RT Journal Article
SR Electronic
T1 Immunophenotypes of anti-SARS-CoV-2 responses associated with fatal COVID-19
JF ERJ Open Research
JO erjor
FD European Respiratory Society
SP 00216-2022
DO 10.1183/23120541.00216-2022
A1 Julij Šelb
A1 Barbara Bitežnik
A1 Urška Bidovec Stojković
A1 Boštjan Rituper
A1 Katarina Osolnik
A1 Peter Kopač
A1 Petra Svetina
A1 Kristina Cerk Porenta
A1 Franc Šifrer
A1 Petra Lorber
A1 Darinka Trinkaus Leiler
A1 Tomaž Hafner
A1 Tina Jerič
A1 Robert Marčun
A1 Nika Lalek
A1 Nina Frelih
A1 Mojca Bizjak
A1 Rok Lombar
A1 Vesna Nikolić
A1 Katja Adamič
A1 Katja Mohorčič
A1 Sanja Grm Zupan
A1 Irena Šarc
A1 Jerneja Debeljak
A1 Ana Koren
A1 Demšar Luzar MSc Ajda
A1 Matija Rijavec
A1 Izidor Kern
A1 Matjaž Fležar
A1 Aleš Rozman
A1 Peter Korošec
YR 2022
UL http://openres.ersjournals.com/content/early/2022/09/16/23120541.00216-2022.abstract
AB Background The relationship between anti-SARS-CoV-2 humoral immune response, pathogenic inflammation, lymphocytes and fatal COVID-19 is poorly understood.Methods Longitudinal prospective cohort of hospitalized patients with COVID-19 (N=254) was followed up to 35 d after admission (median, 8 d). We measured early anti-SARS-CoV-2 S1 antibody IgG levels and dynamic (698 samples) of quantitative circulating T, B, NK lymphocyte subsets and serum interleukin-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 hospitalization. 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- anti-S1-IgGhighThighBmodNKmodIL-6low and anti-S1-IgGhighestThighestBhighNKhighIL-6lowest clusters were characterized 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: The authors have nothing to disclose.