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 (Kd) 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 PaO2/FiO2 (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.
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 (Kd) of 0.05 nanomoles. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL–18 and outcome measures of COVID-19 severity and mortality. Results: Up to symptom day 14, mean fIL–18 levels increase in all patients. Levels in survivors declined thereafter, but remained elevated in non–survivors, due to IL–18 production without commensurate IL–18bp release. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in Pa02/Fi02 (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, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01) in patients with hypoxaemic respiratory failure. In this same sub-group, highest fIL–18 showed a direct correlation with Neutrophil/Lymphocyte ratio, with an increase in fIL–18 by 3.54 pg/ml (p < 0.03) for each unit increase. Conclusions: Loss of IL–18 negative–feedback control, from symptom day 15 onwards is associated with COVID–19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020.
Proning intubated patients with acute respiratory distress syndrome (ARDS) is an established practice to improve oxygenation temporarily. We present two cases of patients on our intensive care unit with ARDS, on non-invasive ventilation (NIV), in whom proning improved oxygenation at a stage when intubation was the next step. We discuss the mechanisms by which proning improves oxygenation as well as the potential risks proning on NIV brings, for which we make specific recommendations.
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