Elrashdy M. Redwan

Considerable research has been done in investigating SARS‐CoV‐2 infection, its characteristics, and host immune response. However, debate is still ongoing over the emergence of post‐acute sequelae of SARS‐CoV‐2 infection (PASC). A multitude of long‐lasting symptoms have been reported several weeks after the primary acute SARS‐CoV‐2 infection that resemble several other viral infections. Thousands of research articles have described various post‐COVID‐19 conditions. Yet, the evidence around these ongoing health problems, the reasons behind them, and their molecular underpinnings are scarce. These persistent symptoms are also known as long COVID‐19. The persistence of SARS‐CoV‐2 and/or its components in host tissues can lead to long COVID. For example, the presence of viral nucleocapsid protein and RNA was detected in the skin, appendix, and breast tissues of some long COVID patients. The persistence of viral RNA was reported in multiple anatomic sites, including non‐respiratory tissues such as the adrenal gland, ocular tissue, small intestine, lymph nodes, myocardium, and sciatic nerve. Distinctive viral spike sequence variants were also found in non‐respiratory tissues. Interestingly, prolonged detection of viral subgenomic RNA was observed across all tissues, sometimes in multiple tissues of the same patient, which likely reflects recent but defective viral replication. Moreover, the persistence of SARS‐CoV‐2 RNA was noticed throughout the brain at autopsy, as late as 230 days following symptom onset among unvaccinated patients who died of severe infection. Here, we review the persistence of SARS‐CoV‐2 and its components as an intrinsic factor behind long COVID. We also highlight the immunological consequences of this viral persistence.