WACEM-ACAIM Joint Global COVID-19 Taskforce- Immunology Division, USA.
Department of Emergency Medicine, Florida State University Sarasota Memorial Hospital, Sarasota, Florida.
Shock. 2020 Oct;54(4):438-450. doi: 10.1097/SHK.0000000000001627.
The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, comorbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1β, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.
目前，世界正处于 2019 年冠状病毒病（COVID-19）大流行之中，这是一种由新型β冠状病毒严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的呼吸道疾病。COVID-19 疾病的严重程度从无症状到致命性急性呼吸窘迫综合征不等。在少数患者中，疾病在急性发病后 7 至 14 天会发生表型分化，要么完全康复，要么症状加重。然而，这种变化的机制尚不清楚，但事实表明，患者的免疫状态、合并症以及病毒感染的全身效应（可能取决于所涉及的 SARS-CoV-2 株）起着关键作用。随后，症状最严重的患者往往预后不良，表现为严重缺氧，并伴有促炎细胞因子（包括 IL-1β、IL-6、IFN-γ 和 TNF-α）水平升高以及抗炎细胞因子 IL-10 水平升高、明显的淋巴细胞减少和中性粒细胞与淋巴细胞比值升高。基于现有证据，我们提出了一种机制，即 SARS-CoV-2 感染既直接导致器官损伤，又引发 IL-6 介导的细胞因子释放综合征（CRS）和缺氧，导致全身炎症加剧、多器官损伤和终末器官衰竭。升高的 IL-6 和缺氧共同使患者易患肺动脉高压，而 COVID-19 中无症状缺氧的存在进一步加剧了这一问题。由于下游介质相似，我们讨论了 SARS-CoV-2 和流感病毒在合并感染时的潜在协同作用和全身影响，我们将这种现象称为“COVI-Flu”。此外，还强调了 CRS 和细胞因子风暴之间的区别。最后，讨论了针对 SARS-CoV-2 和 COVI-Flu 感染的新的管理方法、临床试验和治疗策略，强调了宿主反应优化和全身炎症减轻。
