Case report of long-term postural tachycardia syndrome in a patient after messenger RNA coronavirus disease-19 vaccination with mRNA-1273

Abstract

Background

Postural tachycardia syndrome (POTS) is characterized by orthostatic intolerance and heart rate increase in an upright position without orthostatic hypotension. It has been described after coronavirus disease-19 (COVID-19) as well as after COVID-19 vaccination.

Case summary

A 54-year-old female patient presented with a 9-months history of severe orthostatic intolerance since COVID-19 vaccination with messenger RNA (mRNA)-1273 (Spikevax, Moderna). Except for diet-controlled coeliac disease, the patient was healthy, had no allergies, and did not take regular medication. Tilt table testing revealed a significant heart rate increase to 168 bpm without orthostatic hypotension accompanied by light-headedness, nausea, and syncope, findings consistent with POTS. Potential underlying causes including anaemia, thyroid dysfunction, adrenal insufficiency, pheochromocytoma, (auto)-immune disease, chronic inflammation as well as neurological causes were ruled out. Echocardiography and cardiac stress magnetic resonance imaging (MRI) did not detect structural or functional heart disease or myocardial ischaemia. Forty-eight-hour-electrocardiogram (ECG) showed no tachycardias other than sinus tachycardia. Finally, genomic analysis did not detect an inherited arrhythmia syndrome. Serologic analysis revealed adequate immune response to mRNA-1273 vaccination without signs of previous severe acute respiratory syndrome-coronavirus-2 infection. While ivabradine was not tolerated and metoprolol extended release only slightly improved symptoms, physical exercise reduced orthostatic intolerance moderately. At a 5-months follow-up, the patient remained dependant on assistance for activities of daily living.

Discussion

The temporal association of POTS with the COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment-refractory POTS following COVID-19 vaccination with mRNA1273.

Learning points.

• Postural tachycardia syndrome (POTS) is a clinical syndrome characterized by (i) light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue; (ii) a heart rate increase (≥30 bpm) when moving from a recumbent to a standing position held for more than 30 s (or ≥40 bpm in individuals aged 12–19 years); (iii) without orthostatic hypotension (systolic blood pressure drop >20 mmHg).

• It has been described after coronavirus disease-19 (COVID-19) and COVID-19 vaccination, which should be considered as a potential aetiology after ruling out other causes.

• Non-pharmacological approaches, particularly exercise programmes should be considered in patients with POTS and pharmacological treatment may be used.

Introduction

Postural tachycardia syndrome (POTS) is a clinical syndrome characterized by¹ light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue;² a heart rate increase (≥30 bpm) when moving from a recumbent to a standing position held for more than 30 s (or ≥40 bpm in individuals aged 12–19 years);³ without orthostatic hypotension [systolic blood pressure (BP) drop >20 mmHg].^1–3 Potential underlying mechanisms are heterogeneous and include deconditioning, peripheral autonomic neuropathy, decreased venous return, a hyper-adrenergic state, mast cell activation disorders, and autoimmunity.³ The prevalence of POTS is 0.2% and most patients present at a young age and roughly three quarters are female.¹ The occurrence of POTS has been reported after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection.⁴ In addition, cases of POTS have been described following vaccination with coronavirus disease-19 (COVID-19) vector vaccine (Oxford-AstraZeneca)⁵ and after vaccination with messenger RNA (mRNA) vaccine (BioNTech-Pfizer and Moderna).^6,7 Here we report a case of new-onset, long-term, and treatment-refractory severe POTS following mRNA vaccination with mRNA-1273 (Moderna). This case report is intended to raise awareness of POTS, the possible association between COVID-19 mRNA vaccination (Moderna) and POTS, and to encourage research in COVID-19-associated POTS.

Summary figure

Case presentation

In January 2022, a 54-year-old female patient presented with a 9 months history of severe orthostatic intolerance since her first COVID-19 vaccination with the mRNA vaccine mRNA-1273 (Spikevax, Moderna). A few days after vaccination, she developed headache, dizziness, heart rate increase in an upright position, documented by her smartwatch, and orthostatic intolerance. Due to symptom severity, the self-employed physiotherapist, who had previously been very active in sports and regularly did endurance and resistance exercise training, now spent most of the day in a supine or sitting position and was unable to work. Past medical history included dietary controlled coeliac disease only. The patient did not take regular medication and had no allergies. No previous episodes of orthostatic intolerance were noted and previous vaccination against polio, diphtheria, tetanus, pertussis, hepatitis, and tick-borne encephalitis were all well-tolerated. The family history was negative for connective tissue disease and hypermobility syndrome.

