Postural orthostatic tachycardia syndrome after COVID-19 vaccination: A systematic review

Abstract

Background

The global COVID-19 vaccination campaign, with 13.53 billion doses administered by early 2024, has significantly reduced severe illness and mortality. However, potential adverse effects, such as Postural Orthostatic Tachycardia Syndrome (POTS), have raised concerns. This systematic review evaluates the incidence, mechanisms, and clinical implications of POTS following COVID-19 vaccination.

Methods

A systematic search of PubMed, EMBASE, and Web of Science was conducted up to June 7, 2024, following PRISMA guidelines to identify studies related to COVID-19 vaccines and POTS. Eligible studies included randomized controlled trials, cohort studies, cross-sectional studies, case-control studies, case series, and case reports. Screening, data extraction, and quality assessment were independently performed by two reviewers using the Joanna Briggs Institute Checklists and the Newcastle-Ottawa Scale.

Results

Of the 1,531 articles identified, 10 met the inclusion criteria, encompassing a total of 284,678 participants. These studies included five case reports, two case series, one cross-sectional study, one prospective observational study, and one cohort study. The cohort study reported that the odds of new POTS diagnoses post-vaccination were 1.33 (95% CI: 1.25–1.41) compared to the 90 days prior. In contrast, the post-infection odds were 2.11 (95% CI: 1.70–2.63), and the risk of POTS was 5.35 times higher (95% CI: 5.05–5.68) post-infection compared to post-vaccination. Diagnostic findings across studies included elevated norepinephrine levels and reduced heart rate variability. Reported management strategies involved ivabradine, intravenous therapies, and lifestyle modifications.

Conclusion

The risk of POTS following COVID-19 vaccination is lower than that observed post-SARS-CoV-2 infection; however, existing studies are limited by small sample sizes and methodological variability. Further research is needed to clarify the incidence, mechanisms, and long-term outcomes of vaccine-related POTS to inform effective clinical management strategies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12872-024-04315-x.

Introduction

The emergence of COVID-19 in late 2019 and its subsequent global spread necessitated the rapid development and deployment of vaccines to mitigate the pandemic’s impact. By early January 2024, approximately 70.6% of the global population had received at least one vaccine dose, totaling around 13.53 billion doses worldwide [1]. While the efficacy of these vaccines in reducing severe illness, hospitalizations, and deaths has been well-documented, the extensive vaccination campaigns have also prompted an examination of potential adverse effects. Among these, Postural Orthostatic Tachycardia Syndrome (POTS) has garnered attention due to reported cases following COVID-19 vaccination [2].

POTS, a form of dysautonomia, is characterized by an abnormal increase in heart rate upon standing, often accompanied by symptoms such as dizziness, fatigue, and palpitations, which can significantly impact quality of life [3, 4]. It is defined as an autonomic disorder characterized by a significant increase in heart rate (≥ 30 beats per minute in adults and ≥ 40 beats per minute in adolescents) within 10 min of standing, accompanied by symptoms such as dizziness, palpitations, fatigue, and syncope, without substantial changes in blood pressure [3, 4]. The condition can have a significant impact on patients’ quality of life, and its onset can be triggered by various factors, including viral infections, autoimmune responses, and, in some cases, vaccinations [5].

The relationship between POTS and vaccinations is not entirely novel, as autonomic nervous system dysfunctions have been observed following various immunizations historically [6, 7]. However, the scale and speed of the COVID-19 vaccination rollout present unique challenges and opportunities for identifying and understanding these adverse events [8, 9]. The etiology of POTS is multifactorial, involving genetic predispositions, autoimmune mechanisms, and possibly environmental triggers, making it imperative to discern whether the observed cases post-vaccination are coincidental or indicative of a causal relationship. Additionally, the differentiation between vaccine-induced POTS and the exacerbation of pre-existing autonomic conditions requires careful consideration [8, 10].

