Innate immune response analysis in COVID-19 and kawasaki disease reveals MIS-C predictors.

BACKGROUND/PURPOSE: The association between dysregulated innate immune responses seen in Kawasaki disease (KD) with predisposition to Kawasaki-like multisystem inflammatory syndrome in children (MIS-C) remains unclear. We aimed to compare the innate immunity transcriptome signature between COVID-19 and KD, and to analyze the interactions of these molecules with genes known to predispose to KD. METHODS: Transcriptome datasets of COVID-19 and KD cohorts (E-MTAB-9357, GSE-63881, GSE-68004) were downloaded from ArrayExpress for innate immune response analyses. Network analysis was used to determine enriched pathways of interactions. RESULTS: Upregulations of IRAK4, IFI16, STING, STAT3, PYCARD, CASP1, IFNAR1 and CD14 genes were observed in blood cells of acute SARS-CoV-2 infections with moderate severity. In the same patient group, increased expressions of TLR2, TLR7, IRF3, and CD36 were also noted in blood drawn a few days after COVID-19 diagnosis. Elevated blood PYCARD level was associated with severe COVID-19 in adults. Similar gene expression signature except differences in TLR8, NLRP3, STING and IRF3 levels was detected in KD samples. Network analysis on innate immune genes and genes associated with KD susceptibility identified enriched pathways of interactions. Furthermore, higher expression levels of KD susceptibility genes HLA-DOB, PELI1 and FCGR2A correlated with COVID-19 of different severities. CONCLUSION: Our findings suggest that most enriched innate immune response pathways were shared between transcriptomes of KD and COVID-19 with moderate severity. Genetic polymorphisms associated with innate immune dysregulation and KD susceptibility, together with variants in STING and STAT3, might predict COVID-19 severity and potentially susceptibility to COVID-19 related MIS-C.

Successful Treatment of a Critically Ill COVID-19 Patient Using Continuous Renal Replacement Therapy With Enhanced Cytokine Removal and Tocilizumab: A Case Report.

The COVID-19 pandemic has caused multiple deaths worldwide. Since no specific therapies are currently available, treatment for critically ill patients with COVID-19 is supportive. The most severe patients need sustained life support for recovery. We herein describe the course of a critically ill COVID-19 patient with multi-organ failure, including acute respiratory failure, acute kidney injury, and fulminant cytokine release syndrome (CRS), who required mechanical ventilation and extracorporeal membrane oxygenation support. This patient with a predicted high mortality risk was successfully managed with a careful strategy of oxygenation, uremic toxin removal, hemodynamic support, and most importantly, cytokine-targeted intervention for CRS, including cytokine/endotoxin removal, anti-cytokine therapy, and immune modulation. Comprehensive cytokine data, CRS parameters, and biochemical data of extracorporeal removal were provided to strengthen the rationale of this strategy. In this report, we demonstrate that timely combined hemoperfusion with cytokine adsorptive capacity and anti-cytokine therapy can successfully treat COVID-19 patients with fulminant CRS. It also highlights the importance of implementing cytokine-targeted therapy for severe COVID-19 guided by the precise measurement of disease activity.

Inflammasomes and Childhood Autoimmune Diseases: A Review of Current Knowledge.

Inflammasomes are multiprotein complexes capable of sensing pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and cellular perturbations. Upon stimulation, the inflammasomes activate the production of the pro-inflammatory cytokines IL-1ß and IL-18 and induce gasdermin D-mediated pyroptosis. Dysregulated inflammasome signaling could lead to hyperinflammation in response to environmental triggers, thus contributing to the pathogenesis of childhood autoimmune/autoinflammatory diseases. In this review, we group childhood rheumatic diseases into the autoinflammation to autoimmunity spectrum and discuss about the involvement of inflammasomes in disease mechanisms. Genetic mutations in inflammasome components cause monogenic autoinflammatory diseases, while inflammasome-related genetic variants have been implicated in polygenic childhood rheumatic diseases. We highlight the reported associations of inflammasome signaling-related genetic polymorphisms/protein levels with pediatric autoimmune disease susceptibility and disease course. Furthermore, we discuss about the use of IL-1 receptor antagonist as an adjunctive therapy in several childhood autoimmune diseases, including macrophage activation syndrome (MAS) and multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. A comprehensive multi-cohort comparison on inflammasome gene expression profile in different pediatric rheumatic diseases is needed to identify patient subsets that might benefit from the adjunctive therapy of IL-1ß inhibitors.

Experience of the use of hydroxychloroquine on patients with COVID-19: A perspective on viral load and cytokine kinetics.

Until now, there are no approved treatment against COVID-19. Hydroxychloroquine (HCQ) was hypothesized to be active against SARS-CoV2 via antiviral and anti-inflammatory effect; however, HCQ for COVID-19 in clinical use remained debating. In this preliminary report, we presented six patients with mild to moderate COVID-19. They were treated with HCQ for 14 days from the day of COVID-19 diagnosis. Serial viral load from respiratory specimens were performed every other day. Cytokine profile was checked before HCQ initiation and on the 14th day of HCQ treatment. All patients receiving HCQ completed 14-day course without complication. Among the six patients, the mean duration from symptom onset to last detectable viral load was 34 ± 12 days, which was similar to those without specific treatment in previous reports. Low level of interferon-gamma was noted in all patients of different stage of infection and three patients had elevation of IL-17 level. Prolonged virus shedding is still observed regardless HCQ. The impact of HCQ on cytokine kinetics remained unclear; however, IL-17 could be an inflammatory marker for disease status monitor and a potential therapeutic target.