analyses are needed to shed light on Bp global spread. Understanding the impact of global mobility versus local transmission on the emergence of MRBP is crucial for defining effective strategies to control macrolide-resistant pertussis. Although they emerged 15 years ago in China, MRBP are only emerging in France in 2024, despite disease activity in 2010-2019 ( 1 ). As MRBP initially emerged in China within the ptxP1 branch, we propose that this surprising 15-year delay might be due to the lower fitness of ptxP1 isolates in acellular vaccination countries, compared to ptxP3 isolates. The ptxP3 -MRBP clade emerged in China only around 2016 and became predominant after 2020 ( 4 , 6 ). Besides, the loss of PRN expression provides a further fitness gain, particularly in the fim3 -2 subbranch of ptxP3 ( 12 ). The dissemination in France of the ptxP 3, fim3 -2, PRN-negative MRBP genotype is consistent with its high predicted fitness. Such MRBP may therefore quickly emerge in other countries too. A first PRN-negative ptxP3 -MRBP was also reported in Finland in 2024 ( 20 ). The use of macrolides, and how it differs between countries, might be a factor favouring the transmission of this 23S rRNA A2047G-carrying genotype, relative to MSBP. Whether some of the 7 other mutations shared by these emerging MRBP isolates also contribute to an increased fitness remains to be defined. The rise of MRBP in France in 2024 is exceptional and concerning. Effective control of macrolide resistance will require novel diagnostics, enhanced surveillance and strict adherence to transmission control guidelines. Macrolides are the drug of choice for treating other respiratory pathogens including Mycoplasma pneumoniae, and macrolide resistance is also reported for this species ( 21 ). To slow the rise of MRBP, prudent use of macrolides to treat pertussis and other infections or to limit their spread should be recommended to avoid selective pressure favouring resistant isolates. Besides, defining effective alternative treatments, particularly for newborns, is essential for the clinical management of future macrolide-resistant cases. Data Availability Raw FASTQ data from French isolates are available in the European Nucleotide Archive (https://www.ebi.ac.uk/ena; Projects: PRJEB21744 and PRJEB42353). The qPCR protocol for detection of macrolide-resistant Bordetella pertudssis from clinical samples was posted on protocols.io at https://dx.doi.org/1017504/protocols.io.kqdg3q4y1v25/v1 https://dx.doi.org/1017504/protocols.io.kqdg3q4y1v25/v1 Author contributions CR and SB supervised the collection of isolates and data, with input from JT. VB and NL performed the genomic analyses, with input from CR and SB. VB, CR and SB wrote the manuscript, which was approved by all authors. Transparency declaration The authors declare that they have no conflicts of interest. Funding The National Reference Center for Whooping Cough and Other Bordetella Infections receives support from Institut Pasteur and Public Health France (Santé publique France, Saint Maurice, France). No specific funding was received for this study, as it was performed within the frame of the French national surveillance of whooping cough. The funders had no role in the writing or decision to submit the manuscript for publication. Acknowledgements We thank the Institut Pasteur’s Mutualized Platform for Microbiology (P2M) for genomic sequencing. We acknowledge support to the French whooping cough surveillance from colleagues of the REMICOQ network and Public Health France (Santé Publique France). Nathalie Armatys, Annie Landier and Julien Cordani are acknowledged for conducting the microbiological screening and characterization. Nora Zidane performed the ONT sequencing of MRBP strains. Footnotes ↵ * Co-supervised the work The version additionally includes a qPCR protocol for the detection of macrolide-resistant Bordetella pertussis isolates from clinical samples, as posted on protocols.io at https://dx.doi.org/1017504/protocols.io.kqdg3q4y1v25/v1 ; and is slightly extended with more discussion on the drivers of the epidemic surge. 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Euro Surveill . 2024 Dec ; 29 ( 49 ). 21. ↵ Xie P , Zhang Y , Qin Y , Fang Y , Yang N , Bai Y , et al. Macrolide resistance in Mycoplasma pneumoniae in adult patients . Front Cell Infect Microbiol . 2025 ; 15 : 1496521 . OpenUrl PubMed View the discussion thread. Back to top Previous Next Posted May 21, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Emergence of macrolide-resistant Bordetella pertussis in France, 2024: out of China Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. 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Share Emergence of macrolide-resistant Bordetella pertussis in France, 2024: out of China Valérie Bouchez , Noémie Lefrancq , Julie Toubiana , Carla Rodrigues , Sylvain Brisse medRxiv 2025.03.15.25324024; doi: https://doi.org/10.1101/2025.03.15.25324024 Share This Article: Copy Citation Tools Emergence of macrolide-resistant Bordetella pertussis in France, 2024: out of China Valérie Bouchez , Noémie Lefrancq , Julie Toubiana , Carla Rodrigues , Sylvain Brisse medRxiv 2025.03.15.25324024; doi: https://doi.org/10.1101/2025.03.15.25324024 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Infectious Diseases (except HIV/AIDS) Subject Areas All Articles Addiction Medicine (567) Allergy and Immunology (863) Anesthesia (297) Cardiovascular Medicine (4409) Dentistry and Oral Medicine (443) Dermatology (380) Emergency Medicine (606) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1505) Epidemiology (15203) Forensic Medicine (30) Gastroenterology (1119) Genetic and Genomic Medicine (6571) Geriatric Medicine (666) Health Economics (994) Health Informatics (4510) Health Policy (1365) Health Systems and Quality Improvement (1608) Hematology (537) HIV/AIDS (1263) Infectious Diseases (except HIV/AIDS) (15902) Intensive Care and Critical Care Medicine (1103) Medical Education (620) Medical Ethics (144) Nephrology (665) Neurology (6573) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1139) Occupational and Environmental Health (954) Oncology (3319) Ophthalmology (967) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (662) Pediatrics (1689) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5421) Public and Global Health (9205) Radiology and Imaging (2190) Rehabilitation Medicine and Physical Therapy (1367) Respiratory Medicine (1191) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fe75ca6594bdf88',t:'MTc3OTIzODM4MA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();