Postural Orthostatic Tachycardia Syndrome in COVID-19: A Contemporary Review of Mechanisms, Clinical Course and Management

Figures & data

Figure 1 Proposed mechanisms and subtypes of POTS. Illustrative outline of the proposed mechanisms and subtypes of POTS in a COVID-19 and non-COVID setting.

Table 1 Overview of Clinical Descriptions of COVID-POTS

Author, Country (n)	Title	Time from Infection / Vaccine	Symptoms	COVID Severity	Therapy / Response
Reddy et al, (USA; n = 1)^Citation38	POTS secondary to the Messenger RNA COVID-19 Vaccine	7 days (Pfizer)	Sinus tachycardia, presyncope anxiety, sleep disturbances, and occasional numbness in the lower extremities	N/A	Lifestyle modifications – Good response
Park et al, (South Korea; n = 1)^Citation39	Transient POTS following COVID-19 vaccine	8 weeks (Moderna)	Intermittent headache, palpitation, fatigue, and dyspnea appearance one week after vaccination	N/A	Propranolol - near resolution at 5 months
Umapathi et al, (Singapore; n = 4)^Citation40	Acute hyperhidrosis and postural tachycardia in a COVID-19 patient	2–3 weeks (COVID)	Profound, intermittent bouts of sweating on his trunk and thighs; constipation, nausea and post-meal upper abdominal discomfort; marked tachycardia on standing and during passive 60-degree tilt without decrease in blood pressure	Moderate	Fludrocortisone, sodium tablets, pyridostigmine; symptom improvement
Rudofker et al, (USA; n = 3)^Citation41	An Exercise Prescription as a Novel Management Strategy for Long COVID	5 months (COVID), 1 month (COVID), 3 months (COVID)	Debilitating fatigue, lightheadedness, and brain fog, along with recurrent syncope with orthostasis; severe fatigue, lightheadedness, brain fog, and palpitations; dyspnea, coughing paroxysms, along with an increase in resting HR by 10–15 beats/min for any given work	Mild – 2/3 Moderate – 1/3	8-week prescription of recumbent/semi-recumbent exercise (rowing/biking) - marked symptom improvement for all three patients
Shouman et al, (USA; n = 27)^Citation42	Autonomic dysfunction following COVID-19 infection: an early experience	0–122 days, median: 7 (COVID)	Lightheadedness, orthostatic headache, syncope, hyperhidrosis, and burning pain; orthostatic symptoms without tachycardia or hypotension (41%); 22% postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance	Not specifically mentioned	Rehabilitative reconditioning and low dose beta blockers improved symptoms. Anxiolytics – no significant improvement. Gabapentin and topical lidocaine improved neuropathic symptoms for the small fiber/autonomic neuropathy subtype case; One patients with autoimmune autonomic ganglionopathy - relapse in symptoms following COVID-19 reinfection
Desai et al, (USA; n = 11)^Citation43	Autonomic dysfunction post–acute COVID-19 infection	39.5 ± 57.3 days (COVID)	Palpitations and fatigue, chest discomfort and/or dyspnea	Not specifically mentioned	Beta blockers (5; 4/5 improved), midodrine (1; improved), colchicine (1; unimproved), ibuprofen (2; improved), lifestyle modifications (2)
Agnihotri et al, (USA; n = 1)^Citation44	Autonomic neuropathy post-acute sequela of COVID-19	8 months (COVID)	Lightheadedness, palpitations, persistent hand and feet tingling and burning pain, hyperhidrosis, tremulousness, and dusky red discoloration of the feet on standing	Mild	Small dose of metoprolol, midodrine, and lifestyle modifications, which improved symptoms
Ocher et al, (USA; n = 1)^Citation45	Improvement in Hyperadrenergic Postural Orthostatic Tachycardia Syndrome (POTS) after COVID19 Infection	6 weeks (COVID)	Inappropriate sinus tachycardia	Moderate	Poor compliance metoprolol and ivabradine
Parker et al, (USA; n = 7)^Citation46	COVID-19 and postural tachycardia syndrome: a case series	21 ± 15 days (COVID)	Palpitations, dyspnea, and gastrointestinal complaints	Not specifically mentioned	6/7 did not respond to supportive therapy alone; 2 did not respond to ivabradine, midodrine and/or metoprolol; however 2/3 severely symptomatic patients responded to intravenous immunoglobulin
Hermel et al, (USA; n = 1)^Citation47	COVID-19 Vaccination Might Induce POTS	9 months (COVID) and 2 weeks (Pfizer)	Fatigue, brain fog, headache, sinus tachycardia, and dizziness	Mild	Lifestyle modifications, ivabradine, and dietary supplements to improve autonomic balance and minimize fatigue
O’Sullivan et al, (Ireland; n = 1)^Citation48	COVID-19-induced POTS treated with ivabradine	3 weeks (COVID)	Chest tightness, palpitations, dyspnoea and fatigue on mild exertion	Mild	First prescribed lifestyle modifications without symptom resolution, but significant improvement in symptoms 24 hrs. after treatment with ivabradine
