Long COVID: emerging pathophysiological mechanisms

Post-COVID conditions, also termed "long COVID," are a heterogeneous set of conditions persisting greater than 28 days after initial infection. These conditions, which include fatigue, brain fog, orthostatic intolerance, and pain, are a significant source of morbidity and limited function worldwide. Nonetheless, both the pathophysiology and treatment of long COVID remain poorly understood. Several pathophysiologic mechanisms have been proposed including neuroinflammatory drivers, endothelial dysfunction, neurotransmitter dysregulation, mitochondrial dysfunction, autonomic dysfunction, and central sensitization. In this article, we present a conceptual framework for evaluation of long COVID symptoms, as well as the evidence behind their proposed pathophysiologic mechanisms. Patients may struggle with one or more of the proposed mechanisms listed above, and the contributions from each process may vary depending on the patient. Although no FDA-approved therapies exist for long COVID, we review several potential promising and mechanistically plausible therapies.