Go
Coronavirus (COVID-19) Treating moderate to severe COVID-19 in hospital

Treatments for moderate to severe COVID-19: Cochrane evidence

By // Comment(s)

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.

Page last updated: 31 July 2023 

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

1a

Antiplatelet agents

Key message

In hospitalised people with COVID-19, antiplatelet agents probably slightly reduce thrombotic events but probably do not affect deaths, clinical worsening or improvement in COVID‐19 compared with placebo or standard care. But antiplatelets may result in a slight increase in serious unwanted effects and probably increase major bleeding.

The evidence

The evidence comes from the Cochrane Review Antiplatelet agents for the treatment of adults with COVID‐19 (published July 2023). It includes four studies with 17,541 hospitalised people with moderate to severe COVID‐19 (and two studies with 4209 people with confirmed mild COVID‐19 who were not hospitalised). Treatment with antiplatelets was compared with standard care. The studies were conducted in high‐ to lower-middle-income settings using antiplatelets prior to vaccination roll‐outs. The review authors found a lack of evidence concerning quality of life assessments, adverse events and people with asymptomatic infection. They found ongoing studies that can be considered in future updates of this review.

Potential relevance of this treatment for COVID-19

Antiplatelets are a group of medicines that can prevent potentially fatal blood clots (‘thrombotic events’). People with COVID‐19 might be at risk from blood clots. Antiplatelets prevent clots from forming in the body, and this could in turn prevent complications that lead to death and clinical deterioration.

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 February 2023). The review included 33 studies with 24,861 participants (29 of these studies included people with moderate to severe COVID‐19. The other four studies included people with mild COVID‐19). The studies compared convalescent plasma to placebo treatment or standard care.

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

7a

Hyperimmune immunoglobulin (concentrated antibodies from people who have recovered from COVID‐19 or animals)

Key messages

  • It is uncertain whether hyperimmune immunoglobulin (a preparation made with antibodies from people who have recovered from COVID‐19) reduces deaths or serious unwanted effects in people hospitalized with moderate to severe COVID‐19. The evidence about possible unwanted effects is also uncertain.
  • However, a similar preparation made by injecting animals with certain antibodies may reduce deaths, and serious unwanted effects and may stop people’s condition getting worse.
  • The authors found 10 ongoing studies and will update this review when the results become available.

The evidence

This evidence comes from a Cochrane Review Hyperimmune immunoglobulin for people with COVID‐19 (published January 2023). The authors included five studies with 957 people hospitalised with COVID‐19. They found no studies that investigated people with asymptomatic or mild COVID‐19. The studies took place before or during the emergence of several new COVID‐19 variants and before widespread vaccine rollout.

Potential relevance of this treatment for COVID-19

Plasma from people who have recovered from COVID‐19 contains COVID‐19 antibodies, and can be used to make hyperimmune immunoglobulin. This is a concentrated product, containing high levels of antibodies that target the virus that causes COVID-19. Similar antibodies can be made from animal sources and used in humans.

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 30 days after treatment, in people hospitalised with symptomatic COVID-19, but the evidence is very uncertain on the risk of dying from any cause up to 120 days
  • The review authors found a potential advantage for people aged under 70 and for Black, Asian and people of a minority ethnic group
  • More evidence is needed to establish the most effective type, dose, or timing of systemic corticosteroids
  • There is a lack of, and need for, reliable data on safety
  • The review authors found 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, so their findings may change in the future.

The evidence

This evidence on corticosteroids (mostly dexamethasone) comes from a Living Cochrane Review Systemic corticosteroids for the treatment of COVID‐19 (updated November 2022). The authors included 16 studies with 9549 people hospitalised with COVID‐19 (there are no studies published in populations with asymptomatic infection or mild disease). 

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 to placebo or standard treatment, treatment with tocilizumab:

  • reduces the number of people with COVID-19 who die, of any cause, after 28 days;
  • probably makes little or no difference to clinical improvement (defined as leaving the hospital or improvement in COVID‐19 symptoms) around 28 days;
  • probably results in little or no difference in unwanted effects;
  • we are uncertain about the other effects of tocilizumab.

Compared to placebo or standard treatment, treatment with sarilumab:

  • probably makes little or no difference in clinical improvement around 28 days;
  • There is uncertainty about the other effects of sarilumab, including potential unwanted effects.

The authors found few studies assessing other IL‐6‐blocking medicines (clazakizumab, olokizumab, siltuximab, and levilimab), so we are uncertain about their potential benefits and harms.

