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.