Long‐Term POTS Outcomes Survey: Diagnosis, Therapy, and Clinical Outcomes

Abstract

Background

Limited data exist on long‐term outcomes in individuals with postural orthostatic tachycardia syndrome (POTS). We designed an electronic questionnaire assessing various aspects of outcomes among patients diagnosed and treated in a single‐center pediatric POTS clinical program.

Methods and Results

The LT‐POTS (Long Term POTS Outcomes Survey) included questions about quality of life, symptoms, therapies, education, employment, and social impact of disease. Patients age≤18 years at POTS diagnosis who were managed in the Children's Hospital of Philadelphia POTS Program were included. A total of 227 patients with POTS responded with sufficient data for interpretation. The mean age of respondents was 21.8±3.5 years. The median age of symptom onset was 13 (interquartile range 11–14) years, with mean 9.6±3.4 years symptom duration. Multiple cardiovascular, neurologic, and gastrointestinal symptoms were reported. Symptom prevalence and severity were worse for female patients, with 99% of patients reporting ongoing symptoms. Quality of life showed moderate function and limitation, with more severe limitations in energy/fatigue and general health. Nearly three quarters of patients had diagnostic delays, and over half were told that their symptoms were “in their head.” Multiple medications were used and were felt to be effective, whereas fewer nonpharmacologic interventions demonstrated efficacy. Nearly 90% of patients required continued nonpharmacologic therapy to control symptoms.

Conclusions

POTS is a chronic disorder leading to significant disability with a range of multisystem problems. Although symptoms can be modifiable, it rarely spontaneously resolves. Improved understanding of POTS presentation and therapeutic approaches may inform provider education, improve diagnostic success, and help patients self‐advocate for appropriate medical management approaches.

Nonstandard Abbreviations and Acronyms

CHOP

Children's Hospital of Philadelphia

COMPASS‐31

Composite Autonomic Symptom Score‐31

LT‐POTS

the Long Term POTS Outcomes Survey

POTS

postural orthostatic tachycardia syndrome

QoL

quality of life

SF‐36

36‐Item Short Form Survey

Clinical Perspective.

What Is New?

• Patients with postural orthostatic tachycardia syndrome continue to be symptomatic, despite effective nonpharmacologic and pharmacologic therapies.

What Are the Clinical Implications?

• Female patients with POTS had a greater symptom burden, greater symptom severity, and longer symptom duration than male patients with POTS.

• Various medications are effective in the reduction of POTS symptoms.

It is theorized that postural orthostatic tachycardia syndrome (POTS) was likely first described in the medical literature in 1871 by Da Costa. ¹ In his monograph, he described Civil War soldiers who, in the setting of dysentery‐like illness, presented with multiple orthostatic and gastrointestinal symptoms that caused severe disability. The term “POTS” was subsequently coined in 1982 by Rosen and Cryer in a patient with upright lightheadedness, weakness, palpitations, abdominal and leg pain, and diaphoresis. ² She had reduced plasma volume and poor sodium balance that responded to increased sodium intake plus mineralocorticoid therapy. Since that time, as initial diagnostic features appeared in 1993 ³ and the first consensus document describing diagnostic criteria came out in 2011, ⁴ recognition of the broadening nature of its cardiovascular, neurologic, and gastrointestinal symptoms spread. Although significant progress has been made in the past 40 years toward understanding and managing this autonomic disorder, ⁵ , ⁶ much remains unknown about POTS. Recent discussions on the pathophysiology, ⁷ , ⁸ , ⁹ appropriate therapies, ¹⁰ , ¹¹ , ¹² , ¹³ and the possible role of autoimmune disease ¹⁴ , ¹⁵ , ¹⁶ in POTS have garnered attention as the field slowly advances to gain increasingly advanced insights into these diverse aspects of this disorder. Patients with POTS often present with multiple disease‐related symptoms and multiple associated comorbidities, often in the absence of overt or specific clinical or laboratory findings, which can lead to complicated and prolonged diagnostic journeys. Diagnostic delays, misdiagnoses, ¹⁷ , ¹⁸ and inappropriate attribution of POTS symptoms to psychiatric conditions ¹⁷ have all been seen in these patients. These medical misadventures, either alone or in combination, can cause frustration and mistrust of the medical system, engender online research that may or may not be beneficial, and potentially delay access to an appropriate therapeutic approach as well as prolonging school absence and social isolation.

