POTS is a chronic disorder of the autonomic nervous system characterized by orthostatic tachycardia, which is defined as an increase in heart rate by ≥30 bpm in adults and ≥40 bpm in adolescents 12–19 years old, from supine to standing position, associated with orthostatic symptoms that last for at least 3 months (Freeman et al., 2011; Sheldon et al., 2015) ( Table 1 ). Although it is defined by postural tachycardia, the clinical features of POTS are numerous and include dizziness, headache, fatigue, nausea, generalized weakness, and sleep disturbances (Low et al., 1995; Thieben et al., 2007). The pathophysiologic mechanisms of POTS are also numerous and diverse, including autoimmunity, hypovolemia, hyperadrenergic state, cerebral hypoperfusion, and small fiber neuropathy (Low et al., 1995; Thieben et al., 2007; Shaw et al., 2019). The onset of POTS may be sudden or insidious and can follow various triggers, such as infection, puberty, pregnancy, vaccinations, surgery, concussion, and injury (Shaw et al., 2019). Importantly, patients with POTS have diminished quality of life and functional impairment similar to patients with congestive heart failure and chronic obstructive pulmonary disease, with greater than 50% of patients unable to maintain employment (Benrud-Larson et al., 2002; Bourne et al., 2021).

Prior to the COVID-19 pandemic, POTS was estimated to affect approximately 0.2%–1% of the US population (1–3 million people) (Vernino et al., 2021). After the COVID-19 pandemic, the incidence of POTS was found to have increased 15-fold due to POTS and autonomic dysfunction being common manifestations of Long COVID (Dulal et al., 2025). POTS predominantly affects women of reproductive age, ages of 15–25 (Vernino et al., 2021), but men are also becoming increasingly affected due to post-COVID POTS. Common comorbidities include migraines (at least 40%), gastrointestinal disorders (at least 30%), small fiber neuropathy (at least 50%), Ehlers–Danlos syndrome and hypermobility spectrum disorders (HSDs) (at least 30%), autoimmune disorders (at least 20%), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (at least 20%), and mast cell activation syndrome (at least 20%) (Shaw et al., 2019).

There are no FDA-approved therapies for POTS, but a commonly accepted therapeutic approach to POTS consists of non-pharmacologic and pharmacologic treatment options. Pharmacotherapy includes first-line medications such as beta-blockers, which decrease resting and postural tachycardia by reducing sympathetic overactivity; fludrocortisone, a mineralocorticoid that augments retention of water and sodium and expands plasma volume; midodrine, which is an alpha-1 agonist that causes vasoconstriction and increased peripheral resistance; and pyridostigmine, a parasympathetic nervous system enhancer (Raj et al., 2022; Grubb and Grubb, 2023).

Neurocardiogenic syncope (NCS) (also known as vasovagal syncope or neurally mediated syncope) is defined as a sudden fall in blood pressure, heart rate, and cerebral hypoperfusion on standing or a tilt table test (Freeman et al., 2011; Sheldon et al., 2015) ( Table 1 ). It is usually of rapid onset and short duration and may be preceded by prodromal symptoms, such as pallor, diaphoresis, nausea, headache, and weakness. The loss of consciousness is typically brief and is not usually followed by confusion. NCS can occur after various triggers, including standing, pain, dehydration, heat, and the sight of blood. This form of syncope is common, with 42% of women and 32% of men experiencing at least one episode by age 60. Although when NCS occurs occasionally it is benign, recurrent and frequent NCS can greatly impair quality of life (Sheldon et al., 2015). One common mechanism of syncope involves ineffective reflex response, where baroreceptors fail to perceive drops in venous return upon standing or pathologic vasodilation is triggered. The resulting hypotension causes loss of consciousness and has often been observed together with vagally mediated bradycardia. Recurrent episodes of syncope often involve sympathetic nervous system dysfunction (Sheldon et al., 2015). While autoimmunity is typically not considered the cause of NCS in otherwise healthy individuals, when recurrent NCS occurs in the context of post-acute infectious syndromes, autoimmune disorders, or neurologic conditions, including autonomic neuropathy, autoimmune and immune-mediated etiologies should be considered.

