Infection with SARS-CoV-2 in children may be associated with the acquisition of an unconventional phenotype by neutrophils that might prevent lung infiltration, thus preserving tissue integrity, according to the results of analysis published in the journal EBioMedicine.

Recognizing that the clinical course of COVID-19 infection in children is typically mild and often asymptomatic, with little known about the immune response in this population, investigators sought to analyze the phenotype and function of circulating neutrophils from children with COVID-19. The researchers conducted an observational study in Buenos Aires City and Buenos Aires province, Argentina, between May 2020 and October 2020.   

The current study included 174 children with COVID-19 infection, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy control individuals. Children between 5 months and 15 years of age were recruited for the study. COVID-19 disease severity in the 174 participants was classified into 4 clinical types —asymptomatic in 29 children, mild in 102 children, moderate in 43 children, and severe in zero children.

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Neutrophil phenotype was evaluated by flow cytometry obtained from blood samples. Enzyme-linked immunosorbent assays (ELISA) were used to measure cytokine production, plasma levels of immunoglobulin G (IgG) antibodies directed against the spike protein of SARS-CoV-2, and citrullinated histone H3. Fluorometry was utilized to quantify cell-free DNA.

Results of the study demonstrated that compared with healthy control individuals, the neutrophils from children with COVID-19 infection exhibited a lower expression of CD11b, CD66b, and L-selectin, but a higher expression of the activation markers HLA-DR, CD64, and PECAM-1, as well as the inhibitory receptors LAIR-1 and PD-L1.

There were no differences observed in the production of cytokines and neutrophil extracellular traps (NETs). The expression of CD64 in neutrophils and the serum concentration of IgG antibodies directed against the SARS-CoV-2 spike protein differentiated patients with asymptomatic COVID-19 infection from those with mild and moderate COVID-19 infection.

A major limitation of the current study was the fact that the cohort did not include any children with severe COVID-19. Therefore, the study findings were unable to distinguish severe COVID-19 infection from MIS-C.

The investigators concluded that demonstration of the acquisition of an atypical phenotype by circulating neutrophils among children with COVID-19, which differs distinctly from the phenotype observed in neutrophils from adult patients with COVID-19, might help to preserve lung function among children with the infection by preventing tissue infiltration. Furthermore, either the neutrophil expression of CD64 or the plasma levels of IgG antibodies that are directed against the SARS-CoV-2 spike protein are valuable biomarkers for differentiating asymptomatic from symptomatic children with COVID-19.


Seery V, Raiden SC, Algieri SC, et al; on behalf of the COVID-19 Naval Pediatric Workgroup; COVID-19 Fernández Pediatric Residency Workgroup. Blood neutrophils from children with COVID-19 exhibit both inflammatory and anti-inflammatory markers. EBioMedicine. Published online May 9, 2021. doi:10.1016/j.ebiom.2021.103357