{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T11:01:07Z","timestamp":1771844467298,"version":"3.50.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2019,8,11]],"date-time":"2019-08-11T00:00:00Z","timestamp":1565481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R01AI116596-01"],"award-info":[{"award-number":["1R01AI116596-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32 DK 07760"],"award-info":[{"award-number":["T32 DK 07760"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["T32 DK 07760"],"award-info":[{"award-number":["T32 DK 07760"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Most Clostridioides difficile toxinogenic strains produce both toxins A and B (A+B+), but toxin A\u2013negative, toxin B\u2013positive (A\u2212B+) variants also cause disease. We report the identification of a series of pathogenic clinical C. difficile isolates that produce high amounts of toxin A with low or nondetectable toxin B.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>An ultrasensitive, quantitative immunoassay was used to measure toxins A and B in stool samples from 187 C. difficile infection (CDI) patients and 44 carriers. Isolates were cultured and assessed for in vitro toxin production and in vivo phenotypes (mouse CDI model).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>There were 7 CDI patients and 6 carriers who had stools with detectable toxin A (TcdA, range 23\u201317 422 pg\/mL; 5.6% of samples overall) but toxin B (TcdB) below the clinical detection limit (&amp;lt;20 pg\/mL; median TcdA:B ratio 17.93). Concentrations of toxin A far exceeded B in in vitro cultures of all 12 recovered isolates (median TcdA:B ratio 26). Of 8 toxin A&amp;gt;&amp;gt;B isolates tested in mice, 4 caused diarrhea, and 3 of those 4 caused lethal disease. Ribotyping demonstrated strain diversity. TcdA-predominant samples were also identified at 2 other centers, with similar frequencies (7.5% and 6.8%).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We report the discovery of clinical pathogenic C. difficile strains that produce high levels of toxin A but minimal or no toxin B. This pattern of toxin production is not rare (&amp;gt;5% of isolates) and is consistently observed in vitro and in vivo in humans and mice. Our study highlights the significance of toxin A in human CDI pathogenesis and has important implications for CDI diagnosis, treatment, and vaccine development.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciz727","type":"journal-article","created":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T19:09:51Z","timestamp":1564513791000},"page":"2628-2633","source":"Crossref","is-referenced-by-count":15,"title":["Toxin A\u2013Predominant Pathogenic Clostridioides difficile: A Novel Clinical Phenotype"],"prefix":"10.1093","volume":"70","author":[{"given":"Qianyun","family":"Lin","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China"},{"name":"Divisions of Gastroenterology, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nira R","family":"Pollock","sequence":"first","affiliation":[{"name":"Infectious Diseases, Beth Israel Deaconess Medical Center, Massachusetts"},{"name":"Department of Laboratory Medicine, Boston Children\u2019s Hospital, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Banz","sequence":"first","affiliation":[{"name":"bioMerieux, Marcy L\u2019Etoile, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aude","family":"Lantz","sequence":"first","affiliation":[{"name":"bioMerieux, Marcy L\u2019Etoile, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Xu","sequence":"first","affiliation":[{"name":"Divisions of Gastroenterology, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limei","family":"Gu","sequence":"first","affiliation":[{"name":"Divisions of Gastroenterology, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale N","family":"Gerding","sequence":"first","affiliation":[{"name":"Department of Veterans Affairs, Edward Hines Jr Veterans Affairs Hospital, Hines, Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin W","family":"Garey","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne J","family":"Gonzales-Luna","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingwei","family":"Zhao","sequence":"first","affiliation":[{"name":"Quanterix, Billerica, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linan","family":"Song","sequence":"first","affiliation":[{"name":"Quanterix, Billerica, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C","family":"Duffy","sequence":"first","affiliation":[{"name":"Quanterix, Billerica, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciaran P","family":"Kelly","sequence":"first","affiliation":[{"name":"Divisions of Gastroenterology, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinhua","family":"Chen","sequence":"first","affiliation":[{"name":"Divisions of Gastroenterology, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,8,11]]},"reference":[{"key":"2020061010550737200_CIT0001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5009\/gnl.2014.8.1.1","article-title":"Clostridium difficile infection: a worldwide disease","volume":"8","author":"Burke","year":"2014","journal-title":"Gut Liver"},{"key":"2020061010550737200_CIT0002","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1056\/NEJMra1403772","article-title":"Clostridium difficile infection","volume":"372","author":"Leffler","year":"2015","journal-title":"N Engl J Med"},{"key":"2020061010550737200_CIT0003","doi-asserted-by":"crossref","first-page":"252","DOI":"10.4161\/gmic.2.4.16109","article-title":"Both toxin A and toxin B are important in Clostridium difficile infection","volume":"2","author":"Kuehne","year":"2011","journal-title":"Gut Microbes"},{"key":"2020061010550737200_CIT0004","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1128\/IAI.60.10.4192-4199.1992","article-title":"Molecular, immunological, and biological characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile","volume":"60","author":"Borriello","year":"1992","journal-title":"Infect Immun"},{"key":"2020061010550737200_CIT0005","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ijid.2006.04.003","article-title":"Toxin A-negative, toxin B-positive Clostridium difficile","volume":"11","author":"Drudy","year":"2007","journal-title":"Int J Infect Dis"},{"key":"2020061010550737200_CIT0006","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1128\/CMR.00082-09","article-title":"The changing epidemiology of Clostridium difficile infections","volume":"23","author":"Freeman","year":"2010","journal-title":"Clin Microbiol Rev"},{"key":"2020061010550737200_CIT0007","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/nature09397","article-title":"The