Whole blood gene expression to assess disease severity of omicron-associated acute encephalitis and croup in children: A transcriptomic and immune profiling study

BACKGROUND: The Omicron variant of SARS-CoV-2 has caused severe complications in children, including encephalitis/encephalopathy and croup, yet the underlying pathogenic mechanisms remain unclear. Transcriptome analysis could provide insights into immune responses and guide clinical management strategies. METHODS: We conducted a case-control cohort study of COVID-19 patients across two medical centers in Taiwan from April 17 to November 7, 2022. Blood RNA sequencing was used to analyze differences in gene expression and functional pathways between cases of encephalitis/encephalopathy or croup of varying severity and controls with mild febrile disease. We applied computational analyses to identify transcriptomic signatures linked to COVID-19 associated encephalitis/encephalopathy. RESULTS: This study included 61 patients diagnosed with SARS-CoV-2 infection: 29 with mild febrile disease, 14 with croup, and 18 with encephalitis/encephalopathy. More differentially expressed genes were identified in encephalitis/encephalopathy (n = 834) than in croup (n = 185). Functional enrichment analysis revealed coordinated upregulation of myeloid leukocyte, neutrophil, and macrophage pathways in encephalitis/encephalopathy, accompanied by downregulation of HLA class II expression, antigen presentation, and T-cell activation, with changes tracking disease severity. CIBERSORT analysis revealed increased activated dendritic cells and reduced naïve CD4 T cells, CD8 T cells, naïve B cells, and NK cells. Croup patients showed reduced antigen presentation and low T cell receptor signaling. Gene expression profiles differentiated encephalitis/encephalopathy from mild febrile disease with a positive predictive value of 95.3 %. CONCLUSION: Future interventions aiming at innate immune dysregulation, such as neutrophil inhibition, addressing macrophage activation, and enhancing T-cell responses, could play a promising role in improving outcomes for children infected with emerging, virulent SARS-CoV-2 variants.