Risk Factors for Alloimmune Lung Syndromes after Allogeneic Hematopoietic Cell Transplantation in Children

Risk Factors for Alloimmune Lung Syndromes after Allogeneic Hematopoietic Cell Transplantation in Children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Risk Factors for Alloimmune Lung Syndromes after Allogeneic Hematopoietic Cell Transplantation in Children Coco de Koning, Linde Dekker, Birgitta Versluys, Celina Szanto, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7472129/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Mar, 2026 Read the published version in Bone Marrow Transplantation → Version 1 posted 9 You are reading this latest preprint version Abstract The non-infectious pulmonary complications idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans syndrome (BOS) are important causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). To identifying risk factors for these complications, we retrospectively analyzed baseline characteristics and longitudinal data from 633 pediatric and young adult allo-HCT recipients. Risk factors for IPS included non-malignant diagnosis (HR 2.97; 95% CI 1.27–6.97; P=0.01) and adenovirus reactivation (HR 2.75; 95% CI 1.24–6.14; P=0.01). Conditioning with busulfan-cyclophosphamide ±melphalan (BuCy ±Mel) associated with increased IPS risk compared to busulfan-fludarabine ±clofarabine (HR 5.15; 95% CI 2.36–11.24; P<0.001) and non-myeloablative regimens (HR 9.78; 95% CI 2.48–38.61; P=0.001). BuCy ±Mel conditioning also related to increased BOS risk relative to total body irradiation (TBI)(HR 5.11; 95%CI 1.65–15.83; P=0.005) and non-myeloablative regimens (HR 19.68; 95% CI 2.53–155.76; P=0.005). Moreover, elevated endothelial activation and stress index (EASIX), white blood cell, and lymphocyte counts before day 100 post-transplant correlated with IPS. For BOS, high EASIX and increased activated or effector memory CD4+ T-cells were additional significant correlates. In conclusion, IPS and BOS were associated with both distinct and overlapping risk factors in this study. These findings may inform future strategies to identify high-risk patients and develop targeted preventive interventions. Health sciences/Risk factors Health sciences/Medical research/Translational research allogeneic hematopoietic cell transplantation (allo-HCT) alloimmune lung syndromes (allo-LS) idiopathic pneumonia syndrome (IPS) bronchiolitis obliterans syndrome (BOS) risk factors Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files SupplementaryBMT.pdf Supplementary Cite Share Download PDF Status: Published Journal Publication published 27 Mar, 2026 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 27 Oct, 2025 Review # 2 received at journal 20 Oct, 2025 Review # 1 received at journal 27 Sep, 2025 Reviewer # 2 agreed at journal 20 Sep, 2025 Reviewer # 1 agreed at journal 12 Sep, 2025 Reviewers invited by journal 12 Sep, 2025 Submission checks completed at journal 28 Aug, 2025 Editor assigned by journal 27 Aug, 2025 First submitted to journal 27 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7472129","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":514119047,"identity":"fc40d481-eb36-4959-8744-204289a869c3","order_by":0,"name":"Coco de 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1","display":"","copyAsset":false,"role":"figure","size":208006,"visible":true,"origin":"","legend":"\u003cp\u003eNon-malignant diagnosis and adenovirus reactivation are risk factors for IPS, while type of conditioning is a risk factor for both BOS and IPS. (A-C) Confounder-adjusted cumulative incidence plots of IPS (left) and BOS (right) from the day of allo-HCT stratified by diagnosis type (A), adenovirus reactivation (B), and conditioning regimen (C). Groups were compared using multivariable Fine and Gray Competing Risk models. P values \u0026lt; .05 were considered statistically significant.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7472129/v1/aba59e10190b3459fe8ca735.png"},{"id":91847448,"identity":"cc4af64b-3979-4ff7-b281-21a7c1cee235","added_by":"auto","created_at":"2025-09-22 10:22:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":239783,"visible":true,"origin":"","legend":"\u003cp\u003eHigh EASIX, and high lymphocyte and white blood cell counts on day 50 and day 70 are associated with IPS. (A-C) Cumulative Incidence plots of IPS on day 50 (left) and day 70 (right) stratified by EASIX (A), lymphocyte count (B), and white blood cell count (C). Groups were compared using univariable Fine and Gray Competing Risk models. P values \u0026lt; .05 were considered statistically significant.