Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Department of Anaesthesiology and Intensive Care, University of Leipzig Medical Center, Leipzig, Germany.
Cochrane Database Syst Rev. 2022 Nov 17;11(11):CD014963. doi: 10.1002/14651858.CD014963.pub2.
BACKGROUND: Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. Nonetheless, size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated. OBJECTIVES: To assess whether and at which doses systemic corticosteroids are effective and safe in the treatment of people with COVID-19, to explore equity-related aspects in subgroup analyses, and to keep up to date with the evolving evidence base using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 6 January 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19. We included any type or dose of systemic corticosteroids and the following comparisons: systemic corticosteroids plus standard care versus standard care, different types, doses and timings (early versus late) of corticosteroids. We excluded corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of the evidence using the GRADE approach for the following outcomes: all-cause mortality up to 30 and 120 days, discharged alive (clinical improvement), new need for invasive mechanical ventilation or death (clinical worsening), serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections. MAIN RESULTS: We included 16 RCTs in 9549 participants, of whom 8271 (87%) originated from high-income countries. A total of 4532 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 3766). These studies included participants mostly older than 50 years and male. We also identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 11 RCTs (8019 participants), one of which did not report any of our pre-specified outcomes and thus our analyses included outcome data from 10 studies. Systemic corticosteroids plus standard care compared to standard care probably reduce all-cause mortality (up to 30 days) slightly (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.97; 7898 participants; estimated absolute effect: 274 deaths per 1000 people not receiving systemic corticosteroids compared to 246 deaths per 1000 people receiving the intervention (95% CI 230 to 265 per 1000 people); moderate-certainty evidence). The evidence is very uncertain about the effect on all-cause mortality (up to 120 days) (RR 0.74, 95% CI 0.23 to 2.34; 485 participants). The chance of clinical improvement (discharged alive at day 28) may slightly increase (RR 1.07, 95% CI 1.03 to 1.11; 6786 participants; low-certainty evidence) while the risk of clinical worsening (new need for invasive mechanical ventilation or death) may slightly decrease (RR 0.92, 95% CI 0.84 to 1.01; 5586 participants; low-certainty evidence). For serious adverse events (two RCTs, 678 participants), adverse events (three RCTs, 447 participants), hospital-acquired infections (four RCTs, 598 participants), and invasive fungal infections (one study, 64 participants), we did not perform any analyses beyond the presentation of descriptive statistics due to very low-certainty evidence (high