Diagnosis is based primarily on clinical history, and a tilt table test can be utilized when the origin of syncope is unclear, although it can only point toward a susceptibility to vasovagal syncope and cannot definitively diagnose the condition (Sheldon et al., 2015). Similar to the treatment of POTS, the treatment of NCS involves increased fluid and salt intake, education about counterpressure maneuvers to be performed when prodromal symptoms occur, and wearing compression garments. For those with recurrent episodes with significant impact on daily functioning, medical management can include a trial of midodrine, fludrocortisone, beta-blockers, or selective serotonin reuptake inhibitors (SSRIs), while pacemaker implantation can be considered in treatment-refractory patients with severe and disabling NCS with a predominant cardioinhibitory component (Gampa and Upadhyay, 2018).

Orthostatic hypotension (OH), defined as a reduction in blood pressure ≥20/10 mmHg that occurs within 3 min of standing or during a head tilt test, is often associated with symptoms commonly related to cerebral hypoperfusion, such as lightheadedness, dizziness, presyncope, or syncope (Freeman et al., 2011) ( Table 1 ). OH can be associated with non-neurogenic causes (such as volume depletion or medication side effects) and neurogenic causes (such as senescence, neuropathic disorders, or neurodegenerative diseases). Medications, including vasodilators, nitrates, diuretics, phenothiazines, neuroleptics and antidepressants, can result in OH as a side effect (Medow et al., 2008). The severity of blood pressure reduction may also be influenced by the time of day, food ingestion, prolonged exposure to heat, fever, and alcohol consumption (Freeman et al., 2011). OH most often presents in the elderly, specifically one in five adults older than 60, and patients with neurodegenerative disorders (Freeman et al., 2011; Saedon et al., 2020). However, when OH occurs in the context of systemic autoimmune disorders, post-acute infectious syndromes, or neurologic disorders (such as autoimmune autonomic neuropathy or ganglionopathy), autoimmune and immune-mediated etiologies should be considered.

Mild cases of OH are commonly managed by discontinuing hypotensive medications and lifestyle changes, such as increasing water intake, avoiding alcohol, dietary changes, use of abdominal binders or leg stockings, and head-up tilt sleeping. The pharmacologic treatment approach for OH for patients with persistent symptoms is similar to that for patients with POTS and includes sympathomimetic agents (midodrine, yohimbine, vasopressin agonists, and clonidine), fludrocortisone, erythropoietin, pyridostigmine, selective serotonin reuptake inhibitors, and other medications (non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, caffeine, hydralazine, and ergotamine). Droxidopa, a norepinephrine precursor medication with combined central and peripheral alpha and beta agonist effects, was approved by the FDA for OH in 2014. It is indicated for the treatment of neurogenic OH and has shown improved symptoms and blood pressure elevation in four placebo-controlled randomized controlled trials (RCTs) (Brignole et al., 2018).

Inappropriate sinus tachycardia (IST) is a chronic syndrome defined as an unexplained sinus heart rate of ≥100 bpm at rest or >90 bpm on average for 24 hours without orthostatic changes (Sheldon et al., 2015) ( Table 1 ). IST may be associated with debilitating clinical symptoms, most often palpitations, and commonly occurs in women between the ages of 15 and 45. The pathophysiology of IST involves various proposed mechanisms, including an imbalance between sympathetic and parasympathetic inputs, accelerated intrinsic sinus node rate due to a deficient function of the acetylcholine and adenosine-sensitive potassium channels, and impaired baroreflex control (Ahmed et al., 2022). Since sinus tachycardia can be caused by various factors (including electrolyte abnormalities, dehydration, and hormonal abnormalities), these causes should be ruled out, and cardiac monitoring (such as an event monitor or an implantable loop recorder) should be used to correlate symptoms with heart rates (Ahmed et al., 2022). A 10-min stand test or a tilt table test can be used to distinguish IST from POTS, OH, and NCS (Olshansky and Sullivan, 2019), but sometimes, a patient may have more than one autonomic disorder, such as both POTS and IST.