POTS symptoms also can severely affect the quality of life (QoL) in patients. Patients often require multiple and varied therapeutic interventions to try to control their symptoms. Being able to assess the perceived effects of these treatment approaches as well as demonstrating an overall assessment of variation in symptom burden and QoL is both important for patients as well as providers in their attempts to better enable patients to return to their activities of daily living.

One issue that is not well defined is that of long‐term outcomes in patients with POTS. This has been described in a self‐reported study of adolescent and adults, ¹⁷ and parts of these concepts have been evaluated in other studies. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ However, the spectrum of long‐term outcomes for POTS has not been comprehensively reviewed in pediatric patients. We sought to evaluate these findings in a group of former and present pediatric patients followed longitudinally in the Children's Hospital of Philadelphia (CHOP) POTS Program using a newly constructed survey instrument, the LT‐POTS (Long Term POTS Outcomes Survey).

LT‐POTS was designed to be administered as an online self‐report questionnaire. Survey questions sought to evaluate patient demographics, multisystemic symptoms of POTS and their degree of severity, health‐related QoL, use of medications and their perceived efficacy, use of nonpharmacologic therapies and their perceived efficacy, dietary changes and their perceived efficacy, potential triggers of POTS onset, and interaction with the medical community during the evaluation of symptoms as well as comorbid diagnoses, which are highlighted in this paper; educational, work, and social impacts of disease, and gynecologic findings will be published in subsequent papers. The LT‐POTS survey included the Pediatric Quality of Life Inventory for patients under age 18, ²⁵ the 36‐Item Short Form Survey (SF‐36) for those age 18 or over, ²⁶ and the Composite Autonomic Symptom Score (COMPASS‐31), a validated assessment of autonomic dysfunction. ²⁷

METHODS

The authors declare that all supporting data are available within the article.

Criteria for inclusion were patients diagnosed with POTS at age 18 years or younger by 1 of 2 specific providers in the POTS Program at CHOP between 2007 and 2018. A clinical diagnosis of POTS was based on a combination of at least 3 months of severely disabling symptoms spanning cardiovascular, gastrointestinal, and neurologic symptoms, and a consistent increase in heart rate of at least 30 beats per minute when rising from supine to standing during a 10‐minute standing test. Other potential causes were excluded. No patients were included who had orthostatic hypotension, a drop in at least 20 mm Hg systolic or 10 mm Hg diastolic blood pressure, during upright position.

The survey was performed in the summer of 2021. The study consent form, LT‐POTS survey, and a cover letter were emailed to patients with POTS or families, based on their last known email address in the electronic health record. Where possible, updated email addresses were obtained to reach patients directly. Informed consent was obtained at the beginning of the survey by either the patient, or by their parent if the patient was under age 18 years at the time of survey completion. Surveys were administered as an online questionnaire using the Research Electronic Data Capture system ²⁸ hosted at CHOP. Data were collected and stored within this system.

The LT‐POTS survey was created, in part, based on the questions used in the “Big POTS Survey,” an online‐only questionnaire administered to self‐reporting patients with POTS. ¹⁷ Questions also posed in the single‐center study used by Bhatia et al were incorporated as well. ²² Further questions were added to better ascertain details not addressed by these prior surveys. The list of symptoms, of which a total of 21 were used, was derived from a prior study ¹⁷ as well as a list of symptoms documented in our previous demographic research. ²⁹ A specific section addressing gynecologic health and symptoms was also included, although these details are not included here.

Statistical Analysis

Data were analyzed using mean±SD when normally distributed, or median and interquartile range otherwise. Chi‐square analyses were used for statistical analysis of categorical variables, and Mann–Whitney U tests were used for statistical analysis of nonnormally distributed groups of continuous data with a 2‐tailed hypothesis. Statistical calculations were performed using the website, Social Science Statistics. ³⁰ Significance was set at P<0.05, except in the list of symptoms, where Bonferroni correction gave a P‐value of <0.0024. The LT‐POTS survey and study design was approved by the CHOP Institutional Review Board. One author (J.R.B.) had full access to all data in the study and takes responsibility for its integrity and analysis.

