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Background: Pediatric patients infected with coronavirus disease 2019 (COVID-19) have unique clinical characteristics. Tumor necrosis factor (TNF) is a proinflammatory cytokine that greatly contributes to tumor pathogenesis.Purpose: To describe the presenting characteristics of COVID-19 infection among pediatric patients, and investigate the possible role of the TNF-α signaling pathway.Methods: This prospective case-control study included 50 Egyptian pediatric patients with COVID-19 and 50 healthy controls. Clinical, laboratory, and radiological assessments were performed. Serum TNF-alpha (TNF-α), TNF-α-converting enzyme (TACE), and angiotensin-converting enzyme 2 (ACE2) were measured using enzyme-linked immunosorbent assay. ACE (I/D) (rs4646994), ACE2 rs2285666, and TNF-α-308G/A single nucleotide polymorphisms (SNPs) were performed using conventional polymerase chain reaction techniques with or without restriction fragment length polymorphism.Results: The median age was 1 year (interquartile range [IQR], 0.31–2.50 years) in the case group and 1.45 years (IQR, 1.00–3.00) in the control group. The main presenting symptoms were fever (92%), dry cough (74%), and dyspnea (72%). The lymphocytic count was normal in 14 patients (28%), decreased in 16 patients (32%), and increased in 20 patients (40%) of the case group. Positive chest computed tomography finding of COVID-19 infection were demonstrated among 40% of patients using COVID-19 Reporting and Data System categories (ground-glass opacity with or without consolidations in the lungs). There were significant increased serum TACE and TNF-α with decreased ACE2 levels among cases versus controls (P< 0.001). The GG genotype and G allele of the TNF-α-308G/A SNP were significantly higher in patients than in controls (P<0.05 for both), with insignificant differences in genotype and allelic frequencies in the ACE (I/D) (rs4646994) and ACE2 rs2285666 SNPs.Conclusion: The TNF signaling pathway was significantly activated in pediatric COVID-19 infection. Only the TNF-α-308G/A SNP was significantly associated with pediatric COVID-19 infection.