Blitshteyn and Whitelaw, (USA; n = 20)^Citation16	POTS and other autonomic disorders after COVID-19 infection: a case series of 20 patients	6–8 months (COVID)	Fatigue, postural tachycardia, OI, dizziness, and exercise intolerance that were chronic and disabling	Not specifically mentioned	All prescribed lifestyle modifications, 16 (80%) required pharmacotherapy (beta blockers, fludrocortisone, midodrine, ivabradine, other medication for comorbid conditions); improvement with most patients, but only 3 (15%) had near/complete resolution of symptoms
Jamal et al, (USA; n = 24)^Citation49	Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19	>3 months (COVID)	Poor exertional tolerance, tachycardia with minimal activity or positional change, and palpitations	2/24 – Moderate Remaining - Mild	N/A
Kitsou et al, (Norway; n = 1)^Citation50	Intermittent left bundle branch block with septal flash POTS in a young woman with long COVID	7 months (COVID)	Chest pain, functional dyspnoea, palpitations and an episode of syncope	Mild	Low-dose metoprolol; showed improvement 6 months after discharge
Johansson et al, (Sweden; n = 3)^Citation51	Long-Haul Post–COVID-19 Symptoms Presenting as variant POTS	4 months (COVID), 0 days (COVID), not mentioned	Profound exhaustion with associated sinus tachycardia; chest pain, fatigue, vertigo, headache; extreme fatigue, muscle weakness, insomnia, palpitations, and “brain fog” with trouble concentrating	Mild; severe; severe	Lifestyle modifications and ivabradine - some improvement; lifestyle modifications and propranolol but suspected concomitant mast cell activation syndrome lead to administration of H1 and H2 antihistamines - remains highly symptomatic; lifestyle modifications, pyridostigmine, and propranolol but suspected concomitant mast cell activation syndrome lead to administration of H1 and H2 antihistamines - despite up-titration of propranolol and pyridostigmine, still highly symptomatic
Varanasi et al, (USA; n = 1)^Citation52	Management of Long-COVID POTS With Enhanced External Counterpulsation	5 months (COVID)	Fatigue, “brain fog”, shortness of breath, dyspnea upon exertion, aching chest	Severe	Enhanced external counterpulsation; marked improvement in symptoms 15 hour-long sessions
Kanjwal et al, (USA; n = 1)^Citation53	New-onset POTS Following COVID-19	4 weeks (COVID)	Fatigue, headache, dizziness, chest pain, and palpitations	Mild	Ivabradine and increased water/salt intake improved tachycardia but fatigue lingered
Rao et al, (USA; n = 3)^Citation54	Orthostatic and Exercise Intolerance in Recreational and Competitive Athletes With Long COVID	0 days (mRNA vaccine), 0 days (COVID), not mentioned	Fever, dyspnea, chest pain, intermittent exertional intolerance, and palpitations; decreased exercise tolerance and exertional chest pressure; severe fatigue, headaches, and palpitations that occurred predominantly in an upright position	Mild	Lifestyle modifications and recumbent exercise - significant improvement; pyridostigmine and supine exercise with good results; recumbent exercise with some improvement in symptoms
Sanada et al, (Japan; n = 1)^Citation55	Overlapping Myocarditis and POTS After COVID-19 Messenger RNA Vaccination: A Case Report	2 weeks (Pfizer)	Severe fatigue, headache, and orthostatic symptoms including lightheadedness and palpitations.	N/A	Lifestyle modifications, propranolol, midodrine, and droxidopa treatment led to symptom improvement; myocarditis treated with IVIG
Miglis et al, (USA; n = 1)^Citation56	A case report of POTS after COVID-19	4 months (COVID)	Tachycardia (standing HR of 150 bpm after showering), chest pains, shortness of breath, fatigue and exercise intolerance, along with subjective fevers and insomnia	Moderate	Propranolol prescribed with some improvement but not complete resolution of symptoms
Ishibashi et al, (Japan; n = 1)^Citation57	Post-COVID-19 POTS	3 weeks (COVID)	Fatigue, feeling unwell, intermittent palpitation, dyspnea and chest pain	Not specifically mentioned	Low-dose bisoprolol(marked improvement in symptoms)
Kalia et al, (USA; n = 1)^Citation58	Post-COVID-19 Syndrome: A Novel Diagnosis	3 months (COVID)	Tachycardia, headaches, and near syncopal events	Not specifically mentioned	Metoprolol; showed near resolution of symptoms
Bosco and Titano, (Israel; n = 1)^Citation59	Severe Post-COVID-19 dysautonomia: a case report	3 months (COVID)	Worsening post-exertional fatigue, slowed cognition with increased forgetfulness and difficulty concentrating, headaches, blurred vision and generalized body aches and weakness; palpitations	Mild	Lifestyle modifications and recumbent exercises; some improvement in symptoms but still unable to return to work

