Infection, Dysbiosis and Inflammation Interplay in the COVID Era in Children

Abstract

For over three years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents has generated repercussions, especially a few weeks after infection, for symptomatic patients who tested positive, for asymptomatic ones, or even just the contacts of an infected person, and evolved from severe forms such as multisystem inflammatory syndrome in children (MIS-C) to multifarious clinical manifestations in long COVID (LC). Referred to under the umbrella term LC, the onset of persistent and highly heterogeneous symptoms such as fatigue, post-exertion malaise, cognitive dysfunction, and others have a major impact on the child's daily quality of life for months. The first aim of this review was to highlight the circumstances of the pathophysiological changes produced by COVID-19 in children and to better understand the hyperinflammation in COVID-19 and how MIS-C, as a life-threatening condition, could have been avoided in some patients. Another goal was to better identify the interplay between infection, dysbiosis, and inflammation at a molecular and cellular level, to better guide scientists, physicians, and pediatricians to advance new lines of medical action to avoid the post-acute sequelae of SARS-CoV-2 infection. The third objective was to identify symptoms and their connection to molecular pathways to recognize LC more easily. The fourth purpose was to connect the triggering factors of LC with related sequelae following acute SARS-CoV-2 injuries to systems and organs, the persistence of the virus, and some of its components in hidden reservoirs, including the gut and the central nervous system. The reactivation of other latent infectious agents in the host's immune environments, the interaction of this virus with the microbiome, immune hyperactivation, and autoimmunity generated by molecular mimicry between viral agents and host proteins, could initiate a targeted and individualized management. New high-tech solutions, molecules, probiotics, and others should be discovered to innovatively solve the interplay between RNA persistent viruses, microbiota, and our immune system.

Keywords: ACE-2; autoantibodies; gut; hyperinflammation; immune imbalance; long COVID; microbiome; mimicry; permanent tissue damage; post-infectious; viral persistence.

Figure 1

Clinical manifestations of LC in children and adolescents (Figure 1 was imagined and drawn by L.M.A. using Microsoft Paint 3D for Windows 10 and using completely free picture material from SeekPNG.com (accessed on 20 May 2023), for which we are very grateful).

Figure 2

Persistence of SARS-CoV-2 and its remnants, intestinal dysbiosis, bacterial translocation, reactivation of pathogens, and their influence on the evolution of molecular and cellular processes in LC [168].

Figure 3

The vicious cycle and the progression of inflammatory processes in LC.

Figure 4

The entire complex interplay between infection, dysbiosis and inflammation in pediatric long COVID. The central pathways were drawn by the main author, L.M.A. [168].