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.

Fig. 1. The frequency of the most common symptoms four week or more after the acute Covid-19 infection.

Data presented in meta-analyses, selected on the basis of homogeneous reporting criteria [–20].

Fig. 2. A schematic representation of the pathogenic mechanisms and main targets of PASC.

The drivers, effector molecules, biomarkers, and affected organs are presented in a schematic form, as discussed in the text. The inset suggesting that the host genetics and microbiome may affect the development of Long Covid is based on current evidence on determinants of severe Covid-19. Type 2 diabetes has been shown to increase the risk of developing PASC.

Fig. 3. Schematic representation of SARS-CoV-2 virus infection and its role in PASC.

a The SARS-CoV-2 virus lipid bilayer comprising the spike protein (S, violet), the membrane protein (M, blue) and the envelope protein (E, orange), and the viral RNA (white) associated with the nucleocapsid protein (N, pink) are shown. b Different steps of SARS-CoV-2 replication cycle are illustrated in the cartoon, including binding to the ACE2 receptor (blue), virus entry, viral RNA replication, sub-genomic RNA transcription and translation, virus assembly, and exit from the host cell. RdRp, RNA-dependent RNA polymerase. ER endoplasmic reticulum, ERGIC ER-Golgi intermediate compartment. During acute infection (right), the virus hijacks the host cell transcriptional/translational machinery to make large amounts of viral proteins and RNA (green arrow), while shutting down cellular protein synthesis (red arrow), resulting in infectious virus progeny production, and host cell damage and death. The host immune-response eventually leads to virus clearance (gray box, c). The mechanisms at the basis of virus persistence in the host cell are currently unknown. In the hypothetical model of persistent infection (left) concurrence of molecular and immunological events may allow a metastable equilibrium between SARS-CoV-2 and the host cell (blue arrow), where a virus-directed transcriptional program enables a long-lasting virus-host interaction and cell survival. Evasion of the host immune response may allow the establishment of virus reservoirs (gray box, c). In persistently infected cells viral RNA and/or selected viral proteins might act as constant stimuli causing chronic immune system dysregulation and inflammation (c, left panel).