Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort.
Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort.
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DOI：
10.1097/cce.0000000000000488
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发表时间：
2021-08
影响因子：
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通讯作者：
Singer M
中科院分区：
文献类型：
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作者：
Arulkumaran N;Snow TAC;Kulkarni A;Brealey D;Rickman H;Rees-Spear C;Spyer MJ;Heaney J;Garr E;Williams B;Cherepanov P;Kassiotis G;Lunn M;Houlihan C;McCoy LE;Nastouli E;Singer M
补充数字内容可在文本中找到。已经提出了多种机制来解释2019年冠状病毒病的疾病严重程度。治疗方法需要以合理的生物学原理为基础。我们评估了一系列拟议的2019年冠状病毒病治疗靶点的血清水平是否能区分轻度或重度疾病患者。搜索ClinicalTrials.gov确定了冠状病毒疾病2019免疫药物靶标。我们随后进行了一项回顾性观察性队列研究，调查入院前5天内血清生物标志物与疾病严重程度和结局的关系，这些生物标志物与假定的治疗生物标志物有关。伦敦大学学院是英国的高等学术医学中心。2019年确诊为冠状病毒病入院的患者。一个也没有。招募了86名患者，44名（51%）患有轻度疾病，42名（49%）患有重度疾病。我们测量了与最常见的治疗靶点相关的10种细胞因子/信号蛋白的水平。（粒细胞-巨噬细胞集落刺激因子、干扰素-α2a、干扰素-β、干扰素-γ、白细胞介素-1 β、白细胞介素-1受体拮抗剂、白细胞介素-6、白细胞介素-7、白细胞介素-8、肿瘤坏死因子-α）、针对冠状病毒病2019刺突蛋白或核衣壳蛋白的免疫球蛋白G抗体，和抗体的中和滴度。确定了477项随机试验，包括针对83种不同途径的168种不同疗法。10种标志物中的6种（白细胞介素-6、白细胞介素-7、白细胞介素-8、干扰素-α2a、干扰素-β、白细胞介素-1受体拮抗剂）可区分轻度和重度疾病患者，尽管大多数与健康志愿者相似或仅略微高于健康志愿者。轻度或重度疾病患者中可检测到刺突蛋白或核衣壳蛋白免疫球蛋白G抗体的比例相似，组间水平相当。重症患者的中和滴度较高。一些治疗和预后生物标志物可能有助于识别可能受益于特定免疫调节治疗（特别是白细胞介素-6）的2019冠状病毒病患者。然而，生物标志物绝对值通常不能区分轻度和重度疾病或死亡患者，这意味着这些免疫调节治疗的获益可能有限。
Supplemental Digital Content is available in the text. Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. University College London, a tertiary academic medical center in the United Kingdom. Patients admitted to hospital with a diagnosis of coronavirus disease 2019. None. Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.