Understanding the link between COVID-19 vaccines and POTS is essential for refining vaccine safety monitoring and supporting healthcare providers in identifying and managing potential cases. Addressing concerns related to vaccine safety is also key to sustaining public confidence in immunization efforts, particularly as countries strive to achieve broad protection against COVID-19. This systematic review aims to critically analyze the available literature to understand the incidence and clinical implications of POTS in the context of COVID-19 vaccination. It contributes to ongoing discussions on vaccine safety and autonomic health, helping to improve vaccination policies and patient management. By compiling findings from the current literature, this review provides a clear view of the incidence of POTS following COVID-19 vaccination and guides healthcare professionals in diagnosis and treatment.

Methods

This systematic review and meta-analysis adhered to the PRISMA guidelines (Table S1) [11]. The protocol was registered in the PROSPERO (CRD42024555548), ensuring transparency and accountability in our review process.

Eligibility criteria

We considered all studies reporting POTS following COVID-19 vaccination to capture the full scope of available evidence, irrespective of geographical location, year of publication, language, or participant age. No restriction was applied to the timeframe for the onset of POTS following vaccination. Eligible studies included randomized controlled trials (RCTs) and observational studies, such as cross-sectional, cohort, and case-control studies, as well as case series and case reports. Case series reporting atleast three or more cases of POTS [12, 13]. We excluded editorials, opinion pieces, review articles, and studies that did not differentiate POTS outcomes specifically related to COVID-19 vaccines. Additionally, studies that did not specifically investigate outcomes related to COVID-19 vaccination or that involved different target populations (e.g., those with unrelated comorbidities) were excluded. Studies were also excluded if they did not provide clear diagnostic criteria for POTS.

Search strategy

A comprehensive literature search was conducted across several databases, including PubMed, EMBASE, and Web of Science, to capture all relevant articles published from the inception of these databases up to June 7, 2024. We employed a combination of MeSH terms and free-text searches using terms such as “COVID-19 Vaccines,” “SARS-CoV-2 Vaccine,” “mRNA Vaccine,” “Postural Orthostatic Tachycardia Syndrome,” and “Orthostatic Intolerance.” In addition to electronic database searches, citation chasing was performed using RShiny Apps Citation Chaser to identify additional studies (Table S2).

Screening and data extraction

The screening process was carried out using Nested knowledge software in two phases. Initially, two independent reviewers screened titles and abstracts to determine relevance. Full texts of potentially relevant studies were then retrieved and independently assessed for eligibility by the same reviewers. Any disagreements were resolved through discussion or by involving a third reviewer if necessary. Data extraction was performed using tagging function in the Nested knowledge by adding tags on each variable like study design, country, population description, mean age, gender distribution, sample size of patients receiving the COVID-19 vaccine, follow-up period, vaccine types, number of POTS cases in vaccinated individuals, and odds ratios or risk ratios for POTS where available.

Quality assessment

For the quality assessment of the studies in our systematic review, we applied the Joanna Briggs Institute (JBI) Critical Appraisal Checklists for case reports and case series [14], and the Newcastle-Ottawa Scale (NOS) for observational studies [15], as independently assessed by two reviewers. The JBI Checklists rate studies as ‘High’, ‘Moderate’, or ‘Low’ quality based on adherence to criteria scored by ‘Yes’ answers, with each ‘Yes’ indicating minimal bias. The NOS uses a star system in three domains—selection, comparability, and outcome or exposure to assign up to 9 points, categorizing studies into ‘High’ (7–9 points), ‘Moderate’ (4–6 points), and ‘Low’ (0–3 points) quality. These assessments, resolved through consensus or third-reviewer consultation when discrepancies occurred, ensure methodologically sound conclusions and identify gaps needing further research, thereby enhancing the review’s validity and reliability.

Statistical analysis

Due to the substantial variability in study designs, sample sizes, and outcome measures reported in the included studies, a meta-analysis was not feasible for this systematic review. Therefore, we utilized only descriptive statistical methods to synthesize the findings. The primary data from various study types were summarized to present the incidence, prevalence, and clinical characteristics of POTS following COVID-19 vaccination. Key variables, including the number of POTS cases, participant demographics, type of COVID-19 vaccine received, and timing of symptom onset, were collated and described narratively. We focused on reporting odds ratios and confidence intervals where available but did not conduct any pooled statistical analysis due to the methodological variability and differing outcome definitions across the studies. The findings are presented in tabular and narrative formats to ensure clarity and to provide a comprehensive overview of the current evidence on POTS post-vaccination.

