{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:27:02Z","timestamp":1786685222229,"version":"build-2736575974"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.26070.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000}},{"DOI":"10.12688\/wellcomeopenres.26070.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000}}],"reference-count":119,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["225868"],"award-info":[{"award-number":["225868"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Philantropy"},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Science","award":["2024-I2M-2\u2013001\u20131"],"award-info":[{"award-number":["2024-I2M-2\u2013001\u20131"]}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns5:p>\n                    Background Methodological advances in serological testing have made it feasible to quantify antibodies to multiple pathogens simultaneously. This has been used to study the impact of pathogen burden, i.e., cumulative lifetime exposure to persistent pathogens, on health and mortality outcomes. However, definitions for pathogen burden using serological data vary considerably. It is unclear how to best combine serological data for multiple pathogens for exposure\/outcome definitions in epidemiological studies. Methods Following PRISMA-ScR guidelines, we conducted a scoping review of all relevant publications from MEDLINE, Embase, and Scopus until May 1\n                    <ns5:sup>st<\/ns5:sup>\n                    , 2025, with no language restrictions. We identified epidemiological studies defining pathogen burden, and which included at least three different pathogens. Results We included a total of 74 studies from 19 countries (published 2000\u20132025). Serology data from 50 different pathogens were analysed across all studies, with pathogen burden measured by combining a range of 3\u201317 pathogens across studies into a single metric. Approaches included counts of seropositive result, quantiles of antibody titres, and more complex statistical analyses to group pathogens. No study gave a clinical\/scientific rationale for the approaches chosen. Conclusions Various analytical approaches have been used to define pathogen burden but there was limited justification for the chosen methodological approaches. More integrated approaches are needed for combining scientific and clinical knowledge of the interaction across different pathogens and epidemiological evidence into a meaningful measure of pathogen burden.\n                  <\/ns5:p>","DOI":"10.12688\/wellcomeopenres.26070.3","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T05:39:05Z","timestamp":1783748345000},"page":"192","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sero-epidemiological studies of pathogen burden: A scoping review"],"prefix":"10.12688","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9021-0487","authenticated-orcid":false,"given":"Anne","family":"Suffel","sequence":"first","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology London England London School of Hygiene & Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Turton","sequence":"additional","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology London England London School of Hygiene & Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryin E","family":"Mansfield","sequence":"additional","affiliation":[{"name":"School of Health and Care Sciences Lincoln England University of Lincoln"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-2209","authenticated-orcid":false,"given":"Alexander J","family":"Mentzer","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics Oxford England University of Oxford"},{"name":"Chinese Academy of Medical Science (CAMS) Oxford Institute (COI) Oxford England University of Oxford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1938-5038","authenticated-orcid":false,"given":"Naomi E","family":"Allen","sequence":"additional","affiliation":[{"name":"Nuffield Department of Population Health Oxford England University of Oxford"},{"name":"Stockport England UK Biobank"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2726-6955","authenticated-orcid":false,"given":"Aisha","family":"Babi","sequence":"additional","affiliation":[{"name":"Heidelberg Baden-W\u00fcrttemberg German Cancer Research Center"},{"name":"Faculty of Biosciences Heidelberg Baden-W\u00fcrttemberg Universitat Heidelberg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8304-4302","authenticated-orcid":false,"given":"David","family":"Burgner","sequence":"additional","affiliation":[{"name":"Royal Children\u2019s Hospital Parkville Victoria Murdoch Children's Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Waterboer","sequence":"additional","affiliation":[{"name":"Heidelberg Baden-W\u00fcrttemberg German Cancer Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4524-3180","authenticated-orcid":false,"given":"Charlotte","family":"Warren-Gash","sequence":"additional","affiliation":[{"name":"Department of Non-Communicable Disease Epidemiology London England London School of Hygiene & Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11070732","article-title":"Serology as a Tool to Assess Infectious Disease Landscapes and Guide Public Health Policy.","volume":"11","author":"A Haselbeck","year":"2022","journal-title":"Pathogens."