【Cochrane简语概要】口服或注射皮质类固醇是否COVID-19患者的有效治疗？

关键信息

• 口服或注射全身用皮质类固醇（抗感染药物）可能是COVID-19住院患者的有效治疗。我们不知道它们是否会造成不良影响。

• 我们不知道哪种全身用皮质类固醇最有效。我们未发现有关非无症状或轻症非住院COVID-19患者的证据。

• 我们发现了42项正在进行的研究和16项已完成但尚未发表结果的研究。当我们发现新证据时，我们会更新本综述。

（图片来源于nipic.com）

什么是皮质类固醇？

皮质类固醇是抗感染药物，可以减轻红肿。它们还会降低免疫系统的活动，从而保护机体以抵抗疾病和感染。皮质类固醇可用于治疗多种疾病，例如哮喘、湿疹、关节劳损和类风湿性关节炎。

全身用皮质类固醇可以吞服或注射给药以进行全身治疗。长时间服用高剂量皮质类固醇可能造成不良影响，例如食欲增加、睡眠困难和情绪变化。

为什么皮质类固醇可能会治疗COVID-19？

COVID-19影响肺和呼吸道。免疫系统与病毒斗争时，肺和呼吸道会出现炎症，以致引起呼吸困难。皮质类固醇可减轻炎症，因此降低对呼吸机（一种支持患者呼吸的机器）呼吸支持的需求。有些患者的免疫系统对病毒反应过度，造成进一步的炎症和组织损伤；皮质类固醇可能有助于控制这种反应。

我们想知道什么？

我们想知道全身用皮质类固醇是否是COVID-19患者的有效治疗，以及它们是否会产生不良影响。

我们感兴趣的是：

• 治疗后14天内或更长时间内（若有报告），任何原因所致的死亡；
• 治疗后患者是好转还是恶化，根据其对呼吸支持的需求来判断；
• 生活质量；
• 不良反应和医院内感染。

我们做了什么？
我们检索了关于全身用皮质类固醇治疗轻、中或重症COVID-19患者的研究。患者可为任何年龄、性别或种族。

这些研究会比较：

• 皮质类固醇加常规照护与常规照护和有无安慰剂（假药）；
• 一种皮质类固醇与另一种；
• 皮质类固醇与不同的药物；
• 不同剂量的皮质类固醇；或是
• 早期与晚期治疗。

我们比较并总结了有关研究结果，并根据研究方法和规模等因素进行证据质量评价。

我们发现了什么？

我们发现了11项研究，有8075名受试者。大约3000名受试者接受了皮质类固醇治疗，大多数是地塞米松（2322名受试者）。大多数研究是在高收入国家开展。

我们发现了42项正在进行的研究，以及16项已完成但尚未发表结果的研究。

主要结果

有10项研究比较了皮质类固醇加常规照护和常规照护与有无安慰剂。只有1项研究比较了两种皮质类固醇。这些研究仅包括确诊或疑似COVID-19的住院患者。未见有研究关注非住院者、不同用药剂量或时间，或是提供有关生活质量的信息。

有10项研究比较了皮质类固醇加常规照护和常规照护与有无安慰剂

• 皮质类固醇可能会略微降低任何原因所致的死亡人数，最长是治疗后60天内（9项研究，7930名受试者）。
• 有1项研究（299名受试者）报告到，研究开始时的带机者，使用皮质类固醇后，非带机天数超过常规照护组，所以皮质类固醇可能会改善患者症状。
• 有4项研究（427名受试者）报告到，治疗开始时的未带机者是否会在稍后需要带机，但我们未能合并相关研究结果，因此我们并不确定，与常规照护相比，使用皮质类固醇的患者的症状是否会加重。
• 我们不知道，皮质类固醇是否会增加或降低严重不良反应（2项研究，678名受试者）、任何不良反应（5项研究，660名受试者）或医院内感染（5项研究，660名受试者）。

