Understanding COVID-19 in children: immune determinants and post-infection conditions

Abstract

Coronavirus disease 2019 in children presents with milder clinical manifestations than in adults. On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both protective factors that prevent evolution to severe forms and risk factors for post-infectious conditions are likely to be found in age-related differences in the immune system. The prompt innate response with type I IFN production and the generation of neutralizing antibodies play a crucial role in containing the infection. The greater number of naive and regulatory cells in children helps to avoid the cytokine storm while the causes of the intense inflammatory response in MIS-C need to be elucidated. This review aims to analyze the main results of the recent literature assessing immune response to SARS-CoV-2 over the pediatric age group. We summarized such observations by dividing them into innate and acquired immunity, then reporting how altered immune responses can determine post-infectious conditions. IMPACT: The main immune markers of acute SARS-CoV-2 infection in children are summarized in this review. This paper reports a broad overview of age-related differences in the immune response to SARS-CoV-2 and emerging post-infection conditions. A summary of currently available therapies for the pediatric age group is provided.

Fig. 1. Constitutional risk factors among children are mainly represented by inborn errors that alter innate response pathways.^,,

Innate immunity: in healthy children, frequent exposure to viruses and vaccination in the early years of life could keep the immune system ready in case of first exposure to SARS-CoV-2. Immediate production of type 1 IFN is decisive in preventing the spread of viral infection, while SARS-CoV-2 escape strategies are frustrated by the intervention of specific lymphocytes that limit its inhibitory anti-IFN activity. In adulthood, the type 1 IFN response is delayed and the increased presence of anti-IFN antibodies favors the spread of infection. Infiltration of the lungs by monocytes/macrophages and neutrophil granulocytes, which show a higher presence of adhesion molecules than in children, leads to pneumonia. Adaptative immunity: the higher number of naive and regulatory cells leads to a moderate cytokine response in children, avoiding the risk of the cytokine storm typical of more severe COVID-19 cases in adults.^, Humoral response: the production of neutralizing antibodies is associated with a better outcome of the SARS-CoV-2 infection. Among adults with severe disease, the mechanism of antibody-dependent enhancement (ADE) has been described.^, This would be due to the presence of non-neutralizing antibodies that favor viral propagation and the creation of circulating immune complexes. Created with BioRender.com.

Fig. 2. SARS-CoV-2 infection process of respiratory epithelial cells and main targets of pediatric COVID-19 therapies.

The most commonly used medications in childhood are indicated in bold. Drugs that are rarely used or cannot be used in pediatrics are shown in transparent. Created with BioRender.com.