Blood-based Molecular Endotyping of Fibrotic Hypersensitivity Pneumonitis Identifies Two Immune Subtypes with Divergent Clinical Outcomes

Fibrotic hypersensitivity pneumonitis (fHP) is an antigen driven deadly interstitial lung disease with limited treatment options. Using multiple analysis algorithms, we identified two molecular endotypes with divergent immune signatures in transcriptome of whole blood from a fHP cohort and validated in transcriptomes from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, surgical lung biopsy tissue, and in the proteome from blood plasma. The lymphocytic endotype (L-fHP) comprising two-thirds of fHP cases showed enrichment of adaptive immune pathways and lymphocyte predominance, while the non-lymphocytic endotype (N-fHP) exhibited enrichment of innate pathways with neutrophil and macrophage predominance. The N-fHP cases had lower baseline pulmonary function, and reduced transplant-free survival compared to L-fHP cases, yet corticosteroid therapy was associated with poorer transplant-free survival in L-fHP and without impact in N-fHP. These results show that blood-based molecular endotyping can uncover prognostic and therapeutic insights and advance precision medicine otherwise inaccessible to traditional clinical phenotyping.