Results

Literature search

Initially, 1,531 articles were identified across multiple databases: PubMed (739 records), EMBASE (363 records), and Web of Science (429 records). Following PRISMA guidelines, we removed 411 duplicates and screened 1,120 records by title and abstract. After a detailed evaluation, 22 reports were considered potentially relevant; however, upon full-text assessment, 12 were excluded due to mismatches in study design [6], intended outcomes [2], or target populations [4]. Finally, 10 studies were included in the final synthesis (Figure 1).

Fig. 1.

PRISMA flow diagram depicting the screening process

Summary of study characteristics

Among the 10 studies included, there were five case reports, two case series, one cross-sectional study, one prospective observational study, and one cohort study, totaling 284,678 participants. Geographically, seven studies were conducted in the USA, one was a multi-country study from Europe, and one study each from Korea and Japan. Participants’ ages ranged from 13 to 52 years, and the vaccines investigated included mRNA types, such as Pfizer-BioNTech and Moderna, and the viral vector vaccine AstraZeneca. The identified cases of POTS where symptom onset occurred between 2 and 90 days post-vaccination, within a three-month following COVID-19 vaccination (Table 1). The overall quality assessment indicated that the studies were of moderate quality (Table S3).

Table 1.

Summary characteristics of the included studies

Author Year	Study design	Country	Population	SARS-CoV-2 Infection Status	Time Interval Between Vaccination and POTS Onset	Mean Age	Male %	Follow-up Period (days)	Vaccine Type	No. of Individuals Vaccinated	Individuals Diagnosed with POTS	Key Findings
Eldokla AM 2022 (24)	Case series	USA	Patients evaluated for orthostatic intolerance	Infection-naïve	14 days (median)	22.2	0	NA	Moderna, BioNTech-Pfizer	5	5	Five patients developed POTS with significant HR increase during HUTT tests.
Fanciulli A 2023 (16)	Cross-sectional study	European multi-country	COVID-19 infected/vaccinated	Mixed (Infection-naïve and Prior Infection)	NA	NA	NA	NA	Tozinameran, ChAdOx1-S, elasomeran	45	13	Cardiovascular autonomic disorders post-COVID-19; controversial vaccine link.
Hermel M 2022 (22)	Case report	USA	New-onset POTS in a 46-year-old female	Infection-naïve	2 to 7 days	46	NA	NA	Pfizer-BioNTech (BNT162b2)	NA	1	Reports new-onset POTS following Pfizer vaccination.
Kwan AC 2022 (17)	Cohort study	USA	Cedars-Sinai Health System population	Mixed (Infection-naïve and Prior Infection)	90 days	52	43	90	Mixed, including Pfizer-BioNTech and Moderna	284,592	763	Slightly higher risk of POTS post-vaccination, but lower than post-infection rates.
Maharaj 2023 (19)	Case report	NA	15-year-old male post-vaccine	Infection-naïve	14 days	15s	100	NA	Pfizer-BioNTech	1	1	Teenager developed suspected POTS post-Pfizer booster, managed with medication.
Park J 2022 (21)	Case report	Korea	Transient POTS post-vaccination	Infection-naïve	7 days	40	100	NA	mRNA COVID-19 vaccine	1	1	Stresses need for awareness of autonomic disorders post-vaccination.
Reddy S 2021 (20)	Case report	USA	POTS post mRNA vaccine	Infection-naïve	6 days	42	100	NA	Pfizer BioNTech	1	1	Links POTS onset to mRNA vaccination, suggests autoimmune reaction.
Safavi 2022 (23)	Case series	USA	Patients with new neuropathic symptoms post-vaccine	Mixed (Infection-naïve and Prior Infection)	21 days	40	8	NA	Mixed, including AstraZeneca and Pfizer-BioNTech	23	6	A various neuropathic symptoms post-vaccination, possibly immune-mediated.
Sanada y 2022 (18)	Case report	Japan	Overlapping myocarditis and POTS post-vaccine	Infection-naïve	NA	13	100	NA	Pfizer-BioNTech mRNA vaccine	1	1	Discusses myocarditis and POTS following vaccination, suggests vaccine-induced autonomic dysfunction.
Teodorescu 2024 (2)	Prospective observational study	USA	Patients in a POTS clinic post-vaccination	Mixed (Infection-naïve and Prior Infection)	3.6 days (mean)	41.5	40	417.2 ± 131.4	Moderna mRNA-1273, Pfizer BNT162b2 Comirnaty	10	10	All post-vaccination POTS patients had pre-existing conditions; most improved with standard care.

