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