RESULTS

A total of 932 patients with POTS were eligible for participation in the LT‐POTS survey. There were 70 patients for whom a valid email address was not available or from whom the email invitation was rejected as being sent to an invalid address (Figure 1). A total of 271 surveys were filled out, with 227 respondents (26.3% of eligible patients) having filled out the initial SF‐36/Pediatric Quality of Life Inventory plus LT‐POTS survey, the SF‐36/Pediatric Quality of Life Inventory alone, or the LT‐POTS alone. Surveys were completed by 195 (86%) patients for themselves, and by 32 (14%) parents on behalf of their children.

Figure 1. Flow diagram of survey participation.

CHOP indicates Children's Hospital of Philadelphia; and POTS, postural orthostatic tachycardia syndrome.

The mean age of patients whose data were included in the survey was 21.8 (SD 3.5) years, with a range of 11 to 32 years (Table 1). Over 85% of patients were female (5.9:1 ratio). Nearly 98% of patients were White, with 1% each of patients self‐reporting as either Black or Asian, and 3.5% as Hispanic, with no significant sex differences seen. The mean duration of time from onset of POTS symptoms to time of survey completion was 9.6 (SD 3.4) years.

Table 1.

Demographics

Sex (number, %)
Female	194 (85.5)
Male	33 (14.5)
	All patients	Female	Male
Age, y (mean±SD)	21.8±3.5	22.0±3.5	20.6±3.2
Time from symptom onset to present, y (mean±SD)	9.6±3.4
Race (number, %)
White	222 (97.8)	191 (98.5)	31 (93.9)
Black	2 (0.9)	1 (0.5)	1 (3.0)
Asian	2 (0.9)	1 (0.5)	1 (3.0)
Native American	1 (0.4)	1 (0.5)	0 (0)
Ethnicity (number, %)
Hispanic	8 (3.5)	7 (3.6)	1 (3.0)

Patients reported multiple symptoms as having been significantly disabling for them at any point in time (Figure 2). There was nearly equal reporting of symptoms between female and male patients. However, a significantly higher percentage of female patients reported experiencing palpitations (78.9% versus 48.5%, P=0.0002) and nausea (83.0% versus 57.6%, P=0.0009) as compared with males (Bonferroni correction P<0.0024). The most frequently reported symptoms included fatigue, dizziness, tachycardia, lightheadedness, brain fog, headache, and exercise intolerance. At least 10 symptoms were reported by 85% of patients, over half of patients had at least 15 symptoms, and nearly 15% of patients had at least 20 symptoms (Table 2). A higher percentage of female patients had at least 10 symptoms (88.1% versus 63.6%, P=0.0003), as well as at least 15 symptoms (61.1% versus 30.3%, P=0.001), as compared with male patients.

Figure 2. Reported symptoms (Bonferroni correction P=0.0024).

Was this symptom significant to you at any time?

Table 2.

Patients With Threshold Number of Symptoms, 225 Total Respondents

	All patients	Female patients 193	Male patients 33
10 symptoms	191 (84.9)	170 (88.1)	21 (63.6)*
15 symptoms	128 (56.9)	118 (61.1)	10 (30.3)†
20 symptoms	33 (14.7)	30 (15.5)	3 (9.1)

No., (%).

^* P=0.0003 female vs male patients.

^† P=0.001 female vs male patients.

For each reported symptom, patients were asked to score the severity of that symptom from 0 to 10 at its worst, at its least severe, and on average over the past month. Patients scored all reported symptoms as at least a 7 out of 10 severity at their worst (Figure 3A). However, patients scored all reported symptoms as a 3 out of 10, or less, severity at their least severe (Figure 3B). Of all symptoms reported, patients reported a median severity ranging from 2 to 5 out of 10 over the past month (Figure 3C). There were no differences between sexes in severity of individual symptoms at their worst, at their least, or in the past month. A total of 2 out of 215 patients, or 0.9% of all respondents who completed the severity questions, reported a severity of 0 for all symptoms in the prior month. The median number of symptoms reported in the prior month was 13 (interquartile range [IQR] 10–16.3), with female patients reporting 14 symptoms (IQR 11–17) and male patients reporting 10.5 symptoms (IQR 7.3–14) (P=0.012). When all symptom severity scores were summed by patient, the mean total severity for the prior month was 54 (SD 32). Female patients had a mean total severity of 56 ± 31 and male patients had a total severity of 42 (SD 31) for the prior month (P=0.027). With 21 symptoms reviewed, the worst possible score was 210, assuming all symptoms were present and all were rated as a 10 at their worst. Total severity at its worst was found to be 111.5 (SD 43), with female patients having a severity of 115.1 (SD 42) and male patients having a severity of 93 (SD 41) (P=0.004). Total severity at its least severe was 25.2 (SD 23), with female patients having a severity of 26.2±24 and male patients having a severity of 20±19 (P=0.14).

