How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments

新冠肺炎病毒致死机制是什么？由于病毒的不确定性，医生无法确定治疗方案。



Doctors are reaching for drugs that dampen the immune response — but these also undermine the body’s own fight against the coronavirus.
医生正在寻找抑制免疫力反应的药物，但这些药物同时也会破坏人体自身对抗新型冠状病毒的能力。

How does COVID-19 kill? Uncertainty over whether it is the virus itself — or the response by a person’s immune system — that ultimately overwhelms a patient’s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.
新冠肺炎病毒致死机制是什么？究竟是病毒本身所致，还是人体的免疫系统做出的应激反应击垮了人体的器官。这种不确定性，使得医生很难确定治疗新型冠状病毒重症患者的最佳方案。

Clinical data suggest that the immune system plays a part in the decline and death of people infected with the new coronavirus, and this has spurred a push for treatments such as steroids that rein in that immune response. But some of these treatments act broadly to suppress the immune system, stoking fears that they could actually hamper the body’s ability to keep the viral infection in check.
临床数据表明，免疫系统在这些新型冠状病毒感染者的衰退和死亡中起到了一定的作用。于是抑制这种免疫反应的治疗手段就出现了，比如抑制新型冠状病毒。然而，该治疗手段以抑制免疫系统为主，这引起了人们的恐惧。人们担心这种这种疗法实际上会妨碍人体预防病毒感染的能力。

“My greatest fear is that this gets taken to an extreme, where people are using whatever they can get their hands on to turn off the immune response,” says Daniel Chen, an immunologist and chief medical officer at IGM Biosciences in Mountain View, California. “You can’t knock down the immune system at a time when it’s battling an infection.”
位于加州山景城的IBM生物科学公司的免疫专家兼首席医疗官，丹尼陈说，“我最担心事情发展到另一个极端，人们会用尽所有能够使他们免疫系统关闭的事物。不能在免疫系统与病毒感染做斗争时将其摧毁。”

Race for treatments 
治疗竞赛
随着新冠病毒患者涌入世界各国的医院，医生们正艰难的处理着未经同行审查的不完整数据和预印资料，努力寻找救治患者的方案，并在社交媒体上分享经验。为了拯救生命，一些医生正进行未经证实的鸡尾酒疗法。

“People are watching patients deteriorate before their eyes, and there’s a very strong motivation to reach for any therapy that you think could be effective,” says Kenneth Baillie, an intensive-care anaesthetist at the University of Edinburgh, UK. “When I feel powerless at the end of a bed, I feel the same.”
当人们亲眼见证病人的病情恶化，他们便有了强大的动力去尝试任何疗法。英国爱丁堡大学的一名重症监护麻醉师，肯尼斯·贝利说，“当我站在床边有心无力时，我就产生了拯救病人的动力。”

Some of the earliest analyses of coronavirus patients in China suggested that it might not be only the virus that ravages the lungs and kills; rather, an overactive immune response might also make people severely ill or cause death. Some people who were critically ill with COVID-19 had high blood levels of proteins called cytokines, some of which can ramp up immune responses. These include a small but potent signalling protein called interleukin-6 (IL-6). IL-6 is a call-to-arms for some components of the immune system, including cells called macrophages. Macrophages fuel inflammation and can damage normal lung cells as well. The release of those cytokines, known as a cytokine storm, can also occur with other viruses, such as HIV.
根据中国最早的一些新冠肺炎病毒患者的分析表明，该病毒致死原因不只是因为病毒会破坏肺部；相反，过度活跃的免疫反应，也可能引发重病或导致死亡。一些血液中还有大量较细胞因子的蛋白质，其中一些会增强免疫反应。这里面有一种微量高效的信号蛋白，白介素-6（IL-6）。白介素-6是免疫系统中某些组成成分的武器，如巨噬细胞。巨噬细胞刺激炎症反应也会损害正常的肺细胞。这些细胞因子的释放，被称为细胞因子风暴也可以发生在其他病毒上，如艾滋病毒。