The treatment of IST includes medications that reduce heart rate and symptoms, such as ivabradine (an I_f channel antagonist), beta-blockers, and calcium channel blockers. The combination of beta-blockers and ivabradine may be considered for ongoing management in some patients with IST (Olshansky and Sullivan, 2019). Sinus node modification, surgical ablation, and sympathetic denervation are not typically recommended as a part of routine care for patients with IST (Rodriguez-Manero et al., 2017).

Long COVID describes the health consequences of COVID-19 that persist beyond the initial infection. The World Health Organization defines post-COVID-19 conditions as symptoms that persist more than 12 weeks after probable or confirmed SARS-CoV-2 infection, which last at least 2 months and have no alternative explanations (Post COVID-19 condition (Long COVID), 2022). Similarly, the 2024 National Academies of Sciences, Engineering, and Medicine consensus defines Long COVID as “an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems” (National Academies of Sciences, E. and Medicine, 2024; Ely et al.., 2024). Long COVID can follow either asymptomatic or symptomatic SARS-CoV-2 infection, and the current diagnosis is entirely clinical (National Academies of Sciences, E. and Medicine, 2024), given that there are no reliable and validated biomarkers available to clinicians at this time. A Long COVID Household Pulse Survey showed that the rate of Long COVID is nearly 7% of all adults—roughly 17 million people—as of March 2024 (Statistics, N.C.f.H, 2024). In another study in 2023, the National Health Interview Survey, 8.4% of adults in the USA reported ever having Long COVID, and 3.6% reported currently having Long COVID (Vahratian et al., 2024).

The pathophysiology of Long COVID is multifactorial but frequently involves autonomic dysfunction, including symptoms and signs such as palpitations, orthostatic intolerance, labile blood pressure, fatigue, headaches, and “brain fog” (Larsen et al., 2021). Consequently, many patients with Long COVID have POTS or OCADs (Blitshteyn and Whitelaw, 2021; Davenport et al., 2024), with nearly 70% of patients having a high autonomic symptom burden (Larsen et al., 2022). Autoimmune, inflammatory, and immune dysregulations are identified as other major pathophysiologic mechanisms of Long COVID, which, together with autonomic dysfunction, closely parallel the pathophysiology of POTS and OCADs. Increased prevalence of elevated serum autoimmune and inflammatory markers has been reported in patients with both POTS and Long COVID (El-Rhermoul et al., 2023), and neuroinflammation at the brainstem, specifically at the dorsolateral inferior medulla, has been suggested as a potential central nervous system localization for POTS and Long COVID (Blitshteyn, 2025). Moreover, consensus guidelines on the assessment and treatment of post-COVID autonomic dysfunction have been developed using non-pharmacologic and pharmacologic treatment options similar to POTS and OCADs unrelated to COVID-19 (Blitshteyn et al., 2022).

The pathophysiology of POTS has been deemed largely heterogeneous and traditionally classified as neuropathic, hypovolemic, and hyperadrenergic (Low et al., 2009). In the past decade, however, investigators zeroed in on autoimmunity as one of the major mechanisms. Patients with POTS were found to have a higher prevalence of various non-specific autoimmune markers, including antinuclear antibodies and comorbid autoimmune disorders, than the general population (Blitshteyn, 2015). More specifically to the autonomic nervous system, ganglionic N-type and P/Q-type acetylcholine receptor antibodies, alpha 1, beta 1, and beta 2 adrenergic antibodies, muscarinic M2 and M4 antibodies, angiotensin II type 1 receptor antibodies, and opioid-like 1 receptor antibodies have been identified in patients with POTS and OCADs (Thieben et al., 2007; Li et al., 2014; Watari et al., 2018; Yu et al., 2018; Gunning et al., 2019; Kharraziha et al., 2020). Many of these antibodies have also been identified in patients with chronic fatigue syndrome, small fiber neuropathy, complex regional pain syndromes, and cardiovascular disorders—conditions that have overlapping clinical features with POTS.