Note: Disease severity: Mild: Not hospitalized; Moderate – Hospitalized (Non-ICU); Severe – ICU hospitalization.

Figure 2 Algorithmic approach to diagnosis of POTS. Schematic diagram outlining a diagnostic approach to POTS. Adapted from the HRS 2015 guidelines and CCS position statement 2020.^4,22

Abbreviations: PSWT, Postural symptoms without orthostatic intolerance; POTS, Postural orthostatic tachycardia syndrome; IST, Inappropriate sinus tachycardia.

Table 2 Overview of Management of POTS

Non-Pharmacological	First Line Pharmacological Agents	Second Line / Experimental Agents
Volume optimization: ● Oral hydration ● Salt supplementation ● Compression stockings ● Abdominal binders	Lowering Heart Rate: ● Beta blockers (Propranolol) ● Ivabradine ● Pyridostigmine	Supplements: ● Iron ● Vitamin D ● Alpha lipoic acid
Exercise training (Recumbent preferably) – Rowing / cycling	Volume expansion: ● Fludrocortisone	Droxidopa
Small meals / Avoid dehydration or excess alcohol	Vasoconstriction: ● Midodrine	Desmopressin
	Sympatholytics / Stimulants: ● Clonidine ● Alpha-methyl dopa ● Modafinil	Enhanced extracorporeal counter pulsation therapy (EECP)
		IVIG
		Cardiac Neuromodulation

Note: Italicized therapies are non-guideline recommended options.

Table 3 Ongoing Clinical Trials on POTS in COVID-19

Title	Country	NCT	Status	Description
Efficacy and Safety Study of Efgartigimod in Adults with Post-COVID-19 POTS (POTS)	USA	NCT05633407	Recruiting	Testing safety and efficacy of efgartigimod in treating post-COVID POTS
Physical Training in Patients with POTS After Covid-19 (POTS-ReCOV)	Sweden	NCT05094622	Recruiting	Studying the efficacy of an exercise treatment plan for those with long COVID POTS symptoms
Post-COVID-19 Outpatient Care and Biomarkers (POSTCOV)	Austria	NCT05398952	Recruiting	Study post-acute sequelae of COVID-19 by establishing a blood biobank, examining circulating biomarkers and ncRNAs, testing cfDNA in plasma and serum, and establishing correlations between ncRNAs and cfDNAs
Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort	USA	NCT05481177	Not Yet Recruiting	Study of ivabradine efficacy in reducing heart rate for those with long COVID POTS
Cardiovascular Autonomic and Immune Mechanism of Post COVID-19 Tachycardia Syndrome	USA	NCT05421208	Recruiting	Determine inflammatory and immune profile of post-COVID POTS; measure peripheral nervous system activity using heart rate variation, and use the COMPASS-31 test to assess autonomic symptoms

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