The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast
The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast
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DOI：
10.1016/j.mehy.2020.109883
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发表时间：
2020-10-01
影响因子：
4.7
通讯作者：
Kerrigan, David Daniel
中科院分区：
文献类型：
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作者：
Almerie, Muhammad Qutayba;Kerrigan, David Daniel
人们普遍认为，感染SARS-CoV-2病毒会引发不成比例的免疫反应，导致毁灭性的全身性损伤，特别是在肥胖患者中，肥胖本身就是一种慢性多器官炎症性疾病。免疫细胞在内脏脂肪组织中积累，并与旁分泌脂肪细胞一起释放出广泛的生物活性细胞因子（包括IL-1 ss、IL5、IL6和IL8），可导致局部、肺部和全身炎症。更强烈的“细胞因子风暴”被认为是在严重的COVID-19中看到的极端免疫反应背后的机制。令人惊讶的是，肥胖和COVID-19的结合是多么危险，导致更大的ICU入院风险和更高的死亡率。此外，BAME背景的患者在感染SARS-CoV-2后的死亡率似乎有所增加；他们中心性肥胖及其代谢并发症的患病率也更高。在缺乏有效疫苗的情况下，免疫调节药物的治疗潜力是一个优先事项，但新药的开发既昂贵又耗时。一个更务实的解决方案是寻求重新利用现有药物，特别是那些可能抑制肥胖中细胞因子活性升高的药物，这是COVID-19预后不良的主要风险因素。孟鲁司特是一种半胱氨酸白三烯受体拮抗剂，被许可用于治疗哮喘和过敏性鼻炎。它已被证明可以减少肺对抗原、组织嗜酸性粒细胞和炎症细胞中IL-5表达的反应。与安慰剂治疗的患者相比，它也被证明可以降低病毒性上呼吸道感染患者IL-1 ss和il - 8的升高水平。此外，计算机研究表明，孟鲁司特分子与病毒主要蛋白酶的末端位点具有很高的结合亲和力，而蛋白酶是病毒RNA合成和复制所必需的。孟鲁司特价格便宜、安全且可广泛获得，似乎有可能成为临床试验的理想候选药物，特别是在已经发生不可修复的组织损伤之前的早期疾病。假设：孟鲁司特通过直接抗病毒作用，或通过抑制响应SARS-CoV-2而增加的细胞因子释放，降低COVID-19引起的免疫介导的多器官损伤的严重程度，特别是在中枢性肥胖和代谢综合征患者中。
It is widely believed that infection with the SARS-CoV-2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1 ss, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense `cytokine storm' is postulated as the mechanism behind the extreme immune response seen in severe COVID-19.It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV-2 infection; they also have a higher prevalence of central obesity and its metabolic complications.In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19.Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1 ss and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus's main protease enzyme which is needed for virus RNA synthesis and replication.Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. Hypothesis: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV-2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.