Inflammatory pathways in patients with post-acute sequelae of COVID-19: The role of the clinical immunologist

As the SARS-CoV-2 pandemic progressed, some survivors noted prolonged symptoms after acute infection, termed post-acute sequelae of COVID-19 (PASC) or "long COVID." PASC is a significant clinical and public health concern that adversely affects patients' quality of life, income, and health care expenses. Moreover, PASC symptoms are highly heterogeneous, the most common being fatigue and cognitive impairment, and they likely reflect a spectrum of clinical phenotypes. The proposed role of persistent inflammation is one of leading pathophysiological theories. This review article addresses these proposed mechanisms of persistent and aberrant inflammation, their clinical evaluation, and theoretical approaches to management. A review of public databases was used to collect literature for the review. The literature supports a prominent role of persistent and aberrant inflammation as a major contributor to the symptoms of PASC. Proposed mechanisms for persistent inflammation include reactivation of latent viruses, viral persistence, loss of immunoregulatory pathways, autoimmune mechanisms, and/or mast cell dysregulation. Persistent inflammation may result in constitutional symptoms such as fatigue, brain fog, body aches, and/or organ-specific dysfunction, such as gastrointestinal dysregulation and myocardial inflammation. There are no approved or even proven therapies for PASC at this time, but some studies have identified therapeutic options that may either reduce the risk for progression to PASC or decrease symptom burden. Laboratory evaluation and therapeutic options are limited and require further investigation to establish their clinical value. A more refined definition of PASC is needed to address the wide variety of clinical presentations, pathophysiology, and therapeutic options.