Long Covid: where we stand and challenges ahead

Abstract

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

“…The exact pathophysiology of Long Covid is unknown but is likely multi-factorial, including the inflammatory cascade during acute infection and persistent viral replication. 21 Mechanistic in silico modeling predicts that translation of SARS-CoV-2 viral proteins is an especially sensitive target for inhibition, and previous studies show metformin capable of suppressing protein translation via mTor. 22,23 Experimentally, metformin has in-vitro activity at a physiologically relevant dose against SARS-CoV-2 in cell culture and in human lung tissue, ex vivo, and in a phase 2 clinical trial.…”

Anosmia in COVID-19 could be associated with long-term deficits in the consolidation of procedural and verbal declarative memories

“…Regarding the etiology of long-COVID, studies have not yet reached a definite conclusion, but researchers have drawn hypotheses about the physiological pathways that may lead to the direct consequences of the viral infection in combination with inflammatory or autoimmune responses. Thus, some of the etiological factors for long-term symptoms associated with COVID-19 are viral persistence, either SARS-CoV-2 or RNAemia in tissues, persistent abnormalities in immune cells, changes in the inflammatory response, reactivation of latent pathogens, or autoimmune antibody development (Mantovani et al, 2022).…”

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course

“…Therefore, it is conceivable that the corresponding autoantibodies positively impact the long-term outcome of COVID-19 by antagonizing or otherwise modulating the activation, recruitment and retention of these cell types 55 . In keeping with this observation, persistent immune responses have been proposed as a mechanism for long COVID, and chemokines have been implicated in its pathogenesis 7,31 .…”

“…Accordingly, chemokines recruit neutrophils and monocytes to sites of infection, where they play a key role in the pathophysiology of COVID-19 by sustaining inflammation and causing collateral tissue damage and fibrosis, particularly during the inflammatory phase that follows virus clearance 20, 24, 27–30 . Chemokines have also been implicated in the pathogenesis and as biomarkers of long COVID 31 . Anti-inflammatory treatments, such as steroids and IL-6 blockade, are efficacious in hospitalized COVID-19 patients, and therapies targeting the chemokine system are under development for immunological disorders and have been proposed for COVID-19 18, 22, 32, 33 .…”