학술논문
Immunophenotypes of anti-SARS-CoV-2 responses associated with fatal COVID-19
Document Type
article
Author
Julij Šelb; Barbara Bitežnik; Urška Bidovec Stojković; Boštjan Rituper; Katarina Osolnik; Peter Kopač; Petra Svetina; Kristina Cerk Porenta; Franc Šifrer; Petra Lorber; Darinka Trinkaus Leiler; Tomaž Hafner; Tina Jerič; Robert Marčun; Nika Lalek; Nina Frelih; Mojca Bizjak; Rok Lombar; Vesna Nikolić; Katja Adamič; Katja Mohorčič; Sanja Grm Zupan; Irena Šarc; Jerneja Debeljak; Ana Koren; Ajda Demšar Luzar; Matija Rijavec; Izidor Kern; Matjaž Fležar; Aleš Rozman; Peter Korošec
Source
ERJ Open Research, Vol 8, Iss 4 (2022)
Subject
Language
English
ISSN
2312-0541
23120541
23120541
Abstract
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.