Pathophysiology of Post-COVID syndromes: a new perspective

Abstract

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Keywords: COVID-19; Mast cell activation syndrome; Pathogenesis; Post-COVID syndrome.

Fig. 1

Diagnostic criteria of mast cell activation syndrome

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Post-COVID tachycardia syndrome [77]

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Pathogenesis of Post-COVID syndrome

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Systemic effects of Post-COVID syndrome

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COVID-19 and the risk of Post-COVID pulmonary fibrosis (PCPF)

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Post-COVID syndrome and neurological complications

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Post-COVID syndrome and cardiovascular complications

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Post-COVID syndrome and renal complications

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Post-COVID syndrome and gastrointestinal complications

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Post-COVID syndrome and endocrine complications

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Post-COVID syndrome and thromboembolic complications

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Role of mast cell activation syndrome in the development of Post-COVID syndrome: Stressful conditions during SARS-CoV-2 infection increase the release of corticotropic releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol. Besides, gut stress induces alteration of the gut microbiota, which affects the release of neurotransmitters, tryptophan metabolism, and the release of short-chain free fatty acids (SCFAs). These changes induce activation of mast cells, which releases inflammatory cytokines. Thus, mast cells link the brain and gut through neuronal, immune, and endocrine pathways