},{"key":"ref2","article-title":"Comprehensive serological profiling of human populations using a synthetic human virome.","volume":"348","author":"G Xu","year":"2015","journal-title":"Science (1979)."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1155-1162","DOI":"10.1016\/j.tim.2024.12.006","article-title":"Strengthening serological studies: the need for greater geographical diversity, biobanking, and data-accessibility.","volume":"33","author":"A Menezes","year":"2025","journal-title":"Trends Microbiol."},{"key":"ref4","doi-asserted-by":"crossref","first-page":"84-90","DOI":"10.2174\/187152610790963519","article-title":"Infectious burden: A new risk factor and treatment target for atherosclerosis.","volume":"10","author":"M Elkind","year":"2010","journal-title":"Infect. 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Cardiol."},{"key":"ref24","first-page":"45-51","article-title":"Prospective study of pathogen burden and risk of myocardial infarction or death.","volume":"103","author":"J Zhu","year":"2001","journal-title":"Circulation."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"317-321","DOI":"10.1016\/j.amjcard.2004.09.026","article-title":"Relation of depressive symptoms to C-reactive protein and pathogen burden (cytomegalovirus, herpes simplex virus, Epstein-Barr virus) in patients with earlier acute coronary syndromes.","volume":"95","author":"G Miller","year":"2005","journal-title":"Am. J. Cardiol."},{"key":"ref26","doi-asserted-by":"crossref","first-page":"747-751","DOI":"10.2459\/JCM.0b013e32832cacab","article-title":"Individual pathogens, pathogen burden and markers of subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.","volume":"10","author":"M Szklo","year":"2009","journal-title":"J. Cardiovasc. Med. 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Genet."},{"key":"ref36","doi-asserted-by":"crossref","DOI":"10.1161\/str.45.suppl_1.107","article-title":"Infectious burden and cognitive performance: The northern Manhattan study.","volume":"45","author":"C Wright","year":"2014","journal-title":"Stroke."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"161-168","DOI":"10.1016\/j.bbi.2015.10.014","article-title":"Infectious disease burden and cognitive function in young to middle-aged adults.","volume":"52","author":"S Gale","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref38","doi-asserted-by":"crossref","first-page":"3076-3084","DOI":"10.1017\/S0950268817001881","article-title":"The impact of pathogen burden on leukocyte telomere length in the Multi-Ethnic Study of Atherosclerosis.","volume":"145","author":"A Aiello","year":"2017","journal-title":"Epidemiol. 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Commun."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:34:28Z","timestamp":1786682068000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,11]]},"references-count":119,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.26070.3","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.26070.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/wellcomeopenres.26070.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.29880.r160644","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.29880.r161004","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.29880.r161004","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.29880.r160644","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,11]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.28710.r151934, Gary Lin, Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland, 05 May 2026, version 1, 2 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v1#referee-response-151934","order":0,"name":"referee-response-151934","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Anne Suffel<\/b>; \n<i>Posted: 18 May 2026<\/i>; \n<b>Comment 1:<\/b>&nbsp;The study selection process appears rigorous, but I would like to see more documentation of the process itself. For example, was there documentation of disagreement among reviewers regarding inclusion, or a PRISMA-ScR checklist associated with this study (See https:\/\/www.prisma-statement.org\/scoping)? \n<b>Authors' response:<\/b> In addition to the PRISMA flow chart, we have now added a completed PRISMA-ScR checklist in the supplementary information. &nbsp;  \n<b>Comment 2:<\/b> Not really clear on what the section \u201cDefinitions of pathogen burden\u201d on page 7 is contributing. It seems there should be a table of potential or already-defined definitions. \n<b>Authors' response<\/b>: The section \u201cother pathogen burden definitions\u201d summarises statistical approaches by various studies which go beyond scores based on pathogen counts or categorisations based on antibody titre. &nbsp; We believe this section is necessary to better describe more complex approaches such as weighted regression indices or latent class analysis which don\u2019t fit into the other categories, i.e., counting the number of seropositive pathogens or counts