Sequencing proteins in the blood of children with COVID-19 and multisystem inflammatory syndrome (MIS-C), a complication of SARS-CoV-2 infection, reveals how MIS-C affects children’s bodies. A researcher says that the discovery may also enable more rapid diagnosis of other severe childhood disorders caused by hyperinflammation.
When COVID-19 swept the globe, the media were flooded with stories of people dying from this new disease.
Some were old and frail, others were ordinary people and even children did not escape severe complications, such as MIS-C, in which the immune system goes into overdrive in several organs and makes them extremely ill with a risk of blood clots.
During the pandemic, MIS-C was soon identified and characterised, but researchers have only recently discovered what actually happens in children’s bodies and how an otherwise mild SARS-CoV-2 infection can cause hyperinflammation with severe illness and hospitalisation in an intensive or semi-intensive care unit – rather than a runny nose and a few days in bed.
“This was a new disease in children, and a new complication of SARS-CoV-2 not seen in adults. It raised many questions. Is this caused by viruses or excessive activation of the immune system? And why did many children with MIS-C have multiple organ failure? This study answered these questions,” explains a researcher behind the study, Ulrikka Nygaard, Chair of CAG Host Infections Laboratory Research Drugs (CHILD) and a consultant in the Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
The research has been published in Communications Biology.
Interaction between proteins
The researchers characterised the proteins in the blood of children with MIS-C and compared them with those of children without MIS-C.
A senior researcher involved in the study, Nicolai J. Wewer Albrechtsen, Consultant at the Department of Clinical Biochemistry, Bispebjerg and Frederiksberg Hospital and Associate Professor at the Novo Nordisk Foundation Center for Protein Research of the University of Copenhagen, explains that the positive aspect about determining the expression of all proteins in the blood is that it indicates the current state of the body.
If you go for a walk, sleep or become seriously ill, protein changes in the blood can be identified.
Conversely, the genes are constant, and although they can also be used to determine why some children develop MIS-C and others do not, they do not indicate what exactly happens in the body.
“If a person arrives at an accident and emergency unit at a hospital in Denmark with, for example, a stomach ache or a headache, the standard procedure involves taking a blood sample and then looking for a handful of proteins that may be biomarkers for disease. In this study, we did not look for a handful of specific proteins but instead characterised all the proteins in the blood of children with MIS-C,” says Albrechtsen.
Children with MIS-C
The researchers analysed blood from 27 children with MIS-C and 67 controls who did not have COVID-19 but had a fever and bacterial infection or a fever and viral infection.
Fifteen of the children with COVID-19 and MIS-C had the alpha variant, 11 delta and one Omicron. Just under 90% were hospitalised in an intensive or semi-intensive care unit.
The blood samples were collected before or within 24 hours after treatment started. Several children had additional blood samples taken during the following days, and nine had a blood sample taken after they fully recovered, an average of 39 days after diagnosis.
The researchers measured all the proteins in the blood of the 94 children and looked for differences between children with MIS-C and the controls. By determining which proteins were up- or downregulated, the researchers uncovered what happens in the body during MIS-C.
“We measured thousands of proteins, and since we know what the proteins do, we can determine what MIS-C activates in the body. If, for example, proteins related to the immune system’s T cells, B cells or coagulation factors are upregulated, this indicates that MIS-C activates these parts of the immune system,” Albrechtsen explains.
MIS-C causes the whole body to go haywire
The results showed that MIS-C is associated with mass destruction of many types of cells.
The immune system overreacts to COVID-19 and activates excessively, including the cells of the immune system and the blood coagulation system. Simultaneously, the protein signature differed markedly between children with MIS-C and controls.
“We identified the fingerprint of MIS-C, and we found what is activated in the body when children develop MIS-C. There are many imbalances in the proteins that sustain life,” says Albrechtsen.
Diagnosis with almost 100% precision
Albrechtsen explains that another unique aspect of the study is that the researchers analysed blood samples over time, which means that they can also monitor what happens as the children recover.
He elaborates that the researchers used artificial intelligence to make sense of the extremely large quantity of data, and this analysis enabled them to monitor the protein signature of MIS-C from admission to normalisation when the children recovered.
“The biomarkers for MIS-C monitor the disease activity and treatment response. With this knowledge of the protein signature of MIS-C, we can now make the diagnosis with more than 90% precision based solely on a blood test at admission and by measuring only four proteins. We can also determine whether a treatment works, which we could not do before,” notes Albrechtsen.
Big data relevant for each individual
Albrechtsen says that the study has several perspectives, including understanding how the body can become so seriously ill after COVID-19.
“Understanding this is important because other inflammatory diseases have a phenotype similar to MIS-C. The idea is therefore that we can use this approach to analyse the protein expression not only in MIS-C but also in other diseases. We can determine whether severe illness is an infectious disease or an autoimmune disease. This is very important for the choice of treatment and whether immunosuppressive medication is warranted,” explains Ulrikka Nygaard.
Further, Albrechtsen thinks that the study exemplifies how big data can be used at the individual level. Big data often focuses on data from millions of people and disease at the population level but can also involve the expression of all the proteins in the blood of one person.
“This study enabled us to show how big data can also be relevant for each individual in a disease scenario,” concludes Nicolai J. Wewer Albrechtsen.