Figure 3. Symptom severity (0–10).

A, Symptom severity at their worst (0–10). How severe was each symptom when it was at its worst? B, symptom severity at their least (0–10). How severe was each symptom at its least severe? C, Symptom severity in the past month (0–10). How severe was each symptom in the month before completing the survey? IQR indicates interquartile range.

The median age of onset of POTS symptoms was 13 (IQR 11–14) years, with over half of patients reporting onset within 3 months of a specific event (Table 3), such as infection (45.6%), concussion (22.8%), pubertal changes (7.0%), surgery (12.3%), growth spurt (6.1%), physical trauma/fracture (2.6%), or extreme stress or emotional trauma (1.8%) (Figure 4). The majority of patients reporting triggers identified a single trigger (67.5%), but 25.4% listed 2 triggers, 5.3% listed 3, and 1.8% listed 4 triggers. As many as 9.6% of patients reported that vaccination, specifically the human papillomavirus vaccine or meningitis B vaccine, was the presumed trigger for their POTS onset. There were no differences between female and male patients noted in percentage of reported triggers.

Table 3.

POTS Onset

		Female patients	Male patients
Age of onset, y (Median [interquartile range])	13 (11–14)	13 (11–14)	13 (9–14.5)
	Yes
Did it start within 3 mo of a specific event? (N=203 replies)	114 (56.2)	98 (56.6)	16 (53.3)
If no, how did it start?	N (% of 88 replies)	N (% of 74 replies)	N (% of 14 replies)
Suddenly, but unrelated to any event	19 (21.6)	18 (24.3)	1 (7.1)
Gradually/insidiously	61 (69.3)	48 (64.9)	13 (92.9)*
Cannot recall	8 (9.1)	8 (10.8)	0
Putative triggers	N (% of 114 replies)	N (% of 98 replies)	N (% of 16 replies)
Infection	52 (45.6)	46 (46.9)	6 (37.5)
Concussion	26 (22.8)	23 (23.5)	3 (18.8)
Physical/hormonal changes associated with puberty	8 (7.0)	6 (6.1)	2 (12.5)
Surgery	14 (12.3)	11 (11.2)	3 (18.8)
Accident/nonconcussion trauma	3 (2.6)	3 (3.1)	0
Growth spurt	7 (6.1)	5 (5.1)	2 (12.5)
Extreme stress/emotional trauma	2 (1.8)	2 (2.0)	0
Immunization	11 (9.6)	10 (10.2)	1 (6.3)
Specified vaccine	Human papillomavirus vaccine
	10
	Meningitis B
	1

Number of replies: 227, unless otherwise specified. N, (%), unless otherwise specified.

^* P<0.05.

Figure 4. POTS triggers: presumed triggers within 3 months of symptom onset.

POTS indicates postural orthostatic tachycardia syndrome.

Approximately half of patients went to the emergency department for acute symptom management, both before and after the diagnosis of POTS (Table 4), with a median of 3 visits before diagnosis and 4 visits after diagnosis (P=0.009). Although only about one third of patients felt that they had a specific psychological or psychiatric concern before receiving a POTS diagnosis, nearly 65% of patients were told that they were suffering from a psychological or psychiatric disorder prior being given a POTS diagnosis, with over half of patients reporting being told that their symptoms were “all in your head.” Before POTS diagnosis, 45% of patients were diagnosed with anxiety or panic disorder, 11% with depression, and another 8% with conversion disorder or psychosomatic symptoms (Figure 5). After getting a POTS diagnosis, the numbers of patients told that they had a psychological disorder decreased to 49% and that their disorder was imaginary decreased to 31.6%; however, 46% of patients stated that they were currently being treated for a psychiatric disorder. No significant differences between female and male patients were noted.

Table 4.

