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Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients
BACKGROUND: Divergence between deterioration to life-threatening COVID-19 or clinical improvement occurs for most within the first 14 days of symptoms. Life-threatening COVID-19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin-18 (IL-...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949911/ https://www.ncbi.nlm.nih.gov/pubmed/36823262 http://dx.doi.org/10.1186/s40635-022-00488-x |
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author | Nasser, Syed M. T. Rana, Anas A. Doffinger, Rainer Kafizas, Andreas Khan, Tauseef A. Nasser, Shuaib |
author_facet | Nasser, Syed M. T. Rana, Anas A. Doffinger, Rainer Kafizas, Andreas Khan, Tauseef A. Nasser, Shuaib |
author_sort | Nasser, Syed M. T. |
collection | PubMed |
description | BACKGROUND: Divergence between deterioration to life-threatening COVID-19 or clinical improvement occurs for most within the first 14 days of symptoms. Life-threatening COVID-19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin-18 (IL-18) due to failure of negative-feedback release of IL-18 binding protein (IL-18bp). We, therefore, designed a prospective, longitudinal cohort study to examine IL-18 negative-feedback control in relation to COVID-19 severity and mortality from symptom day 15 onwards. METHODS: 662 blood samples, matched to time from symptom onset, from 206 COVID-19 patients were analysed by enzyme-linked immunosorbent assay for IL-18 and IL-18bp, enabling calculation of free IL-18 (fIL-18) using the updated dissociation constant (K(d)) of 0.05 nmol. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL-18 and outcome measures of COVID-19 severity and mortality. Re-calculated fIL-18 values from a previously studied healthy cohort are also presented. RESULTS: Range of fIL-18 in COVID-19 cohort was 10.05–1157.7 pg/ml. Up to symptom day 14, mean fIL-18 levels increased in all patients. Levels in survivors declined thereafter, but remained elevated in non-survivors. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in PaO(2)/FiO(2) (primary outcome) for each 37.7 pg/ml increase in highest fIL-18 (p < 0.03). Per 50 pg/ml increase in highest fIL-18, adjusted logistic regression gave an odds-ratio (OR) for crude 60-day mortality of 1.41 (1.1–2.0) (p < 0.03), and an OR for death with hypoxaemic respiratory failure of 1.90 [1.3–3.1] (p < 0.01). Highest fIL-18 was associated also with organ failure in patients with hypoxaemic respiratory failure, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01). CONCLUSIONS: Elevated free IL-18 levels from symptom day 15 onwards are associated with COVID-19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-022-00488-x. |
format | Online Article Text |
id | pubmed-9949911 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-99499112023-02-24 Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients Nasser, Syed M. T. Rana, Anas A. Doffinger, Rainer Kafizas, Andreas Khan, Tauseef A. Nasser, Shuaib Intensive Care Med Exp Research Articles BACKGROUND: Divergence between deterioration to life-threatening COVID-19 or clinical improvement occurs for most within the first 14 days of symptoms. Life-threatening COVID-19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin-18 (IL-18) due to failure of negative-feedback release of IL-18 binding protein (IL-18bp). We, therefore, designed a prospective, longitudinal cohort study to examine IL-18 negative-feedback control in relation to COVID-19 severity and mortality from symptom day 15 onwards. METHODS: 662 blood samples, matched to time from symptom onset, from 206 COVID-19 patients were analysed by enzyme-linked immunosorbent assay for IL-18 and IL-18bp, enabling calculation of free IL-18 (fIL-18) using the updated dissociation constant (K(d)) of 0.05 nmol. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL-18 and outcome measures of COVID-19 severity and mortality. Re-calculated fIL-18 values from a previously studied healthy cohort are also presented. RESULTS: Range of fIL-18 in COVID-19 cohort was 10.05–1157.7 pg/ml. Up to symptom day 14, mean fIL-18 levels increased in all patients. Levels in survivors declined thereafter, but remained elevated in non-survivors. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in PaO(2)/FiO(2) (primary outcome) for each 37.7 pg/ml increase in highest fIL-18 (p < 0.03). Per 50 pg/ml increase in highest fIL-18, adjusted logistic regression gave an odds-ratio (OR) for crude 60-day mortality of 1.41 (1.1–2.0) (p < 0.03), and an OR for death with hypoxaemic respiratory failure of 1.90 [1.3–3.1] (p < 0.01). Highest fIL-18 was associated also with organ failure in patients with hypoxaemic respiratory failure, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01). CONCLUSIONS: Elevated free IL-18 levels from symptom day 15 onwards are associated with COVID-19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-022-00488-x. Springer International Publishing 2023-02-24 /pmc/articles/PMC9949911/ /pubmed/36823262 http://dx.doi.org/10.1186/s40635-022-00488-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles Nasser, Syed M. T. Rana, Anas A. Doffinger, Rainer Kafizas, Andreas Khan, Tauseef A. Nasser, Shuaib Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title | Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title_full | Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title_fullStr | Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title_full_unstemmed | Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title_short | Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients |
title_sort | elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised covid-19 patients |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949911/ https://www.ncbi.nlm.nih.gov/pubmed/36823262 http://dx.doi.org/10.1186/s40635-022-00488-x |
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