risk of bias, heterogeneous definitions, and underreporting). Different types, dosages or timing of systemic corticosteroids We identified one RCT (86 participants) comparing methylprednisolone to dexamethasone, thus the evidence is very uncertain about the effect of methylprednisolone on all-cause mortality (up to 30 days) (RR 0.51, 95% CI 0.24 to 1.07; 86 participants). None of the other outcomes of interest were reported in this study. We included four RCTs (1383 participants) comparing high-dose dexamethasone (12 mg or higher) to low-dose dexamethasone (6 mg to 8 mg). High-dose dexamethasone compared to low-dose dexamethasone may reduce all-cause mortality (up to 30 days) (RR 0.87, 95% CI 0.73 to 1.04; 1269 participants; low-certainty evidence), but the evidence is very uncertain about the effect of high-dose dexamethasone on all-cause mortality (up to 120 days) (RR 0.93, 95% CI 0.79 to 1.08; 1383 participants) and it may have little or no impact on clinical improvement (discharged alive at 28 days) (RR 0.98, 95% CI 0.89 to 1.09; 200 participants; low-certainty evidence). Studies did not report data on clinical worsening (new need for invasive mechanical ventilation or death). For serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections, we did not perform analyses beyond the presentation of descriptive statistics due to very low-certainty evidence. We could not identify studies for comparisons of different timing and systemic corticosteroids versus other active substances. Equity-related subgroup analyses We conducted the following subgroup analyses to explore equity-related factors: sex, age (< 70 years; ≥ 70 years), ethnicity (Black, Asian or other versus White versus unknown) and place of residence (high-income versus low- and middle-income countries). Except for age and ethnicity, no evidence for differences could be identified. For all-cause mortality up to 30 days, participants younger than 70 years seemed to benefit from systemic corticosteroids in comparison to those aged 70 years and older. The few participants from a Black, Asian, or other minority ethnic group showed a larger estimated effect than the many White participants. Outpatients with asymptomatic or mild disease There are no studies published in populations with asymptomatic infection or mild disease. AUTHORS' CONCLUSIONS: Systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in people hospitalised because of symptomatic COVID-19, while the evidence is very uncertain about the effect on all-cause mortality up to 120 days. For younger people (under 70 years of age) there was a potential advantage, as well as for Black, Asian, or people of a minority ethnic group; further subgroup analyses showed no relevant effects. Evidence related to the most effective type, dose, or timing of systemic corticosteroids remains immature. Currently, there is no evidence on asymptomatic or mild disease (non-hospitalised participants). Due to the low to very low certainty of the current evidence, we cannot assess safety adequately to rule out harmful effects of the treatment, therefore there is an urgent need for good-quality safety data. Findings of equity-related subgroup analyses should be interpreted with caution because of their explorative nature, low precision, and missing data. We identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, suggesting there may be possible changes of the effect estimates and certainty of the evidence in the future.
