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Discrete T-Cell and Inflammatory Profiles in the Blood Define Pulmonary Phenotypes After COVID-19 Illness.

2023; Elsevier BV; Volume: 151; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2022.12.793

1097-6825

Glenda Canderan, Lyndsey M. Muehling, Alexandra Kadl, Jeffrey M. Sturek, Catherine A. Bonham, Deborah Murphy, Sierra Barone, Claire Cross, In Su Cheon, Jie Sun, Jonathan irish, Judith A. Woodfolk,

COVID-19 Clinical Research Studies

Pulmonary complications arising from severe COVID-19 illness are common. However, patient variability presents a barrier to defining the immune mechanisms involved. We describe a novel method that leverages hundreds of cellular and molecular combinations within a large recovery cohort to identify immune profiles linked to discrete pulmonary phenotypes. Circulating cells and plasma mediators were monitored longitudinally for up to 2 years after acute illness using spectral flow cytometry, SARS-CoV-2 peptide stimulation assays, and multiplex bead assays (76 analytes) in a cohort of COVID-19 patients who presented for pulmonary follow-up care (n=110). Most patients were hospitalized (80%) during acute illness, and 51% received mechanical ventilation. Unsupervised machine-learning approaches (UMAP, self-organizing maps, T-REX) were used to define discrete pulmonary phenotypes and associated T-cell signatures. Analysis of multiple lung physiology measures identified 5 distinct pulmonary phenotypes that discriminated patients by clinical severity and fibrosis, and mapped trajectories of recovery versus persistence over time across these phenotypes. The most severe phenotypes were characterized by oxygen desaturation on exertion, lung restriction, and fibrosis. Related immune profiles comprised novel mixtures of complex CD4+ and CD8+ T-cell signatures that were persistently activated and marked by T-bet, PD-1 and lung-homing receptors, and increased virus-responsive T cells. Notably, CXCL13 and IFN-g discriminated the most severe pulmonary phenotype. Our novel approaches implicate dynamic pro-fibrotic, type 1-like cell networks in pulmonary complications arising after severe COVID-19. The findings deviate from current paradigms of fibrotic lung disease, and identify new mechanistic opportunities for studying lung disease in at-risk patients.