Treatments for moderate to severe COVID-19: Cochrane evidence

Sarah Chapman and Selena Ryan-Vig highlight Cochrane evidence on treatments that have been investigated for people in hospital with moderate-to-severe COVID-19.

The blog will be kept up to date with the most recent version of each Cochrane Review. This is a fast-moving field. You can view NICE’s rapid guideline on managing COVID-19 for the latest information about treating COVID-19 in the UK. You can also view the living guideline by topic area.

You can either scroll through this page or click on any of the links below to jump to the relevant section. You can also read our blog on treatments for mild COVID-19: Cochrane evidence.

1

Antibiotics (Azithromycin)

Key messages

  • There is high-certainty evidence that azithromycin has no effect on the number of deaths in the 28 days after treatment.
  • It probably has no effect on the patient’s condition, heart rhythm problems, or on the number of serious unwanted events.
  • It may slightly increase unwanted effects.

The evidence

The evidence comes from the Cochrane Review Antibiotics for the treatment of COVID‐19 (published October 2021). It included 11 studies with 11,281 people, comparing antibiotics with placebo (a dummy treatment that looks the same as the medicine but lacks the active ingredient), standard care alone or another antibiotic. Seven of the studies included people with moderate to severe COVID‐19 in hospital. Azithromycin was the only antibiotic investigated so we do not know the effects of other antibiotics for treating COVID-19.

Potential relevance of this treatment for COVID-19

Antibiotics are cheap medicines, widely used to treat bacterial infections. Antibiotics have been studied as a potential treatment for COVID-19. This is because some laboratory studies have suggested that some antibiotics slow the reproduction of certain viruses, including SARS-CoV-2, the virus that causes COVID-19. There has been particular interest in one antibiotic, azithromycin, as some laboratory studies have indicated it may reduce inflammation and viral activity. But we need good evidence before using antibiotics for COVID-19. This is because overuse and/or misuse of antibiotics can lead to ‘antimicrobial resistance’ where, ultimately, antibiotics stop working.

Find out more

Cochrane Clinical Answer: For adults hospitalized with moderate to severe COVID‐19, what are the effects of azithromycin?

2

Anticoagulants (blood thinners)

Key messages

  • People hospitalised with COVID-19 who receive anticoagulants (blood thinners) may be less likely to die than people who do not receive blood thinners, but the evidence is very uncertain.
  • Higher doses of blood thinners, compared to lower doses, make little to no difference to the risk of dying. However, people on higher doses are more likely to experience minor bleeding compared to those on lower doses, and are probably slightly more likely to experience major bleeding. Higher doses of blood thinners probably reduce pulmonary embolism, but they may have little to no effect on the risk of deep vein thrombosis or on the length of time patients spend in hospital.

The evidence

The evidence comes from a Cochrane Review, Anticoagulants for people hospitalised with COVID‐19 (published March 2022). The review authors found seven studies with 16,185 people hospitalised with COVID‐19 in either intensive care units, hospital wards or emergency departments. 

 It is very likely that new studies will not change the evidence about the effects of different doses of blood thinners on death rate and minor bleeding. However, high‐quality studies are still needed to address uncertainties. For example, how does giving blood thinners compare to no treatment? How do different blood thinners compare? 

Potential relevance of this treatment for COVID-19

Around 16% of people hospitalised with COVID‐19 experience problems with their blood and blood vessels, leading to blood clots forming in the arteries, veins and lungs. These clots can travel to other parts of the body, where they may cause blockages leading to heart attacks or strokes. Nearly half of all people with severe COVID‐19, in intensive care units, may develop clots in their veins or arteries. 

Anticoagulants are blood-thinning medicines that can prevent harmful blood clots from forming (deep vein thrombosis). Some guidelines recommend giving anticoagulants when people are first admitted to hospital with COVID‐19 to prevent clots from developing, rather than waiting to see whether clots develop and then treating them with blood thinners. It’s important to know what the potential benefits and harms are.

Find out more

3

Care bundles for people with COVID-19 or related conditions in intensive care

Key message

A Cochrane scoping review has described the existing evidence. There now needs to be a systematic review of this evidence.

The evidence

The authors of the scoping review care bundles for improving outcomes in patients with COVID-19 or related conditions in intensive care (published December 2020), describing (rather than synthesising) the existing evidence, found 21 published studies and three ongoing studies. Seven included patients with COVID-19. There now needs to be a systematic review of this evidence.

Most care bundles involved practices related to breathing support or ventilator settings, or the positioning of a patient, and COVID‐19‐specific studies also focused on infection control and use of personal protective equipment (PPE). 