背景:全身性皮质类固醇用于治疗 COVID-19 患者,因为它们可以对抗过度炎症。现有的综合证据表明,皮质类固醇对死亡率有轻微的益处。然而,作用大小、最佳治疗方案以及最有可能受益的患者的选择仍有待评估。
目的:评估全身性皮质类固醇治疗 COVID-19 患者的有效性和安全性,探讨亚组分析中的公平性问题,并通过使用实时系统评价方法及时更新证据基础。
检索方法:我们检索了 Cochrane COVID-19 研究注册库(包括 PubMed、Embase、CENTRAL、ClinicalTrials.gov、WHO ICTRP 和 medRxiv)、Web of Science(科学引文索引、新兴引文索引)和世界卫生组织 COVID-19 全球冠状病毒疾病文献,以确定截至 2022 年 1 月 6 日已完成和正在进行的研究。
选择标准:我们纳入了评估 COVID-19 患者全身性皮质类固醇治疗的随机对照试验(RCTs)。我们纳入了任何类型或剂量的全身性皮质类固醇,以及以下比较:全身性皮质类固醇加标准治疗与标准治疗、不同类型、剂量和时间(早期与晚期)的皮质类固醇。我们排除了皮质类固醇与其他活性物质的组合与标准治疗、局部或吸入皮质类固醇以及皮质类固醇治疗长 COVID 的比较。
数据收集和分析:我们遵循了标准的 Cochrane 方法。使用 Cochrane“风险偏倚”2 工具评估纳入研究的风险偏倚,我们使用 GRADE 方法评估以下结局的证据确定性:30 天和 120 天的全因死亡率、出院时(临床改善)、新需要有创机械通气或死亡(临床恶化)、严重不良事件、不良事件、医院获得性感染和侵袭性真菌感染。
主要结果:我们纳入了 16 项 RCTs,涉及 9549 名参与者,其中 8271 名(87%)来自高收入国家。4532 名参与者被随机分配到皮质类固醇组,其中大多数接受了地塞米松(n=3766)。这些研究包括年龄大多在 50 岁以上和男性的参与者。我们还确定了 42 项正在进行的和 23 项已完成的研究,这些研究缺乏已发表的结果或研究设计的相关信息。
确诊或疑似有症状 COVID-19 的住院患者
全身性皮质类固醇加标准治疗与标准治疗加/不加安慰剂
我们纳入了 11 项 RCTs(8019 名参与者),其中一项研究没有报告我们预先指定的任何结局,因此我们的分析包括了 10 项研究的数据。与标准治疗相比,全身性皮质类固醇可能会稍微降低全因死亡率(30 天)(风险比(RR)0.90,95%置信区间(CI)0.84 至 0.97;7898 名参与者;估计绝对效应:与不接受全身性皮质类固醇相比,每 1000 人中每 1000 人中死亡人数减少 274 人(95%CI 每 1000 人中 230 至 265 人);中度确定性证据)。关于全因死亡率(120 天)的证据非常不确定(RR 0.74,95%CI 0.23 至 2.34;485 名参与者)。临床改善(28 天出院)的可能性可能会略有增加(RR 1.07,95%CI 1.03 至 1.11;6786 名参与者;低确定性证据),而临床恶化(新需要有创机械通气或死亡)的风险可能会略有降低(RR 0.92,95%CI 0.84 至 1.01;5586 名参与者;低确定性证据)。对于严重不良事件(两项 RCT,678 名参与者)、不良事件(三项 RCT,447 名参与者)、医院获得性感染(四项 RCT,598 名参与者)和侵袭性真菌感染(一项研究,64 名参与者),由于低确定性证据(高风险偏倚、定义不明确和报告不足),我们无法进行除描述性统计以外的任何分析。
不同类型、剂量或时间的全身性皮质类固醇
我们发现了一项比较甲泼尼龙和地塞米松的 RCT(86 名参与者),因此,关于地塞米松对全因死亡率(30 天)的影响的证据非常不确定(RR 0.51,95%CI 0.24 至 1.07;86 名参与者)。这项研究没有报告其他感兴趣的结局。我们纳入了四项 RCTs(1383 名参与者),比较了高剂量地塞米松(12 毫克或更高)与低剂量地塞米松(6 毫克至 8 毫克)。与低剂量地塞米松相比,高剂量地塞米松可能会降低全因死亡率(30 天)(RR 0.87,95%CI 0.73 至 1.04;1269 名参与者;低确定性证据),但关于高剂量地塞米松对全因死亡率(120 天)的影响的证据非常不确定(RR 0.93,95%CI 0.79 至 1.08;1383 名参与者),并且它可能对临床改善(28 天出院)没有影响或影响很小(RR 0.98,95%CI 0.89 至 1.09;200 名参与者;低确定性证据)。研究没有报告新需要有创机械通气或死亡的临床恶化的数据。对于严重不良事件、不良事件、医院获得性感染和侵袭性真菌感染,我们没有进行除描述性统计以外的任何分析,因为证据的确定性非常低。我们无法对不同时间和全身性皮质类固醇与其他活性物质的比较进行分析。
公平性相关的亚组分析
我们进行了以下亚组分析,以探讨公平性相关因素:性别(男性;女性)、年龄(<70 岁;≥70 岁)、种族(黑人、亚洲或其他种族与白人种族;未知种族)和居住地(高收入国家与低收入和中等收入国家)。除了年龄和种族,没有证据表明存在差异。对于 30 天的全因死亡率,年龄小于 70 岁的参与者与年龄大于 70 岁的参与者相比,接受全身性皮质类固醇治疗可能会获益。少数来自黑人、亚洲或其他少数族裔的参与者的估计效果大于许多白人参与者。无症状或轻度疾病的门诊患者
目前没有在无症状感染或轻度疾病人群中发表的研究。
作者结论:全身性皮质类固醇可能会稍微降低因有症状 COVID-19 而住院的患者的全因死亡率,30 天内的死亡率,而关于 120 天内的死亡率的证据非常不确定。对于年龄较小(<70 岁)的人,以及黑人、亚洲人或少数族裔的人,可能会有优势;进一步的亚组分析表明没有相关的益处。关于最有效类型、剂量或时间的全身性皮质类固醇的证据仍不成熟。目前,对于无症状或轻度疾病(非住院患者)的患者,没有证据。由于当前证据的确定性低至非常低,我们无法充分评估治疗的安全性以排除有害影响,因此迫切需要高质量的安全性数据。公平性相关亚组分析的结果应谨慎解释,因为其具有探索性、精度低和数据缺失的特点。我们确定了 42 项正在进行的和 23 项已完成的研究,这些研究缺乏已发表的结果或研究设计的相关信息,这表明未来可能会改变效应估计值和证据的确定性。
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