POTS and OCADs are commonly comorbid with other autoimmune disorders, with the most common being Hashimoto’s thyroiditis (Blitshteyn, 2015). Their association with Sjögren’s syndrome, antiphospholipid syndrome, and celiac disease has also been reported (Schofield et al., 2014; Penny et al., 2016; Mannan and Pain, 2023). In addition, many patients with autonomic dysfunction, small fiber neuropathy, and positive autoimmune or inflammatory markers are diagnosed with undifferentiated connective tissue disease (UCTD) when they do not meet the diagnostic criteria of defined autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease, Sjögren’s syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis. In clinical practice, the presence of undifferentiated connective tissue disease can be common.

Like POTS, UCTD predominantly affects women of reproductive age and is thought to be heterogeneous in mechanisms and presentations. UCTD is caused by an autoimmune etiology and may precede the onset of lupus or another defined classical autoimmune disease. UCTD includes the following diagnostic criteria: 1) clinical presentation suggestive of a defined connective tissue disease, but not meeting its criteria; 2) positive serological markers on two separate occasions, including positive antinuclear antibody marker; and 3) the duration of symptoms is at least 3 years (Mosca et al., 1999).

Positive serological markers are essential in the diagnostic criteria for UCTD and should include routine screening tests, such as complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine, urinalysis with microscopic analysis, rheumatoid factor (RF), antinuclear antibodies (ANAs), anti-Ro/SSA/anti-SSB antibodies, and anti-U1-RNP (Marwa and Anjum, 2025). Treatment typically includes symptomatic management with non-steroidal anti-inflammatory medications, such as ibuprofen, naproxen, and celecoxib; corticosteroids, such as prednisone, methylprednisolone, and hydrocortisone; calcium channel blockers, such as diltiazem and nifedipine; and immunomodulatory therapy with an anti-malarial drug, hydroxychloroquine. In more severe cases, immunosuppressive medications, such as methotrexate and azathioprine, can be used, especially when there is evidence of significant organ damage or involvement (Rubio and Kyttaris, 2023). Further research is needed to elucidate whether POTS and OCADs with positive autoimmune markers represent a sizable subset of patients with UCTD, what longitudinal monitoring is required in this subset, and whether early intervention with treatment (such as hydroxychloroquine or low-dose naltrexone) can alter the natural history and potentially prevent further progression of the disease process.

POTS and OCADs can often occur as part of, or in the context of, autonomic neuropathy. Experts who originally described POTS have considered it to be a limited or restricted form of autonomic neuropathy (Schondorf and Low, 1993; Vernino et al., 2008). Approximately half of patients with POTS have a length-dependent distribution (Low et al., 1994; Low et al., 2009) with distal postganglionic sudomotor denervation demonstrated by the quantitative sudomotor axon reflex test (QSART) or the thermoregulatory sweat test (Low, 1993). These tests commonly reveal sudomotor denervation in the feet and toes: adrenergic impairment in the lower extremity can be seen in neuropathic POTS as impaired norepinephrine spillover in the leg, while the arm response remains normal (Jacob et al., 2000). However, a non-length-dependent or patchy distribution of small fiber neuropathy can also occur, especially in conjunction with systemic autoimmune disorders (Gemignani et al., 2022). Autoimmune and immune-mediated etiologies have been suggested as among the major underlying mechanisms in autonomic neuropathy, with immunotherapy being recommended as the first-line treatment (Gavrilova et al., 2022; Maier et al., 2022; Gendre, 2024; Nakane et al., 2024).

