Onset of Postural Orthostatic Tachycardia Syndrome (POTS) Following COVID-19 Infection: A Pediatric Case Report

Introduction

Orthostatic intolerance (OI) is a disorder of the autonomic nervous system characterized by the provocation of symptoms with standing and the improvement in symptoms with recumbency.¹ In adolescents, postural orthostatic tachycardia syndrome (POTS), a form of OI, is defined by a sustained heart rate (HR) increment of at least 40 beats/minute (bpm) within 10 minutes of standing or head-up tilt in addition to chronic orthostatic symptoms for at least 3 months duration.² Typically, a head-up tilt test or a 10-minute standing test is required to establish the diagnosis²; however, there is currently no consensus on the exact type of orthostatic stress test needed to provoke symptoms.³ Common symptoms of POTS include lightheadedness, palpitations, fatigue, and generalized weakness². Treatment of POTS generally starts with non-pharmacologic measures such as increasing dietary fluid and salt intake, wearing compression garments, and gradually increasing physical activity; in cases where non-pharmacologic management is insufficient, a variety of medications can be tried, including vasoconstrictions, volume expanders, and medicines that control HR.³

POTS is most commonly triggered by viral infections, pregnancy, fever, surgery, or trauma.² Specifically, Sandroni et al⁴ have reported that up to 50% of patients with POTS reported a history of infection closely preceding the onset of their POTS symptoms. Thus, it is not surprising that several case reports have recently been published documenting the onset of POTS following COVID-19 infection in adults^5-7; in contrast, documented cases of POTS following COVID-19 infection in pediatric patients are scarce. Rowe et al⁸ describe a case of a 19-year-old male with confirmed COVID-19, who developed orthostatic symptoms within 2 weeks of diagnosis. An orthostatic standing testing revealed a striking 70 bpm increase in HR from supine to standing, consistent with a diagnosis POTS.

Interestingly, in a case series of 20 adults who developed POTS and other forms of OI after COVID-19 infection, many reported significant improvement in symptoms upon treatment targeted to POTS, including both non-pharmacologic and pharmacologic therapies.⁹ This case series highlights the importance of recognizing POTS as a possible complication after COVID-19 infection since the diagnosis can significantly alter treatment and outcome for these patients.

We report one of the first documented cases of POTS after COVID-19 infection in a pediatric patient.

Case Report

A 16-year-old boy with no past medical history presented to a multi-disciplinary Post-Acute/Long COVID clinic in April, 2021; the clinic model has previously been described.¹⁰

The patient had been diagnosed with COVID-19 in January 2021, confirmed by a positive nucleic acid test. The patient was not vaccinated against COVID-19 infection as he was 15 at the time of infection, and FDA (Food and Drug Administration) approval for vaccination had not yet occurred for this age group. His clinical presentation of COVID was mild, consisting of minimal fatigue and rhinorrhea for 24 hours. He did experience some intermittent constipation and diarrhea over the subsequent month; however, he attributed these symptoms to school-related stress. Two weeks after infection, he successfully returned to school as well as to 20 hours per week of basketball practice.

Roughly 6 weeks after infection, the patient began experiencing a significant decline in his exercise tolerance in addition to episodes of vomiting after running. He also reported new-onset headaches, chest pain, brain fog, lightheadedness, and fatigue, none of which he experienced prior to this time. His symptoms progressed over the next few weeks until he was no longer able to attend school in person. Due to the orthostatic nature of his symptoms, he was forced to spend most of his day lying supine in bed and to limit his time in an upright position.

At his initial evaluation in the Post-Acute/Long COVID clinic, he underwent a comprehensive physical examination by a pediatric neurologist, which was unremarkable. Blood work including complete blood count, complete metabolic panel, C-reactive protein, erythrocyte sedimentation rate, vitamin D, vitamin B₁₂, tissue transglutaminase IgA, ferritin, iron, urinalysis, thyroid-stimulating hormone, free t4 (FT4), and Borrelia burgdorferi antibody test returned within normal limits, thus ruling out other common causes of his symptoms. In light of his severe and progressive headaches, a magnetic resonance imaging of the brain with and without contrast was ordered, which was also normal. Finally, as part of the clinic assessment, a 10-minute passive standing test as described by Roma et al¹¹ was performed, consisting of 5 minutes of supine positioning, followed by 10 minutes of standing with the shoulders leaning against a wall and the feet 6 inches away from the wall, followed by an additional 2 minutes in the supine position. This test revealed an increase in HR of 64 bpm, ranging from 49 bpm supine to a peak of 113 bpm standing, associated with worsening orthostatic symptoms, and in the absence of orthostatic hypotension. Thus, this test was consistent with a diagnosis of POTS.¹² As several studies have identified an increased risk of developing POTS in those with joint hypermobility, a Beighton score, which assesses joint hypermobility on a 9-point scale, was performed on the patient at a later date.¹³ He was found to be hypermobile with a Beighton score of 5/9; he was not assessed for further signs of a connective tissue disorder as his hypermobility was asymptomatic.