甲基强的松龙与地塞米松（1项研究，86名受试者）

• 我们不知道，在治疗后28天内，与地塞米松相比，皮质类固醇甲基强的松龙是否减少了任何原因所致的死亡人数。
• 我们不知道，与地塞米松相比，甲基强的松龙是否使患者症状恶化，这是根据其在治疗后28天内是否需要机械通气判断的。
• 此研究并未提供其他任何我们所感兴趣的信息。

证据的局限性有什么？

关于皮质类固醇对任何原因所致的死亡方面的影响，我们有中等可信度证据。然而，我们在其他证据方面的可信度却是低到极低，因为相关研究未采用最严谨的方法，对研究结果的记录和报告方式也各有差异。我们未发现有任何关于生活质量的证据，也未见有来自低收入国家或COVID-19轻症或无症状非住院者的有关证据。

证据的更新时效如何？

我们的证据更新至2021年4月16日。

结论: 

中等质量证据表明，全身用皮质类固醇可能会略微降低因有症状而住院的COVID-19患者的全因死亡率。低质量证据表明，可能也会降低无呼吸机天数。我们既然无法调整早亡对后续终点的影响，机械通气结局和危害的相关发现在治疗决策方面的应用是有限的。目前，未见有关无症状者或轻症者（非住院受试者）的研究证据。

急需针对特定病情程度的患病亚组人群的高质量证据，我们提议根据呼吸支持程度进行随机分组。这也适用于对不同类型和剂量的皮质类固醇的比较或亚组间的比较。除了死亡率，其他结局也应测量和适当分析，若适用，应考虑死亡造成的混杂。

我们在临床试验注册库中找到了42项正在进行的和16项已完成但尚未发表的RCTs，这表明，效应估计和证据质量在未来可能有变化。大多数正在进行的研究是针对基线时就需要有呼吸支持者。本综述采用实时法（living approach），因此我们会继续更新我们的检索，并纳入符合条件的临床试验和所发表的数据。

作者：Wagner C, Griesel M, Mikolajewska A, Mueller A, Nothacker M, Kley K, Metzendorf M-I, Fischer A-L, Kopp M, Stegemann M, Skoetz N, Fichtner F；译者：臧渝梨，Cochrane Hong Kong, 香港中文大学医学院那打素护理学院；审校：徐添天，北京中医药大学循证医学中心；编辑排版：索于思、张晓雯，北京中医药大学循证医学中心

相关文章链接

【Cochrane Plain Language Summary】

Are corticosteroids (anti-inflammatory medicines) given orally or by injection an effective treatment for people with COVID-19?

Key messages

• Corticosteroids (anti-inflammatory medicines) given orally or by injection (systemic) are probably effective treatments for people hospitalised with COVID-19. We don’t know whether they cause unwanted effects. 

• We don’t know which systemic corticosteroid is the most effective. We found no evidence about people without symptoms or with mild COVID-19 who were not hospitalised. 

• We found 42 ongoing studies and 16 completed studies that have not published their results. We will update this review when we find new evidence.    

What are corticosteroids?

Corticosteroids are anti-inflammatory medicines that reduce redness and swelling. They also reduce the activity of the immune system, which defends the body against disease and infection. Corticosteroids are used to treat a variety of conditions, such as asthma, eczema, joint strains and rheumatoid arthritis. 

Systemic corticosteroids can be swallowed or given by injection to treat the whole body. High doses of corticosteroids taken over a long time may cause unwanted effects, such as increased appetite, difficulty sleeping and mood changes. 

Why are corticosteroids possible treatments for COVID-19? 

COVID-19 affects the lungs and airways. As the immune system fights the virus, the lungs and airways become inflamed, causing breathing difficulties. Corticosteroids reduce inflammation, so may reduce the need for breathing support with a ventilator (a machine that breathes for a patient). Some patients’ immune systems overreact to the virus causing further inflammation and tissue damage; corticosteroids may help to control this response.

