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The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.

Gajewski Thomas, Rouhani Sherin, Trujillo Jonathan, Pyzer Athalia, Yu Jovian, Fessler Jessica, Cabanov Alexandra, Higgs Emily, Cron Kyle, Zha Yuanyuan, Lu Yihao, Bloodworth Jeffrey, Abasiyanik Mustafa, Okrah Susan, Flood Blake, Hatogai Ken, Leung Michael, Pezeshk Apameh, Kozloff Lara, Reschke Robin, Strohbehn Garth, Chervin Carolina Soto, Kumar Madan, Schrantz Stephen, Madariaga Maria Lucia, Beavis Kathleen, Yeo Kiang-Teck, Sweis Randy, Segal Jeremy, Tay SavaÅŸ, Izumchenko Evgeny, Mueller Jeffrey, Chen Lin