based on antibody titres. Table 1 summarises all included studies ordered by different approaches taken, e.g., Studies with pathogen index as count, Studies using a count as pathogen burden and titres, other approaches for pathogen burden. &nbsp;  \n<b>Comment 3:<\/b> Was there an assessment of study methodologies to measure serology? Will test accuracy be an issue for studies trying to understand pathogen burden? \n<b>Authors' response:<\/b> We did not critically assess the methodologies to measure serology as the focus of this study was to identify how pathogen burden has been defined in epidemiological research studies. Scoping reviews do not typically assess risk of bias formally as they aim to map the evidence rather than to provide a definitive answer to a research question (Munn et al. (2018)). &nbsp;Nevertheless, we agree that test accuracy is an important consideration for future studies and systematic reviews of studies of pathogen burden. We have added the following text to the discussion to highlight this issue: \u201cWe did not assess risk of bias in the included studies as the main interest of this review was to assess the scope of methods used to conceptualise pathogen burden rather than to assess the quality of the epidemiological research. \n<i>The quality of serological assays evolves over time; and sensitivity and specificity vary by the assays used. Test accuracy should be considered in future epidemiological studies using pathogen burden and when critically appraising the findings of such studies in systematic reviews<\/i>.\u201d &nbsp; Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol. 2018 Nov 19;18(1):143. doi: 10.1186\/s12874-018-0611-x. PMID: 30453902; PMCID: PMC6245623. &nbsp;  \n<b>Comment 4:<\/b> In the \u201cRationale behind pathogen scores\u201d section, what was the rationale exactly? I\u2019m not sure I can trace where each study lists its rationale. I would like to see more critical appraisal of the study rationale. Examples would be good in this section. \n<b>Authors' response:<\/b> We agree with the reviewer that a more detailed description and critical appraisal for the rational of defining pathogen burden would be crucial. However, none of the included studies provided a scientific rationale for the approaches taken and neither was this available in the review paper they referred to. The cited review paper states the following: \u201c\n<i>There is at present no standard definition of infectious burden. There is no consensus as to which organisms or clinical infections should be considered, or whether optimal measures should be based on serological evidence of past exposure, or on a history of past exposures derived from questionnaires, or from independent sources of information, such as chart review or administrative databases.\u201d <\/i>From: Elkind MS. Infectious burden: a new risk factor and treatment target for atherosclerosis. Infect Disord Drug Targets. 2010 Apr;10(2):84-90. doi: 10.2174\/187152610790963519. PMID: 20166973; PMCID: PMC2891124. Hence, we concluded that referencing the Elkind review from 2010 is not sufficient justification for any of the approaches taken. &nbsp;  \n<b>Comment 5: <\/b>The discussion could be strengthened by more clearly outlining how the findings inform clinical or public health practice, especially changes to health surveillance that could improve understanding of pathogen burden. \n<b>Authors' response:<\/b> We agree with the reviewer that research on the relationships between pathogen burden and other health outcomes could improve clinical practice and public health. We added the following sentence to the discussion: \u201cIdentifying specific patterns of pathogens and infection history in relation to other health outcomes can improve the prevention of both infectious diseases and associated long-term health outcomes. Enhanced surveillance of relevant pathogens, combining repeated serological assays with clinical data, may support risk assessment and guide vaccination and other preventive strategies. \u201c &nbsp;  \n<b>Comment 6:<\/b>&nbsp;Is there a justification for including studies with &gt;3 pathogens? Why were studies with two pathogens not included? \n<b>Author's response: <\/b>This paper aimed to provide an overview of definitions for pathogen burden arising from the challenge of testing several pathogens at the same time with multiplex assays. We selected \u22653 pathogens pragmatically to reflect more complex definitions. This is stated in the methods section: \u201cWe chose studies with at least three pathogens to capture studies with more complex exposure\/outcome definitions of multiple infections.