The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial has found that treatment with methylprednisolone as a first-line treatment and tocilizumab as a second-line treatment can reduce the length of hospital stays for children (aged under 18) with paediatric multisystem inflammatory syndrome (PIMS) associated with COVID-19. The results are published in The Lancet Child & Adolescent Health.
PIMS, also known as multisystem inflammatory syndrome in children (MIS-C), causes inflammation throughout the body weeks after someone has had the virus that causes COVID-19. It can result in fever, pain, vomiting, headache, or fatigue, or heart problems or shock in the worst cases.
The first cases of PIMS associated with a COVID-19 infection appeared during the first few months of the pandemic. Similarities between PIMS and other conditions such as toxic shock syndrome and Kawasaki disease initially led clinicians to use an antibody treatment called immunoglobulin that can improve the immune system’s ability to fight disease.
The RECOVERY trial aimed to assess whether or not immunoglobulin or methylprednisolone, a type of corticosteroid known to help reduce inflammation, had any effect on how long children with PIMS following COVID-19 needed to stay in hospital when compared with usual care.
The trial also assessed two treatments for children whose symptoms did not improve with the first treatment. The second treatments were tocilizumab and anakinra, both of which are usually used to reduce inflammation in people with rheumatoid arthritis. Additionally, the RECOVERY trial has previously reported that tocilizumab is effective at reducing deaths in adults with severe COVID-19.
Overall, 237 children participated in the trial. In the first phase of the trial, 73 children received immunoglobulin, 61 children received methylprednisolone, and 80 children received usual care. In the second phase of the trial, 28 children received tocilizumab, 14 children received anakinra, and 28 children received usual care. The average age of the children was 9.5 years for the first phase and 9.6 years for the second phase.
The trial researchers looked at how long the children needed to stay in hospital and assessed a range of other factors, including whether or not the children needed heart support medicines and measures of body inflammation. The trial also assessed the safety of each of the tested treatments.
To assess how effective the treatments were, the researchers used a statistical analysis method called Bayesian analysis which answers research questions about unknown factors by calculating how likely something is to happen. This sort of analysis also allows researchers to study how medicines work where small numbers of people have taken part in a trial.
- In the first phase of the trial, the children who received immunoglobulin stayed in hospital for an average of 7.4 days and those who received methylprednisolone stayed in hospital for an average of 6.9 days compared with 7.6 days for children who received usual care. The Bayesian analysis showed that the immunoglobulin was not of clinical benefit, but that methylprednisolone had a more than 87% probability of benefit in reducing the length of their stay in hospital;
- In the second phase of the trial, the children who received tocilizumab stayed in hospital for an average of 6.6 days and those who received anakinra stayed in hospital for an average of 8.5 days compared with 9.9 days for children assigned to usual care. The Bayesian analysis showed that the tocilizumab had a more than 99% probability of benefit in reducing the length of the children’s stay in hospital when compared with usual care. The numbers of children treated with anakinra were too small to be certain of the effect;
- Both treatments found to be effective were associated with an increased use of heart support medicines when compared with the children who received usual care;
- There were few harmful safety outcomes. Two persistent coronary artery aneurysms (a problem with a blood vessel in the heart) were reported in the usual care group in the first phase and none in any of the treatment groups or in the usual care group in the second phase.
Saul Faust, Professor of Paediatric Immunology and Infectious Diseases at the University of Southampton and lead paediatric author of the study, said ‘With the help of patients and clinicians in the UK, we now know that treatment with methylprednisolone in the first instance and tocilizumab when inflammation is persistent can be beneficial in reducing inflammation and the length of hospital stays for children with paediatric multisystem inflammatory syndrome associated with COVID-19. We also found that treatment with immunoglobulin and anakinra have no beneficial effect on these outcomes. We recommend that the trial results be used to inform updates of clinical guidelines.’
Richard Haynes, Professor of Renal Medicine and Clinical Trials at Oxford Population Health and the coordinator of the RECOVERY trial, said ‘We are enormously grateful to all of the children, their parents and guardians, and the clinical staff who participated in the trial. They have not only enabled the discovery of two treatments that may benefit future patients but they have also helped us to demonstrate that it is feasible to recruit children into trials during a pandemic to generate reliable evidence for effective treatments.’
51 hospitals in the UK participated in the first phase of the trial which compared treatment with immunoglobulin or methylprednisolone with usual care. 25 hospitals in the UK participated in the second phase of the trial which compared treatment with tocilizumab or anakinra with usual care alone in children who required further treatment. RECOVERY was the first randomised controlled trial to open recruitment to children with PIMS following COVID-19.