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7472129/v1/906f7f040ec4f41942c7e2c4.png"},{"id":91847450,"identity":"ccc14863-58e7-4f1a-9094-3de49f9ca940","added_by":"auto","created_at":"2025-09-22 10:22:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":335398,"visible":true,"origin":"","legend":"\u003cp\u003eHigh EASIX on day 100 and high CD4+ T cell counts on day 30, 70 and 100 are associated with BO. (A-G) Confounderadjusted cumulative incidence plots (A-C,E,F) and cumulative incidence plots (D,G) of BOS stratified by EASIX on day 100 (A), CD4+ T cells on day 30 (B), day 70 (C) and day 100 (D), CD4+ EM T cells on day 30 (E), and activated CD4+ T cells on day 70 (F) and day 100 (G). Groups were compared with either univariable (D,G) or multivariable (A-C,E,F) Fine and Gray Competing Risk models. P values \u0026lt; .05 were considered statistically significant.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7472129/v1/41e55a1cd38e2d5caabeeefe.png"},{"id":105618268,"identity":"2bf80e8a-eb3e-497a-ac58-184b9671eeab","added_by":"auto","created_at":"2026-03-28 07:11:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1196135,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptTextfileBMT.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7472129/v1_covered_d42e5ac5-80de-4ec5-b24c-65d135de26b3.pdf"},{"id":91847989,"identity":"926186f9-4569-4604-a11d-86cfdedc9d70","added_by":"auto","created_at":"2025-09-22 10:30:58","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":952546,"visible":true,"origin":"","legend":"Supplementary","description":"","filename":"SupplementaryBMT.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7472129/v1/4ad6cac1f3eb036e47fe6019.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Risk Factors for Alloimmune Lung Syndromes after Allogeneic Hematopoietic Cell Transplantation in Children","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"allogeneic hematopoietic cell transplantation (allo-HCT), alloimmune lung syndromes (allo-LS), idiopathic pneumonia syndrome (IPS), bronchiolitis obliterans syndrome (BOS), risk factors","lastPublishedDoi":"10.21203/rs.3.rs-7472129/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7472129/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The non-infectious pulmonary complications idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans syndrome (BOS) are important causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). To identifying risk factors for these complications, we retrospectively analyzed baseline characteristics and longitudinal data from 633 pediatric and young adult allo-HCT recipients. Risk factors for IPS included non-malignant diagnosis (HR 2.97; 95% CI 1.27–6.97; P=0.01) and adenovirus reactivation (HR 2.75; 95% CI 1.24–6.14; P=0.01). Conditioning with busulfan-cyclophosphamide ±melphalan (BuCy ±Mel) associated with increased IPS risk compared to busulfan-fludarabine ±clofarabine (HR 5.15; 95% CI 2.36–11.24; P\u003c0.001) and non-myeloablative regimens (HR 9.78; 95% CI 2.48–38.61; P=0.001). BuCy ±Mel conditioning also related to increased BOS risk relative to total body irradiation (TBI)(HR 5.11; 95%CI 1.65–15.83; P=0.005) and non-myeloablative regimens (HR 19.68; 95% CI 2.53–155.76; P=0.005). Moreover, elevated endothelial activation and stress index (EASIX), white blood cell, and lymphocyte counts before day 100 post-transplant correlated with IPS. For BOS, high EASIX and increased activated or effector memory CD4+ T-cells were additional significant correlates. In conclusion, IPS and BOS were associated with both distinct and overlapping risk factors in this study. These findings may inform future strategies to identify high-risk patients and develop targeted preventive interventions.","manuscriptTitle":"Risk Factors for Alloimmune Lung Syndromes after Allogeneic Hematopoietic Cell Transplantation in Children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 10:22:53","doi":"10.21203/rs.3.rs-7472129/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-10-27T14:12:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-20T22:02:10+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-27T18:49:31+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-20T20:07:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-12T10:14:54+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-09-12T09:50:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T13:42:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-27T13:21:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2025-08-27T13:21:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3ccc0e74-83ee-42f0-86d9-896fee9a11c1","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54619865,"name":"Health sciences/Risk factors"},{"id":54619866,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2026-03-28T07:10:51+00:00","versionOfRecord":{"articleIdentity":"rs-7472129","link":"https://doi.org/10.1038/s41409-026-02829-w","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2026-03-27 04:00:00","publishedOnDateReadable":"March 27th, 2026"},"versionCreatedAt":"2025-09-22 10:22:53","video":"","vorDoi":"10.1038/s41409-026-02829-w","vorDoiUrl":"https://doi.org/10.1038/s41409-026-02829-w","workflowStages":[]},"version":"v1","identity":"rs-7472129","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7472129","identity":"rs-7472129","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}