COVID-19: focus on pediatrics and the immune response to SARS-CoV-2
Significant morbidity and mortality secondary to COVID-19 infection have largely spared the pediatric population, including pediatric hematology, oncology and hematopoietic cell transplant patients.9In general, immunocompetent pediatric patients with COVID-19 experience less severe disease than adult patients,10,11particularly adults with co-morbidities like cardiovascular disease, chronic lung disease, and diabetes.12,13 Children identified at higher risk for severe COVID-19, as defined by the need for hospitalization or intensive care, include those with chronic cardiovascular or lung diseases, infants under one year of age, and immunocompromised patients receiving immunosuppression.14
SARS-CoV-2 viral loads correlate with disease severity, as patients with severe disease have higher viral loads and longer decay times than those with mild or moderate symptoms.15 In contrast to viral dynamics, the immune response to SARS-CoV-2 remains undefined, though decreases in CD8+ T-cells and B cells in adults have been correlated with severe COVID-19 and poor response to therapy16 while CD8+ T-cells and B cell recovery have been associated with moderate disease.17 Decreases in regulatory T cells have also been linked with a hyperinflammatory response in adults,18 requiring the use of monoclonal blocking antibodies like tocilizumab, an anti-interleukin 6 (IL-6) agent.19 Interestingly, immune dysregulation and hyperinflammation as measured by whole blood transcription profiles have also been shown to correlate with severe respiratory syncytial virus (RSV) disease in infants,20 who also have higher viral loads and more protracted viral decay than infants with mild RSV.21 Similarly, reports are emerging that some children with COVID-19 are experiencing clinical symptoms and signs consistent with Kawasaki Disease,22,23 a multi-system inflammatory disease of unclear etiology but often associated with respiratory viral infections.24
Despite their generally experiencing milder COVID-19, immunocompetent pediatric patients have high viral loads25 and may shed SARS-CoV-2 for weeks from the upper respiratory and lower gastrointestinal tracts after primary infection.26This discrepancy between having milder COVID-19 despite having high viral loads and prolonged viral shedding suggests that children may differ from adults in their immune response to SARS-CoV-2. To this end, children and adults have defined differences in both innate27 and adaptive immune responses28. As adults have a more pro-inflammatory background, they may be predisposed to more severe COVID-19 via a hyperinflammatory response to SARS-CoV-2.
Adults and children also differ in their immune response to viral challenge29. Type I interferons (IFN) are key cytokines that have direct viral cytotoxic effects30as well as immunomodulatory effects on both innate and adaptive immune cells.31 Deficits in type I IFN have been correlated with persistent viral load and exacerbated inflammatory response in adult patients with severe COVID-19.32,33Interestingly, children with mild RSV disease (outpatient care) have recently been shown to have higher viral loads, greater induction of IFN genes and decreased gene expression of inflammation and neutrophils versus children with severe RSV (inpatient care).34
Taken together, epidemiologic and immunologic data on SARS-CoV-2 infection are emerging that may be helpful to explore why pediatric patients experience less severe COVID-19 and to implement potential therapies that would either augment helpful or inhibit harmful immune responses to SARS-CoV-2.35