Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies

Introduction

The SARS-CoV-2 (COVID-19) pandemic has caused unprecedented morbidity, mortality and disruption across the world. Following the initial phase, healthcare services are focusing now on controlling new cases and planning rehabilitation strategies. ‘Post-acute COVID’¹ refers to persistent symptoms 3 weeks after COVID-19 infection, while ‘Chronic COVID’ describes symptoms lasting more than 12 weeks.²

Results of the COVID Symptom Study (based on a smartphone tracker app where users enter their symptoms, which had over 2.8 million recorded users by May 2020)^3,4 are awaited, but smaller studies reveal that protracted symptoms following COVID-19 infection are common. In Italian inpatients, 53% had fatigue, 43% were dyspnoeic and 22% were experiencing chest pain after 2 months.² Halpin et al reported that after 4–8 weeks, ongoing fatigue is present in more than two thirds, followed by breathlessness and symptoms of post-traumatic stress disorder.⁵ Mainstream media are giving publicity to patient-coined terms ‘long COVID’⁶ and ‘long-haul COVID’.⁷ The popularity and visibility of patient support groups such as wearebodypolitic.com (who according to their website have 14,000 subscribers) and the Long COVID SOS group (longcovidsos.org), and the frequent trending of the hashtag #longcovid on Twitter, suggest that patient need is high, and under-recognised by clinicians.

‘Long COVID’ and orthostatic intolerance syndromes

In our tertiary syncope unit, we have encountered patients with debilitating symptoms following viral infections who were subsequently found to have orthostatic intolerance syndromes. A summary is shown in Table 1. While only one case in this series had confirmed COVID-19, the others had symptoms consistent with a debilitating viral illness in early 2020 and were suspected cases during a period where COVID testing was not recommended or widely available. Of note, all of the individuals in this short series were female and were between the ages of 26 and 50 years old. They all had orthostatic intolerance with either resting or postural hypotension and/or tachycardia. We propose that some symptoms of the so-called ‘long COVID’ infection may be related to a virus- or immune-mediated disruption to the autonomic nervous system, resulting in transient or long-term orthostatic intolerance syndromes.

Orthostatic intolerance syndromes include orthostatic hypotension (OH), vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS). The pathophysiology hinges on an abnormal autonomic response to orthostasis (standing up). When a healthy person stands, blood pools in the pelvis and legs, reducing venous return to the heart. This is detected by baroreceptors in the heart and aorta, which respond by increasing sympathetic neural and adrenergic tone (mediated by norepinephrine and epinephrine respectively). This results in tachycardia (thus compensating for reduced stroke volume). This is then followed by vasoconstriction in the splanchnic vascular bed, which increases venous return to the heart.

In orthostatic intolerance, the release of epinephrine and norepinephrine causes pronounced tachycardia, which is experienced as palpitations, breathlessness and chest pain (common symptoms of ‘long COVID’). Very high catecholamine levels can lead to paradoxical vasodilatation, sympathetic activity withdrawal and activation of the vagus nerve resulting in hypotension, dizziness and ultimately syncope.^8–11

These syndromes may be exacerbated by hypovolaemia resulting from the initial infection or due to deconditioning by bedrest. Prolonged bedrest (there have been extensive studies of head-down bedrest simulating chronic weightlessness in astronauts) leads to reduced cardiac output and stroke volume, hypovolaemia, baroreflex impairment, and withdrawal of the sympathetic neural response.^12–15

COVID-19, autoimmunity and the autonomic nervous system

It has been hypothesised that COVID-19 infection affects the autonomic nervous system.¹⁶ The relationship between the two is complex: the well-documented cytokine response storm of COVID-19¹⁷ results from sympathetic activation inducing pro-inflammatory cytokine release.^18,19 Conversely, vagal stimulation results in an anti-inflammatory responses,¹⁷ suggesting possible therapeutic targets in the autonomic nervous system.

Alternatively, COVID-19 related autonomic dysfunction could be mediated by the virus itself. Immune-mediated neurological syndromes have been described.²⁰ It is also well established that autonomic disorders such as OH and POTS are associated with autoantibodies,²¹ for example to α-/β-adrenoceptors and muscarinic receptors.^22–25 Cohort studies describe commonly preceding infections in POTS,²⁶ as well as a link with autoimmune biomarkers and autoimmune disorders.²⁷ Thus, we speculate that there is an underlying autoimmune component to the post-COVID syndromes that we report.

Identifying autonomic dysfunction following COVID-19 infection

Any individuals presenting with breathlessness, palpitations, fatigue, chest pain, presyncope or syncope should be evaluated carefully. Cardiovascular, respiratory and neurological examination with vital signs and pulse oximetry are essential. Electrocardiogram, blood tests and imaging should be considered to identify other important diagnoses such as organising pneumonia, pulmonary embolism and myocarditis.

An active stand test should be undertaken, measuring blood pressure and heart rate after 5 minutes lying supine, and then 3 minutes after standing. Orthostatic hypotension is defined as a fall of >20 mmHg systolic and >10 mmHg diastolic after standing for 3 minutes.²⁸ POTS is characterised by orthostatic symptoms (in the absence of orthostatic hypotension) with an increase in heart rate of 30 beats per minute or more when standing for more than 30 seconds, or 40 beats per minute or more in those aged 12–19 years.²⁹ A continuous blood pressure and heart rate trace during a tilt table test of an individual with orthostatic intolerance post-COVID is shown in Fig 1. After adopting the upright position, a marked and continuous rise in heart rate was seen, corresponding with the onset of clinical symptoms and mirrored by blood pressure oscillations in keeping with an adrenergic response. The average heart rate rise was under 30 beats per minute, thus not fulfilling criteria for POTS.

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Fig 1.

Continuous heart rate and blood pressure monitoring during a head-up tilt table test from an individual with long COVID and orthostatic intolerance following COVID-19 infection in March 2020.

Management of orthostatic intolerance

We suggest the following methods of management. This is based on published international guidance, consensus statements, and the authors’ own experience and practice in managing orthostatic intolerance syndromes.^8,29–31