At presentation, the patient was on metoprolol extended release 25 mg once daily, cautiously prescribed by the general practitioner, which only slightly decreased orthostatic symptoms. Yet, the best symptom improvement was achieved by previous regular physiotherapy-guided exercise including aerobic and resistance exercise preferentially in sitting and supine positions as well as orthostatic training. Vital signs and clinical examination were unremarkable. Blood pressure was 153/89 mmHg, heart rate was 99 bpm and oxygen saturation was 98% while breathing ambient air. She had no jugular venous distension, no lower leg oedema, cardiac auscultation revealed no murmurs, and lung auscultation was unremarkable. Body-mass index was 20.4 kg/m². Twelve-lead surface ECG showed sinus rhythm without conduction delays and normal repolarisation pattern (Figure 1). Head-up tilt testing resulted in severe orthostatic symptoms, including light-headedness, nausea, and syncope and was paralleled by heart rate increase from ∼95 bpm to 168 bpm in sinus rhythm without orthostatic hypotension, findings consistent with the definition of POTS^1,3 (Figure 2). Blood count and basic laboratory values (creatinine, electrolytes, transaminases, bilirubin, HbA1c, C-reactive protein, thyroid stimulating hormone) were within normal range. High-sensitivity troponin T, creatine kinase, and ferritin were normal. Plasma metanephrine, normetanephrine, and 3-methoxytyramine were low ruling out pheochromocytoma. Eight a.m. cortisol level was not significantly elevated. Immunoglobulins, lymphocyte subpopulations, complement C3c and C4, anti-nuclear and anti-neutrophil cytoplasmatic antibodies, neopterin, cytokine profile (interleukin-1 β, soluble interleukin-2 receptor, interleukin-6, tumour necrosis factor α) were normal and did not suggest systemic autoimmune disease or chronic inflammation. A genomic analysis covering a large channelopathy panel (see Supplementary material online, Table S1) did not identify pathogenic, likely pathogenic, or variants of uncertain significance for inherited arrhythmia syndromes. Finally, the serologic analysis showed an adequate immune response to COVID-19 mRNA vaccination (immunoglobulin G subunit 1 index 25.8 and immunoglobulin G receptor binding domain index 36.4) without signs of previous SARS-CoV-2 infection (immunoglobulin M and immunoglobulin G nucleocapsid index negative).⁸

Figure 1.

Twelve-lead electrocardiogram.

Figure 2.

Heart rate and blood pressure during head-up tilt table examination. Heart rate in the supine position was ∼95 bpm. Upon head-up tilt, the heart rate increased to 168 bpm, without a decrease in blood pressure. During the head-up tilt, the patient suffered from severe orthostatic symptoms, including light-headedness, nausea, and syncope. These findings were consistent with the diagnosis of POTS. BP, blood pressure; bpm, beats per minute.

A 48-h Holter-ECG found episodes of sinus tachycardia and was otherwise unremarkable. Transthoracic echocardiography and cardiac stress MRI did not reveal structural or functional heart disease and no myocardial ischaemia. Clinical neurologic examination was not suggestive for peripheral polyneuropathy and brain magnetic resonance imaging did not detect cerebral brain lesions. Due to headache in an upright position, cerebrospinal fluid hypotension was ruled out by lumbar puncture [cerebrospinal fluid opening pressure 17 cmH₂O (normal range 10–25 cmH₂O)]. During the hospital stay metoprolol extended release was substituted by ivabradine 2.5 mg twice daily,⁹ which resulted in increased orthostatic intolerance; ivabradine was stopped and instead metoprolol extended release was up titrated to a maximal tolerated dose of 25 mg twice daily. In addition, a multidisciplinary approach with regular physiotherapy was implemented and non-pharmacological approaches such as sufficient water and salt intake, compression stockings, strict avoidance of deconditioning, and regular aerobic exercise were recommended. Nine days after discharge, the patient was able to keep a sitting position for 20 min, a standing position for 3 min, and walk 300 m with breaks in between. On follow-up, 5 months after discharge and 14 months after vaccination, the patient was on metoprolol extended release 25 mg twice daily and midodrine 2.3 mg once daily. Midodrine was started shortly before follow-up but stopped again after 3–4 weeks due to a lack of symptom improvement. Rehabilitation programmes resulted in partial symptom improvement and the patient was able to ride a recumbent bike for up to 1 h. After a SARS-CoV-2 infection 2 months before follow up she experienced a symptom relapse and despite slight symptom improvement, she was still unable to attend work and dependant on assistance for activities of daily living. On her own initiative, the patient arranged the determination of auto-antibodies against adrenergic and muscarinic receptors. Anti-apha1 and anti-alpha-2 adrenergic antibodies as well as anti-muscarinic receptor 2, 3, 4, and 5 antibodies were elevated. The patient did not receive a second COVID-19 vaccination.

