Introduction
In December 2019, a new coronavirus, SARS-CoV-2, led to a surge in cases of pneumonia in Wuhan, China.1,2 This respiratory illness, coronavirus disease 2019 (COVID-19), subsequently spread rapidly, and on March 11, 2020, World Health Organization (WHO) classified COVID-19 as a world-wide pandemic.
COVID-19 is highly contagious with a transmissibility rate ranging from 1.4-6.9 in different case series,3 meaning one infected individual will infect up to seven people, thus facilitating rapid spread of the infection. Case reports indicate about one in six children in the United States with confirmed SARS-CoV-2 infection are asymptomatic4 and up to a half of infections are transmitted by people with no symptoms or mild symptoms.5 Asymptomatic and mildly symptomatic children are a true concern in the propagation of this pandemic. Not only is COVID highly contagious, the disease carries a high mortality with an estimated case fatality rate (CFR) of a striking 1.38% with CFR reaching a staggering 13.4% in patients over 80 years.6 In comparison, seasonal influenza usually has a CFR well below 0.1% with those at highest risk of severe complications having a bimodal distribution including adults over 65 years of age and children less than 5 years of age. Much of the burden of COVID-19, in terms of morbidity and mortality, is being carried by older adults.
Children less than 19 years, however, are less likely to become acutely ill from SARS-CoV-2 infection, and although COVID-19-related deaths have been reported in this age group, they make up less than 1% of COVID-19 associated ICU admissions and death.7 Although children are equally likely to be infected by SARS-CoV-2,8 20% remain asymptomatic,9 while others report mild symptoms of the upper respiratory infection, including fever, dry cough, rhinorrhea, ageusia, and anosmia.10,11 Very few children progress to any significant respiratory distress.12 In fact, only 1.7% of reported SARS-CoV-2 infections have occurred in children less than 18 years of age though this may reflect lower testing in this population.13 In children 0-9 years old and 10-19 years old, the fatality rates have been markedly lower compared to adults at only 0.0026% and 0.0148% respectively.6SARS-CoV-2 is speculated to be contained in the upper airways of children by the innate and adaptive immune system; when the virus progresses to the lower airway, as in adults, SARS-CoV-2 is associated with high lethality.14 However, ground glass opacities with surrounding halo on CT imaging in a majority of pediatric patients and clinical symptoms of pneumonia in some patients are strong evidence that, even in children, the virus is not always contained in the upper airway.15,16 Children’s ability to better contain the virus, therefore, is likely a function of the immune response rather than the viral exposure.
Although children tend to have milder presentations with COVID-19 acute infection,17 a newly recognized SARS-CoV-2 associated syndrome called Multisystem Inflammatory Syndrome in Children (MIS-C) or Pediatric Multisystem Inflammatory Syndrome (PMIS) has been described worldwide.18 Initially reported as hyperinflammatory shock19 and “Kawasaki-like” illness,20 this syndrome has been observed to have overlapping features with toxic shock syndrome, atypical Kawasaki disease, macrophage activation syndrome, cardiogenic and septic shock. Dilated coronary arteries have been reported in 17-25% of the patients with rare development of coronary artery aneurysms. Laboratory abnormalities include significant elevation of inflammatory markers (high CRP, ESR, D-dimer, ferritin, IL-6), neutrophilia, lymphopenia, elevated NT-proBNP with or without troponin elevation.21 No acute or past significant respiratory illness has been seen in these patients. Early estimates report this syndrome occurs in between 0.011% and 0.31% of children with SARS-CoV-2 infection.22 These reports likely underestimate and only reflect the cases with severe disease presentation. Figure 1 outlines the time course in adults and children infected with SARS-CoV-2.
The difference in morbidity and mortality between adult and pediatric COVID-19 infections is dramatic. Understanding pediatric-specific acute and delayed immune responses to SARS-CoV-2 is critical for the development of vaccination strategies, immune-targeted therapies, and treatment and prevention of MIS-C. The goal of this review is to highlight research developments in understanding of the immune responses to SARS-CoV-2 infections, with a specific focus on age-related immune responses.