tetano
Editor, Senior Moderator
Intensive Care Med Exp
. 2023 Feb 24;11(1):9.
doi: 10.1186/s40635-022-00488-x.
Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients
Syed M T Nasser[SUP] 1 2 [/SUP], Anas A Rana[SUP] 3 [/SUP], Rainer Doffinger[SUP] 4 [/SUP], Andreas Kafizas[SUP] 5 6 [/SUP], Tauseef A Khan[SUP] 7 [/SUP], Shuaib Nasser[SUP] 8 [/SUP]
Affiliations
Abstract
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[SUB]d[/SUB]) 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[SUB]2[/SUB]/FiO[SUB]2[/SUB] (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.
Keywords: Autoimmunity; Coronavirus; Cytokines; Inflammasomes; Pneumonia; Viral.
. 2023 Feb 24;11(1):9.
doi: 10.1186/s40635-022-00488-x.
Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients
Syed M T Nasser[SUP] 1 2 [/SUP], Anas A Rana[SUP] 3 [/SUP], Rainer Doffinger[SUP] 4 [/SUP], Andreas Kafizas[SUP] 5 6 [/SUP], Tauseef A Khan[SUP] 7 [/SUP], Shuaib Nasser[SUP] 8 [/SUP]
Affiliations
- PMID: 36823262
- DOI: 10.1186/s40635-022-00488-x
Abstract
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[SUB]d[/SUB]) 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[SUB]2[/SUB]/FiO[SUB]2[/SUB] (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.
Keywords: Autoimmunity; Coronavirus; Cytokines; Inflammasomes; Pneumonia; Viral.