Immune transcriptomic differences in paediatric patients with SARS-CoV-2 compared to other lower respiratory tract infections

Abstract

The clinical severity of SARS-CoV-2 infection in children varies, with asymptomatic or mild illness predominating and a minority developing severe disease. However, studies of the transcriptional responses to SARS-CoV-2 infection in children are limited. Understanding the immunological responses that underlie severity of disease may guide future development of preventive or therapeutic interventions. Whole blood transcriptomes of healthy children ( N  = 127) were compared to children with mild/asymptomatic SARS-CoV-2 infection ( N  = 71) and to children hospitalised with severe SARS-CoV-2 ( N  = 41), lower respiratory tract illness (LRTI), LRTI due to Respiratory Syncytial Virus (RSV-LRTI) ( N  = 47), or Pulmonary Tuberculosis (PTB) ( N  = 47). We identified > 5000 differentially expressed genes including: OLFM4 , IFI27 , CBX7 , IGF2BP3 , OTOF for severe SARS-CoV-2; IFI27 , OTOF , SIGLEC1 , IFI44L and USP18 for RSV-LRTI, and MMP8 , LTF , IGF2BP3 , GPR84 , CD177 , C1QC and DEFA4 for PTB, at false discovery rate (FDR) < 0.05. Pathway analysis identified enrichment for neutrophil degranulation, interferon gamma signalling, overexpression of ribosomal proteins and depletion of immune response in severe SARS-CoV-2 compared to healthy (SAR-CoV-2 uninfected) children. Weighted Gene Co-expression Network Analysis ( WGCNA ) identified 10 correlated gene modules shared between LRTIs showing similar underlying response mechanisms. Cellular decomposition analysis identified the depletion of 22 cell types in severe SARS-CoV-2, 16 for RSV-LRTI and 21 for PTB compared to healthy children. Severe COVID-19 in children exhibits a similar cellular response as previously reported in adults. We identified genes important for discriminating asymptomatic/mild from severe SARS-CoV-2, healthy children from severe SARS-CoV-2, RSV-LRTI and PTB, highlighting future therapeutic targets.