Autoimmunity has been implicated as one of the major mechanisms of Long COVID, leading to a higher risk, overall incidence, and range of autoimmune conditions after SARS-CoV-2 infection (Sharma and Bayry, 2023). A variety of antibodies have been linked to Long COVID, including autoantibodies to inflammatory cytokines such as IgG to IL-2, D8B, thyroglobulin, and IFNδ (Rojas et al., 2022; El-Rhermoul et al., 2023; Peluso and Deeks, 2024). These autoantibodies have been associated with anti-SARS-CoV-2 IgG antibodies (Rojas et al., 2022; El-Rhermoul et al., 2023; Peluso and Deeks, 2024). G protein-coupled receptor antibodies, including against alpha- and beta-adrenergic antibodies and muscarinic antibodies, previously identified in patients with POTS, as well as autoantibodies to antinuclear and extractable nuclear antigens, have also been found in patients with Long COVID (Wallukat et al., 2021; El-Rhermoul et al., 2023; Son et al., 2023). The pro-inflammatory mediators, non-specific antibodies, and antibodies important to the function of the autonomic nervous system are thought to be implicated in the development of post-COVID autonomic disorders, such as POTS and OCADs (El-Rhermoul et al., 2023).

Immunotherapies documented in Long COVID case reports and cohort studies include IVIG, immunoadsorption, convalescent plasma (CP), TPE, and LDN. Due to their proposed therapeutic role in autoimmune POTS and OCADs, these therapies could be considered potential therapeutic options for Long COVID-associated dysautonomia, but their use is extremely limited due to a lack of access and insurance coverage.

Three case reports have documented the utility of IVIG, TPE, and CP treatments in Long COVID. Novak reported improvement in headache and fatigue, with complete symptom resolution of all other symptoms (Novak, 2020). Minor adverse effects, such as headaches, were alleviated by dose down-titration. Tomisti et al. treated two patients with CP who reported complete symptom resolution within 1 month after their final treatment dose and reported no side effects (Tomisti et al., 2023). Lastly, Seeley et al. treated one patient with TPE who reported improved cognitive function, peripheral pain, and ambulation capacity from 5 to 12 m (Seeley et al., 2025). They also did not report side effects ( Table 2 ).

Four prospective studies, although limited in sample size, have demonstrated clinical improvements in Long COVID and post-COVID syndromes following treatment with LDN (n = 38), immunoadsorption (n = 20), and immunoglobulin (n = 9) (O’Kelly et al., 2022; McAlpine et al., 2024; Stein et al., 2025). O’Kelly et al. conducted an open-label prospective study with 38 patients receiving 1 mg of LDN, assessing improved outcomes by self-reported questionnaires (O’Kelly et al., 2022). They found the biggest effect of symptom reduction in joint pain. Additionally, Isman et al. investigated LDN in an open-label prospective study with 36 Long COVID subjects over 12 weeks. They reported significant improvements in the patient’s quality of life and fatigue, measured by their 36-Item Short Form Health Survey (SF-36) and CFS scores. Approximately half of their participants were identified as clinical responders (Isman et al., 2024) ( Table 2 ).