The ideal counter, then, would be a drug that blocks IL-6 activity and reduces the flow of macrophages into the lungs. Such drugs, known as IL6 inhibitors, already exist for the treatment of rheumatoid arthritis and other disorders. One called Actemra (tocilizumab), made by the Swiss pharmaceutical firm Roche, has been approved in China to treat coronavirus patients, and researchers around the world are working furiously to test it and other drugs of this type.
因此理想的计数器应该是一种阻断IL-6活性并减少巨噬细胞流入肺部的药物，这种被称为IL-6抑制剂的药物，已经用于治疗类风湿性关节炎和其他疾病。 瑞士罗氏制药公司生产的一种名为Actemra（tocilizumab）的药物已在中国获得批准，用于治疗新冠肺炎病人，世界各地的研究人员都在火热地对其进行测试，并测试其他该类型的药物。

Immune challenges 
免疫挑战

But globally there is not enough of the drug to go round, and many clinicians are turning to steroids, which more broadly dampen the immune system, says James Gulley, an immuno-oncologist at the National Cancer Institute in Bethesda, Maryland. IL-6 inhibitors may suppress only those immune responses that are governed by IL-6, allowing other immune responses that might help the body fight COVID-19 to continue. But steroids and some other therapies that act more generally might significantly reduce the body’s ability to fight infection overall. These drugs will not only suppress macrophages, but also immune cells called CD4 T cells, which are crucial for initiating immune responses, and also CD8 T cells, which are the body’s antiviral assassins, capable of destroying infected cells with more precision than macrophages. “When things get really bad, they’ll throw on steroids,” says Gulley. “I am a bit worried about where some people are going.”
马里兰州贝塞斯达市国家癌症研究所的免疫肿瘤学家詹姆斯·古利说到，但是在全球范围内，这种药物的流通量还不够，许多临床医生都在转向类固醇，这种类固醇会更广泛地削弱免疫系统。 IL-6抑制剂可能只抑制那些受IL-6控制的免疫反应，从而允许可能帮助机体抵抗COVID-19的其他免疫反应继续进行。 但是类固醇和其他一些更普遍起作用的疗法可能会大大降低人体抵抗感染的能力。 这些药物不仅会抑制巨噬细胞，而且还会抑制称为CD4 T细胞的免疫细胞（对启动免疫反应至关重要），以及抑制CD8 T细胞（是人体的抗病毒刺客），能够比巨噬细胞更精确地破坏受感染的细胞。 Gulley说：“当情况真的变得很糟时，它们会抛出类固醇。” “我有点担心人们该去往何方。”

Chen notes that although IL-6 levels are high in some acutely ill patients, viral loads are high as well, suggesting that the body is still fighting off an active viral infection. “You have to assume that there’s an ongoing antiviral immune response that is important to these patients,” he says. If so, then reducing CD4 and CD8 T cells could undermine that response.
陈专家指出，虽然一些重症患者的IL-6水平很高，但是病毒载量也很高，这表明身体仍然在抵抗活跃的病毒感染，“必须假设存在一种持续的抗血清免疫反应，这对这些患者很重要。”如果是这样的话，那么重新调节CD4T细胞和CD8T细胞可能会破坏免疫反应。

Steroids and other immune suppressants are already being tested against coronavirus in clinical trials. In March, UK researchers launched the RECOVERY study, a randomized clinical trial that will evaluate the steroid dexamethasone and other potential treatments for COVID-19. This worries rheumatologist Jessica Manson at University College Hospital in London. Evidence from previous outbreaks caused by related coronaviruses suggests that steroids hold little benefit, and might even delay the time it takes for patients to rid themselves of the virus, she says. And the RECOVERY trial calls for giving the treatments before patients become critically ill and have no other recourse.
类固醇和其他免疫抑制剂已经在运用到临床试验中了。今年3月，英国研究人员启动了REGOVERM研究，这是一项随机临床试验，将会评估类固醇地塞米松以及其他潜在的新冠病毒疗法。伦敦大学医学院的类风湿病学家，杰西卡·曼森对此感到担忧。杰西卡·曼森说，据以前有相关冠状病毒引起的疾病爆发资料显示，内固醇几乎没有什么益处，甚至可能会推迟患者摆脱病毒的时间。康复试验要求在重症患者无计可施之前进行治疗。