role of toxin A and toxin B in Clostridium difficile infection","volume":"467","author":"Kuehne","year":"2010","journal-title":"Nature"},{"key":"2020061010550737200_CIT0008","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1086\/516324","article-title":"Isolation of a toxin B-deficient mutant strain of Clostridium difficile in a case of recurrent C. difficile-associated diarrhea","volume":"26","author":"Cohen","year":"1998","journal-title":"Clin Infect Dis"},{"key":"2020061010550737200_CIT0009","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1086\/315248","article-title":"Analysis of the pathogenicity locus in Clostridium difficile strains","volume":"181","author":"Cohen","year":"2000","journal-title":"J Infect Dis"},{"key":"2020061010550737200_CIT0010","doi-asserted-by":"crossref","first-page":"15023","DOI":"10.1038\/srep15023","article-title":"Clostridium difficile: new insights into the evolution of the pathogenicity locus","volume":"5","author":"Monot","year":"2015","journal-title":"Sci Rep"},{"key":"2020061010550737200_CIT0011","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1128\/JCM.01334-15","article-title":"Development and validation of digital ELISAs for ultrasensitive detection and quantification of C. difficile toxins in stool","volume":"53(10)","author":"Song","year":"2015","journal-title":"J Clin Microbiol"},{"key":"2020061010550737200_CIT0012","first-page":"78","article-title":"Comparison of C. difficile stool toxin concentrations in adults with symptomatic infection and asymptomatic carriage using an ultrasensitive quantitative immunoassay","volume":"68","author":"Pollock","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2020061010550737200_CIT0013","first-page":"29761","article-title":"Clostridium difficile infection worsen outcome of hospitalized patients with inflammatory bowel disease","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci Rep"},{"key":"2020061010550737200_CIT0014","doi-asserted-by":"crossref","first-page":"5480","DOI":"10.1128\/IAI.68.10.5480-5487.2000","article-title":"Toxin gene analysis of a variant strain of Clostridium difficile that causes human clinical disease","volume":"68","author":"Sambol","year":"2000","journal-title":"Infect Immun"},{"key":"2020061010550737200_CIT0015","doi-asserted-by":"crossref","first-page":"5710","DOI":"10.1128\/JCM.42.12.5710-5714.2004","article-title":"Multiplex PCR targeting tpi (triose phosphate isomerase), tcdA (Toxin A), and tcdB (Toxin B) genes for toxigenic culture of Clostridium difficile","volume":"42","author":"Lemee","year":"2004","journal-title":"J Clin Microbiol"},{"key":"2020061010550737200_CIT0016","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1093\/clinids\/13.6.1053","article-title":"Use of the polymerase chain reaction for the specific and direct detection of Clostridium difficile in human feces","volume":"13","author":"Gumerlock","year":"1991","journal-title":"Rev Infect Dis"},{"key":"2020061010550737200_CIT0017","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1053\/j.gastro.2008.09.002","article-title":"A mouse model of Clostridium difficile-associated disease","volume":"135","author":"Chen","year":"2008","journal-title":"Gastroenterology"},{"key":"2020061010550737200_CIT0018","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.anaerobe.2014.03.002","article-title":"Investigation of potentially pathogenic Clostridium difficile contamination in household environs","volume":"27","author":"Alam","year":"2014","journal-title":"Anaerobe"},{"key":"2020061010550737200_CIT0019","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1128\/JCM.03591-14","article-title":"Evaluation of portability and cost of a fluorescent PCR ribotyping protocol for Clostridium difficile epidemiology","volume":"53","author":"Martinson","year":"2015","journal-title":"J Clin Microbiol"},{"key":"2020061010550737200_CIT0020","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1128\/CMR.18.2.247-263.2005","article-title":"Clostridium difficile toxins: mechanism of action and role in disease","volume":"18","author":"Voth","year":"2005","journal-title":"Clin Microbiol Rev"},{"key":"2020061010550737200_CIT0021","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/infdis\/jit426","article-title":"Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain","volume":"209","author":"Kuehne","year":"2014","journal-title":"J Infect Dis"},{"key":"2020061010550737200_CIT0022","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1128\/IAI.47.2.349-352.1985","article-title":"Effects of Clostridium difficile toxins given intragastrically to animals","volume":"47","author":"Lyerly","year":"1985","journal-title":"Infect Immun"},{"key":"2020061010550737200_CIT0023","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/nature07822","article-title":"Toxin B is essential for virulence of Clostridium difficile","volume":"458","author":"Lyras","year":"2009","journal-title":"Nature"},{"key":"2020061010550737200_CIT0024","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1128\/JCM.03419-14","article-title":"Differential immunodetection of toxin B from highly virulent Clostridium difficile BI\/NAP-1\/027","volume":"53","author":"Pollock","year":"2015","journal-title":"J Clin Microbiol"},{"key":"2020061010550737200_CIT0025","doi-asserted-by":"crossref","first-page":"S327","DOI":"10.1093\/ofid\/ofy210.928","article-title":"1093. Single molecule counting technology for ultrasensitive quantification of Clostridium difficile toxins A and B","volume":"5","author":"Katzenbach","year":"2018","journal-title":"Open Forum Infect Dis"},{"key":"2020061010550737200_CIT0026","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/femsre\/fux048","article-title":"The role of toxins in Clostridium difficile infection","volume":"41","author":"Chandrasekaran","year":"2017","journal-title":"FEMS Microbiol Rev"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciz727\/30042313\/ciz727.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/70\/12\/2628\/33375560\/ciz727.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/70\/12\/2628\/33375560\/ciz727.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,6,10]],"date-time":"2020-06-10T17:28:02Z","timestamp":1591810082000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/70\/12\/2628\/5545999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,11]]},"references-count":26,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,8,11]]},"published-print":{"date-parts":[[2020,6,10]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciz727","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6,15]]},"published":{"date-parts":[[2019,8,11]]}}}