Discussion

POTS is a clinical syndrome characterized by (i) light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue; (ii) a heart rate increase (≥30 bpm) when moving from a recumbent to a standing position held for more than 30 s (or ≥40 bpm in individuals aged 12–19 years); (iii) without orthostatic hypotension (systolic BP drop >20 mmHg).^1–3 Despite the precise definition of this subtype of orthostatic intolerance, the time to diagnosis is often prolonged. The suggested underlying mechanisms of POTS are heterogeneous including peripheral autonomic denervation, hypovolaemia, hyper-adrenergic state, deconditioning, anxiety, and hypervigilance often with multiple mechanisms coexisting in the same patient.¹ Our patient met the definition criteria of POTS, yet a potential underlying cause was not detected other than the COVID-19 mRNA vaccination. Severe orthostatic intolerance following vaccination forced the patient to spend a significant time of the day in a supine or sitting position over a substantial time period. Exercise testing could not be performed, however, physical deconditioning is likely to have contributed to the clinical syndrome,¹⁰ although we did not detect objective markers such as reduced left ventricular mass.¹¹ In line with this, rehabilitation programmes have improved symptoms emphasizing the importance of a multidisciplinary and non-pharmacological approach to POTS. Switching medical therapy from metoprolol extended release to ivabradine during hospital stay resulted in worsening of orthostatic symptoms; it is unclear, whether this was due to the omission of metoprolol extended release or to ivabradine intolerance. Although non-selective beta-blockers are primarily recommended in POTS,² metoprolol extended release was reinitiated since the patient gained symptom improvement.

Considering the temporal association of POTS with mRNA vaccination, an immunological phenomenon was hypothesized but markers of systemic autoimmune disease or chronic inflammation were not detected. Auto-antibodies against adrenergic (α1 and α2) and muscarinic receptors (2–5) were elevated in our patient consistent with previous reports in POTS patients,¹² however, these findings have recently been found to be non-specific and thus, do not necessarily support the diagnosis of immune-mediated POTS.¹³

Although our patient did not report previous SARS-CoV-2 infection, she reported post-vaccine reactions that could mimic post-acute COVID-19 sequela. Negative immunoglobulin M and immunoglobulin G nucleocapsid index did not suggest previous SARS-CoV-2 infection.⁸ However, asymptomatic or oligosymptomatic infection cannot be ruled out, since antibodies against the nucleocapsid decrease over time.⁸ Serological analysis revealed adequate immune response to COVID-19 mRNA vaccination. Due to the severe and long-term POTS, which occurred in temporal association with the first vaccination, the patient decided not to complete the basic COVID-19 vaccination despite the risk of contracting COVID-19 and its potentially serious consequences.

Vaccinations have not yet been considered as classical triggers of POTS.^2,3 Some case reports have suggested an association with human papillomavirus vaccination, however, whether there is a causal relationship remains unclear.¹⁴ A recent systematic literature review summarized autoimmune phenomena after COVID-19 vaccination, such as Guillain-Barré syndrome, rheumatoid arthritis, and immune thrombotic thrombocytopenia.¹⁵ Potential mechanisms have been proposed and include production of auto-antibodies, molecular mimicry triggered by vaccine components, and autoimmunity through activation of inflammasomes by vaccine adjuvants.¹⁵ Whether such mechanisms may also apply to COVID-19 vaccination-induced POTS remains to be determined in future studies.

The temporal association of POTS with COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative underlying aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment refractory POTS potentially triggered by COVID-19 mRNA1273 (Spikevax, Moderna) vaccination. Further studies are needed to elucidate the underlying immunopathological mechanisms.

Lead author biography

Martin F. Reiner, March 2021–dato Resident, Cardiology, University Hospital Zurich, Switzerland; January 2020 to October 2020 Chief Resident, Internal Medicine, Cantonal Hospital Baden, Switzerland; April 2019 to December 2019 Resident, Medical Intensive Care Unit, University Hospital Zurich, Switzerland; March 2018–2019 Resident, Internal Medicine, University Hospital Zurich, Switzerland; December 2015 to January 2018 Resident, Internal Medicine, Cantonal Hospital Baden, Switzerland. Education and degrees: August 2020 Certificate in Internal Medicine (FMH), Switzerland; 2012–2017 MD-PhD, Center for Molecular Cardiology, Faculty of Science, University of Zurich, Switzerland; 2014–2016 Medical thesis, Faculty of Medicine, University of Zurich, Switzerland; 2006–2012 Medical school, Medical University Innsbruck, Austria.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports.

Consent: The authors confirm that written consent for submission and publication of the case report has been obtained from the patient in line with COPE guidance.

Funding: None declared.

Data availability

All data are available from the corresponding author.