POTS Evaluation

	Yes	No	Female patients	Male patients
Before your POTS diagnosis, did you go to the emergency department for your symptoms? (N=205 replies)	97 (47.3)	108 (52.7)	85 (48.6)	12 (40.0)
Estimate the number of times that you went to the emergency department for your symptoms before diagnosis. (Median [IQR])	3 (1–5)		3 (1–5)	2 (1–3)
	Yes	No
After you were diagnosed with POTS, did you ever go to the emergency department for your POTS symptoms? (N = 207 replies)	107 (51.7)	100 (48.3)	97 (55.1)	10 (32.3)
Estimate the number of times that you went to the emergency department for your symptoms after your diagnosis. (Median [IQR])	4 (2–9)		4 (2–8)	4 (2–11)
Emergency departmentvisits after vs before diagnosis of POTS		P=0.009
BEFORE you were diagnosed with POTS	Yes	No
did a doctor acknowledge a physical illness but was unsure how to proceed?	146 (73.4)	53 (26.6)	122 (71.8)	24 (82.8)
did any doctor tell you that you were suffering from a psychological or psychiatric problem (eg, depression, panic disorder, generalized anxiety disorder, somatoform disorder, conversion disorder)?	134 (64.7)	73 (35.3)	115 (65.3)	19 (61.3)
did any doctor tell you that your symptoms were “all in your head” or something similar?	113 (54.9)	93 (45.1)	98 (56.0)	15 (48.4)
in your own opinion, were you suffering from a psychological or psychiatric problem?	69 (33.3)	138 (66.7)	63 (35.8)	6 (19.4)
did you suggest that you had POTS to your doctor before he/she suggested it?	36 (17.5)	170 (82.5)	34 (19.2)	2 (6.9)
did you do Internet‐based research to try to understand your medical condition?	114 (55.6)	91 (44.4)	102 (58.3)	12 (40.0)
AFTER you were diagnosed with POTS:	Yes	No
did any doctor tell you that you were suffering from a psychological or psychiatric problem (eg, depression, panic disorder, generalized anxiety disorder, somatoform disorder, conversion disorder)?	101 (49.0)	105 (51.0)	87 (49.7)	14 (45.2)
did any doctor tell you that your symptoms were “all in your head” or something similar?	65 (31.6)	141 (68.4)	61 (34.9)	4 (12.9)
are you currently being treated for a psychological or psychiatric disorder?	95 (46.3)	110 (53.7)	82 (47.1)	13 (41.9)
have you seen one or more doctors who told you that they had never heard of POTS?	155 (74.9)	52 (25.1)	137 (77.8)	18 (58.1)
did you do Internet‐based research to try to understand your medical condition?	199 (96.1)	8 (3.9)	171 (97.2)	28 (90.3)
If you tried to explain POTS to your doctor(s), did you feel that they listened to you? (N=154 replies)
I feel that my doctor(s) listened to me when I tried to explain POTS	40 (26.0)		33 (24.1)	7 (41.2)
I feel that some of my doctor(s) listened to me and some did not when I tried to explain POTS	69 (44.8)		66 (48.2)	3 (17.6)*
I feel that my doctor(s) listened to me, but did not feel the information was relevant	31 (20.1)		25 (18.2)	6 (35.3)
I feel that my doctor(s) did not listen to me	13 (8.4)		12 (8.8)	1 (5.9)
I didn't try to explain POTS to my doctor(s)	1 (0.6)		1 (0.7)	0

Number of replies: 227, unless otherwise specified. N, (%), unless otherwise specified. IQR indicates interquartile range; and POTS, postural orthostatic tachycardia syndrome.

^* P=0.02 male vs female patients.

Figure 5. Diagnoses given before receiving POTS diagnosis.

Number of replies: 116. POTS indicates postural orthostatic tachycardia syndrome.

