{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:02:41Z","timestamp":1791590561385,"version":"4.3.4"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Plasma Protein Therapeutics Association"},{"DOI":"10.13039\/100007723","name":"Takeda Pharmaceuticals U.S.A.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007723","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients <jats:italic>without<\/jats:italic> an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and analysis<\/jats:title>\n<jats:p>We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for \u2018unclassified antibody deficiency\u2019, \u2018deficiency of specific IgG\u2019, \u2018IgA with IgG subclass deficiency\u2019, \u2018isolated IgG subclass deficiency\u2019, \u2018selective IgM deficiency\u2019, \u2018selective IgA deficiency\u2019 or \u2018common variable immunodeficiency\u2019 will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0266083","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T17:35:59Z","timestamp":1648229759000},"page":"e0266083","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Protocol for the unclassified primary antibody deficiency (unPAD) study: Characterization and classification of patients using the ESID online Registry"],"prefix":"10.1371","volume":"17","author":[{"given":"Lisanne M. A.","family":"Janssen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ineke C. G. M.","family":"Reijnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Milito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Edgar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Chapel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-3550","authenticated-orcid":true,"given":"Esther","family":"de Vries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the unPAD consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"issue":"1","key":"pone.0266083.ref001","first-page":"108","article-title":"Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update","volume":"167","author":"E. de Vries","year":"2012","journal-title":"Clin Exp Immunol"},{"issue":"Suppl:3","key":"pone.0266083.ref002","first-page":"11","article-title":"The European internet-based patient and research database for primary immunodeficiencies: results 2006\u20132008.","volume":"157","author":"B Gathmann","year":"2009","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"pone.0266083.ref003","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s10875-020-00758-x","article-title":"Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification","volume":"40","author":"A Bousfiha","year":"2020","journal-title":"J Clin Immunol"},{"issue":"1","key":"pone.0266083.ref004","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s10875-019-00737-x","article-title":"Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.","volume":"40","author":"SG Tangye","year":"2020","journal-title":"J Clin Immunol"},{"key":"pone.0266083.ref005","article-title":"Patient-centred screening for primary immunodeficiency: A multi-stage diagnostic protocol designed for non-immunologists","author":"E. De Vries","year":"2006","journal-title":"Clin Exp Immunol"},{"key":"pone.0266083.ref006","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1477-7525-3-31","article-title":"Coping, quality of life, and hope in adults with primary antibody deficiencies.","volume":"3","author":"HMH Sigstad","year":"2005","journal-title":"Health Qual Life Outcomes"},{"issue":"7","key":"pone.0266083.ref007","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1007\/s10875-014-0072-x","article-title":"Quality of life in children with primary antibody deficiency","volume":"34","author":"P Titman","year":"2014","journal-title":"J Clin Immunol"},{"issue":"5","key":"pone.0266083.ref008","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10875-017-0404-8","article-title":"Health-Related Quality of Life in Adult Patients with Common Variable Immunodeficiency Disorders and Impact of Treatment","volume":"37","author":"NL Rider","year":"2017","journal-title":"J Clin Immunol"},{"issue":"1","key":"pone.0266083.ref009","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s10875-017-0464-9","article-title":"International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity","volume":"38","author":"C Picard","year":"2018","journal-title":"J Clin Immunol"},{"issue":"1","key":"pone.0266083.ref010","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jaip.2015.07.025","article-title":"International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J allergy","volume":"4","author":"FA Bonilla","year":"2016","journal-title":"Clin Immunol Pract"},{"issue":"6","key":"pone.0266083.ref011","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/j.1365-2141.2009.07669.x","article-title":"Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.","volume":"145","author":"H Chapel","year":"2009","journal-title":"Br J Haematol"},{"issue":"1","key":"pone.0266083.ref012","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12016-019-08765-6","article-title":"Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID).","volume":"59","author":"R Ameratunga","year":"2020","journal-title":"Clin Rev Allergy Immunol"},{"issue":"6","key":"pone.0266083.ref013","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1016\/j.jaip.2019.02.004","article-title":"The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity.","volume":"7","author":"MG Seidel","year":"2019","journal-title":"J allergy Clin Immunol Pract"},{"key":"pone.0266083.ref014","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.3389\/fimmu.2018.02384","article-title":"Mild Hypogammaglobulinemia Can Be a Serious Condition.","volume":"9","author":"LMA Janssen","year":"2018","journal-title":"Front Immunol."