背景:严重的COVID-19并不常见,限制在总人口的19%。为了应对第一次病毒波(SARS-CoV-2的α变体),我们调查了生物标志物是否表明疾病的严重程度,特别是,如果血液中血管紧张素转换酶2(ACE2)的可变表达可能会澄清这种风险和COVID-19后疾病(PCC)的差异。
方法:IRB批准的研究将重症COVID-19住院患者与健康对照进行了比较。严重感染被定义为需要氧气或入院时从基线开始增加氧气需求,COVID-19PCR阳性。在入院的一天内从患者获得单个血液样本。通过RT-PCR测定法测量血细胞中的ACE2RNA表达。通过荧光肽定量血浆ACE1和ACE2酶活性。通过ELISA定量血浆TIMP-1、PIIINP和MMP-9抗原。将数据输入REDCap并使用STATAv14和GraphPadPrismv10进行分析。
结果:在大流行期间招募了48名患者和72名健康对照。在严重COVID-19期间,外周血单核细胞(PBMC)中的ACE2RNA表达很少被急性检测到,但在对照组中很常见(未检测到的ACE2的OR:12.4[95%CI:2.62-76.1])。PBMC中ACE2的RNA表达并没有测定血浆ACE1和ACE2的活性,提示替代的细胞信号传导途径。纤维化标志物(TIMP-1和PIIINP)和血管病变(MMP-9)也升高。严重COVID-19期间的ACE2RNA表达通常在数小时内对恢复期血浆有反应。类似于肿瘤发生,我们推测,持久性,COVID-19(肾素-血管紧张素系统(RAS),纤维化和血管病变)在易感个体中引发或促进COVID-19后病症(PCC)。
结论:这项工作阐明了ACE2,TIMP1,PIIINP和MMP-9在PCC发病机理中的生物学和时间合理性。这些独立系统的交叉并不常见,可能在一定程度上解释了PCC的稀有性。
BACKGROUND: Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC).
METHODS: The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10.
RESULTS: Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals.
CONCLUSIONS: This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.