Data Base COVID proyect

COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology as it is involved in inflammation, vascular homeostasis, and coagulation. We aim to study the bradykinin cascade and its involvement in severity of patients with COVID-19. This is an observational cohort study involving 63 consecutive patients with severe COVID-19 pneumonia and 27 healthy subjects as control group. Clinical laboratory findings and plasma protein concentration of KKS peptides [bradykinin (BK), BK1-8], KKS proteins [high-molecular weight kininogen (HK)], and KKS enzymes [carboxypeptidase N subunit 1 (CPN1), kallikrein B1 (KLKB1), angiotensin converting enzyme 2 (ACE2), and C1 esterase inhibitor (C1INH)] were analyzed. We detected dysregulated KKS in patients with COVID-19, characterized by an accumulation of BK1-8 in combination with decreased levels of BK. Accumulated BK1-8 was related to severity of patients with COVID-19. A multivariate logistic regression model retained BK1-8, BK, and D-dimer as independent predictor factors to intensive care unit (ICU) admission. A Youden's optimal cutoff value of -0.352 was found for the multivariate model score with an accuracy of 92.9%. Multivariate model score-high group presented an odds ratio for ICU admission of 260.0. BK1-8 was related to inflammation, coagulation, and lymphopenia. Our data suggest that BK1-8/BK plasma concentration in combination with D-dimer levels might be retained as independent predictors for ICU admission in patients with COVID-19. Moreover, we reported KKS dysregulation in patients with COVID-19, which was related to disease severity by means of inflammation, hypercoagulation, and lymphopenia.

过去两年间，新型冠状病毒肺炎（COVID-19）已演变为极具破坏性的传染病。诸多学者均强调了激肽释放酶-激肽系统（kallikrein-kinin system, KKS）在COVID-19病理生理学中的重要作用，因其参与炎症反应、血管稳态及凝血过程。本研究旨在探讨缓激肽级联反应及其与COVID-19患者病情严重程度的关联。
本研究为观察性队列研究，共纳入63例连续性重症COVID-19肺炎患者，以及27名健康受试者作为对照组。研究分析了临床实验室检测结果，以及血浆中激肽释放酶-激肽系统相关肽类[缓激肽（bradykinin, BK）、BK1-8]、激肽释放酶-激肽系统相关蛋白[高分子量激肽原（high-molecular weight kininogen, HK）]与激肽释放酶-激肽系统相关酶[羧肽酶N亚基1（carboxypeptidase N subunit 1, CPN1）、激肽释放酶B1（kallikrein B1, KLKB1）、血管紧张素转换酶2（angiotensin converting enzyme 2, ACE2）及C1酯酶抑制剂（C1 esterase inhibitor, C1INH）]的血浆浓度。
研究发现，COVID-19患者体内激肽释放酶-激肽系统存在失调，表现为BK1-8水平升高，同时BK水平降低。升高的BK1-8水平与COVID-19患者的病情严重程度显著相关。多因素logistic回归模型筛选出BK1-8、BK及D-二聚体作为重症加强护理病房（intensive care unit, ICU）收治的独立预测因子。该多因素模型得分的尤登最优临界值为-0.352，模型准确率达92.9%。多因素模型得分高组患者的ICU收治比值比（odds ratio）为260.0。BK1-8水平与炎症反应、凝血功能异常及淋巴细胞减少症密切相关。
本研究数据表明，血浆BK1-8/BK浓度联合D-二聚体水平可作为COVID-19患者ICU收治的独立预测指标。此外，本研究证实COVID-19患者体内存在激肽释放酶-激肽系统失调，该失调可通过介导炎症反应、高凝状态及淋巴细胞减少症影响疾病严重程度。