Laboratory of Experimental Medicine and Paediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.
Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.
Cell Death Differ. 2023 Sep;30(9):2066-2077. doi: 10.1038/s41418-023-01204-2. Epub 2023 Aug 15.
Critical COVID-19 patients admitted to the intensive care unit (ICU) frequently suffer from severe multiple organ dysfunction with underlying widespread cell death. Ferroptosis and pyroptosis are two detrimental forms of regulated cell death that could constitute new therapeutic targets. We enrolled 120 critical COVID-19 patients in a two-center prospective cohort study to monitor systemic markers of ferroptosis, iron dyshomeostasis, pyroptosis, pneumocyte cell death and cell damage on the first three consecutive days after ICU admission. Plasma of 20 post-operative ICU patients (PO) and 39 healthy controls (HC) without organ failure served as controls. Subsets of COVID-19 patients displayed increases in individual biomarkers compared to controls. Unsupervised clustering was used to discern latent clusters of COVID-19 patients based on biomarker profiles. Pyroptosis-related interleukin-18 accompanied by high pneumocyte cell death was independently associated with higher odds at mechanical ventilation, while the subgroup with high interleuking-1 beta (but limited pneumocyte cell death) displayed reduced odds at mechanical ventilation and lower mortality hazard. Meanwhile, iron dyshomeostasis with a tendency towards higher ferroptosis marker malondialdehyde had no association with outcome, except for the small subset of patients with very high catalytic iron independently associated with reduced survival. Forty percent of patients did not have a clear signature of the cell death mechanisms studied in this cohort. Moreover, repeated moderate levels of soluble receptor of advanced glycation end products and growth differentiation factor 15 during the first three days after ICU admission are independently associated with adverse clinical outcome compared to sustained lower levels. Altogether, the data point towards distinct subgroups in this cohort of critical COVID-19 patients with different systemic signatures of pyroptosis, iron dyshomeostasis, ferroptosis or pneumocyte cell death markers that have different outcomes in ICU. The distinct groups may allow 'personalized' treatment allocation in critical COVID-19 based on systemic biomarker profiles.
重症 COVID-19 患者经常因严重的多器官功能障碍和广泛的细胞死亡而入住重症监护病房（ICU）。铁死亡和细胞焦亡是两种有害的细胞死亡形式，可能成为新的治疗靶点。我们在一项两中心前瞻性队列研究中纳入了 120 名重症 COVID-19 患者，以监测 ICU 入院后连续 3 天内铁死亡、铁代谢紊乱、细胞焦亡、肺泡细胞死亡和细胞损伤的系统标志物。20 名术后 ICU 患者（PO）和 39 名无器官衰竭的健康对照（HC）的血浆作为对照。与对照组相比，部分 COVID-19 患者的个别生物标志物水平升高。基于生物标志物谱，我们采用无监督聚类方法来识别 COVID-19 患者的潜在亚群。与机械通气相关的细胞焦亡相关的白细胞介素-18 伴高肺泡细胞死亡，与机械通气的可能性更高独立相关，而白细胞介素-1β水平较高（但肺泡细胞死亡有限）的亚组机械通气的可能性降低，死亡率也降低。同时，铁代谢紊乱伴有较高的铁死亡标志物丙二醛的趋势与预后无关，除了一小部分患者因独立与存活率降低相关的催化铁含量非常高除外。该队列中 40%的患者没有明显的研究细胞死亡机制的特征。此外，在 ICU 入院后前 3 天内反复出现中等水平的可溶性晚期糖基化终产物受体和生长分化因子 15 与不良临床结局独立相关，而持续较低水平则没有相关性。总之，这些数据表明，该重症 COVID-19 患者队列中存在不同的亚组，其细胞焦亡、铁代谢紊乱、铁死亡或肺泡细胞死亡标志物的系统特征不同，在 ICU 中的预后也不同。这些不同的组可能允许根据系统生物标志物谱对重症 COVID-19 患者进行“个体化”治疗分配。
