Understanding Long COVID in Children

A masked boy in a hospital bed looks at his healthcare provider, who is checking his vital signs. She is wearing a mask and face shield.

Since the pandemic started, NICHD has led research to study the effects of COVID-19 on children, including a long-term complication called Multisystem Inflammatory Syndrome in Children, or MIS-C.

The NICHD-led initiative—Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence, or PreVAIL kIds—reached its one-year milestone in December. The eight awardees have enrolled more than 4,500 prospective and 27,000 retrospective participants, including 700 with MIS-C, across the United States, Canada, United Kingdom, and South America. Several investigators are looking for biomarkers to help differentiate MIS-C from Kawasaki Disease, severe COVID-19, and other childhood illnesses. 
Since the program began, investigators have published more than 30 peer-reviewed papers.

One study supported by PreVAIL kIds helped explain how a treatment for MIS-C works. The treatment, called intravenous immune globulin (IVIG), depletes specific immune cells—activated neutrophils—that drive inflammation. Although more work is needed to learn why some MIS-C patients need additional anti-inflammatory treatments, the findings can help healthcare providers as they determine the most effective methods to treat patients with MIS-C.

Another group of PreVAIL kIds researchers presented biomarker findings at the annual American Academy of Pediatrics conference in October. They reported that higher levels of the cytokine CXCL10, when measured in saliva, were associated with more severe forms of COVID-19 in children. They also identified several microRNAs, also from saliva samples, that correlate with severe infection in children. Further testing and validation of such biomarkers can help predict a child’s risk for complications and enable early monitoring and preventive treatment.

PreVAIL kIds investigators also compared immune responses among children hospitalized for COVID-19. Children diagnosed with MIS-C had activated (i.e., more inflammatory) immune profiles, similar to adults with severe COVID-19. Researchers also found a key role for CD8+ T cells, a type of specialized immune cell that helps clear viral infections. Children with MIS-C also had waning inflammatory immune activity over time, whereas other pediatric COVID-19 patients had sustained immune activation. These differences can help researchers and healthcare providers better tailor treatments for children with COVID-19 who have MIS-C and those who do not.

Another team of PreVAIL kIds researchers evaluated more than 1,400 proteins in children with COVID-19, including those with MIS-C. This “proteomic profiling” enabled the study team to classify children with MIS-C, including those who go on to develop additional complications, such as organ damage caused by small blood clots and overactive immune responses. The researchers found that dysregulation of the interferon gamma (IFNγ) pathway—a type of inflammatory response—contributes significantly to the development of MIS-C. The study team also identified candidate biomarkers and predictors of disease severity, which can help healthcare providers treat pediatric patients. For example, a patient’s level of IFNγ inversely correlated with disease severity; those with high IFNγ levels tended to have less severe disease while those with low IFNγ levels needed additional treatments for heart and vascular injuries. If the study’s results are validated, testing for these proteins in the hospital can help doctors identify patients at risk for MIS-C-related heart problems.

PreVAIL kIds researchers also looked at whether children and young adults with inflammatory bowel disease who receive anti-inflammatory drugs as part of their treatment can develop protective antibodies after COVID-19 infection or vaccination. The study team found that patients on anti-inflammatory treatments who were infected naturally did not develop robust antibody responses, whereas vaccinated patients did. The findings underscore the importance of COVID-19 vaccination among children and young adults with inflammatory bowel disease.

In March, NICHD co-launched a research effort called CARING for Children with COVID with NHLBI. The program investigates why some children are at greater risk for infection and why symptoms vary. Researchers are also studying how to identify children at risk for severe illness, including MIS-C. Although each of the studies supported by CARING for Children with COVID have slightly different goals, all will collect data on a core set of health measures that can later be analyzed across studies. Data will be made available to allow researchers to conduct additional analyses and make more discoveries.

NICHD also supports NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative external link, which launched in September to study the long-term effects of COVID-19 by following participants across the country. This diverse group of participants includes some of NICHD’s populations of interest—pregnant people and children. Pregnancy and pediatric COVID-related common data elements, which were developed by NICHD-led working groups, have also been shared with RECOVER investigators for potential inclusion in their work.

As part of RECOVER, NICHD is supporting the Collaborative Long-term study of Outcomes of COVID-19 in Kids (CLOCK) consortium external link, a critical partnership that includes several PreVAIL kIds investigators. The $30 million endeavor will study the long-term and delayed impacts of COVID-19 on children across the United States. The researchers seek to better understand long COVID, identify risk factors, develop treatments, and ultimately prevent the development of this serious condition.

NICHD is also investigating the Delta variant, which has caused more hospitalizations among infants and children. One group of NICHD-supported researchers developed a pediatric COVID-19 severity dashboard external link to track the impact of the SARS-CoV-2 pandemic on children. The dashboard, which provides new data on an approximately weekly basis, leverages electronic health records data from the National COVID Cohort Collaborative. It will also provide critical information if other variants, such as Omicron—first identified in the United States by a PreVAIL kIds investigator—become predominant.

Research led by NICHD continues to help infants, children, and their families as the COVID-19 pandemic continues.

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