In assessing overall physician performance, 73.4% patients were seen by doctors who were able to recognize a physical illness before the diagnosis of POTS but did not provide further management planning or therapeutic options. Up to 74.9% of patients had doctors who said that they had never heard of POTS, despite the patient already having been given the clinical diagnosis somewhere else. As many as 17.5% of patients suggested to their providers that their diagnosis might be POTS before the provider brought it up with them (Table 4). Up to 26% of patients subsequently felt that their doctors listened to them when explaining POTS, 20.1% felt their doctors believed the information was irrelevant, and 8.4% felt their doctors did not listen to them. Female patients were more likely to have “some doctors listen to them while others did not” (48.2% versus 17.6%, P=0.02). Those providers most frequently diagnosing POTS included cardiologists (66.8%), neurologists (11.9%), and primary care providers, such as pediatricians or family practitioners (8.8%) (Figure 6). Once diagnosed, >80% of patients reported that they were diagnosed with another condition besides their POTS, with migraine, Ehlers–Danlos syndrome, vitamin D deficiency, gastroparesis, and mast cell activation syndrome among the most common comorbidities, present in 20% to 40% of patients (Figure 7). Over 80% of patients reported other health conditions in addition to POTS, with female patients reporting more comorbid diagnoses than male patients (84.1% versus 61.3%, P=0.003).

Figure 6. What type of provider diagnosed your POTS?

Adol Med indicates adolescent medicine; FP, family practice; and POTS, postural orthostatic tachycardia syndrome.

Figure 7. Comorbid diagnoses.

AMPS indicates amplified musculoskeletal pain syndrome; CRPS, complex regional pain syndrome; and RND, reflex neurovascular dystrophy.

QoL surveys were completed by 218 participants. Among the 28 pediatric POTS respondents (100% of responding pediatric age patients) who filled out the Pediatric Quality of Life Inventory (scale 0–100, higher scores associated with better health‐related QoL), the following mean subscores were seen: physical functioning 51.2 (SD 21.6), emotional functioning 54.8 (SD 19.6), social functioning 61.4 (SD 20.9), school functioning 50.4 (SD 19.2), and total score 54.0 (SD 16.1) (Table 5). The SF‐36 was completed by 190 adult patients with POTS (95.5% of responding adult patients; scale 0–100, higher scores associated with better quality of life), with the following mean scores: physical functioning 80 (IQR 50–90), limitations due to physical health 25 (IQR 0–75), limitations due to emotional problems 66.7 (IQR 33–100), energy/fatigue 30 (IQR 15–45), emotional well‐being 60 (IQR 48–76), social functioning 62.5 (IQR 50–75), pain 57.5 (IQR 45–79.4), and general health 35 (IQR 25–50). Female adult patients had significantly lower SF‐36 scores than males in the domain of pain, indicating greater impact of pain on their QoL. No other significant sex differences were evident in QoL domains. A total of 219 patients completed the COMPASS‐31 (scale 0–100, higher scores associated with worse autonomic dysfunction), with the following median scores: orthostatic intolerance 20 (IQR 12–24), vasomotor dysfunction 2.5 (IQR 0–3.3), secretomotor dysfunction 2.1 (IQR 0–6.4), gastrointestinal dysfunction 8.9 (IQR 4.5–11.6), bladder dysfunction 0 (IQR 0–1.1), pupillomotor dysfunction 1.7 (IQR 1.0–2.7), and total score 35.3 (IQR 26.0–45.2). Except for a significantly higher score in the gastrointestinal domain for female patients, indicating worse symptoms, there were no significant differences between sexes in COMPASS‐31 domains.

Table 5.

PedsQL/SF‐36 and COMPASS‐31

PedsQL: scale 0–100 (higher score=better QoL), N=28; mean±SD	Total	Female patients	Male patients
Physical functioning	51.2±21.6	49.1±21.1	56.6±23.2
Emotional functioning	54.8±19.6	50.8±18.7	65.0±19.5
Social functioning	61.4±20.9	61.5±20.2	61.3±24.2
School functioning	50.4±19.2	50.5±20.3	50.0±17.7
Total score	54.0±16.1	52±15.3	58.0±18.6
SF‐36: scale 0–100 (higher score=better QoL), N=190; median (IQR)
Physical functioning	80 (50–90)	77.5 (50–90)	80 (60–93.8)
Role limitations due to physical health	25 (0–70)	25 (0–75)	50 (6.3–100)
Role limitations due to emotional problems	66.7 (33.3–100)	66.7 (33–100)	100 (8.3–100)
Energy/fatigue	30 (15–45)	30 (15–41.3)	30 (16.3–52.5)
Emotional well‐being	60 (48–76)	62 (48–76)	60 (48–72)
Social functioning	62.5 (50–75)	62.5 (50–75)	68.8 (40.6–87.5)
Pain	57.5 (45–79.4)	57.5 (45–77.5)	77.5 (60–90)*
General health	35 (25–50)	35 (25–50)	35 (35–58.8)
COMPASS‐31: scale 0–100 (higher score=worse symptoms), N=219; median (IQR)
Orthostatic intolerance	20 (12–24)	20 (16–24)	18 (11–24)
Vasomotor	2.5 (0–3.3)	2.5 (0–3.3)	1.2 (0–3.3)
Secretomotor	2.1 (0–6.4)	2.1 (0–6.4)	2.1 (0–4.3)
Gastrointestinal	8.9 (4.5–11.6)	8.9 (4.5–12.5)	5.4 (3.6–9.8)†
Bladder	0 (0–1.1)	0 (0–1.1)	0 (0–1.7)
Pupillomotor	1.7 (1.0–2.7)	2.0 (1.2–2.7)	1.7 (0.9–2.1)
Total	35.3 (26.0–45.2)	36.0 (26.8–45.2)	27.2 (16.4–43.9)

