Treatments for mild COVID-19: Cochrane evidence

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

Page last updated: 06 February 2024

• Antibiotics (Azithromycin)
• Antiplatelet agents
• Colchicine
• Convalescent plasma
• Favipiravir
• Inhaled corticosteroids
• Ivermectin
• Monoclonal antibodies
• Nirmatrelvir combined with ritonavir
• Remdesivir
• Vitamin D supplementation

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Antibiotics (Azithromycin)

Key messages 

• For people with mild COVID-19, treated as outpatients, azithromycin may have little to no benefit.
• The evidence about possible serious harms is uncertain.
• There is not enough information about possible mild side effects, heart rhythm problems, or quality of life.

The evidence

The evidence comes from the Cochrane Review Antibiotics for the treatment of COVID‐19 (published October 2021). Four studies compared antibiotics with placebo (a dummy treatment that looks the same as the medicine but lacks the active ingredient), standard care alone or another antibiotic in people with mild COVID-19. Seven other studies looked at people with moderate-to-severe COVID-19. (Read more: Treatments for moderate to severe COVID-19: Cochrane evidence). 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 with asymptomatic or mild COVID‐19, what are the effects of azithromycin?

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Antiplatelet agents

Key message

In non‐hospitalised people, antiplatelets slightly decrease thrombotic events. They may result in little to no difference in deaths or serious unwanted effects, but the evidence on admission to hospital or death and major bleeding events is very uncertain.

The evidence

The evidence comes from the Cochrane Review Antiplatelet agents for the treatment of adults with COVID‐19 (published July 2023). It includes two studies with 4209 people with confirmed mild COVID‐19 who were not hospitalised (and four studies with over 17000 hospitalised people with moderate to severe COVID‐19). Treatment with antiplatelets was compared with standard care. The studies were conducted in high‐ to lower-middle-income settings using antiplatelets before 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.

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Colchicine

Key message

In non‐hospitalised people with no symptoms or mild COVID‐19, it is uncertain whether colchicine prevents deaths or side effects. However, it probably slightly reduces the risk of hospitalisation and serious side effects.

The evidence

The evidence comes from the 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). The study in non-hospitalised people compared colchicine to placebo or standard care alone. 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 asymptomatic or mild COVID‐19?

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Convalescent plasma

Key message

Convalescent plasma may have little to no benefit for the treatment of people with mild COVID-19, or people without symptoms.

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. However, only four of these studies included people with mild COVID-19. Most of them (29 studies) included people with moderate to severe 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 viral infections. This has led some researchers to consider convalescent plasma as a potential treatment for COVID-19.

Find out more

• Evidently Cochrane blog: Convalescent plasma to treat people with COVID-19: the evidence so far

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Favipiravir 

Key message

It is unclear whether favipiravir provides any benefit in the treatment of people with COVID‐19 who do not require hospital admission (as well as those admitted to hospital).

Compared to placebo, standard of care, or other antiviral medications (lopinavir/ritonavir or umifenovir), it is uncertain whether favipiravir:

• reduces the risk of dying
• reduces the need to be put on a ventilator
• speeds up the time it takes for people to improve

Favipiravir may make little to no difference to:

• the need to be hospitalised (in people with mild illness)
• the need to have oxygen treatment

Favipiravir might lead to mild side effects but doesn’t seem to increase the risk of major or severe side effects.

The evidence

The evidence comes from the Cochrane Review Favipiravir for treating COVID‐19 (published February 2024). It includes 25 studies with 5750 adults (most under 60 years of age). Most participants were in hospital with mild to moderate disease. In most of the studies (22 out of 25), favipiravir was compared to placebo or standard of care and in the other three studies favipiravir was compared with another antiviral medicine (lopinavir/ritonavir in two studies, and umifenovir in one study).

Potential relevance of this treatment for COVID-19

Favipiravir is an antiviral medicine that has been used to treat other viral infections. It has been suggested as a potential treatment for COVID-19 as it might prevent the reproduction of the virus.

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Inhaled corticosteroids

Key message

For people with mild COVID-19 infection, compared with usual care or placebo, inhaled corticosteroids (budesonide or ciclesonide):

• probably reduce the risk of admission to hospital or of dying up to day 30
• probably increase the likelihood that COVID‐19 symptoms will have gone by day 14 and may shorten the time it takes for symptoms to go away
• may make little to no difference to death from any cause up to day 30
• may make little to no difference to the number of unwanted effects or additional infections

The evidence is very uncertain about potential serious harms of inhaled corticosteroids.

