Using saliva to predict COVID-19 severity in children

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Children's Health
Banner (1) Thought LeadersDr. Usha SethuramanProfessor of PediatricsCentral Michigan University

In this interview, News-Medical speaks to Dr. Usha Sethuraman about her research into COVID-19 and how saliva could be used to help predict COVID-19 severity in children.

The COVID-19 pandemic has received a great deal of scientific and medical attention since the start of last year. What provoked your latest research efforts into the ongoing COVID-19 pandemic?

Most children with SARS-CoV-2 infection have a mild disease whereas some of them develop more severe disease. However, at the time of presentation to the Emergency Department (ED) symptoms and signs in these children are very similar to other common viral illnesses. Hence many children are discharged and come back sicker later.

As an ED physician, I understood firsthand the frustration of not being able to predict which child with the infection is going to become very ill. Additionally, almost all markers of inflammation are currently only detected in blood or serum.

Children do not like to be poked for blood draws especially when they are already not feeling well. Therefore, we wanted to analyze biomarkers profiles in the saliva of children with, and without, severe SARS-CoV-2 infection. Saliva would be noninvasive and easy to obtain from children.

Research has shown that children are less likely to contract COVID-19 compared to adults and the older population, and if contracted, the majority of children will have a mild illness. Why is this and why is it still important to investigate the few cases where children have developed more severe complications?

Although it is true that compared to adults, children have a much lesser disease burden, several thousands of children have developed severe diseases such as multisystem inflammatory syndrome (MIS) which has affected their hearts. Some children have also died from severe COVID-19.

Furthermore, nearly one-fifth of those who recover seem to have long-term heart issues after MIS. Hence it is important we identify these sicker kids early so that we can treat them appropriately.

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In your latest research, you looked at the two biomarkers cytokines and microRNAs, and their involvement within infection. What role do these biomarkers play within COVID-19 infection?

MicroRNAs are small, noncoding units that seem to have a role in immune regulation during infections. They do this by either upregulating or downregulating inflammatory proteins secreted by cells, thus controlling the immune response. They can also promote the death of an infected cell, removing its harmful effects from the body.

Reports in adults have suggested that the SARS-Cov-2 virus may have receptors on its surface that are capable of sponging the microRNAs in the host that is responsible for immune regulation. Additionally, studies in adults have also shown immune signatures with specific inflammatory markers called cytokines (IL-6, etc).  These are pro-inflammatory proteins that cause the exaggerated immune response responsible for all the severe features of COVID-19. But, the profile of these biomarkers (miRNA and cytokines) in saliva is unknown.

Please can you describe how you carried out your latest research into predicting the severity of COVID-in children?

We plan on recruiting 400 children </= 18 years with SARS-CoV-2 infection at Emergency Departments (Children’s Hospital of Michigan and Children’s Pittsburgh) and obtaining two saliva samples from them (one for miRNA and one for cytokines) in the ED. However, for our preliminary study, we used 129 saliva samples for miRNA and 180 saliva samples for cytokines.

Furthermore, we obtained a survey from the parents that explores the social determinants of health as well. The saliva samples are analyzed at Penn State and the modeling is done at Wayne State. We extracted clinical data on all patients also. This study is supported by the NIH’s RADx program (1R61HD105610).

What did you discover?

This presentation was a preliminary analysis of 129 saliva samples for miRNA and 180 samples for cytokines. We found that 3 cytokines were significantly elevated in children with severe disease (CXCL-10, CXCL9, TNF R1).

However, when these cytokines were included in a predictive model, they were unable to help differentiate between severe and nonsevere cases. We found 63 miRNAs were differentially expressed in children with severe disease and more than 60% were downregulated.

A model that included the miRNAs was able to differentiate between severe and nonsevere cases with high sensitivity.

Why did you choose to use salvia as your sample compared to blood where these biomarkers are still found?

Saliva is noninvasive which is a deal-breaker with children who generally dislike being poked. This was important to us as clinicians that we use noninvasive tests. Studies have shown high satisfaction amongst both parents and kids with saliva as a test rather than blood or serum.

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What role did artificial intelligence (AI) play in your research?

Predictive modeling using a combination of SDOH, cytokines/miRNA, and clinical data will be done using AI.

How will your research help people to further understand the effects of COVID-19 and its varying severity?

If the final study results mirror what we found in this preliminary analysis, this could be a game-changer in the ED. If we are able to obtain a saliva sample and use it as a bedside tool for predicting severe disease, it would help with disposition in the ED and early treatment. This may help improve outcomes in our children with severe COVID-19.

Do you believe that with continued research into these biomarkers and COVID-19, we can help to better predict the severity of the virus in both children and adults?

I believe that saliva biomarkers especially miRNAs will someday change the way we diagnose and arrive at dispositions of patients in the ED. More work is necessary to confirm and validate these findings.

What are the next steps for your research into COVID-19?

We are continuing the enrollment of patients currently. Once all 400 children have been enrolled, we will perform a more detailed analysis of the data and see if there is a difference in these biomarkers levels with varying types of severe infections (eg respiratory or cardiac, etc). Then, we hope to develop a bedside tool that we can use to analyze saliva rapidly to help predict severe disease.

About Dr. Usha Sethuraman

I am a pediatric emergency medicine physician and have been in this role for more than 20 years. I am also a professor of pediatrics at Central Michigan University. My areas of research in the past have included obesity, metabolic syndrome, sepsis and inflammatory markers, prescriptions errors in the ED, and recently  COVID-19 in children.Bio

I am a principal investigator (PI)  on this study termed SPITS MISC which is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the National Institute of Health’s Rapid Acceleration of Diagnostics (RADx) program (1R61HD105610).

The other two PIs on the study are Dr. Steven Hicks (Penn State) and Dr. Dongxiao Zhu (Wayne state university). Dr. Hicks is a pediatrician and an expert on miRNA. Dr. Zhu is the artificial intelligence expert.

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