The Delayed Immune Response
In viral infections, the dendritic cells serve as the key link to the
adaptive immune response. MHC class II molecules on the cells present
viral peptides to T cell receptors on naïve T cells allowing for the
maturation of T cells. Activation of the T lymphocyte leads to massive
cell proliferation and generation of T helper cells (CD4+), cytotoxic T
cells (CD8+), and antibody-producing B cells to recognize the antigen. T
helper cells are crucial in generating cytokines that recruit phagocytes
and activate other leukocytes. In established lung infection, the major
mechanism for eliminating the virus from the body is by CD8+ T cells
killing virally infected cells. CD8+ T cells can detect and selectively
kill virally infected epithelial through release of specialized lytic
granules which in turn induce apoptosis of the infected cell. Antibodies
produced by B cells neutralize the virus by binding to viral surface
proteins, thus preventing viral entry into further host
cells.56 These three roles of the adaptive immune
system – generation of cytokines by helper T cells, cell-mediated
immunity, and generation of antibodies – differ in pediatric and adult
populations.
As SARS-CoV-2 is a novel virus, no specific IgG memory antibodies are
present, and the host is reliant on the innate immune response until IgM
and IgG seroconversion at day 12 and day 14 of the virus
respectively.14,57 In a study of 285 patients, within
19 days of infection, all patients had antiviral
IgG.58 Specifically, these antibodies were shown to
bind a recombinant antigen containing the nucleoprotein and a peptide
from the spike protein of SARS-CoV-2.58 If limited to
the upper respiratory tract, the systemic immune response is
hypothesized to be less robust, antibody production may be of a shorter
duration. As children often have limited infections, children may be
more vulnerable to recurrent infections.59 This
short-lived immunity was specifically noted in endemic coronavirus where
an upper respiratory infection with endemic coronavirus left children
vulnerable to reinfection within one year.59
In general, the best immune strategy for prevention of a viral infection
is to prevent initial entry into the host cell, which can effectively
stop the infection. However, once a high intracellular viral load is
reached, there is a release of a large numbers of viral particles which
overwhelm antibody neutralization capacity which further limits the
body’s ability to contain viral spread. This is the typical situation in
SARS-CoV-2, where the level of antibody does not correlate with
effective immune control. However, if neutralizing antibodies persist
after a patient recovers from COVID-19, and the virus is eliminated,
then the patient should be protected from reinfection for an unknown
duration.60 Although production of neutralizing
antibodies to the S protein would theoretically limit SARS-CoV2
infection, the virus can escape. The RNA-dependent polymerase of RNA
viruses, such as coronaviruses, is intrinsically error-prone and inserts
wrong nucleotide into the RNA products every 10,000 bases. Some of these
nucleotide substitutions may change the amino acid sequence of the S
protein61 leaving the antibody binding impaired but
not viral attachment.
In the elderly, immune evasion might be exacerbated by reduced myeloid
cell antigen-presenting cell (APC) function or
availability.62 Aging is also associated with a
decline in the adaptive immune function. Since T cells are necessary for
virus clearance in infected animals, prior studies have focused on
virus-specific T cell response in the elderly. Oligoclonal expansion of
virus specific T cells which decrease diversity of the T cell repertoire
in aged hosts have been previously shown to be associated with increased
susceptibility to viral infections.63,64 Decreased T
cell function with age is also caused by progressive involution of the
thymus, a central immune organ that instructs T cell maturation and
specificity.65,66 Thymic involution leads to a decline
in naïve T cell output while existing memory T cells are relatively
preserved.65,66 This might explain why the capacity to
respond to a novel/changing antigen is particularly poor in older
individuals. Since the immune evasion by SARS-CoV-2 is exacerbated and
since the T cells may be dysfunctional,67 it is
conceivable that late T cell response may amplify pathogenic
inflammatory outcomes in the presence of sustained high viral loads in
the lungs.68,69
MIS-C is an emerging disease and very little is understood about its
pathophysiology. Early case reports of COVID-related inflammatory
disease include a classical “Kawasaki-like” illness in a six-month old
girl who was admitted due to Kawasaki disease and tested positive for
COVID-19 prior to discharge.70 Other reports include a
14-year-old boy with hyperferritemia, cytokine storm, acute respiratory
distress syndrome (ARDS), and hypotension requiring inotropic
support.71 Further reports from Italy and London also
describe this picture of multi-organ involvement with hypotension often
refractory to intravenous fluid resusitation.19,20,72This picture of a cytokine storm in the setting of SARS-CoV-2 exposure
is similar to the cytokine storm in adults, yet the presentation is
roughly a month delayed from the peak of cases in each city. Belhadjer
et al. reported 90% positive testing for SARS-CoV-2 infection in
children with MIS-C.18 In their case series, positive
antibody assays were seen in 86%, positive nasopharyngeal PCR in 34%
and positive fecal PCR in 6% of the patients. This suggests that the
virus has been cleared from the upper respiratory tract and the clinical
presentation is likely a post-viral syndrome.22
Of note, as one ages, thymus hypoplasia leads to a decrease in function
and number of both T cells and T regulatory cells leaving elderly more
susceptible to viral infection and immune dysregulation such as that
seen in cytokine storm.73 Serological signatures also
differ vastly between healthy children and elderly, with higher
cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas
children displayed elevated SARS-CoV-2 IgM. Theoretically, the
less-experienced humoral immunity in children, as evidenced by the
higher IgM, may induce more potent antibodies upon SARS-CoV-2
infection.74