Title: Longitudinal analyses reveal immunological misfiring in severe COVID-19
Author: Carolina Lucas, Patrick Wong, Jon Klein, Tiago B. R. Castro, Julio Silva, Maria Sundaram, Mallory K. Ellingson, Tianyang Mao, Ji Eun Oh, Benjamin Israelow, Takehiro Takahashi, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Subhasis Mohanty, Haowei Wang, Anne L. Wyllie, Chantal B. F. Vogels, Rebecca Earnest, Sarah Lapidus, Isabel M. Ott, Adam J. Moore, M. Catherine Muenker, John B. Fournier, Melissa Campbell, Camila D. Odio, Arnau Casanovas-Massana, Roy Herbst, Albert C. Shaw, Ruslan Medzhitov, Wade L. Schulz, Nathan D. Grubaugh, Charles Dela Cruz, Shelli Farhadian, Albert I. Ko, Saad B. Omer, Akiko Iwasaki
Abstract: Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1–4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in T cell number. We identify an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. Unsupervised clustering analysis identified 4 immune signatures, representing (A) growth factors, (B) type-2/3 cytokines, (C) mixed type-1/2/3 cytokines, and (D) chemokines that correlated with three distinct disease trajectories of patients. The immune profile of patients who recovered with moderate disease was enriched in tissue reparative growth factor signature (A), while the profile for those with worsened disease trajectory had elevated levels of all four signatures. Thus, we identified development of a maladapted immune response profile associated with severe COVID-19 outcome and early immune signatures that correlate with divergent disease trajectories.