Incidence and prevalence of POTS post-vaccination

The incidence and prevalence of POTS following COVID-19 vaccination have been assessed in a limited number of studies, providing preliminary observations rather than definitive findings. In a cross-sectional study by Fanciulli et al. (2023), the prevalence of cardiovascular autonomic disorders, including POTS, was evaluated in 45 patients across 46 European autonomic centers. The study identified 13 cases of POTS, with a notably higher frequency post-infection (61%) compared to post-vaccination. Clinicians generally deemed a causal link between POTS and vaccination unlikely, indicating a disparity in the development of POTS following infection versus vaccination. These findings suggest a lower frequency of POTS following COVID-19 vaccination compared to post-infection scenarios. However, caution is warranted in interpreting these results, as many of the reported estimates, such as those from Fanciulli et al. (2023), were not adjusted for potential confounding variables, including age, gender, or pre-existing conditions. This lack of adjustment may affect the observed association, making it difficult to draw definitive conclusions regarding the comparative risk of POTS in these groups [16].

Additionally, a cohort study by Kwan et al. (2022) analyzed data from 284,592 individuals in the Cedars-Sinai Health System who received various COVID-19 vaccines, including Pfizer-BioNTech, Moderna, Johnson & Johnson, AstraZeneca, Novavax, and Sinovac. The study found that the odds of developing new POTS diagnoses were significantly elevated post-COVID-19 vaccination compared to the baseline period. The odds ratio (OR) for new POTS diagnoses in the 90 days following vaccination was 1.33 (95% CI: 1.25–1.41, p < 0.001) when referenced against the 90 days before the first COVID-19 vaccine dose. In contrast, the odds of developing POTS following SARS-CoV-2 infection were notably higher, with an OR of 2.11 (95% CI: 1.70–2.63, p < 0.001). When POTS incidence post-SARS-CoV-2 infection was compared directly with that post-vaccination, the odds were 5.35 times higher (95% CI: 5.05–5.68, p < 0.001), using the post-vaccination POTS diagnoses as the reference. Similarly, when using the 90 days prior to documented SARS-CoV-2 infection as the baseline, the odds of developing new POTS diagnoses post-infection were 1.52 (95% CI: 1.36–1.71, p < 0.001), indicating that the risk of POTS following natural infection was significantly greater than that observed following vaccination [17].

Diagnostic assessments and biomarkers

The diagnostic assessments and biomarkers, Teodorescu (2024) conducted a prospective observational study in the USA, tracking 34 patients from a POTS clinic over an average period of 417.2 ± 131.4 days post-COVID-19 vaccination. Among these patients, 10 developed POTS following vaccination. Diagnostic assessments in these cases revealed elevated standing norepinephrine levels (> 600 pg/mL) in four patients, decreased heart rate variability (HRV) (46.19 ± 24 ms compared to control 72.49 ± 40.8 ms), and reduced skin sympathetic nerve activity (SKNA) mean amplitude (0.97 ± 0.052 mV compared to control 1.2 ± 0.31 mV). Most patients showed improvement with standard POTS management protocols, although two experienced symptom relapses that coincided with COVID-19 reinfection. These findings highlight the complexity of POTS diagnosis and management post-vaccination and emphasize the need for personalized treatment approaches [2].

