TY - JOUR T1 - Immunophenotypes of anti-SARS-CoV-2 responses associated with fatal COVID-19 JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00216-2022 VL - 8 IS - 4 SP - 00216-2022 AU - Julij Šelb AU - Barbara Bitežnik AU - Urška Bidovec Stojković AU - Boštjan Rituper AU - Katarina Osolnik AU - Peter Kopač AU - Petra Svetina AU - Kristina Cerk Porenta AU - Franc Šifrer AU - Petra Lorber AU - Darinka Trinkaus Leiler AU - Tomaž Hafner AU - Tina Jerič AU - Robert Marčun AU - Nika Lalek AU - Nina Frelih AU - Mojca Bizjak AU - Rok Lombar AU - Vesna Nikolić AU - Katja Adamič AU - Katja Mohorčič AU - Sanja Grm Zupan AU - Irena Šarc AU - Jerneja Debeljak AU - Ana Koren AU - Ajda Demšar Luzar AU - Matija Rijavec AU - Izidor Kern AU - Matjaž Fležar AU - Aleš Rozman AU - Peter Korošec Y1 - 2022/10/01 UR - http://openres.ersjournals.com/content/8/4/00216-2022.abstract N2 - Background The relationship between anti-SARS-CoV-2 humoral immune response, pathogenic inflammation, lymphocytes and fatal COVID-19 is poorly understood.Methods A longitudinal prospective cohort of hospitalised patients with COVID-19 (n=254) was followed up to 35 days after admission (median, 8 days). We measured early anti-SARS-CoV-2 S1 antibody IgG levels and dynamic (698 samples) of quantitative circulating T-, B- and natural killer lymphocyte subsets and serum interleukin-6 (IL-6) response. We used machine learning to identify patterns of the immune response and related these patterns to the primary outcome of 28-day mortality in analyses adjusted for clinical severity factors.Results Overall, 45 (18%) patients died within 28 days after hospitalisation. We identified six clusters representing discrete anti-SARS-CoV-2 immunophenotypes. Clusters differed considerably in COVID-19 survival. Two clusters, the anti-S1-IgGlowestTlowestBlowestNKmodIL-6mod, and the anti-S1-IgGhighTlowBmodNKmodIL-6highest had a high risk of fatal COVID-19 (HR 3.36–21.69; 95% CI 1.51–163.61 and HR 8.39–10.79; 95% CI 1.20–82.67; p≤0.03, respectively). The anti-S1-IgGhighestTlowestBmodNKmodIL-6mod and anti-S1-IgGlowThighestBhighestNKhighestIL-6low cluster were associated with moderate risk of mortality. In contrast, two clusters the anti-S1-IgGhighThighBmodNKmodIL-6low and anti-S1-IgGhighestThighestBhighNKhighIL-6lowest clusters were characterised by a very low risk of mortality.Conclusions By employing unsupervised machine learning we identified multiple anti-SARS-CoV-2 immune response clusters and observed major differences in COVID-19 mortality between these clusters. Two discrete immune pathways may lead to fatal COVID-19. One is driven by impaired or delayed antiviral humoral immunity, independently of hyper-inflammation, and the other may arise through excessive IL-6-mediated host inflammation response, independently of the protective humoral response. Those observations could be explored further for application in clinical practice.By employing unsupervised machine learning, this study identified multiple anti-SARS-CoV-2 immune response profiles and observed major differences in #COVID19 mortality between these profiles https://bit.ly/3SgMh6n ER -