Post-COVID dysautonomias: what we know and (mainly) what we don’t know

Following on from the COVID-19 pandemic is another worldwide public health challenge that is referred to variously as long COVID, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC comes in many forms and affects all body organs. This heterogeneous presentation suggests involvement of the autonomic nervous system (ANS), which has numerous roles in the maintenance of homeostasis and coordination of responses to various stressors. Thus far, studies of ANS dysregulation in people with PASC have been largely observational and descriptive, based on symptom inventories or objective but indirect measures of cardiovascular function, and have paid little attention to the adrenomedullary, hormonal and enteric nervous components of the ANS. Such investigations do not consider the syndromic nature of autonomic dysfunction. This Review provides an update on the literature relating to ANS abnormalities in people with post-COVID syndrome and presents a theoretical perspective on how the ANS might participate in common features of PASC. Autonomic nervous system dysregulation contributes to the chronic, debilitating disorders referred to as ‘long COVID’ or post-acute sequelae of SARS-CoV-2 infection (PASC). Here, Goldstein describes a multisystem, multidisciplinary approach to understanding PASC-induced alterations in feedback-regulated, plastic networks that determine homeostasis and allostasis. Key points The diverse nature of post-COVID syndrome suggests involvement of the autonomic nervous system (ANS), which plays numerous roles in homeostasis and coordinates responses to essentially all stressors. The ANS concept was promulgated before the discoveries of neuroendocrine systems, immune and inflammatory systems, and the central autonomic network; the extended autonomic system theory is a necessary update. Publications on post-COVID dysautonomias have not considered the syndromic nature of autonomic dysfunctions. Such studies have been largely observational and descriptive, based on symptom inventories or objective but indirect cardiovascular measures; the hormonal and enteric components of the ANS have generally been ignored. Understanding of multisystem disorders of regulation, such as post-COVID syndrome, requires a shift towards consideration of the feedback-regulated, plastic networks that, via the extended autonomic system, determine homeostasis and allostasis.