Clinical management

Several case reports and case series have illustrated the clinical manifestations and management of POTS following COVID-19 vaccination. Sanada et al. (2022) presented a 13-year-old male who developed myocarditis and POTS after receiving the second dose of the Pfizer-BioNTech vaccine, initially presenting with severe fatigue, headache, and sleep disturbances. Despite initial treatment with intravenous saline, pregabalin, and ramelteon, the symptoms persisted, leading to intravenous immunoglobulin (IVIG) therapy, which improved his myocarditis markers but not his POTS. Propranolol and droxidopa were eventually added, resulting in symptom reduction and improved orthostatic tolerance [18].

Similarly, Maharaj et al. (2023) described a 15-year-old male who developed suspected POTS two weeks after receiving a Pfizer booster, characterized by recurrent presyncope and up to 10 syncopal episodes daily. He was managed successfully with fludrocortisone, ivabradine, and lifestyle modifications, achieving significant symptom relief within one month [19]. Reddy et al. (2021) reported a case of a 42-year-old male who developed POTS six days after receiving the first dose of the Pfizer-BioNTech vaccine, presenting with persistent sinus tachycardia, presyncope, and severe fatigue. His symptoms were managed conservatively with lifestyle modifications, including compression socks and increased sodium intake, but intermittent symptoms persisted, suggesting a potential chronic nature of POTS post-vaccination [20]. Park et al. (2022) described a 40-year-old male with transient POTS one week after receiving the Moderna vaccine, whose symptoms of headache, palpitations, and fatigue were managed effectively with propranolol, leading to complete resolution by the five-month follow-up [21]. Lastly, Hermel et al. (2022) reported a 46-year-old female who developed new-onset POTS within two to seven days post-Pfizer vaccination, presenting with fatigue, dizziness, and palpitations. She responded well to lifestyle modifications, dietary supplements, and ivabradine, with gradual recovery over time [22].

In a more extensive case series, Safavi et al. (2022) examined 23 patients with neuropathic symptoms following vaccination, with six patients developing POTS. These patients improved with treatments such as corticosteroids or IVIG [23]. Eldokla et al. (2022) reported on five patients who developed POTS after mRNA vaccination, managed with medications like ivabradine, metoprolol, fludrocortisone, and propranolol [24].

Treatment strategies and outcomes

Pharmacological treatment

The management of POTS following COVID-19 vaccination often requires a multifaceted pharmacological approach due to the heterogeneous presentation of symptoms. Initial treatments may include intravenous saline, pregabalin, ramelteon, and IVIG, which have demonstrated significant improvement in patient outcomes [24]. For example, in one case, a 40% reduction in overall symptom severity and a 50% improvement in cardiovascular function, as measured by autonomic testing, was observed after six months of IVIG therapy [25]. Corticosteroids are another therapeutic option, particularly for patients with suspected autoimmune-mediated POTS. Studies report an average 30% improvement in symptom scores with corticosteroid therapy, reflecting its potential to reduce inflammatory processes associated with POTS [26]. However, long-term corticosteroid use requires careful monitoring due to adverse effects such as a 20% increased risk of hypertension, electrolyte imbalances, and a 15% risk of adrenal suppression [27].

IVIG has emerged as a potential treatment option in immune-mediated POTS cases, showing a 50% improvement in HRV in some patients after six months of therapy [28]. However, approximately 10–15% of patients may experience infusion-related adverse effects, necessitating premedication with corticosteroids or antihistamines to prevent these reactions [29]. In a case series, Safavi et al. documented a 40% reduction in autonomic symptom scores following IVIG administration in patients diagnosed with POTS after COVID-19 vaccination. Corticosteroids, such as prednisone, have also demonstrated efficacy in managing symptoms by enhancing sodium and water retention, which can alleviate orthostatic intolerance [23]. In a cohort study, corticosteroid therapy led to a 35% increase in orthostatic tolerance and a 30% reduction in overall symptom severity [30]. Despite these benefits, the long-term use of corticosteroids must be approached with caution due to risks including electrolyte imbalances and adrenal suppression.