Find out more

Cochrane Clinical Answer: What evidence is available on care bundles for improving outcomes in people with COVID‐19 in the intensive care unit (ICU)?

4

Chloroquine or hydroxychloroquine

Key messages

  • There is high-certainty evidence that hydroxychloroquine (HCQ) makes little to no difference to the risk of dying from the disease, compared with standard care or placebo.
  • There is moderate-certainty evidence that it probably does not reduce the chances of needing mechanical ventilation.
  • The risks of adverse events are probably increased with HCQ.

The evidence

The evidence is from the Cochrane Review Chloroquine or hydroxychloroquine for prevention and treatment of COVID‐19 (published February 2021). Of the 12 included trials, nine were in hospitalised patients and three in non-hospitalised patients. All the studies currently included in the review investigated hydroxychloroquine and not chloroquine. This Cochrane Review was a joint winner of the Harding Prize for Useful and Trustworthy Communication in 2021.

Potential relevance of this treatment for COVID-19

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antimalarial drugs since the 1940s. Some researchers have suggested that both CQ and HCQ could be clinically effective against COVID‐19. 

Find out more

5

Colchicine

Key message

Colchicine probably has little to no benefit for hospitalised people with moderate-to-severe COVID‐19, and the evidence about its side effects is very uncertain.

The evidence

The evidence comes from a Cochrane Review Colchicine for the treatment of COVID‐19 (published October 2021). It includes four studies (three with 11,525 hospitalised people and one with 4488 non‐hospitalised people). Two studies compared colchicine plus usual care with usual care alone. The other two studies compared colchicine with usual care and placebo. There are many ongoing studies that may help give a clearer answer about the possible benefits and harms of colchicine. The reviewers are searching for new evidence on a weekly basis and will update the review when they identify new, relevant evidence.

Potential relevance of this treatment for COVID-19

Colchicine is an anti‐inflammatory drug used to reduce swelling and inflammation. It is often used to treat gout, a condition where people’s joints become painful and swollen. Researchers are interested in colchicine as a possible COVID-19 treatment as it might help reduce inflammation caused by COVID-19. It is also important to know about its possible side effects, as it is known that colchicine may be harmful to people with certain health conditions, such as kidney or liver problems, or if you take too much of it.

Find out more

Cochrane Clinical Answer: What are the effects of colchicine for treatment of moderate to severe COVID‐19?

6

Convalescent plasma

Key message

There is high-certainty evidence that convalescent plasma has little to no benefit for the treatment of people with moderate to severe COVID‐19. 

The evidence

The evidence is from a Cochrane Review Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review (last updated May 2021). There is reliable evidence from 12 studies on 48,349 people with moderate-to severe COVID-19. Nine of the studies compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma.

Potential relevance of this treatment for COVID-19

People who have recovered from a viral infection carry virus-specific antibodies in their blood plasma. Convalescent plasma (plasma from people who have recovered from the viral infection) has been used effectively to treat some treat viral infections. This has led some researchers to consider convalescent plasma as a potential treatment for COVID-19.

Find out more

7

Corticosteroids, given orally or by injection

Key messages

  • Compared with placebo or usual care, corticosteroids given by mouth or injection probably slightly reduce the risk of dying from any cause, up to 60 days after treatment.
  • They may also improve symptoms.
  • It is uncertain whether they reduce the likelihood of needing mechanical ventilation and whether they cause unwanted effects.

The evidence

This evidence on corticosteroids (mostly dexamethasone) comes from a Cochrane Review Systemic corticosteroids for the treatment of COVID‐19 (published August 2021). The authors found 11 studies with 8075 people hospitalised with COVID‐19. There are many ongoing studies. The review will be updated to include their findings and hopefully resolve some of these unanswered questions.

Potential relevance of this treatment for COVID-19

Corticosteroids are anti‐inflammatory medicines, commonly used to treat a variety of conditions. As the immune system fights COVID-19, the lungs and airways become inflamed, causing breathing difficulties. Corticosteroids are a possible treatment for COVID-19 because they may reduce this inflammation, thereby reducing the need for breathing support with a ventilator. Some patients’ immune systems overreact to the virus, causing further inflammation and tissue damage; corticosteroids may also help to control this response.

Find out more

8

Interleukin‐1 blocking medicines

Key messages

Compared with usual care (alone or with placebo), treating patients using either anakinra or canakinumab:

  • probably results in little to no improvement in COVID‐19 symptoms at 28 days after treatment – and it is uncertain whether they make a difference at 60 days.
  • probably results in little to no increase in any unwanted effects.

