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.