Fludrocortisone, a mineralocorticoid that increases plasma volume, is widely used in patients with hypovolemic POTS, yielding a 25–30% improvement in orthostatic tolerance [31]. Nevertheless, adverse effects such as hypokalemia (up to 20% of cases) and fluid retention (15%) warrant careful monitoring. Ivabradine, a selective sinus node inhibitor, has shown promise in reducing heart rate by 40% in patients with excessive tachycardia without significant impact on blood pressure, making it a favorable option for individuals predisposed to hypotension [3]. Beta-blockers, such as propranolol and metoprolol, are frequently employed to manage tachycardia and palpitations, with propranolol reducing heart rate by approximately 20 beats per minute (bpm). However, these agents may exacerbate fatigue in 30% of patients, limiting their applicability [3]. For patients with neuropathic pain and sleep disturbances, pregabalin and ramelteon may be beneficial, reducing neuropathic pain severity by 50% and improving sleep quality by 70% in clinical trials [32].

Pharmacological treatment should be personalized, taking into account the patient’s specific symptoms and underlying comorbidities. In severe or refractory cases, agents such as midodrine, clonidine, or pyridostigmine may be employed [33]. Midodrine, an alpha-1 adrenergic agonist, has been shown to improve orthostatic blood pressure by 15–20% through systemic vasoconstriction but requires frequent dosing and carries a risk of supine hypertension (15–25%) and urinary retention (10–15%) [34]. Clonidine and alpha-methyldopa, both central-acting sympatholytic agents, have demonstrated a reduction in systolic blood pressure by 10–15 mmHg in hyperadrenergic subtypes [35]. Pyridostigmine, an acetylcholinesterase inhibitor, enhances cholinergic transmission and reduces standing heart rate by 10 bpm but is limited by gastrointestinal side effects, such as nausea and cramping, which affect up to 30% of patients [36].

Non-pharmacological treatment

Non-pharmacological interventions are crucial in managing POTS and can significantly improve patient outcomes. Key strategies include increased fluid and salt intake, physical counter-maneuvers, exercise training, and the use of compression garments [37]. A structured regimen comprising 2–3 L of daily fluid intake, supplemented by 6–10 g of salt, has been shown to effectively increase plasma volume and reduce orthostatic intolerance, resulting in a 35% reduction in dizziness and fatigue symptoms in patients [38, 39]. Compression garments providing 20–30 mmHg pressure to the lower limbs have been associated with a 40% improvement in venous return and stabilization of blood pressure, thus reducing symptoms of blood pooling and enhancing orthostatic tolerance [40].

Physical exercise plays a critical role in the management of POTS, particularly when tailored to the patient’s subtype and tolerance levels. Initial exercise regimens should involve low-intensity, recumbent activities such as rowing or swimming to minimize excessive upright positioning, progressing gradually over a three-month period [41]. Clinical studies have shown that this approach can increase maximal oxygen uptake by 11%, improve left ventricular mass by 12%, and reduce orthostatic symptoms, with 53% of patients no longer meeting the diagnostic criteria for POTS after completing the program [37]. These benefits are particularly notable for patients with hypovolemic or deconditioned phenotypes, where improved cardiovascular conditioning contributes to reduced orthostatic intolerance and enhanced quality of life.

Exercise and physical counter-maneuvers, such as muscle contraction and leg crossing, are essential for promoting venous return and maintaining hemodynamic stability. The incorporation of these non-pharmacological strategies into daily routines has been associated with a 40% reduction in HRV and a significant decrease in orthostatic symptoms, making them a cornerstone of POTS management [42]. Compression garments, when combined with physical conditioning and fluid/salt optimization, can further improve blood flow and reduce symptoms of dizziness and fatigue [43].

Overall, a combination of non-pharmacological and pharmacological strategies is often required for optimal management of POTS following COVID-19 vaccination. The choice of treatment should be individualized based on the patient’s symptom profile, underlying pathophysiology, and response to initial therapies. Further research is warranted to establish standardized treatment protocols and long-term outcomes for POTS in the context of COVID-19 vaccination.

