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Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study
BACKGROUND: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, no curative intent therapy has been identified to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerg...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915800/ https://www.ncbi.nlm.nih.gov/pubmed/36778407 http://dx.doi.org/10.21203/rs.3.rs-2479844/v1 |
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author | Herrera, Victoria L.M. Bosch, Nicholas A. Lok, Judith J. Nguyen, Mai Q. Lenae, Kaitriona A. deKay, Joanne T. Ryzhov, Sergey V. Seder, David B. Ruiz-Opazo, Nelson Walkey, Allan J. |
author_facet | Herrera, Victoria L.M. Bosch, Nicholas A. Lok, Judith J. Nguyen, Mai Q. Lenae, Kaitriona A. deKay, Joanne T. Ryzhov, Sergey V. Seder, David B. Ruiz-Opazo, Nelson Walkey, Allan J. |
author_sort | Herrera, Victoria L.M. |
collection | PubMed |
description | BACKGROUND: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, no curative intent therapy has been identified to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating neutrophil-extracellular trap (NET)-forming neutrophils [NET+Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. METHODS: We conducted a prospective observational study of circulating levels of CD11b+[NET+N] immunotyped for dual endothelin-1/signal peptide receptor, (DEspR±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET+N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. RESULTS: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r(S)=0.80) and ICUFD (r(S)=−0.76); circulating DEspR+[NET+Ns] with t1-SOFA (r(S)= 0.71), t2-SOFA (r(S) =0.62), and ICUFD (r(S) =−0.63), and ANC with t1-SOFA (r(S)=0.71), and t2-SOFA (r(S)=0.61). Causal mediation analysis identified DEspR+[NET+Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR+[NET+Ns] were theoretically reduced to zero. Concordantly, DEspR+[NET+Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR+[NET+Ns] were reduced to zero. In patients with t1-SOFA >1, the indirect effect of a hypothetical treatment eliminating DEspR+[NET+Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR+[NET+Ns], and no significant mediation of SOFA-score through ANC. CONCLUSIONS: Despite equivalent correlations, DEspR+[NET+Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR+[NET+Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19. |
format | Online Article Text |
id | pubmed-9915800 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-99158002023-02-11 Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study Herrera, Victoria L.M. Bosch, Nicholas A. Lok, Judith J. Nguyen, Mai Q. Lenae, Kaitriona A. deKay, Joanne T. Ryzhov, Sergey V. Seder, David B. Ruiz-Opazo, Nelson Walkey, Allan J. Res Sq Article BACKGROUND: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, no curative intent therapy has been identified to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating neutrophil-extracellular trap (NET)-forming neutrophils [NET+Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. METHODS: We conducted a prospective observational study of circulating levels of CD11b+[NET+N] immunotyped for dual endothelin-1/signal peptide receptor, (DEspR±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET+N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. RESULTS: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r(S)=0.80) and ICUFD (r(S)=−0.76); circulating DEspR+[NET+Ns] with t1-SOFA (r(S)= 0.71), t2-SOFA (r(S) =0.62), and ICUFD (r(S) =−0.63), and ANC with t1-SOFA (r(S)=0.71), and t2-SOFA (r(S)=0.61). Causal mediation analysis identified DEspR+[NET+Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR+[NET+Ns] were theoretically reduced to zero. Concordantly, DEspR+[NET+Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR+[NET+Ns] were reduced to zero. In patients with t1-SOFA >1, the indirect effect of a hypothetical treatment eliminating DEspR+[NET+Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR+[NET+Ns], and no significant mediation of SOFA-score through ANC. CONCLUSIONS: Despite equivalent correlations, DEspR+[NET+Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR+[NET+Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19. American Journal Experts 2023-02-01 /pmc/articles/PMC9915800/ /pubmed/36778407 http://dx.doi.org/10.21203/rs.3.rs-2479844/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. https://creativecommons.org/licenses/by/4.0/License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/) |
spellingShingle | Article Herrera, Victoria L.M. Bosch, Nicholas A. Lok, Judith J. Nguyen, Mai Q. Lenae, Kaitriona A. deKay, Joanne T. Ryzhov, Sergey V. Seder, David B. Ruiz-Opazo, Nelson Walkey, Allan J. Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title | Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title_full | Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title_fullStr | Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title_full_unstemmed | Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title_short | Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study |
title_sort | circulating neutrophil extracellular trap (net)-forming ‘rogue’ neutrophil subset, immunotype [despr+cd11b+], mediate multi-organ failure in covid-19 - an observational study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915800/ https://www.ncbi.nlm.nih.gov/pubmed/36778407 http://dx.doi.org/10.21203/rs.3.rs-2479844/v1 |
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