Severe pediatric COVID-19: a review from the clinical and immunopathophysiological perspectives

Abstract

Background: Coronavirus disease 2019 (COVID-19) tends to have mild presentations in children. However, severe and critical cases do arise in the pediatric population with debilitating systemic impacts and can be fatal at times, meriting further attention from clinicians. Meanwhile, the intricate interactions between the pathogen virulence factors and host defense mechanisms are believed to play indispensable roles in severe COVID-19 pathophysiology but remain incompletely understood.

Data sources: A comprehensive literature review was conducted for pertinent publications by reviewers independently using the PubMed, Embase, and Wanfang databases. Searched keywords included "COVID-19 in children", "severe pediatric COVID-19", and "critical illness in children with COVID-19".

Results: Risks of developing severe COVID-19 in children escalate with increasing numbers of co-morbidities and an unvaccinated status. Acute respiratory distress stress and necrotizing pneumonia are prominent pulmonary manifestations, while various forms of cardiovascular and neurological involvement may also be seen. Multiple immunological processes are implicated in the host response to COVID-19 including the type I interferon and inflammasome pathways, whose dysregulation in severe and critical diseases translates into adverse clinical manifestations. Multisystem inflammatory syndrome in children (MIS-C), a potentially life-threatening immune-mediated condition chronologically associated with COVID-19 exposure, denotes another scientific and clinical conundrum that exemplifies the complexity of pediatric immunity. Despite the considerable dissimilarities between the pediatric and adult immune systems, clinical trials dedicated to children are lacking and current management recommendations are largely adapted from adult guidelines.

Conclusions: Severe pediatric COVID-19 can affect multiple organ systems. The dysregulated immune pathways in severe COVID-19 shape the disease course, epitomize the vast functional diversity of the pediatric immune system and highlight the immunophenotypical differences between children and adults. Consequently, further research may be warranted to adequately address them in pediatric-specific clinical practice guidelines.

Keywords: Immunopathophysiology; MIS-C; Pediatric critical care; Severe pediatric COVID-19.

Fig. 1

Potentially life-threatening manifestations of severe pediatric COVID-19 and organ systems implicated in MIS-C. The MIS-C diagnostic criteria are adapted from the Centers of Disease Control and Prevention of the United States. pCOVID-19 pediatric COVID-19, CRP C-reactive protein, ESR erythrocyte sedimentation rate, LDH lactate dehydrogenase, IL-6 interleukin 6, NEUT neutrophils, LYM lymphocytes, RT-PCR reverse transcription polymerase chain reaction

Fig. 2

ACE-2-TMPRSS2-mediated SARS-CoV-2 cell entry and type 1 interferon pathway. SARS-CoV-2-associated molecules are recognized by a wide range of PRRs located in different compartments, including TLR2, 4 and 6 on the plasma membrane, TLR3, 7 and 8 in endosomes, and RIG-1 and MDA-5 in the cytoplasm, each with its respective ligands. Ligand binding causes TLRs to dimerize and instigate the downstream signaling pathways in an MyD88-dependent or TRIF-dependent manner. Activation of TLR2, 4, 7, and 8 recruits the canonical adaptor protein MyD88, which sequentially mobilizes the IRAK complex, TRAF6, and TAK1. TAK1 is then capable of initiating the IKK-NFκB and the MAPK-AP1 pathways, stimulating production of various proinflammatory cytokines. In addition, activation of TLR7 or TLR8 also triggers IRAK, TRAF6, TRAF3, and IKKα-dependent phosphorylation and thus activation of IRF7. Contrarily, TRAF3 may be activated by TRIF recruitment following TLR3 and TLR4 activation, or MAVS recruitment secondary to RIG-1 or MDA5 activation. TRAF3 in turn gives rise to TBK1 and IKKε activation that potentiates IRF3. Both IRF3 and IRF7 act as transcription factors that promote T1IFN gene expression. T1IFNs bind to the heterodimeric IFNAR1/IFNAR2 receptor complex, which triggers the receptor-associated kinases TYK2 and JAK1 to phosphorylate STAT1 and STAT2 proteins. The phosphorylated STAT1 and STAT2 combine with IRF9 to form the ISGF3, which binds to IRSE in the nucleus to upregulate transcription of ISGs, exerting multitudinous antiviral effects. PPRs pattern recognition receptors, ACE2 angiotensin-converting enzyme 2, TMPRSS2 transmembrane serine protease 2, (+)/(–)ssRNA positive-/negative-sense single-stranded ribonucleic acid, S spike protein, N nucleocapsid protein, M membrane protein, E envelop protein, Nsps non-structural proteins, dsRNA double-stranded ribonucleic acid, TLR toll-like receptor, RIG-1 retinoic acid-inducible gene I, MDA5 melanoma differentiation-associated protein 5, MyD88 myeloid differentiation primary response factor 88, IRAKs interleukin-1 receptor-associated kinases, TRIF toll-interleukin-1 receptor-domain-containing adaptor-inducing interferon-‍β, MAVS mitochondrial antiviral signaling protein, TRAF tumor necrosis factor receptor-associated factor, TAK1 transforming growth factor-β activated kinase 1, IKK inhibitor of nuclear factor-κB (IκB) kinase, TBK1 TANK-binding kinase 1, IRF interferon regulatory factor, NF-κB nuclear factor kappa B, MAPK mitogen-activated protein kinase, AP-1 activator protein 1, T1IFNs type 1 interferons, IFNAR interferon-alpha receptor, TYK2 tyrosine kinase 2, JAK1 Janus kinase, STAT signal transducer and activator of transcription, ISGF3 interferon-stimulated gene factor 3, ISRE interferon-sensitive response element