Based on given recommendations for POTS management, the patient increased his daily intake of fluids to approximately 4 L and of sodium chloride (NaCl) to 5 g. In addition, he was started on fludrocortisone 0.1 mg for volume expansion. This dose was increased to 0.2 mg after 3 weeks as the patient reported no noticeable effects on the lower dose; however, even after an additional 3 weeks on the increased dose, he continued to report progression of symptoms. He was subsequently started on 1 L of 0.9% saline intravenous infusions 2 times a week for a month, a treatment also aimed at volume expansion.¹⁴ As with the fludrocortisone, he did not notice any relief in symptoms after a month of the infusions and actually reported an increase in headaches.

Next, we purposefully chose a medication with a different mechanism of action, as targeting volume expansion had not proven effective. He was therefore prescribed midodrine, an alpha-adrenergic agonist that promotes vasoconstriction. The patient experienced almost immediate improvement in symptoms on midodrine; he reported being able to tolerate more physical activity, albeit still from a supine position. Midodrine was slowly titrated up from 5 mg 3 times a day to 10 mg 3 times a day. At a dose of 10 mg 3 times a day, he reported a subjective estimate of feeling 20% back to his baseline level of function and was able to tolerate more seated activity.

For completeness, the patient was referred to pediatric cardiology for further evaluation. Auscultation revealed normal first and second heart sounds with no murmur, click, or gallop. His ECG (electrocardiogram) was unremarkable, and his echocardiogram showed trivial mitral and aortic valve regurgitation, which were deemed insignificant. While adhering to his aggressive fluid and NaCl regimen and taking 5 mg of midodrine 3 times a day, a repeat orthostatic standing test in the cardiology clinic was performed and revealed an increase in HR of 48 bpm, ranging from 57 bpm supine to a peak of 105 bpm standing, still consistent with a diagnosis of POTS.

In light of his persistent orthostatic tachycardia, ivabradine, an I(f) current blocker that acts in the sino-atrial node to lower HR, was added. Ivabradine was chosen rather than a β-blocker due to lower risk of side effects, specifically fatigue and lightheadedness which the patient was already experiencing, in addition to higher rate of success anecdotally in reducing symptoms of POTS after infection. Due to his low resting HR, he was initially started on only 2.5 mg of ivabradine once daily. After a couple weeks, his ivabradine dose was increased to 2.5 mg twice a day. Days after increasing to this dose, the patient was able to tolerate a 10-minute walk outside, which was the longest he had been completely upright in months.

The patient successfully returned to in-person school in the fall with the creation of a 504 plan to provide school accommodations. At his most recent follow-up visit occurring roughly 1 year after his COVID diagnosis, the patient reported feeling 50% back to his baseline health. He was doing well in school and was participating in physical therapy 2 times a week; however, due to ongoing exercise intolerance, he was not able to return to sports and could still only walk 1/3 mile at a time.

Discussion

This report is one of the first documented cases of POTS associated with COVID-19 infection in a pediatric patient. It is interesting to note that the patient developed POTS symptoms roughly 6 weeks after COVID-19 infection. While we cannot be certain that this association was causal, this delayed response is less consistent with an immediate and direct effect of the virus on the autonomic nervous system and instead suggests an immune-mediated response, occurring after the development of SARS-CoV-2 antibodies. Although there are likely several underlying mechanisms and etiologies of POTS, growing evidence is emerging to suggest that POTS may be an autoimmune condition.^15,16

The concomitant use of midodrine and ivabradine proved immensely helpful to our patient. Several case series^17-19 and a randomized controlled trial²⁰ in adults as well as case series in pediatric patients²¹ identify benefits from ivabradine in POTS. Unfortunately, its use for POTS is often limited by insurance policies due to cost despite evidence of efficacy in POTS, inappropriate sinus tachycardia,²² and vasovagal syncope.²³ Consistent with our report, O’Sullivan et al²⁴ describe a 22-year-old female diagnosed with debilitating POTS after COVID-19 infection, who also experienced significant clinical improvement on ivabradine.

While our patient was fortunate to be evaluated at one of the few existing Post-Acute/Long COVID pediatric clinics in the nation at which he was diagnosed with POTS, most patients do not have easy access to one of these specialized clinics. Thus, it is important for all medical providers to recognize POTS as a possible sequela of COVID-19 infection in both children and adult patients. We believe further research is needed to determine the prevalence, risk factors, duration, and optimal treatment of POTS following COVID-19 infection.

Author Contributions

CK: Contributed to conception and design; Contributed to analysis; Drafted the manuscript; critically revised the manuscript; Gave final approval; Agrees to be accountable for all aspects of work ensuring integrity and accuracy.

LM: Critically revised the manuscript; Gave final approval; Agrees to be accountable for all aspects of work ensuring integrity and accuracy. KB: Critically revised the manuscript; Gave final approval; Agrees to be accountable for all aspects of work ensuring integrity and accuracy.

AM: Critically revised the manuscript; Gave final approval; Agrees to be accountable for all aspects of work ensuring integrity and accuracy.

PCR: Contributed to analysis; critically revised the manuscript; Gave final approval; Agrees to be accountable for all aspects of work ensuring integrity and accuracy.