What did we want to find out?

We wanted to know whether systemic corticosteroids are an effective treatment for people with COVID-19 and whether they cause unwanted effects.

We were interested in:

• deaths from any cause up to 14 days after treatment, or longer if reported;
• whether people got better or worse after treatment, based on their need for breathing support;
• quality of life;
• unwanted effects and infections caught in hospital.

What did we do? 
We searched for studies that investigated systemic corticosteroids for people with mild, moderate or severe COVID-19. People could be any age, sex or ethnicity.

Studies could compare:

• corticosteroids plus usual care versus usual care with or without placebo (sham medicine);
• one corticosteroid versus another;
• corticosteroids versus a different medicine;
• different doses of a corticosteroid; or
• early versus late treatment.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find? 

We found 11 studies with 8075 people. About 3000 people received corticosteroids, mostly dexamethasone (2322 people). Most studies took place in high-income countries. 

We also found 42 ongoing studies, and 16 completed studies that have not yet published their results. 

Main results

Ten studies compared corticosteroids plus usual care versus usual care with or without placebo. Only one study compared two corticosteroids. The studies included only hospitalised people with confirmed or suspected COVID-19. No studies looked at non-hospitalised people, different doses or timing, or provided information about quality of life.

Corticosteroids plus usual care compared to usual care with or without placebo (10 studies)

• Corticosteroids probably reduce the number of deaths from any cause slightly, up to 60 days after treatment (9 studies, 7930 people).
• One study (299 people) reported that people on a ventilator at the start of the study were ventilation-free for more days with corticosteroids than with usual care, so corticosteroids may improve people’s symptoms.
• Four studies (427 people) reported whether people not on a ventilator at the start of treatment later needed to be put on a ventilator, but we could not pool the studies’ results, so we are unsure if people’s symptoms get worse with corticosteroids or usual care.
• We don’t know if corticosteroids increase or reduce serious unwanted effects (2 studies, 678 people), any unwanted effects (5 studies, 660 people), or infections caught in hospital (5 studies, 660 people).

Methylprednisolone versus dexamethasone (1 study, 86 people)

• We don’t know whether the corticosteroid methylprednisolone reduces the number of deaths from any cause compared to dexamethasone in the 28 days after treatment.
• We don’t know if methylprednisolone worsens people’s symptoms compared to dexamethasone, based on whether they needed ventilation in the 28 days after treatment.
• The study did not provide information about anything else we were interested in.

What are the limitations of the evidence?

We are moderately confident in the evidence about corticosteroids’ effect on deaths from any cause. However, our confidence in the other evidence is low to very low, because studies did not use the most robust methods, and the way results were recorded and reported differed across studies. We did not find any evidence on quality of life and there was no evidence from low-income countries or on people with mild COVID-19 or no symptoms, who were not hospitalised. 

How up to date is this evidence?

Our evidence is up to date to 16 April 2021.

Authors' conclusions: 

Moderate-certainty evidence shows that systemic corticosteroids probably slightly reduce all-cause mortality in people hospitalised because of symptomatic COVID-19. Low-certainty evidence suggests that there may also be a reduction in ventilator-free days. Since we are unable to  adjust for the impact of early death on subsequent endpoints, the findings for ventilation outcomes and harms have limited applicability to inform treatment decisions. Currently, there is no evidence for asymptomatic or mild disease (non-hospitalised participants). 

There is an urgent need for good-quality evidence for specific subgroups of disease severity, for which we propose level of respiratory support at randomisation. This applies to the comparison or subgroups of different types and doses of corticosteroids, too. Outcomes apart from mortality should be measured and analysed appropriately taking into account confounding through death if applicable. 

We identified 42 ongoing and 16 completed but not published RCTs in trials registries suggesting possible changes of effect estimates and certainty of the evidence in the future. Most ongoing studies target people who need respiratory support at baseline. With the living approach of this review, we will continue to update our search and include eligible trials and published data.

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