\u201d","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3#referee-comment-6577","order":1,"name":"referee-comment-6577","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.29880.r160644, Timothy R Julian, Eawag Swiss Federal Institute of Aquatic Science and Technology, D\u00fcbendorf, Zurich, 21 Jul 2026, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3#referee-response-160644","order":2,"name":"referee-response-160644","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.29880.r161004, Andrea Haselbeck, The University of Edinburgh, Edinburgh, Scotland, 22 Jul 2026, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3#referee-response-161004","order":3,"name":"referee-response-161004","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Anne Suffel<\/b>; \n<i>Posted: 13 Aug 2026<\/i>; \n<b>Comment 1: <\/b> This scoping review, conducted according to PRISMA-ScR, characterises how epidemiological studies have combined serological data on three or more pathogens into a composite measure of &quot;pathogen burden.&quot; Searching MEDLINE, Embase and Scopus to 1 May 2025 without language restriction, the authors screened 3,561 records and included 74 studies published between 2000 and 2025, spanning 19 countries and 50 pathogens. This is a useful and well-motivated review addressing a real and under-recognised methodological problem. My only reservation would be that this review seems to focus on non-communicable disease, as mentioned briefly in the search strategy &quot;links between infections and NCDs. This should be acknowledge in title or in the background for clarity. \n<b>Author\u2019s response:<\/b> We added a sentence about the focus on NCDs in Version 3 of the manuscript which states the following: \u201cAn optimal definition of pathogen burden could improve studies investigating the links between infection history and non-communicable disease outcomes.\u201d We also stated this more explicitly in the aims of the study: \u201cWe aimed to summarise how definitions of the burden of serologically defined infections have been conceptualised and operationalised in seroepidemiological studies to inform future research using measures of pathogen burden \n<u>in relation to non-communicable diseases<\/u>.\u201d  \n<b>Comment 2:<\/b> A stratified presentation by pathogen (viral vs bacterial vs others) is done, but then not further followed through. I would be interested if definitions of pathogen burden are more aligned within one pathogen grouping as compared to just overall. \n<b>Author\u2019s response:<\/b> We included an additional paragraph differentiating between the types of pathogens included in the definition of pathogen count. \u201c\n<b><i>Pathogen burden by types of pathogens<\/i><\/b> The majority of studies included a mix of bacteria and viruses in their definition of pathogen burden independent of their approach how to define pathogen burden. Five studies using pathogen counts included viruses only (Jafarzadeh et al., 2011; Jonker et al., 2017; Karachaliou et al., 2018; Miller et al., 2014; Steptoe et al., 2007) and one study using counts included bacteria only (Ngeh &amp; Goodbourn, 2005). &nbsp;Out of the studies using a mixture of viruses, bacteria and other pathogens, six used a pathogen count (Alcantara-Neves et al., 2012; Janson et al., 2007; Lobzin et al., 2005; Pearce et al., 2018; Rubicz et al., 2015; van der Ven et al., 2003), five used the titers of pathogens for their index (Beydoun et al., 2023; Green et al., 2024; Lu et al., 2021, 2022; Shi et al., 2024) and five studies used other statistical methods (Gale et al., 2016; Hedges et al., 2017; Sealy-Jefferson et al., 2013; Stebbins et al., 2019; Zeng et al., 2025).\u201d  \n<b>Comment 3:<\/b> Has it been considered to distinguish between pathogens for which seropositivity is a lifetime marker versus for which it vanishes? There is no mention of this in methods or the paragraph on use of antibody levels in the results. \n<b>Author\u2019s response:<\/b> The primary focus of this review was to understand different methodological approaches taken to define pathogen burden in epidemiological research. We agree that it would be interesting to distinguish between pathogens with serological lifetime markers versus those with waning antibody levels. To differentiate between pathogens with lifetime antibody markers and those without is quite challenging. For some pathogens such as Helicobacter pylori this is highly dependent on the antigen itself, some pathogens with more local infections such as HPV tend to have lower antibody titres in general. However, we acknowledge that especially for acute respiratory and gastrointestinal pathogens, quickly waning antibody responses are often observed. Hence, we decided to add this to the result sections. \u201cThree studies including pathogens with shorter-lived antibody responses such as RSV used antibody titres to define pathogen burden (Lu et al., 2021, 2022; Shi et al., 2024). In contrast, two studies used counts of seropositivity for influenza viruses (Niu et al., 2019; Rubicz et al., 2015).\u201d","URL":"https:\/\/wellcomeopenresearch.org\/articles\/11-192\/v3#referee-comment-6698","order":4,"name":"referee-comment-6698","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported, in part, by Open Philanthropy. CWG is supported by a Wellcome Career Development Award (225868\/Z\/22\/Z). AJM is supported through the Nuffield Department of Medicine Career Development Scheme and receives funding from the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2024-I2M-2\u2013001\u20131). AJM is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}