Fig. 3

Hyperinflammation and immunothrombosis in severe COVID-19. Virus-related factors like the N protein and potassium efflux and calcium influx set off by envelope and ORF3a “viroporin” proteins, and host-related factors such as extracellular ATP, complement C5a, ROS, and phagocytosis of antibody-opsonized viral particles into otherwise ACE2⁻ monocytes have all been proposed to trigger assembly of inflammasomes, most notably NLRP3, in myeloid-derived immune cells and pulmonary cells. Inflammasome activation recruits the caspase-1 canonically, which proteolytically potentiates pro-IL-1β and/or pro-IL-18 and concomitantly cleaves GSDMD into NT and CT fragments. GSDMD-NT oligomerization and translocation to plasma membrane create pores through which activated IL-1β and IL-18 can directly enter the extracellular space, mediating hyperinflammation, and simultaneously trigger pyroptosis, leading to LDH and HMGB1 release, among other pro-inflammatory DAMPs. Meanwhile, endothelial dysfunction in the hyperinflammatory milieu initiates immunothrombosis. Adhesion molecules are markers of activated endothelial cells over-expressed in COVID-19 that exhibit strong anchoring effects on monocytes and neutrophils, the former of which reciprocate with active TFs that directly institute the extrinsic coagulation pathway. Conversely, neutrophils may be prompted by direct SARS-CoV-2 entry, SAR-CoV-2-induced ROS generation, complement activation, and/or a self-sustaining loop of IL-8 production to undergo NETosis, defined by the release of large extracellular web-like structures termed NETs, which may also be triggered by the inflammasome/GSDMD pathway in COVID-19. NETs consist of decondensed chromatin embellished with histones and proteins that act as a scaffold for erythrocyte and platelet settling and fibrin deposition, while its constituents exert a range of pro-thrombotic effects with varying mechanisms. Furthermore, circulating platelets adopt a hyperactive state in the context of SARS-CoV-2 infection. Platelets recruited in response to NETs and other stimuli such as vWF on the activated endothelial cells in turn amplify NETosis via secretion of chemokines such as PF4, and may induce further expression of TF by monocytes and complementarily augment monocytic secretion of inflammatory cytokines. N protein nucleocapsid protein, ORF3a open reading frame 3a, ATP adenosine triphosphate, ROS reactive oxygen species, NLRP3 NOD-like receptor containing pyrin domain 3, IL-1β interleukin-1β, IL-18 interleukin-18, GSDMD gasdermin-D, NT N-terminal, CT C-terminal, LDH lactate dehydrogenase, HMGB1 high mobility group box 1, DAMPs damage-associated molecular patterns, TF transcription factor, IL-8 interleukin-8, NETs neutrophil extracellular traps, vWF von Willebrand Factor, PF4 platelet factor 4