COMPASS‐31 indicates Composite Autonomic Symptom Score‐31; IQR, interquartile range; PedsQL, Pediatric Quality of Life Inventory; QoL, quality of life; and SF‐36, 36‐Item Short‐Form Survey.

^* P=0.006 female vs male patients.

^† P=0.04 female vs male patients.

Patients reported a wide variety of medications as having been prescribed or used for their POTS clinical management (Figure 8A). The most commonly used medications reportedly used at any time since their POTS diagnosis were melatonin, salt supplements, fludrocortisone, methylphenidate, ondansetron, mixed amphetamine salts, and midodrine. The most commonly used medications still in use at the time of survey completion included ondansetron, salt supplements, clonidine, metoprolol, and melatonin (Figure 8B). Ondansetron, fludrocortisone, modafinil, citalopram, and salt supplements were reported by patients as at least 50% effective in managing POTS symptoms (Figure 8C). The large majority of medications had at least 20% perceived efficacy, such that symptoms improved at least 50%, with very few reported as having <20% efficacy. There were no significant sex differences in either assessment of medication use or in perceived efficacy.

Figure 8. Medication use.

A, Medications used. Was this medication in the management of your symptoms? B, If used, medications currently being used. Is this medication still being used for symptom management? C, Was this medication at least 50% effective for symptoms? Did this medication reduce symptom severity by at least 50%?

In additional to medications, alternative and complementary therapies were widely used (Figure 9A). The most commonly used nonpharmacologic interventions included the Levine exercise protocol, ³¹ dietary changes, aerobic exercise, stretching, and cognitive behavioral therapy. Of the therapies still being used the most common were stretching, aerobic exercise, resistance training, dietary changes, cognitive behavioral therapy, over‐the‐counter topical agents, and meditation (Figure 9B). Those with the highest perceived efficacy included aerobic exercise, the Levine exercise protocol, resistance training exercise, dietary changes, stretching, cognitive behavioral therapy, and yoga (Figure 9C). Of the dietary changes, the most frequently attempted were gluten‐free and dairy‐free diets (Table 6). Those diets were maintained by between one third and one half of patients, as was the low carbohydrate/high protein diet. Significant sex differences were found in the continued use of topical agents (P=0.03) and yoga (P=0.002). The other alternative and complementary therapies demonstrated no significant sex differences in usage, continued use, or efficacy.

Figure 9. Alternative/complementary therapy use.

A, Alternative/complementary therapy use. Was this alternative/complementary therapy used for management of your symptoms? B, If used, are you currently using this therapy? Is this alternative/complementary therapy still being used for symptom management? C, Was this complementary/alternative therapy at least 50% effective in reducing symptoms? Did this complementary/alternative therapy reduce symptom severity by at least 50%? OTC indicates over the counter.

Table 6.

Dietary Changes

Dietary change	Did you use this diet? N, (%)	Female patients N, (%)	Male patients N, (%)	Are you currently using this diet? N, (%)	Female patients %	Male patients %
Gluten‐free	79 (36.1)	70 (37.4)	9 (29.0)	34 (15.5)	30 (16.0)	4 (12.9)
Dairy‐free	83 (37.9)	70 (37.4)	13 (41.9)	32 (14.6)	25 (13.4)	7 (22.6)
Low intake of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols	43 (19.6)	38 (20.3)	5 (16.1)	7 (3.2)	4 (2.1)	3 (9.7)
Low carbohydrate/high protein	42 (19.2)	34 (18.2)	8 (25.8)	14 (6.4)	12 (6.4)	2 (6.5)
Paleolithic diet	14 (6.4)	10 (5.3)	4 (12.9)	0	0	0

Number of replies: 219.