But Peter Horby, who studies infectious diseases at Oxford University in the UK and leader of the RECOVERY trial, notes that the trial will be using relatively low doses of steroid. “Higher doses are not routinely recommended, but the jury is out on lower doses,” he says. “And many authorities, including the World Health Organization, recommend a trial.”
但是在牛津大学研究传染病的皮特·赫比指出，这项试验将使用相对低剂量的类固醇。他说，“高剂量并不是常规推荐的，但低剂量还有待商讨。”包括世界卫生组织在内的许多权威机构都建议进行试验。

Combination therapy
联合治疗

A combination of damage from both a virus and the immune response to it is not uncommon, says Rafi Ahmed, a viral immunologist at Emory University in Atlanta, Georgia. The effects of 'hit-and-run' viruses such as norovirus, which make people sick almost immediately after infection, are more probably due to the virus itself, he says. By contrast, people infected with viruses such as coronavirus do not show symptoms until several days after infection. By then, collateral damage from the immune response often contributes to the illness.
佐治亚州亚特兰大市埃默里大学的病毒免疫学家拉菲·艾哈迈德（Rafi Ahmed）说，病毒和因病毒而产生的免疫反应，共同造成的损害并不罕见。像诺如病毒这样“打了就跑”的病毒所产生的影响，更可能是由于病毒本身。诺如病毒，在感染后会立即发作，相比之下感染冠状病毒等病毒的人，直到感染后几天才出现症状，到那时免疫反应的附带损伤往往会导致其他疾病。

“It’s very hard to dissect what per cent of it is due to the virus itself, and what per cent is the immune response,” Ahmed says. “But it’s almost always a combination of the two.”
艾哈迈德说，“很难剖析这其中有百分之几是由病毒本身引起的，又有百分之几是因免疫反应而引起的。”

In the absence of an answer, Ahmed is hopeful that researchers will arrive at a combination therapy, such as an IL-6 inhibitor that does not completely suppress the immune system, combined with an antiviral drug that directly targets the virus. Other drugs that target the immune system are also being tested, including one called anakinra, which targets a signalling protein called IL-1, and may provide a way to reduce specific immune responses without hampering CD4 and CD8 T cells, says Chen.
在没有答案的情况下，艾哈迈德希望研究人员能够找到一种联合疗法，比如一种不会完全抑制免疫系统的白介素-6抑制剂，以及一种直接针对病毒的抗病毒药物。陈教授说，其他针对免疫系统的药物也在测试中，包括一种叫阿纳金拉的药物，它针对一种叫白介素-1的信号蛋白，可能提供一种在不妨碍CD4T细胞和CD8T细胞的情况下，减少特异性免疫反应的方法。

But Baillie says that given the widespread use of steroids to treat people with coronavirus already, it is important to collect data on the practice. And although he is also concerned about suppressing immune responses in coronavirus patients, he notes that it is still possible that the practice could hold some benefit. “The only responsible thing to do is to use them in the context of a randomized clinical trial,” he says. “There’s no other way to know if a treatment is working.”
但是贝利说，鉴于类固醇已经被广泛用于治疗冠状病毒患者收集这方面的数据很重要，尽管他也担心抑制冠状病毒患者的免疫反应，但他指出这种做法仍有可能带来一些好处。“唯一负责任的做法是在随机临床试验中使用，他们没有其他方法可以知道治疗是否有效。”

https://www.sogou.com/link?url=DSOYnZeCC_qDcfM_FskR2T1S3J7oRWO3
作者：Hedi Ledford 译者：枝几