The evidence is very uncertain about whether either anakinra or canakinumab:

  • make a difference to the risk of dying.
  • have any serious unwanted effects.

The evidence

The evidence comes from the Cochrane Review Interleukin‐1 blocking agents for treating COVID‐19 (published January 2022). The review includes six studies with 2132 people with COVID-19. All the people in the studies were in hospital, but some were more seriously ill than others. Three interleukin-1 blocking medicines are available: anakinra, canakinumab and rilonacept – but the authors found no studies looking at rilonacept. Four studies looked at anakinra and two looked at canakinumab. The authors found 16 ongoing studies and will update their review when new data are available.

Potential relevance of this treatment for COVID-19

Interleukin‐1 is a type of protein which triggers inflammation to help fight infection. In some people with COVID-19, the immune system can overreact, producing dangerously high levels of inflammation and tissue damage. Interleukin-1 blockers are medicines that reduce inflammation and may help the immune system to fight COVID‐19.

Find out more

Cochrane Clinical Answer: For people with moderate, severe or critical COVID‐19 illness, what are the effects of interleukin 1 (IL‐1) blocking agents (anakinra or canakinumab)?

9

Interleukin‐6 blocking medicines

Key messages

Compared with placebo or standard care, tocilizumab:

  • reduces the number of people who die, of any cause, after 28 days.
  • probably makes little to no difference to time to leaving hospital or clinical symptoms. 
  • probably slightly reduces the number of serious unwanted effects such as life-threatening conditions or death. 
  • its effect on the severity of COVID-19 is uncertain. 

Compared with  placebo or standard care, sarilumab:

  • probably does not cause more unwanted effects than placebo.
  • There is uncertainty about the other effects of sarilumab

The evidence

This evidence comes from the Cochrane Review Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review (published March 2021). The review includes 10 studies with almost 7000 people with COVID-19, comparing one of two interleukin-6 blocking medicines, tocilizumab and sarilumab, with placebo or standard care. The review authors found some ongoing trials of interleukin-blocking medicines used to treat COVID-19 that haven’t yet reported results. This is a living systematic review and the results will be updated with new data as soon as possible.

Potential relevance of this treatment for COVID-19

Interleukin-6 is a protein involved in immune responses. Medicines that block interleukin-6 are used to treat other conditions, like rheumatoid arthritis, that involve an ‘over-reactive’ immune system. They have been used for treating severe COVID-19.

Find out more

Cochrane Clinical Answer: For adults with COVID-19, what are the effects of the interleukin-6 blocking agents tocilizumab and sarilumab?

10

Interventions for palliative symptom control in people with COVID-19

Key messages

  • There is a lack of evidence on interventions for palliative symptom control in specifically in people with COVID-19.
  • Commenting on the review, Scott Murray, Emeritus Professor of Primary Palliative Care (University of Edinburgh) pointed out that evidence among people with other conditions suggests there are benefits of a holistic approach to breathlessness (based on the physical, psychological, social and spiritual needs of individual patients, and their families or carers).

The evidence

A Cochrane Review Interventions for palliative symptom control in COVID‐19 patients (published August 2021), and its associated Cochrane Clinical Answer, has highlighted the need for evidence to guide healthcare staff and other caregivers caring for people dying from COVID-19, who may be experiencing distressing symptoms such as delirium and breathlessness. For this review, the authors identified just four retrospective cohort studies from the United Kingdom and Sweden. None of the studies included a comparator, or provided information on quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; or adverse events and serious adverse events. Nor were outcomes for symptom relief assessed by patients themselves. The review authors conclude “we cannot draw any conclusions about the effectiveness or safety [of interventions] based on the identified evidence” and will update the review when new evidence becomes available.

Commenting on the review, Scott Murray, Emeritus Professor of Primary Palliative Care (University of Edinburgh), said “However, it would be unethical to deny people dying of COVID-19 a palliative care approach as there is a great deal that is known about the general care of people with other conditions that could be applied to people with COVID-19. Also there is much evidence that a holistic approach to breathlessness (based on the physical, psychological, social and spiritual needs of individual patients, and their families or carers) improves quality of life. See:

11

Ivermectin

Key message

The effectiveness and safety of ivermectin to prevent or treat COVID-19 are uncertain.

The evidence

The evidence comes from the Cochrane Review Ivermectin for preventing and treating COVID‐19 (published July 2021). It includes 14 studies with 1678 people comparing ivermectin to no treatment, placebo, or standard care.

