{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:53:32Z","timestamp":1781697212773,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,15]]},"group-title":"Allergy and Immunology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01HL171918"],"award-info":[{"award-number":["R01HL171918"]}]},{"name":"National Institute of Health","award":["UG3HL145266"],"award-info":[{"award-number":["UG3HL145266"]}]},{"name":"National Institute of Health","award":["R03AG085239"],"award-info":[{"award-number":["R03AG085239"]}]},{"name":"National Institute of Health","award":["R01HL176659"],"award-info":[{"award-number":["R01HL176659"]}]},{"name":"National Institute of Health","award":["HL170961"],"award-info":[{"award-number":["HL170961"]}]},{"name":"National Institute of Health","award":["AG090337"],"award-info":[{"award-number":["AG090337"]}]},{"name":"National Institute of Health","award":["R01HL69166"],"award-info":[{"award-number":["R01HL69166"]}]},{"name":"National Institute of Health","award":["R01HL166290"],"award-info":[{"award-number":["R01HL166290"]}]},{"name":"National Institute of Health","award":["R01HL132177"],"award-info":[{"award-number":["R01HL132177"]}]},{"name":"National Institute of Health","award":["R01HL132287"],"award-info":[{"award-number":["R01HL132287"]}]},{"name":"National Institute of Health","award":["R01HL167202"],"award-info":[{"award-number":["R01HL167202"]}]},{"name":"National Institute of Health","award":["R01HL179312"],"award-info":[{"award-number":["R01HL179312"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Rationale<\/jats:title>\n                  <jats:p>Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.11.26355382","type":"posted-content","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T01:30:10Z","timestamp":1781573410000},"source":"Crossref","is-referenced-by-count":0,"title":["Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis"],"prefix":"10.64898","author":[{"given":"Yong","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shwu-Fan","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Strickland","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brody A.","family":"Receveur","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"},{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine S.","family":"Bonham","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessy K.","family":"Paul","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C.","family":"Mannem","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Numaan F.","family":"Malik","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Sturek","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun Michael","family":"Shim","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Velez","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel B.","family":"Konkol","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Su","family":"Cheon","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"name":"Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Sun","sequence":"additional","affiliation":[{"name":"Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA"},{"name":"Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA"},{"name":"Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani","family":"Manichaikul","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayodeji","family":"Adegunsoye","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Strek","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan R. 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