Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involvement, which occurs within a few weeks following the resolution of acute SARS-CoV-2 infection. The complement system is a vital part of the innate immune system and plays a role in COVID-19 pathogenesis. Objective: To examine and compare the levels of complement components and regulators along with complement activation products in the different clinical spectrum of children with SARS-CoV-2 and a control group. Design, Setting, and Participants: This cross-sectional study analyzed children with MIS-C admitted to a single hospital in India from June through September 2020. Eligible participants were children who were hospitalized of either sex, aged 1 to 18 years. Data were analyzed August 2022. Measures: Levels of complement components and regulators along with complement activation products in all the groups of children. Mann-Whitney U test and Kruskal-Wallis analysis were used to compare the complement component levels, and Spearman rank correlation analysis was used to describe the association between complement components and laboratory and biochemical parameters. Results: A total 145 children were included (median age, 5 years [range, 1 month-17 years); 84 [58%] male): 44 children with MIS-C, 33 with acute COVID-19 (reverse transcriptase-polymerase chain reaction [RT-PCR] positive), 47 with convalescent COVID-19 (immunoglobulin G-positive non-MIS-C) and 21 children for a control group (both serology and RT-PCR negative). Children with MIS-C and COVID-19 had higher levels of C1q (geometric mean [SD]: MIS-C, 61.5 [18.5] ng/mL; acute COVID-19, 56.9 [18.6] ng/mL; controls, 24.1 [3.3] ng/mL), C2 (MIS-C, 605.8 [219.7] ng/mL; acute COVID-19, 606.4 [167.7] ng/mL; controls, 255.9 [73.3] ng/mL), C3 (MIS-C, 318.2 [70.7] ng/mL; acute COVID-19, 237.7 [61.8] ng/mL; controls, 123.4 [15.7] ng/mL), C4b (MIS-C, 712.4 ng/mL; acute COVID-19, 640.7 ng/mL; controls, 351.5 ng/mL), C5 (MIS-C, 1487 ng/mL; acute COVID-19, 1364 ng/mL; controls, 561.9 ng/mL), C5a, (MIS-C, 2614.0 [336.2] ng/mL; acute COVID-19, 1826.0 [541.0] ng/mL; controls, 462.5 [132.4] ng/mL), C3b/iC3b (MIS-C, 3971.0 [635.1] ng/mL; acute COVID-19, 3702.0 [653.9] ng/mL; controls, 2039.0 [344.5] ng/mL), and factor B (MIS-C, 47.6 [7.8] ng/mL; acute COVID-19, 44.6 [6.3] ng/mL; controls, 27.5 [5.0] ng/mL), factor D (MIS-C, 44.0 [17.2] ng/mL; acute COVID-19, 33.8 [18.4] ng/mL; controls, 21.3 [6.1] ng/mL), and factor H (MIS-C, 53.1 [4.0] ng/mL; acute COVID-19, 50.8 [5.7] ng/mL; controls, 43.6 [3.8] ng/mL) in comparison with convalescent and control children. In addition, children with MIS-C had significantly elevated levels of C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) support as compared with those who did not require PICU support, and in children with COVID-19 who developed moderate to severe disease compared with those who developed mild disease. Overall, MIS-C and acute COVID-19 were associated with the hyperactivation of complement components and complement regulators. Conclusions and Relevance: In this cross-sectional study, the complement system was associated with the pathogenesis of MIS-C and COVID-19 in children; complement inhibition could be further explored as a potential treatment option.

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children.

Introduction: Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. Methods: To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Results: Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Discussion: Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

Unique cellular immune signatures of multisystem inflammatory syndrome in children.