Maria Popp and Stephanie Weibel, the main authors of the review, said: “Current evidence does not support using ivermectin for treating or preventing of COVID-19 unless they are part of well-designed randomized trials.” The authors found 31 ongoing studies which they will assess for inclusion in the review when the results become available.

Potential relevance of this treatment for COVID-19

Ivermectin, a medicine used to treat parasites, has been found in laboratory tests to slow the reproduction of the COVID-19 (SARS-CoV-2) virus, but very big doses would be needed in humans to have this effect.

Find out more

12

Monoclonal antibodies

Key message

“…current evidence is insufficient to draw meaningful conclusions” about whether monoclonal antibodies are an effective and safe treatment for COVID-19. 

The evidence

This evidence comes from the Cochrane Review SARS‐CoV‐2‐neutralising monoclonal antibodies for treatment of COVID‐19 (published September 2021). Commenting on the evidence gap, the review authors also noted that there are 36 ongoing studies which they hope will address these uncertainties.

Potential relevance of this treatment for COVID-19

Antibodies are made by the body as a defence against disease. They can also be produced in a laboratory, from cells taken from people who have recovered from a disease.

Antibodies that are designed to target only one specific protein – in this case, a protein on the virus that causes COVID‐19 – are ‘monoclonal’. They attach to the COVID‐19 virus and stop it from entering and reproducing in human cells. This may help to fight the infection.

Find out more

13

Oxygen therapy for adults in intensive care with acute respiratory distress syndrome (ARDS)

Key messages

It is very uncertain whether a higher or lower oxygen target is more beneficial in patients with ARDS who are receiving mechanical ventilation in an intensive care setting.

The evidence

The authors of a Cochrane rapid review on oxygen targets in the intensive care unit during mechanical ventilation for acute respiratory distress syndrome (published September 2020) found just one small study with 205 people. 

Potential relevance of this treatment for COVID-19

The review authors explain: “Acute respiratory distress syndrome (ARDS) is a very severe breathing problem with a high mortality rate (chance of dying). It has many potential causes, including viral infections such as COVID‐19, and there are no specific treatments for it except for giving patients oxygen via a ventilator (artificial breathing machine) on an intensive care unit, often for long periods of time. However, large amounts of oxygen (either a high concentration of oxygen or oxygen administered for a long period of time) are associated with increased harm due to other illnesses (e.g. heart attack or stroke).”

Find out more

You may also be interested in Cochrane Reviews on:

14

Remdesivir

Key messages

  • Remdesivir probably has little to no effect on deaths from any cause up to 28 days after treatment compared with placebo or usual care.
  • It is uncertain whether remdesivir improves or worsens patients’ condition, based on whether they needed more or less help with breathing.

The evidence

The evidence comes from the Cochrane Review Remdesivir for the treatment of COVID-19 (published August 2021). It includes 5 studies with 7452 people hospitalised with COVID‐19.

Potential relevance of this treatment for COVID-19

Remdesivir is a medicine that fights viruses. In laboratory studies, there have been some indications that it may stop the virus that causes COVID-19 from reproducing. 

Find out more

15

Vitamin D supplementation

Key message

The benefits and harms of vitamin D supplementation as a treatment of COVID‐19 are uncertain.

The evidence

A Cochrane Review on Vitamin D supplementation for the treatment of COVID‐19: a living systematic review (published May 2021) includes just three studies with 356 people with COVID-19 (including asymptomatic, mild, moderate and severe disease), comparing vitamin D supplementation with placebo or standard care. The authors found 21 ongoing studies and three completed studies without published results, so their findings are likely to change when the review is updated.

Potential relevance of this treatment for COVID-19

The review authors explain: “Vitamin D is important for healthy bones, teeth and muscles. It helps to regulate blood sugar, the heart and blood vessels, and the lungs and airways. It also has a role in boosting the body’s immune system. These are areas affected by COVID‐19, so giving vitamin D to people with COVID‐19 might help them to recover more quickly or have the disease less severely.”

Find out more

 

References (pdf)

Join in the conversation on Twitter with @CochraneUK or leave a comment on the blog.

Please note, we cannot give medical advice and do not publish comments that link to individual pages requesting donations or to commercial sites, or appear to endorse commercial products. We welcome diverse views and encourage discussion but we ask that comments are respectful and reserve the right to not publish any we consider offensive. Cochrane UK does not fact check – or endorse – readers’ comments, including any treatments mentioned.

Sarah and Selena have nothing to disclose.



Treatments for moderate to severe COVID-19: Cochrane evidence by Sarah Chapman and Selena Ryan-Vig

is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International

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