Nasser Syed M T, Rana Anas A, Doffinger Rainer, Kafizas Andreas, Khan Tauseef A, Nasser Shuaib
Intensive Care Department, Surrey and Sussex NHS Foundation Trust, Redhill, UK.
Intensive Care Department, Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX, UK.
Intensive Care Med Exp. 2023 Feb 24;11(1):9. doi: 10.1186/s40635-022-00488-x.
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.
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) 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.
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/FiO (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).
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.
大多数人在出现症状的前14天内，病情会恶化为危及生命的新冠肺炎，或出现临床改善。危及生命的新冠肺炎与巨噬细胞活化综合征有临床相似之处，后者可能由白细胞介素18结合蛋白（IL-18bp）负反馈释放失败导致游离白细胞介素18（IL-18）升高所驱动。因此，我们设计了一项前瞻性纵向队列研究，以检查从症状出现第15天起，IL-18负反馈控制与新冠肺炎严重程度和死亡率的关系。
对206例新冠肺炎患者的662份与症状出现时间匹配的血样进行酶联免疫吸附测定，检测IL-18和IL-18bp，使用更新后的解离常数（K）0.05 nmol计算游离IL-18（fIL-18）。采用调整后的多变量回归分析评估最高fIL-18与新冠肺炎严重程度和死亡率的结局指标之间的关系。还展示了从先前研究的健康队列重新计算的fIL-18值。
新冠肺炎队列中fIL-18的范围为10.05-1157.7 pg/ml。在症状出现的第14天之前，所有患者的平均fIL-18水平均升高。此后，幸存者的水平下降，但非幸存者的水平仍居高不下。从症状出现第15天起的调整回归分析显示，最高fIL-18每增加37.7 pg/ml，动脉血氧分压/吸入氧分数（主要结局）降低100 mmHg（p<0.03）。最高fIL-18每增加50 pg/ml，调整后的逻辑回归得出60天粗死亡率的优势比（OR）为1.41（1.1-2.0）（p<0.03），因低氧性呼吸衰竭死亡的OR为1.90[1.3-3.1]（p<0.01）。最高fIL-18还与低氧性呼吸衰竭患者的器官衰竭相关，每增加一个接受支持的器官，fIL-18增加63.67 pg/ml（p<0.01）。
从症状出现第15天起游离IL-18水平升高与新冠肺炎严重程度和死亡率相关。国际标准随机对照试验编号：#13450549；注册日期：2020年12月30日。
