{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T01:25:14Z","timestamp":1767144314465,"version":"build-2238731810"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drugs R D"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hematological and clinical chemistry measurements are an integral part of vaccine safety monitoring. While adopting a conservative approach is important to exclude potential risks for patients, the rationale and methodology underlying the assessment of given adverse events have to be well grounded to avoid raising unfounded concerns. Using asymptomatic transient neutropenia as an example, this paper aims to address the complexity of interpreting abnormal hematological values in vaccine clinical trials and to evaluate the validity of using neutrophil count cut-off points to assess neutropenia in the context of safety monitoring. The validity of the neutrophil count cut-off point methodology was assessed in terms of content validity (i.e., the extent to which a single neutrophil count below the cut-off point corresponds to a clinically significant adverse event), criterion validity (i.e., the extent to which a neutrophil count below a given cut-off point correlates with another manifestation of neutropenia, namely bacteremia), and construct validity (i.e., the exactness of the assumption that a neutrophil count below a given cut-off point corresponds to a reactogenic event caused by the vaccination). We argue that, because of within-individual physiological fluctuations, variations according to population demographics, and poor predictive potential with regard to neutropenia-associated infection, the application of the cut-off point methodology to neutropenia safety monitoring presents major limitations. Based on this assessment, we conclude that hematological laboratory values must be evaluated on a case-by-case basis by investigators to determine their clinical significance.<\/jats:p>","DOI":"10.1007\/s40268-021-00370-3","type":"journal-article","created":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T10:02:28Z","timestamp":1639821748000},"page":"1-8","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Pitfalls of Abnormal Laboratory Value Interpretation in Vaccine Clinical Trials: The Example of Asymptomatic Transient Neutropenia"],"prefix":"10.1007","volume":"22","author":[{"given":"Venanzio","family":"Vella","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes E.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia Luna","family":"Cilio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3044-1117","authenticated-orcid":false,"given":"Iris","family":"De Ryck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audino","family":"Podda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0416-952X","authenticated-orcid":false,"given":"Valentino","family":"Conti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Auerbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,12,18]]},"reference":[{"key":"370_CR1","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1084\/jem.20122220","volume":"210","author":"A Mocsai","year":"2013","unstructured":"Mocsai A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med. 2013;210:1283\u201399. https:\/\/doi.org\/10.1084\/jem.20122220.","journal-title":"J Exp Med"},{"key":"370_CR2","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1093\/rheumatology\/keq045","volume":"49","author":"HL Wright","year":"2010","unstructured":"Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford). 2010;49:1618\u201331. https:\/\/doi.org\/10.1093\/rheumatology\/keq045.","journal-title":"Rheumatology (Oxford)"},{"key":"370_CR3","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.immuni.2010.11.011","volume":"33","author":"N Borregaard","year":"2010","unstructured":"Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33:657\u201370. https:\/\/doi.org\/10.1016\/j.immuni.2010.11.011.","journal-title":"Immunity"},{"key":"370_CR4","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1182\/blood-2010-01-259028","volume":"116","author":"J Pillay","year":"2010","unstructured":"Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, Borghans JAM, et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116:625\u20137. https:\/\/doi.org\/10.1182\/blood-2010-01-259028.","journal-title":"Blood"},{"key":"370_CR5","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1189\/jlb.1112571","volume":"94","author":"T Tak","year":"2013","unstructured":"Tak T, Tesselaar K, Pillay J, Borghans JAM, Koenderman L. What\u2019s your age again? Determination of human neutrophil half-lives revisited. J Leukoc Biol. 2013;94:595\u2013601. https:\/\/doi.org\/10.1189\/jlb.1112571.","journal-title":"J Leukoc Biol"},{"key":"370_CR6","unstructured":"BMJ Best Practice. Assessment of neutropenia. 2020. https:\/\/bestpractice.bmj.com\/topics\/en-gb\/893. Accessed 8 Oct 2021."},{"key":"370_CR7","doi-asserted-by":"publisher","first-page":"e0157385","DOI":"10.1371\/journal.pone.0157385","volume":"11","author":"V Muturi-Kioi","year":"2016","unstructured":"Muturi-Kioi V, Lewis D, Launay O, Leroux-Roels G, Anemona A, Loulergue P, et al. Neutropenia as an adverse event following vaccination: results from randomized clinical trials in healthy adults and systematic review. PLoS ONE. 2016;11:e0157385. https:\/\/doi.org\/10.1371\/journal.pone.0157385.","journal-title":"PLoS ONE"},{"key":"370_CR8","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.cegh.2015.12.001","volume":"4","author":"R Kumar","year":"2016","unstructured":"Kumar R. Evaluation of diagnostic tests. Clin Epidemiol Glob Health. 2016;4:76\u20139. https:\/\/doi.org\/10.1016\/j.cegh.2015.12.001.","journal-title":"Clin Epidemiol Glob Health."},{"key":"370_CR9","unstructured":"US Food and Drug Administration. Guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 2007. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical. Accessed 8 Oct 2021."},{"key":"370_CR10","doi-asserted-by":"publisher","first-page":"486","DOI":"10.7326\/0003-4819-146-7-200704030-00004","volume":"146","author":"MM Hsieh","year":"2007","unstructured":"Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. 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AP, IDR, JA, JES, and VV hold shares in the GSK group of companies. JA reports grants from the Gates Foundation and Welcome Trust during the conduct of this work. The authors have no non-financial conflicts of interests to declare.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}},{"value":"Not applicable.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"JES, IDR, AP, JA, VC, VV, and GLC proposed the research question. JES, IDR, AP, JA, VC, and VV participated in the collection of the research data. JES, AP, VC, and VV performed the methodology review. JES, IDR, AP, JA, VC, and GLC interpreted the results. All authors contributed to the development of the manuscript and approved the final version.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author contributions"}}]}}