Discussion

This systematic review evaluated the incidence, clinical characteristics, and management strategies of POTS following COVID-19 vaccination, focusing on studies reporting POTS at varying intervals after vaccination. By including studies with different symptom onset timelines, the review aims to present a comprehensive analysis of real-world cases, offering a broader perspective on POTS occurrence post-vaccination. Findings suggest that while an elevated risk of developing POTS exists following COVID-19 vaccination, the absolute risk remains significantly lower than that associated with SARS-CoV-2 infection. Most cases documented POTS symptom onset within days to a few weeks, up to three months after COVID-19 vaccination. Based on these patterns, POTS cases emerging within three months of vaccination are considered potentially related to the vaccine’s immunogenic response [17].

The clinical presentations of POTS following COVID-19 vaccination are typically characterized by persistent tachycardia, dizziness, fatigue, and palpitations, often emerging within two weeks after vaccine administration. In some cases, diagnostic evaluations revealed elevated norepinephrine levels, reduced heart rate variability, and evidence of small fiber neuropathy, suggesting a possible hyperadrenergic subtype of POTS or broader autonomic dysfunction [44]. However, small sample sizes and variability in clinical presentation limit the ability to define a definitive clinical profile for vaccine-related POTS. Although the observed temporal association between vaccination and symptom onset raises the possibility of a vaccine-triggered phenomenon, causality remains uncertain, and it is unclear whether vaccination precipitates new-onset POTS or unmasks pre-existing subclinical dysautonomia [45]. Cases of myocarditis and POTS following Pfizer-BioNTech vaccination in adolescents have been managed successfully with intravenous saline, pregabalin, and IVIG, underscoring the importance of recognizing POTS as a potential vaccine-related adverse event and the need for tailored clinical management [37]. Standard treatment strategies for POTS, including lifestyle modifications and pharmacological agents such as ivabradine and corticosteroids, have demonstrated efficacy in mitigating symptoms even in vaccine-related cases [46]. However, variability in therapeutic responses across patients highlights the need for Personalized treatment approaches.

The diagnostic challenges associated with POTS post-vaccination are illustrated by findings from Teodorescu et al. (2024), which reported elevated norepinephrine levels, decreased HRV, and reduced SKNA in affected individuals [37]. These biomarkers suggest significant autonomic dysfunction and emphasize the importance of thorough diagnostic evaluations in patients presenting with postural tachycardia symptoms following vaccination [47]. Diagnosing POTS requires a detailed clinical assessment, including standing tests, tilt table testing, and autonomic function evaluations. Management typically involves a combination of non-pharmacological interventions, such as increased fluid and salt intake, and pharmacological therapies, including beta-blockers, ivabradine, and, in more complex cases, advanced options such as IVIG or corticosteroids [48].

Management strategies for post-vaccination POTS mirrored standard treatments for idiopathic POTS, emphasizing the importance of individualized care [49]. The therapeutic approach typically began with lifestyle modifications, including increased salt and fluid intake, physical counter-maneuvers, and the use of compression garments to support hemodynamic stability [49]. Pharmacologic interventions, such as beta-blockers, ivabradine, fludrocortisone, and midodrine, were used to address specific symptoms like tachycardia and orthostatic intolerance [50]. In more refractory cases, intravenous therapies like saline infusions and IVIG were considered, particularly in suspected autoimmune-mediated POTS [51]. However, the variability in treatment response, as reported across cases, highlights the challenge in managing this condition post-vaccination and suggests that the underlying pathophysiology may differ from classical POTS [50]. Furthermore, there was a noted risk of adverse effects with long-term pharmacological interventions, particularly corticosteroids, which, while effective in improving symptoms, were associated with hypertension, adrenal suppression, and electrolyte imbalances, necessitating cautious use [52].

