Braz-de-Melo Heloísa Antoniella, Faria Sara Socorro, Pasquarelli-do-Nascimento Gabriel, Santos Igor de Oliveira, Kobinger Gary P, Magalhães Kelly Grace
Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasilia, Brazil.
Département de Microbiologie-Infectiologie et d'Immunologie, Université Laval, Quebec City, QC, Canada.
Front Med (Lausanne). 2021 Apr 23;8:615333. doi: 10.3389/fmed.2021.615333. eCollection 2021.
COVID-19 is spreading worldwide at disturbing rates, overwhelming global healthcare. Mounting death cases due to disease complications highlight the necessity of describing efficient drug therapy strategies for severe patients. COVID-19 severity associates with hypercoagulation and exacerbated inflammation, both influenced by ACE2 downregulation and cytokine storm occurrence. In this review, we discuss the applicability of the anticoagulant heparin and the anti-inflammatory corticosteroid dexamethasone for managing severe COVID-19 patients. The upregulated inflammation and blood clotting may be mitigated by administrating heparin and its derivatives. Heparin enhances the anticoagulant property of anti-thrombin (AT) and may be useful in conjunction with fibrinolytic drugs for severe COVID-19 patients. Besides, heparin can also modulate immune responses, alleviating TNF-α-mediated inflammation, impairing IL-6 production and secretion, and binding to complement proteins and leukotriene B (LTB). Moreover, heparin may present anti-SARS-CoV-2 potential once it can impact viral infectivity and alter SARS-CoV-2 Spike protein architecture. Another feasible approach is the administration of the glucocorticoid dexamethasone. Although glucocorticoid's administration for viral infection managing is controversial, there is increasing evidence demonstrating that dexamethasone treatment is capable of drastically diminishing the death rate of patients presenting with Acute Respiratory Distress Syndrome (ARDS) that required invasive mechanical ventilation. Importantly, dexamethasone may be detrimental by impairing viral clearance and inducing hyperglycemia and sodium retention, hence possibly being deleterious for diabetics and hypertensive patients, two major COVID-19 risk groups. Therefore, while heparin's multitarget capacity shows to be strongly beneficial for severe COVID-19 patients, dexamethasone should be carefully administered taking into consideration underlying medical conditions and COVID-19 disease severity. Therefore, we suggest that the multitarget impact of heparin as an anti-viral, antithrombotic and anti-inflammatory drug in the early stage of the COVID-19 could significantly reduce the need for dexamethasone treatment in the initial phase of this disease. If the standard treatment of heparins fails on protecting against severe illness, dexamethasone must be applied as a potent anti-inflammatory shutting-down the uncontrolled and exacerbated inflammation.
新冠病毒肺炎(COVID-19)正在以惊人的速度在全球范围内传播,使全球医疗系统不堪重负。因疾病并发症导致的死亡病例不断增加,凸显了为重症患者描述有效药物治疗策略的必要性。COVID-19的严重程度与高凝状态和炎症加剧有关,这两者均受血管紧张素转换酶2(ACE2)下调和细胞因子风暴发生的影响。在本综述中,我们讨论了抗凝剂肝素和抗炎皮质类固醇地塞米松在治疗重症COVID-19患者中的适用性。通过使用肝素及其衍生物,可能减轻炎症和凝血的上调。肝素可增强抗凝血酶(AT)的抗凝特性,对于重症COVID-19患者,它可能与纤溶药物联合使用有益。此外,肝素还可调节免疫反应,减轻肿瘤坏死因子-α(TNF-α)介导的炎症,抑制白细胞介素-6(IL-6)的产生和分泌,并与补体蛋白和白三烯B(LTB)结合。此外,一旦肝素能够影响病毒感染性并改变SARS-CoV-2刺突蛋白结构,它可能具有抗SARS-CoV-2的潜力。另一种可行的方法是使用糖皮质激素地塞米松。尽管使用糖皮质激素治疗病毒感染存在争议,但越来越多的证据表明,地塞米松治疗能够大幅降低患有急性呼吸窘迫综合征(ARDS)且需要有创机械通气的患者的死亡率。重要的是,地塞米松可能会因损害病毒清除、导致高血糖和钠潴留而有害,因此可能对糖尿病患者和高血压患者有害,这两类是COVID-19的主要高危人群。因此,虽然肝素的多靶点作用对重症COVID-19患者显示出极大益处,但使用地塞米松时应根据基础疾病状况和COVID-19疾病严重程度谨慎给药。因此,我们建议肝素作为一种抗病毒、抗血栓和抗炎药物在COVID-19早期的多靶点作用可显著减少该疾病初始阶段对地塞米松治疗的需求。如果肝素的标准治疗未能预防重症疾病,则必须使用地塞米松作为强效抗炎药物来抑制失控和加剧的炎症。