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.

Read the full abstract...
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. So far, systemic corticosteroids are one of the few treatment options for COVID-19. Nonetheless, size of effect, certainty of the evidence, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated.

Objectives: 

To assess whether systemic corticosteroids are effective and safe in the treatment of people with COVID-19, and to keep up to date with the evolving evidence base using a living systematic review approach.

Search strategy: 

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 16 April 2021.

Selection criteria: 

We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19, irrespective of disease severity, participant age, gender or ethnicity. 

We included any type or dose of systemic corticosteroids. We included the following comparisons: systemic corticosteroids plus standard care versus standard care (plus/minus placebo), dose comparisons, timing comparisons (early versus late), different types of corticosteroids and systemic corticosteroids versus other active substances. 

We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome or Middle East respiratory syndrome), 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 evidence using the GRADE approach for the following outcomes: all-cause mortality, ventilator-free days, new need for invasive mechanical ventilation, quality of life, serious adverse events, adverse events, and hospital-acquired infections.

Main results: 

We included 11 RCTs in 8075 participants, of whom 7041 (87%) originated from high-income countries. A total of 3072 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 2322). We also identified 42 ongoing studies and 16 studies reported as being completed or terminated in a study registry, but without results yet. 

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 10 RCTs (7989 participants), one of which did not report any of our pre-specified outcomes and thus our analysis included outcome data from nine studies. 

All-cause mortality (at longest follow-up available): systemic corticosteroids plus standard care probably reduce all-cause mortality slightly in people with COVID-19 compared to standard care alone (median 28 days: risk difference of 30 in 1000 participants fewer than the control group rate of 275 in 1000 participants; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.80 to 1.00; 9 RCTs, 7930 participants; moderate-certainty evidence). 

Ventilator-free days: corticosteroids may increase ventilator-free days (MD 2.6 days more than control group rate of 4 days, 95% CI 0.67 to 4.53; 1 RCT, 299 participants; low-certainty evidence). Ventilator-free days have inherent limitations as a composite endpoint and should be interpreted with caution. 

New need for invasive ventilation: the evidence is of very low certainty. Because of high risk of bias arising from deaths that occurred before ventilation we are uncertain about the size and direction of the effects. Consequently, we did not perform analysis beyond the presentation of descriptive statistics. 

Quality of life/neurological outcome: no data were available.

Serious adverse events: we included data on two RCTs (678 participants) that evaluated systemic corticosteroids compared to standard care (plus/minus placebo); for adverse events and hospital-acquired infections, we included data on five RCTs (660 participants). Because of high risk of bias, heterogeneous definitions, and underreporting we are uncertain about the size and direction of the effects. Consequently, we did not perform analysis beyond the presentation of descriptive statistics (very low-certainty evidence).   

Different types, dosages or timing of systemic corticosteroids 

We identified one study that compared methylprednisolone with dexamethasone. The evidence for mortality and new need for invasive mechanical ventilation is very low certainty due to the small number of participants (n = 86). No data were available for the other outcomes.

We did not identify comparisons of different dosages or timing.

Outpatients with asymptomatic or mild disease

Currently, there are no studies published in populations with asymptomatic infection or mild disease.

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