Pathways to severe COVID-19 in children discovered

The study, led by the Murdoch Children’s Research Institute (MCRI) and University of Melbourne and published in Nature Communications, has identified disease mechanisms in children with COVID-19 who present with multisystem inflammatory syndrome in children (MIS-C).
 
MIS-C can cause different body parts to become inflamed, including the heart, lungs, and brain, as well as potential acute respiratory distress syndrome (ARDS), a type of lung disease.
 
By identifying that blood clotting and how proteins in the immune system reacted to the virus as the main triggers for severe COVID-19 in children, the researchers hope the study will pave the way for earlier diagnosis and more targeted treatments.
 
However, according to co-author, MCRI researcher and University of Melbourne PhD student, Conor McCafferty, it is difficult to know at this stage when a diagnostic might be available or what it would even look like.
 
‘In the study, we looked at hundreds and hundreds of proteins and started filtering that down to a smaller number,’ he told newsGP.
 
‘We’ve taken all of the body systems and narrowed it down to a handful, so the next researchers will know exactly where to look, exactly which pathways are impacted, and which drugs might be needed.
 
‘From there, future research will go in and narrow that down even more – that’s still a way away, but this is the first big step towards getting us somewhere.’
 
Although children are in general less susceptible to COVID-19 and present with milder symptoms, Mr McCafferty said it remains unclear what causes some to develop very severe disease – but the results of the study make some progress on this.
 
‘Our research was the first to uncover the specific blood clotting and immune protein pathways impacted in children with COVID-19 who developed serious symptoms,’ he said.
 
According to MCRI, 1.7% of reported paediatric cases hospitalised for COVID-19 resulted in admission to an intensive care unit.
 
The Omicron wave at the beginning of 2022 saw more children being admitted to hospital, but overall, paediatric admissions were lower compared to adults.
 
COVID-19-associated ARDS is one of the major manifestations of severe cases, characterised by hypoxemic respiratory failure with bilateral lung infiltrate, as well as multi-organ dysfunction and extensive microthrombus formation.
 
In addition, a minority of children with COVID-19 present with MIS-C or paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS).
 
For the study, blood samples from 20 healthy children were collected at Melbourne’s Royal Children’s Hospital, along with samples from 33 SARS-CoV-2 infected children with MIS-C or COVID-19-associated ARDS collected from the Hôpital Necker-Enfants Malades, Greater Paris University Hospitals.
 
The sample size was limited by the availability of MIS-C and COVID-19-associated ARDS patients.
 
Collaborating to collect samples in order to further describe the mechanisms of these syndromes is of ‘vital importance’ in the efforts to improve treatment and outcomes, according to the research team.
 
They found 85 and 52 proteins were specific to MIS-C and ARDS, respectively. Both syndromes are major potential outcomes of severe COVID-19.
 
The authors said the discoveries were possible due to proteomics, an experimental approach that allowed them to investigate almost 500 proteins circulating in the blood at once.
 
Children with COVID-19 who present with MIS-C also show similar clinical features to Kawasaki disease and toxic shock syndrome, such as fever, abdominal pain, vomiting, skin rash and conjunctivitis. This makes it difficult to quickly diagnose patients.
 
Co-author, MCRI Professor Vera Ignjatovic said the study results provide an understanding of the processes that underly severe COVID-19 in children, which would help in the development of diagnostic tests for early identification of children at risk, as well as therapeutic targets to improve the outcomes for those with severe cases.
 
‘Knowing the mechanisms associated with severe COVID-19 in children and how the blood clotting and immune systems in children react to the virus will help diagnose and detect acute COVID-19 cases and allow us to develop targeted treatment,’ she said. 
 
Mr McCafferty added that the study helps to clearly identify what is happening ‘underneath the disease’ and the underlying physiology, and how this can be applied in primary care.
 
‘At the moment … this is … something for [GPs] to have on their radar and look out for what comes next,’ he said.
 
‘The main message is that it’s a step towards better diagnosis and treatment.’
 
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children’s health COVID-19 multisystem inflammatory syndrome paediatrics