The evidence

The evidence comes from the Cochrane Review Inhaled corticosteroids for the treatment of COVID‐19 (published March 2022). It includes three studies with 3607 people, of whom 2490 had confirmed mild COVID-19. Most were aged over 50 and had other health problems such as lung disease or high blood pressure. The studies took place in high-income countries before wide-scale COVID-19 vaccination programmes. The inhaled steroids used in the studies were budesonide and ciclesonide, compared with placebo or usual care.

The review authors found no data for people without symptoms and no studies of this treatment in people with moderate to severe COVID-19.

Potential relevance of this treatment for COVID-19

Inhaled corticosteroids are medicines that are breathed into the lower airways through an inhaler where they reduce inflammation in the lungs. They are used to treat inflammatory respiratory conditions like asthma and chronic obstructive pulmonary disease. They might have the potential to reduce the risk of severe COVID‐19 illness.

Find out more

• Cochrane Clinical Answer: For people with mild COVID‐19, what are the effects of inhaled corticosteroids? 
• COVID-NMA living data: COVID-NMA. Pharmacologic treatments for COVID-19 patients: Corticosteroids
• Related NICE COVID-19 living guideline: Corticosteroids
• Related World Health Organization living guidance:
  • • Corticosteroids for COVID-19: living guidance
    • Therapeutics and COVID-19: living guideline

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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:

“For outpatients, there is currently low‐ to high‐certainty evidence that ivermectin has no beneficial effect for people with COVID‐19.” They also say “In this update, certainty of evidence increased through higher quality trials including more participants. According to this review’s living approach, we will continually update our search.”

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.

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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). There were four studies with people with COVID-19 who were not in hospital, and two studies with hospitalised people. 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

• Cochrane Clinical Answer: For adults with asymptomatic or mild COVID‐19, what are the effects of SARS‐CoV‐2‐neutralising monoclonal antibodies (alone or combined)?
• Cochrane podcast: Are laboratory-made, COVID-19-specific monoclonal antibodies an effective treatment for COVID-19?

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Nirmatrelvir combined with ritonavir

Key message

In people with mild COVID-19, or with no symptoms, the combination of nirmatrelvir plus ritonavir may reduce the risk of being admitted to hospital or dying within 28 days, compared to placebo. Compared with placebo, nirmatrelvir/ritonavir may reduce serious harms, but probably increases the risk of side effects including diarrhoea or an unpleasant taste in the mouth.

The evidence

The Cochrane Review Nirmatrelvir combined with ritonavir for preventing and treating COVID‐19 (published November 2023) includes two studies with 2510 people that investigated nirmatrelvir/ritonavir compared to placebo or standard of care, including inpatients and outpatients. The people included in the studies were mainly unvaccinated and at high risk of becoming unwell because they had another illness or risk factor (for example, they also smoked).

Potential relevance of this treatment for COVID-19

The review authors explain: “The combination of nirmatrelvir with ritonavir (Paxlovid®) is a new medicine developed to treat infection with the SARS‐CoV‐2 virus and aims to avoid severe COVID‐19 in people without symptoms, or those with mild symptoms. Ritonavir increases the effectiveness of nirmatrelvir, however it can interact with many other drugs which can increase side effects.”

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Remdesivir

Key messages

• It’s unclear whether remdesivir (an antiviral medicine) has an impact on the risk of dying among people with mild COVID-19. (This is because usually patients who have mild symptoms and are not hospitalised are less likely to die).
• Remdesivir probably reduces the risk of getting worse and being hospitalised, compared with placebo or standard care, but we cannot say if it affects recovery (e.g. relief in symptoms).
• People may suffer fewer serious unwanted effects with remdesivir than with placebo or standard care. The rates of unwanted effects of any severity were similar between the compared groups.

The evidence

The evidence comes from the Cochrane Review Remdesivir for the treatment of COVID-19 (published January 2023). It includes 9 studies but only one of the studies, with 562 participants, looked at people with mild COVID-19. (The other 8 studies looked at people hospitalized with moderate to severe 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

• There is a section on remdesivir in COVID-19 rapid guideline: Managing COVID-19 from the National Institute for Health and Care Excellence (NICE).

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Vitamin D supplementation

Key message

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

The evidence

The 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’. Only one of these studies looked at patients with mild illness and the study did not give any information about the outcomes of interest (such as effects on patients’ condition, or possible side effects).

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

• Podcast: Is vitamin D an effective and safe treatment for COVID-19?

 

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References (pdf)

Sarah Chapman and Selena Ryan-Vig have nothing to disclose.