The evidence

This evidence comes from the Cochrane Review Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review (published June 2023). The review includes 32 studies in 12,160 people with COVID‐19, comparing one of six interleukin-6 blocking medicines (tocilizumab, sarilumab, clazakizumab, siltuximab, olokizumab, and levilimab) with placebo or standard care. The most tested medicines were tocilizumab (20 studies) and sarilumab (nine studies). This is likely to be the last update of this living systematic review as there are few ongoing studies with few participants, and these are unlikely to change the conclusions of the latest version of this review.

Potential relevance of this treatment for COVID-19

When a person has COVID-19, their immune system is disrupted and overreacts. Interleukin-6 is a protein involved when the body’s immune system overreacts. Medicines that block interleukin-6 are used to treat other conditions, like rheumatoid arthritis, that involve an ‘over-reactive’ immune system. So the idea is that these medicines can help reduce inflammation and help the immune system to fight COVID-19. Interleukin-6 blocking agents have been used for treating severe COVID-19. 

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

“We found no evidence to support the use of ivermectin for treating COVID‐19 or preventing SARS‐CoV‐2 infection. The evidence base improved slightly in this update, but is still limited.”

The evidence

The evidence comes from the Cochrane Review Ivermectin for preventing and treating COVID‐19 (updated June 2022). It includes 11 trials with 3409 participants investigating ivermectin plus standard of care compared to standard of care plus/minus placebo. The review authors excluded seven trials that were in the previous version of the review (not prospectively registered or non-randomised) and included four new ones.

The review authors conclude:

“Based on the very low‐certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low‐certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events.”

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.

11a

Janus kinase inhibitors

Key messages

  • In hospitalised people, systemic Janus kinase inhibitors (JAK) probably result in fewer deaths and probably reduce the number of people who deteriorate clinically (for example, the number who go on to need mechanical ventilation)
  • Systemic JAK inhibitors probably make little or no difference to the occurrence of unwanted effects, but probably slightly decrease the occurrence of serious unwanted effects.
  • Systemic JAK inhibitors may result in little or no difference in the number of people getting infections in hospital.

The evidence

The evidence comes from the Cochrane Review Janus kinase inhibitors for the treatment of COVID‐19 (published June 2022). It included six studies with 11,145 people with COVID‐19. All the studies were in hospitalised people; most needed oxygen supplementation and few were mechanically ventilated at the time they entered the study.

The studies compared systemic JAK inhibitors (baricitinib in four studies, tofacitinib in one study and ruxolitinib in one study) to usual care (in addition to placebo). The review only looked at ‘systemic’ JAK inhibitors (taken orally, rather than those which are inhaled). The review authors found 13 ongoing studies and nine studies that are completed/terminated but not yet published. They will update this review in time.

Potential relevance of this treatment for COVID-19

In COVID‐19, the immune system sometimes overreacts, which can lead to a severe course of disease. JAK inhibitors can block parts of the immune system and counteract these effects. This is why JAK inhibitors might help treat COVID-19.

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 the risk of dying (from any cause) up to 150 days after treatment compared with placebo or usual care.
  • Remdesivir probably slightly increases the chance of hospitalized patients improving and getting discharged from hospital. It may also decrease the risk of becoming worse, based on whether patients needed more or less help with breathing.
  • Remdesivir may make little or no difference to the risk of adverse events (including serious adverse events).

The evidence

The evidence comes from the Cochrane Review Remdesivir for the treatment of COVID-19 (published January 2023). It includes 9 studies (8 of which looked at 10,656 people hospitalized with moderate to severe COVID‐19, the other study looked at people with mild 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.


Sarah Chapman and Selena Ryan-Vig

About Sarah Chapman and Selena Ryan-Vig

view all posts

Sarah and Selena are Cochrane UK’s Knowledge Brokers. Their role involves sharing evidence in accessible ways with those who could find it helpful for their health decision-making, and encouraging engagement with it through social media. Sarah trained and worked as a nurse, has degrees in History from the Universities of Oxford and Reading, and worked in health services research before joining Cochrane UK in 2007. She is a recent cochlear implant recipient (2021) and is a Patient Ambassador for the COACH Trial, a randomised controlled trial of cochlear implantation versus hearing aids in adults with severe hearing loss. Sarah tweets @SarahChapman30. Selena has a psychology degree from the University of Bath and has previously worked for a national charity that provides support for young women. With a colleague, Selena delivers interactive sessions to students from Years 10 to 13 to teach about evidence-based practice and to encourage critical thinking, particularly around healthcare claims made in the media.

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