{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:00:01Z","timestamp":1790172001376,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp;amp; Cancer"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pediatric hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that can be classified into three principal etiologies (primary HLH [pHLH], Epstein\u2013Barr\u2010virus\u2010driven HLH [EBV\u2010HLH], and secondary HLH [sHLH]) and is associated with disparate outcomes. Treatment escalation decisions remain largely empirical, guided by clinical presentation and conventional laboratory results rather than by an integrated biomarker framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Procedure<\/jats:title>\n                    <jats:p>\n                      We prospectively enrolled 180 consecutive pediatric patients with HLH at Children's Hospital 1, Ho Chi Minh City, Vietnam (October 2022\u2013October 2025): pHLH,\n                      <jats:italic>n<\/jats:italic>\n                      = 40; EBV\u2010HLH,\n                      <jats:italic>n<\/jats:italic>\n                      = 46 (CD27 intact,\n                      <jats:italic>n<\/jats:italic>\n                      = 19; CD27 dim,\n                      <jats:italic>n<\/jats:italic>\n                      = 27); and sHLH,\n                      <jats:italic>n<\/jats:italic>\n                      = 94. A 15\u2010analyte multiplex cytokine panel and six\u2010marker lymphocyte subset flow cytometry were performed at diagnosis (T0) and Day 7 (T1). Logistic regression models were developed and internally validated using bootstrap optimism correction (1000 iterations), 5\u2010fold stratified cross\u2010validation, and a temporal split.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall mortality was 31.1% (EBV\u2010HLH 67.4%, pHLH 45.0%, and sHLH 7.4%). Three discrete cytokine and subset phenotypes emerged: EBV\u2010HLH showed massive elevations in IFN\u2010\u03b3 and sCD25, with profound CD4+ and double\u2010negative T\u2010cell depletion; pHLH showed elevated tumor necrosis factor\u2010\u03b1 with preserved subsets; sHLH had low\u2010amplitude profiles with the highest CD4+ counts. Day\u20107 IFN\u2010\u03b3 T1\/T0 ratio (threshold 0.376) stratified mortality 6\u2010 to 27\u2010fold within each etiology. Cytokine drivers of escalation were etiology specific (sCD25 in pHLH, sCD25+IL\u201018 in EBV\u2010HLH, and IL\u201010\/IL\u20106 in sHLH). The integrated three\u2010component model achieved an apparent AUC of 0.963, a bias\u2010corrected AUC of 0.947 (95% CI: 0.92\u20130.97), a 5\u2010fold CV AUC of 0.942 \u00b1 0.05, and a temporal validation AUC of 0.946\u2014all three methods were convergent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Integrating etiology, cytokine phenotype, and lymphocyte subset profile provides biology\u2010grounded prediction of mortality and treatment escalation in pediatric HLH. Multicenter external validation is the next essential step.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/1545-5017.70654","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:34:58Z","timestamp":1788420898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Three\u2010Component Immune Framework Stratifies Treatment Response and Escalation in Pediatric Hemophagocytic Lymphohistiocytosis: A Prospective Single\u2010Center Cohort Study"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8762-0082","authenticated-orcid":false,"given":"Mai Anh Thi","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine University of Medicine and Pharmacy at Ho Chi Minh City  Ho Chi Minh City Vietnam"},{"name":"Children's Hospital 1  Ho Chi Minh City Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0815-8504","authenticated-orcid":false,"given":"Truong Nhat","family":"Trinh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine University of Medicine and Pharmacy at Ho Chi Minh City  Ho Chi Minh City Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6217-604X","authenticated-orcid":false,"given":"Duong Ngoc","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine University of Medicine and Pharmacy at Ho Chi Minh City  Ho Chi Minh City Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2444-1786","authenticated-orcid":false,"given":"Phung Nguyen The","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine University of Medicine 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