NOT-HL-22-004 Notice of Special Interest (NOSI) Pediatric COVID-19 and Respiratory Viral Co-infection

As of October 14 2021, 6,177,946 SARS-CoV-2 positive pediatric cases (0-18 years) have been reported in the USA since the pandemic began. 925,000 children were SARS CoV-2 positive in August 2021, representing an almost six-fold increase since July 2021. 850,000 new cases have been reported in September and October 2021. Severe respiratory illness with COVID-19 remains less common in children than in adults. However, during September and October 2021, pediatric hospitalizations for COVID-19 related respiratory illness (1.4 % of pediatric COVID-19 cases in states that reported) have increased five-fold. Hospitalization for COVID-19 in younger children (0- 4 years) and unvaccinated adolescents has increased ten-fold. While there is Emergency Use Authorization (EUA) of the COVID-19 vaccine in children who are 5 years of age or older, children younger than 5 years of age continue to be unvaccinated and hence vulnerable to infection, particularly during the coming winter months, when most respiratory viruses also peak in incidence and severity, particularly in younger, unvaccinated children.

People with SARS-CoV-2 infection tend to be more predisposed to co- infection with other respiratory microbes than those who are not SARS-CoV-2 positive . A higher incidence of viral co-infection in SARS-CoV-2 infected children (12%) compared to SARS-CoV-2 infected adults has also been reported. Earlier in the pandemic, non-pharmacological interventions (NPI), such as masking and physical distancing, resulted in dramatic reduction in illness and hospitalization from other respiratory viruses, such as the respiratory syncytial virus (RSV). Relaxation of lockdown measures/NPI has led to co-emergence of respiratory viruses and SARS-CoV-2 (particularly the Delta variant), the latter predominantly in children who are not vaccinated yet. Further, an unseasonal increase in RSV infections has been reported, with a documented surge in infections in the summer months from May 2021 that is significantly increased compared to previous years. Co-infection with respiratory viruses, particularly RSV with SARS-CoV-2 is resulting, in preliminary surveys, in severe respiratory disease in children and young adults, with a few reports of evidence of chronic ongoing lung damage in babies.

A survey of weekly pediatric intensive care unit (PICU) admissions of children (0-18 years of age) with COVID-19 in the USA and worldwide during September and October 2021 suggests that severe disease from COVID-19 with respiratory manifestations may be becoming more common, with the majority of patients in the PICU being unvaccinated, and greater than 50% of admissions being severely critically ill. A significant percentage of patients admitted to intensive care units demonstrate co-infection predominantly with Rhinovirus or RSV, and also enteroviruses and influenzas.

Viral co-infections may influence the trajectory of the virus as it makes its way around the globe. However, the impact of co-infection with COVID-19 and other viruses (e.g., RSV, Influenza, Rhinovirus, Parainfluenza and Metapneumovirus) in children, and whether co-infections increase vulnerability to SARS-CoV-2 disease or vice versa remains unknown. The pathobiology of innate and adaptive immunity in the setting of co-infection and the impact of co-infections to vaccines (e.g., primary vaccinations, COVID-19 and/or the influenza vaccine) and vice versa need elucidation. The increased severity of RSV may also provide an opportunity to study severe RSV in existing cohorts enriched for genetic susceptibility to severe disease.

This NOSI is intended to support projects that will employ existing and new clinical trial cohorts/observational cohorts to screen for co-infection, phenotype and collect biospecimens to answer some of these questions and to encourage investigator-initiated applications for basic, translational and human subject research (not clinical trials) in this space.