A placebo-controlled clinical trial was conducted for efgartigimod in 53 patients with post-COVID POTS, but preliminary outcomes showed no benefit of efgartigimod compared to placebo (A phase 2 randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of efgartigimod IV in adult patients with post-COVID-19 postural orthostatic tachycardia syndrome (POTS, 2022). The clinical trial was stopped in 2024, and its outcome data have yet to be released (SE, 2024) ( Table 2 ). Currently, eight immunotherapy clinical trials are ongoing for Long COVID and post-COVID autonomic disorders. These clinical trials are investigating IVIG, immunoadsorption, infliximab compared to imatinib, tocilizumab, baricitinib, and an anti-SARS-CoV-2 monoclonal antibody therapy. Four clinical trials are being held in North America (the USA and Canada), including one as part of the NIH-RECOVER autonomic study, with the other trials taking place in Germany, Finland, and the United Kingdom (Long-term follow-up of a randomized multicenter trial on impact of imatinib and infliximab on long-COVID in hospitalized COVID-19 patients, 2022; Aerium, 2023; A single-blinded sham-controlled crossover trial to evaluate the effect of immunoadsorption on post-corona virus disease (COVID)-syndrome, 2023; Double-blinded, randomized, sham-controlled trial of immunoadsorption (IA) in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS), 2023; Double-blind, randomized, placebo-controlled phase 3 study evaluating efficacy and safety of igPro20 (Subcutaneous immunoglobulin, HIZENTRA®) in post-COVID-19 postural orthostatic tachycardia syndrome (POTS), 2024; Randomized double-blind placebo-controlled trial EValuating baricitinib on PERSistent NEurologic and cardiopulmonary symptoms of long COVID (REVERSE-LC, 2024; RECOVER-AUTONOMIC (IVIG): randomized trial of the effect of IVIG versus placebo on long COVID symptoms, 2024) ( Table 3 ).

ME/CFS has overlapping clinical features with POTS, OCADs, and Long COVID and is therefore relevant to this review. A number of immunologic therapies have been studied in ME/CFS, including IVIG, SCIG, and IgG depletion by immunoadsorption (McAlpine et al., 2024; Sjogren et al., 2024; Stein et al., 2025). Four double-blind placebo-controlled RCTs of IVIG for ME/CFS were conducted in the 1990s: one study reported that immunoglobulin is effective in a “significant number of patients”, and another reported that IVIG “is unlikely to be of clinical benefit in CFS” (Lloyd et al., 1990; Peterson et al., 1990). The third study reported a beneficial effect of IVIG in adolescent patients, but a fourth trial reported that IVIG was ineffective (Rowe, 1997; Vollmer-Conna et al., 1997). Despite these conflicting results from clinical trials, some authors believe that IVIG presents a potentially curative treatment for a proportion of patients with ME/CFS and that further randomized controlled trials should be conducted with urgency, especially since many patients with Long COVID met the criteria for ME/CFS (Brownlie and Speight, 2021).

More recently, in a case–control study of patients with post-COVID SFN who had comorbid ME/CFS, IVIG administered to nine patients resulted in decreased allodynia and neuropathic symptoms compared to patients who were not treated with IVIG (McAlpine et al., 2024). Subcutaneous low-dose immunoglobulin therapy has also been shown to be effective in 17 patients with ME/CFS (Sjogren et al., 2024). In a cohort of 20 patients, immunoadsorption was used to remove select immunoglobulins and autoantibodies from plasma, which led to symptomatic improvement in some patients (Stein et al., 2025). Further research involving more robust, controlled study designs with larger sample sizes is needed to elucidate the efficacy of these immunologic therapies for the treatment of ME/CFS.

Since POTS, OCADs, and Long COVID have been increasingly linked to autoimmunity and immune system dysregulation, new and repurposed immunologic therapies present a potentially effective treatment option and should be explored in future clinical trials. These therapies may be used either as a last resort in patients who failed standard non-pharmacologic and pharmacologic therapies or as a first-line treatment in patients with POTS and OCADs of suspected autoimmune or inflammatory etiologies, or comorbid SFN, UCTD, and other systemic autoimmune disorders. Many immunologic therapies have already been approved for other indications that could have the potential to treat POTS and OCADs, including immunoglobulin, plasmapheresis, immunoadsorption, corticosteroids, hydroxychloroquine, mycophenolate, azathioprine, methotrexate, monoclonal antibody treatments, and various receptor inhibitors ( Table 4 ). Availability and accessibility of these immunotherapies to patients with POTS, OCADs, and Long COVID may present a potentially effective treatment option and prevent future disability incurred as a result of progressive disease course.