Please Note: The information below is intended for healthcare professionals, specifically primary care providers. These are not meant to be guidelines or supplant individual provider discretion in the management of PASC, as evidence-based consensus guidelines for the diagnosis of management of this new disease do not exist currently. The following represents the expert opinions of an interprofessional group that is appraising emerging evidence and should be interpreted as recommendations and clinical guidance rather than the standard of care.
Dysautonomia in PASC
Written September 14, 2021 by: Matthew Seghers, MS4, Mary Kelley, DO, Faith Noah, MS4, and W. Michael Brode, MD
Dysautonomia is an umbrella term used to describe a clinical presentation of fatigue, palpitations, orthostatic tachycardia or hypotension, sweating, bladder dysfunction, and GI dysmotility. Dysautonomia has been widely recognized following viral illnesses and is a prominent feature of PASC, which appears independent of the initial COVID-19 illness severity.
A combination of post-infectious cellular damage, an induced pro-inflammatory response, and autoimmunity may all contribute to dysautonomia. Small nerve fibers are thought to be particularly affected; these control heart rate, blood pressure, GI function, and other sympathetic and parasympathetic functions.
Evaluation should focus on close history taking for systemic manifestations of dysautonomia and obtaining orthostatic vital signs. Diagnosis of dysautonomia is clinical, but some neurology clinics may offer tilt-table testing to further classify the autonomic dysfunction and/or skin punch biopsies to confirm the diagnosis of small fiber neuropathy.
Dysautonomia refers to a disorder of autonomic nervous system (ANS) function that generally involves failure of the sympathetic or parasympathetic components of the ANS.1 Patients with PASC have been shown to have a variety of orthostatic intolerance syndromes, including orthostatic hypotension, vasovagal syncope, and postural orthostatic tachycardia syndrome (POTS), in addition to symptoms, such as fatigue and “brain fog.”2
- Sympathetic preganglionic neurons from T1 to L2 are activated in response to orthostatic stress, exposure to heat and cold, hypoglycemia, exercise, and emotion. Sympathetic output is important for maintenance of blood pressure, regulation of blood flow, thermoregulation, and responses to stressors.
- Parasympathetic preganglionic neurons in the brainstem or from S2-S4 are responsible for pupil constriction and accommodation, lacrimation and salivation, and control of heart rate, gastrointestinal motility, micturition, defecation, and erectile function.
Clinicians have observed overlapping symptoms of PASC, dysautonomia, and mast cell activation syndrome (MCAS), another umbrella term characterized by excessive mast cell degranulation. Clinical features include fatigue and brain fog, but more specifically, allergic symptoms of flushing, urticaria, diarrhea, wheezing, and syncope. It is unclear if PASC patients have distinct phenotypes or share underlying mechanisms leading to MCAS or dysautonomia.
The true prevalence of dysautonomia in PASC is unclear given the diffuse constitutional symptoms without standardized reporting, but in a small cohort of patients presenting to a specialty PASC clinic, 63% of patients had abnormalities on formal dysautonomia testing.3
SARS-CoV-2 can infect the central nervous system (CNS) by hematogenous spread to cerebral circulation, which may explain the high rate of neuro-inflammation in patients with acute COVID-19 and PASC.
Once in the CNS, proposed methods by which COVID-19 affects the autonomic nervous system include:
- Blood-brain barrier damage leading to pathological permeability and dysregulation
- Long-term activation of glial cells which chronically damage neurons
- Autoimmunity in both central and peripheral neurons or supporting structures, although specific cellular targets have not been identified
- Chronic inflammation and cytokine excess leading to sympathetic activation4
Dysautonomia remains principally a clinical diagnosis based on history and an exam/workup to exclude focal CNS or large fiber nerve lesions. Symptoms of dysautonomia following COVID-19 infection include chest pain, fatigue, presyncope, syncope, palpitations, and dyspnea.
Orthostatic blood pressure measurements should be taken, either by measuring BP and HR while supine and standing, or via a tilt table test.3
- When obtaining orthostatic vital signs, the patient should rest in the supine posture for at least 2 minutes before baseline measurements are taken. Standing measurements are best taken after at least 1 minute of standing, as the autonomic response to standing takes 20 to 30 seconds to equilibrate. Sustained HR > 30 or drop in SBP > 20 mmHg are positive for POTS or orthostatic hypotension, respectively.
Formal autonomic function tests require specialty equipment and training, and access can be limited. It may include tilt-table testing for evaluation of sympathetic and parasympathetic function and/or skin punch biopsies to measure intraepidermal nerve fiber density. Referral to a neurologist or other specialist is recommended for patients with suspected or functionally limiting dysautonomia symptoms.
Treatment of dysautonomia is largely symptomatic, focused on a graduated exercise program for reconditioning and medications, such as gabapentin for neuropathy or pyridostigmine for GI dysmotility.
Treatment of POTS is focused on maintenance of vascular tone. This includes lifestyle measures to increase vascular volume, exercise for reconditioning, and pharmacologic agents.
Structured exercise programs using non-upright methods, including swimming and recumbent cycling due to potential for orthostasis are recommended. Evidence-based exercise regimens for dysautonomia can be found here, or for POTS, we recommend the CHOP protocol.
Nonpharmacologic management of dysautonomia includes:
- Fluid and salt repletion (2-3 liters of water consumption per day) are important to maintain plasma volume and avoid hypovolemia
- Avoiding dehydration, prolonged standing, and heat for extended periods of time may help with symptom management as well
- Physical counterpressure maneuvers and compression garments to reduce venous pooling
Pharmacologic management varies from patient to patient and may include:
- Discontinuing medications that increase norepinephrine (SSRIs, SNRIs, or TCAs, such as nortriptyline)
- Fludrocortisone may be used for fluid expansion
- Midodrine can increase vasoconstriction and venous return to treat orthostasis
- Other medications that may be used to decrease hyperadrenergic POTS: propranolol, metoprolol, pyridostigmine, methyldopa, and ivabradine5,6
For patients with more allergic symptoms concerning for MCAS, a trial antihistamine blockade for 4 weeks is reasonable and well-tolerated. We recommend cetirizine 10mg twice daily; if a patient has symptomatic improvement but persistent flushing or GI symptoms, may consider adding montelukast 10mg daily or famotidine 20mg twice daily.7
1. Eshak N, Abdelnabi M, Ball S, et al. Dysautonomia: An Overlooked Neurological Manifestation in a Critically ill COVID-19 Patient. Am J Med Sci. 2020;360(4):427-429. doi:10.1016/j.amjms.2020.07.022
2. Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg. 2020;194:105921. doi:10.1016/j.clineuro.2020.105921
3. Shouman K, Vanichkachorn G, Cheshire WP, et al. Autonomic dysfunction following COVID-19 infection: an early experience. Clin Auton Res. 2021;31(3):385-394. doi:10.1007/s10286-021-00803-8
4. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid—mechanisms, risk factors, and management. BMJ. 2021;374:n1648. doi:10.1136/bmj.n1648
5. Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clinical Medicine. 2021;21(1):e63-e67. doi:10.7861/clinmed.2020-0896
6. Mar PL, Raj SR. Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies. Annual Review of Medicine. 2020;71(1):235-248. doi:10.1146/annurev-med-041818-011630
7. Mast cell disorders: An overview - UpToDate. Accessed September 11, 2021. https://www.uptodate.com/conte…