The pathophysiological mechanisms of POTS following COVID-19 vaccination are not well understood and are likely multifactorial [53]. Proposed hypotheses include an exaggerated immune response triggering transient autonomic dysfunction or a molecular mimicry phenomenon wherein vaccine antigens interact with autonomic pathways [54]. This potential interaction could be mediated by either the spike protein component of the vaccine or the lipid nanoparticle delivery system, both of which have been implicated in immune modulation [55]. Alternatively, POTS could represent a post-viral autonomic syndrome similar to that seen after other viral infections [56]. Given the known immunological and inflammatory effects of COVID-19, it is plausible that even mild vaccine-induced inflammation could trigger dysautonomia in genetically susceptible individuals [57]. However, given that the observed incidence of POTS post-vaccination is significantly lower than that following natural infection, it is likely that these mechanisms are either less severe or less sustained after vaccination.

The clinical implications of monitoring for potential POTS following COVID-19 vaccination are particularly important for individuals with pre-existing autonomic disorders or a history of dysautonomia [53]. Although the risk of developing POTS post-vaccination is significantly lower compared to the risk post-SARS-CoV-2 infection, healthcare providers should remain vigilant for symptoms such as dizziness, fatigue, palpitations, and tachycardia in patients presenting after vaccination [45]. Early diagnosis and tailored management—employing non-pharmacological strategies such as increased fluid and salt intake and the use of compression garments, alongside pharmacological treatments like beta-blockers and ivabradine—can greatly improve outcomes and quality of life for affected patients [58].

From a public health perspective, the implications for vaccine policy and communication strategies. The relatively lower risk of POTS post-vaccination compared to post-infection should be a critical component of public health messaging to mitigate vaccine hesitancy. Clear communication about the potential risks and benefits of vaccination, supported by evidence-based insights from this review, can enhance public trust and informed decision-making. Additionally, these findings can inform guidelines for monitoring and managing adverse events post-vaccination, ensuring timely identification and intervention for POTS cases.

This systematic review presents several limitations, including variability in study designs, outcome measures, and population characteristics, which restrict the ability to perform a formal statistical synthesis. Additionally, given the limited evidence, defining an exact time window for attributing POTS cases to vaccination remains challenging, as autonomic dysfunctions like POTS can be influenced by multiple factors over time. Instances of POTS occurring several months or even a year after vaccination are more challenging to attribute directly to vaccination, as other factors may play a role. To draw more definitive conclusions, future research should employ rigorous methodologies. Investigations should prioritize exploring these mechanisms through comprehensive immunological and autonomic function assessments conducted both pre- and post-vaccination. Furthermore, longitudinal studies with larger and more diverse cohorts are essential to establish the temporal association between vaccination and POTS onset while accounting for potential confounders such as pre-existing conditions and baseline autonomic function. Comparative studies evaluating the risk of POTS across different vaccine platforms, including mRNA and viral vector vaccines, are also needed to provide deeper insights into the safety profiles of these vaccines. As global vaccination efforts continue and new vaccine platforms are developed, such research will be critical in refining vaccination strategies and ensuring patient safety.

Conclusion

The risk of developing POTS post-vaccination appears to be lower than the risk following COVID-19 infection; however, the current evidence is limited and lacks robust study quality. While vaccination remains essential for public health, clinicians should remain vigilant for rare cases of POTS and implement personalized management strategies when necessary. Further research is needed to better understand the incidence, underlying mechanisms, and long-term outcomes of vaccine-related POTS.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

Ganesh Bushi and Shilpa Gaidhane: Conceptualization, review and editing of drafts, Methodology. Suhas Ballal, Sanjay Kumar, and Mahakshit Bhat: Data Curation, Formal Analysis. Shilpa Sharma and M Ravi Kumar, Ganesh Bushi: Investigation, Supervision. Sarvesh Rustagi and Mahalaqua Nazli Khatib: Project Administration, Resources. Nishant Rai, Sanjit Sah: Software, Validation. Ganesh Bushi, Muhammed Shabil, and Shilpa Gaidhane: Writing - Original Draft, Writing - Review & Editing.

Funding

This study received no funding.

Data availability

All data generated or analyzed during this study are included in this published article (and its Supplementary information files).

Declarations

Ethical approval

Not required.

Conflict of interest

The authors report no conflict of interest.