The Acute Immune Response
When a respiratory virus enters the airway, the innate immune response rapidly responds. Resident airway macrophages and dendritic cells are actively patrolling the airspace. Toll-like receptors reflexively trigger an inflammatory response when viral particles are identified. Macrophages, dendritic cells and epithelial cells release cytokines, including TNF, IL-1β, IL-6, IL-8, and IL-12 to activate the immune system.36 Neutrophils swarm to the response, attempting to either phagocytose pathogens or kill invaders in the explosive web of extracellular trap. Natural killer cells and endothelial cells release type 1 interferon in an antiviral response to contain the virus.1 Natural killer cells recognize infected cells by sensing the down regulation of Major histocompatibility complex (MHC) class I module. The natural killer cell then attempts to kill the infected cell by forming and immune synapse where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol.37 Key points of interest in this early immune response that vary in the pediatric population are the release of interferon, response of neutrophils, the hyperactivation of macrophages and the resulting cytokine storm. Figure 2 highlights hypothesized areas of infection and immune responses that are altered between adults and children and could account for the age-related differences seen in morbidity and mortality related to COVID-19.
Innate immunity includes the early detection of coronavirus infection of the cell and the rapid generation of anti-viral mechanisms, such as the production of interferons (IFN). Specifically, type I IFN has an antiviral role via induction of interferon inducible genes and stimulation of apoptosis in infected cells. Notably, type I IFN decreases viral mRNA expression in SARS-CoV-2 infection, but SARS-CoV-2, like SARS-CoV, dodges this immune response via early antagonism of type I and type III IFN release.38 This antagonism of IFN response aids in viral reproduction allowing for further aberrant inflammatory responses, as the IFN response is delayed by about 48 hours.39,40 Children, however, have a lower threshold to inducing an IFN antiviral response compared to their adult counterparts40 and upregulated type I and type III IFN-associated gene expression in tracheobronchial epithelium prior to infection.41 This early IFN response in the incubation period of the virus theoretically prevents higher viral loads.40
Neutrophils are the initial cell responder to viral invasion, but cytokines, including IL-8, and eicosanoids, including leukotriene B4 (LTB4), continue to propagate a further neutrophilic inflammation. The vast majority of children with COVID-19 have normal neutrophil counts with only 4.6% of children with neutropenia and 6.0% neutrophilia.42 In adults, however, severe COVID-19 infections in adults are associated with neutrophilia43,44 although low neutrophil counts also portend poor outcomes,45 perhaps related to neutrophil activation, extravasation, feed-forward hyperinflammation and resultant tissue destruction. Indeed, lung neutrophil infiltration has also been reported in multiple reports on the pathological findings from autopsied COVID-19 patients.43,46 Although leukocytosis and neutrophilia are hallmarks of acute infection; neutrophils might be responsible for pathogenic inflammation in the setting of COVID-19. In SARS-CoV-2, neutrophils are believed to create neutrophil extracellular traps (NETs),43 and these web-like structures of DNA, histones and proteases have the unintended effect of trapping, platelets, red blood cells, and neutrophils driving systemic inflammation, vascular instability, and hypercoagulability. In patients with COVID-19, extensive NET formation has been associated with endothelial damage and cytokine release.43 It has not yet been assessed as to whether there is a difference in neutrophil activation between pediatric and adult COVID-19 patients.
Age-dependent monocyte and macrophage differences could also explain the differences between COVID-19 in pediatric and adult patients. Blood-circulating monocytes are recruited to the area by the potent CCL2 and CCL7 chemokines and differentiate to macrophages at sites of inflammation.47 Monocytes from older adults have both increased CD11b48 but decreased L-selectin,49 resulting in aberrant monocyte transendothelial migration. Macrophages clean up the inflammatory battle site by phagocytosing both pathogen and cellular debris which in turn results in additional release of inflammatory molecules. T helper cells, specifically Th1 cells, release IFN-γ (type III IFN) to enhance the ability of macrophages activity. Phagocytosis and cytokine release has been shown to be altered in monocytes with age.50Impaired clearance of infected cells and elimination of activated macrophages ultimately results in end-organ damage.51Uncontrolled macrophage activation has been associated with decreased natural killer cell and cytotoxic T cell function which further limits the ability to contain infection.52 These age-dependent inflammatory responses could partially explain clinical differences seen in COVID-19.
Additionally, severe COVID-19 is marked by hyperactivation of macrophages either through direct viral sensing or cytokine exposure, hyperinflammation and coagulation.47,51 Cytokines are released in early SARS-CoV-2 infection; viral invasion leads to increases in inflammatory IL-1β, IL-6, IL-12, TNF-α.1As the adaptive response develops, a second peak in cytokine occurs. This peak is modest in mild infection or exaggerated in severe presentation. Both SARS-CoV and MERS-CoV infection result in macrophage and neutrophil invasion resulting in high levels of pro-inflammatory cytokine-induced acute lung injury, ARDS, and death.53Critically ill adult patients with COVID-19 frequently have features of a similar cytokine storm. The most severe COVID-19 infections are associated with a similar cytokine profile with a marked increase IL-6 and ferritin levels.54 The inflammatory markers, such as IL-6, IL-10, myeloperoxidase, and p-selectin, increase with age during critical illness50,55 suggesting that perhaps the macrophage hyperactivation in older adults accounts for the increased morbidity and mortality seen in this acute infection.