The clinical presentation of MIS-C overlaps with other infectious/non-infectious diseases such as acute COVID-19, Kawasaki disease, acute dengue, enteric fever, and systemic lupus erythematosus. We examined the ex-vivo cellular parameters with the aim of distinguishing MIS-C from other syndromes with overlapping clinical presentations. MIS-C children differed from children with non-MIS-C conditions by having increased numbers of naïve CD8+ T cells, naïve, immature and atypical memory B cells and diminished numbers of transitional memory, stem cell memory, central and effector memory CD4+ and CD8+ T cells, classical, activated memory B and plasma cells and monocyte (intermediate and non-classical) and dendritic cell (plasmacytoid and myeloid) subsets. All of the above alterations were significantly reversed at 6-9 months post-recovery in MIS-C. Thus, MIS-C is characterized by a distinct cellular signature that distinguishes it from other syndromes with overlapping clinical presentations. Trial Registration: ClinicalTrials.gov clinicaltrial.gov. No: NCT04844242.

Systemic Inflammation and Microbial Translocation Are Characteristic Features of SARS-CoV-2-Related Multisystem Inflammatory Syndrome in Children.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that can result in increased morbidity and mortality. The inflammatory underpinnings of MIS-C have not been examined in detail. METHODS: We examined the plasma levels of acute phase proteins and microbial translocation markers in children with MIS-C, children with acute coronavirus disease 2019 (COVID-19) infection, SARS-CoV-2-seropositive children, and controls. RESULTS: MIS-C children exhibited significantly higher levels of C-reactive protein (CRP), alpha2 macroglobulin (α2M), serum amyloid P (SAP), lipopolysaccharide (LPS), sCD14, and LPS binding protein (LBP) and significantly lower levels of haptoglobin (Hp) in comparison with seropositive, control, and/or COVID-19 children. In addition, COVID-19 children exhibited significantly higher levels of most of the above markers in comparison with seropositive and control children. Principal component analysis using a set of these markers could clearly discriminate MIS-C and COVID-19 from seropositive and control children. MIS-C children requiring pediatric intensive care unit admission and COVID-19 children with severe disease had higher levels of CRP, SAP, and/or sCD14 at admission. CONCLUSIONS: Our study describes the role of systemic inflammation and microbial translocation markers in children with MIS-C and COVID-19 and therefore helps in advancing our understanding of the pathogenesis of different presentations of SARS-CoV-2 infection in children.

Plasma biomarker profiling of PIMS-TS, COVID-19 and SARS-CoV2 seropositive children - a cross-sectional observational study from southern India.

BACKGROUND: SARS-CoV-2 infection in children can present with varied clinical phenotypes and understanding the pathogenesis is essential, to inform about the clinical trajectory and management. METHODS: We performed a multiplex immune assay analysis and compared the plasma biomarkers of Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), acute COVID-19 infection (COVID-19), SARS-CoV-2 seropositive and control children admitted to a tertiary care children's hospital in Chennai, India. Pro-inflammatory cytokines, chemokines and growth factors were correlated with SARS-CoV-2 clinical phenotypes. FINDINGS: PIMS-TS children had significantly elevated levels of cytokines, IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNß, IL-6, IL-15, IL-17A, GM-CSF, IL-10, IL-33 and IL-Ra; elevated chemokines, CCL2, CCL19, CCL20 and CXCL10 and elevated VEGF, Granzyme B and PDL-1 in comparison to COVID-19, seropositive and controls. COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNß, IL-6, IL-17A, IL-10, CCL2, CCL5, CCL11, CXCL10 and VEGF in comparison to seropositive and/or controls. Similarly, seropositive children had elevated levels of IFNγ, IL-2, IL-1α, IFNß, IL-17A, IL-10, CCL5 and CXCL10 in comparison to control children. Plasma biomarkers in PIMS-TS and COVID-19 children showed a positive correlation with CRP and a negative correlation with the lymphocyte count and sodium levels. INTERPRETATION: We describe a comprehensive plasma biomarker profile of children with different clinical spectrum of SARS-CoV-2 infection from a low- and middle-income country (LMIC) and observed that PIMS-TS is a distinct and unique immunopathogenic paediatric illness related to SARS-CoV-2 presenting with cytokine storm different from acute COVID-19 infection and other hyperinflammatory conditions.