},{"issue":"5","key":"pone.0266083.ref015","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/bioinformatics\/btl675","article-title":"The ESID Online Database network","volume":"23","author":"D Guzman","year":"2007","journal-title":"Bioinformatics"},{"issue":"1","key":"pone.0266083.ref016","first-page":"47","article-title":"Health-related quality of life in primary antibody deficiency","volume":"10","author":"A Aghamohammadi","year":"2011","journal-title":"Iran J Allergy Asthma Immunol"},{"issue":"2","key":"pone.0266083.ref017","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s11136-013-0491-9","article-title":"Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL.","volume":"23","author":"GH Jorgensen","year":"2014","journal-title":"Qual Life Res"},{"issue":"3","key":"pone.0266083.ref018","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3349\/ymj.2012.53.3.603","article-title":"Health related quality of life in common variable immunodeficiency.","volume":"53","author":"I Quinti","year":"2012","journal-title":"Yonsei Med J"},{"key":"pone.0266083.ref019","unstructured":"Registry Working Party Informed Patient Consent [Internet]. Available from: https:\/\/esid.org\/Working-Parties\/Registry-Working-Party\/Informed-Patient-Consent."},{"issue":"2","key":"pone.0266083.ref020","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1111\/j.1365-2249.2006.03292.x","article-title":"The European internet-based patient and research database for primary immunodeficiencies: results 2004\u201306","volume":"147","author":"A-M Eades-Perner","year":"2007","journal-title":"Clin Exp Immunol"},{"issue":"5","key":"pone.0266083.ref021","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1182\/blood.V99.5.1544","article-title":"Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease.","volume":"99","author":"K Warnatz","year":"2002","journal-title":"Blood"},{"issue":"5","key":"pone.0266083.ref022","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1023\/A:1025373601374","article-title":"Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects","volume":"23","author":"B Piqueras","year":"2003","journal-title":"J Clin Immunol"},{"issue":"1","key":"pone.0266083.ref023","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1182\/blood-2007-06-091744","article-title":"The EUROclass trial: defining subgroups in common variable immunodeficiency","volume":"111","author":"C Wehr","year":"2008","journal-title":"Blood"},{"key":"pone.0266083.ref024","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1471-2172-15-13","article-title":"T-cell activation discriminates subclasses of symptomatic primary humoral immunodeficiency diseases in adults","volume":"15","author":"M-Q Picat","year":"2014","journal-title":"BMC Immunol"},{"issue":"1","key":"pone.0266083.ref025","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jaci.2014.06.022","article-title":"Classification of common variable immunodeficiencies using flow cytometry and a memory B-cell functionality assay.","volume":"135","author":"AL R\u00f6sel","year":"2015","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"pone.0266083.ref026","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1182\/blood-2007-11-124545","article-title":"Common variable immunodeficiency disorders: division into distinct clinical phenotypes","volume":"112","author":"H Chapel","year":"2008","journal-title":"Blood"},{"issue":"10","key":"pone.0266083.ref027","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.3324\/haematol.2013.085076","article-title":"Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum.","volume":"98","author":"GJ Driessen","year":"2013","journal-title":"Haematologica"},{"key":"pone.0266083.ref028","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1399-3038.2010.01085.x","article-title":"Clinical complications in pediatric CVID are not restricted to patients with severely reduced class-switched memory B cells.","volume":"22","author":"AAJM van de Ven","year":"2011","journal-title":"Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology. England"},{"issue":"4","key":"pone.0266083.ref029","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.jaip.2018.12.004","article-title":"Differentiation of Common Variable Immunodeficiency From IgG Deficiency","volume":"7","author":"CA Filion","year":"2019","journal-title":"J allergy Clin Immunol Pract"},{"issue":"7","key":"pone.0266083.ref030","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/j.1399-3038.2008.00845.x","article-title":"The outcome of patients with unclassified hypogammaglobulinemia in early childhood","volume":"20","author":"N Kutukculer","year":"2009","journal-title":"Pediatr Allergy Immunol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0266083","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T17:36:33Z","timestamp":1648229793000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0266083"}},"subtitle":[],"editor":[{"given":"Elsayed","family":"Abdelkreem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0266083","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}