{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T02:42:58Z","timestamp":1794278578953,"version":"4.9.0"},"reference-count":22,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:sec>\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether precision immunotherapy guided by the presence of macrophage activation\u2013like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation\u2013like syndrome (blood ferritin &amp;amp;gt;4420 ng\/mL) or sepsis-induced immunoparalysis (blood ferritin \u22644420 ng\/mL and &amp;amp;lt;5000 human leukocyte antigen DR receptors on CD45\/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation\u2013like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%];\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u2009.002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>Among patients with sepsis, precision immunotherapy targeting macrophage activation\u2013like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov Identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04990232\">NCT04990232<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jama.2025.24175","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T22:30:25Z","timestamp":1765233025000},"page":"775","source":"Crossref","is-referenced-by-count":131,"title":["Precision Immunotherapy to Improve Sepsis Outcomes"],"prefix":"10.1001","volume":"335","author":[{"given":"Evangelos J.","family":"Giamarellos-Bourboulis","sequence":"first","affiliation":[{"name":"Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Greece"},{"name":"Hellenic Institute for the Study of Sepsis, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antigone","family":"Kotsaki","sequence":"additional","affiliation":[{"name":"Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Greece"},{"name":"Hellenic Institute for the Study of Sepsis, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Kotsamidi","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Ippokrateion General Hospital of Thessaloniki, Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, AHEPA Thessaloniki University General Hospital, Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Koutsoukou","sequence":"additional","affiliation":[{"name":"Polyvalent Intensive Care Unit, Sotiria Athens General Hospital of Chest Diseases, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Ehler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Paridou","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Asklipeion General Hospital, Voula, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frantzeska","family":"Frantzeskaki","sequence":"additional","affiliation":[{"name":"Second Department of Critical Care Medicine, National and Kapodistrian University of Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella C. 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