Overall, the various types of interventions for POTS shown to be most helpful included the addition of medication(s), increased fluid and salt intake, and increased exercise (Table 7). Nearly 90% of patients continued to require increased salt and water intake as well as exercise to manage their POTS symptoms, with a median fluid intake of 64 ounces per day (IQR 48–96).

Table 7.

Interventions for POTS

Most beneficial intervention	N (%); 206 replies	Female patients N (%)	Male patients N (%)
Increased fluid and salt intake	59 (28.6)	48 (27.4)	11 (35.5)
Dietary changes	11 (5.3)	7 (4.0)	4 (12.9)
Nonmedication/nonexercise intervention	16 (7.8)	14 (8.0)	2 (6.5)
Increased exercise	43 (20.9)	37 (21.1)	6 (19.4)
Addition of medication(s)	77 (37.4)	69 (39.4)	8 (25.8)
Need for Nonpharmacologic Interventions	N (%), 216 replies
Do you still need increased salt, water, and exercise to manage your symptoms?	194 (89.8)	92.9	71.9*

Fluid Intake	Median (interquartile range), 204 replies
How many 8‐ounce glasses of fluid do you drink daily?	8 (6–12)	8 (6–12)	9 (6–12)

POTS indicates postural orthostatic tachycardia syndrome.

^* P=0.0003.

DISCUSSION

POTS is estimated to affect 1 to 3 million adults and children in the United States. ⁵ It is typically diagnosed in adolescence ¹⁷ , ²⁹ and causes significant disability that interferes with school, social activities, sports, and maturation. Improved understanding of POTS symptom presentation and historical features can inform provider education, improve diagnostic outcomes, and help patients self‐advocate when their health care providers are failing them.

Our LT‐POTS survey, with >225 patients and a mean duration of 9.6 years since symptom onset, is one of the largest and longest studies evaluating outcomes in patients with POTS. It is also one of the most wide‐ranging in scope, with its review of multiple aspects of evaluation, care, and downstream effects. Our data revealed numerous points of interest in pediatric patients with POTS, some of which confirm findings from prior studies, and some of which are novel. Female patients are significantly overrepresented in this sample, similar to the demographic overrepresentation seen in the Big POTS Study report ¹⁷ as well as in our 2018 demographics assessment within our pediatric POTS program. ²⁹ In reviewing the symptomatology of the patients, a wide range of symptoms was seen, as has been shown previously (Figure 3). ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²⁹ Female patients were more likely to have a higher symptom burden. These symptoms were felt to be quite severe at their worst, yet the large majority of symptoms either disappeared or was quite mild at their least noticeable. The worst symptom reported was fatigue, which also had one of the higher relative scores when symptoms were reported at their least severe, indicating that neither it nor heat intolerance ever fully improved, even when other symptoms may have resolved. Importantly, only 0.9% (2/215 of patients) reported that they had had no symptoms in the prior month. This is in sharp contrast to the prior studies that have described a high rate of spontaneous resolution of symptoms in patients. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ This drastic difference between our findings and the historical documentation warrants further exploration. It may be related to the framing of the questions, how many questions and follow‐up questions were asked, or possibility a product of confirmation bias of previous research, where researchers sought evidence confirming the theory that POTS was a nonpermanent condition and completely self‐resolving. However, the median number of symptoms reported in the month before completing the survey was 13, suggesting that although severity of symptoms could be improved, multiple varied symptoms are still experienced by these patients. Although symptom severity was worse for female patients as compared with male patients when symptoms were at their worst, there was no significant difference between sexes when symptom severity was at its least. This indicates that both sexes had the potential to have equal reduction of the severity in their various symptoms, although in a month‐by‐month basis, overall symptom severity was worse in female patients. Diseases that have disparate manifestation between sexes has previously been reported, ³² in which certain disorders demonstrate more severity in female patients, whereas others are worse in male patients. Overall, POTS appears to be a medical condition that is worse in female patients. It is important to recognize that the severity totals when symptoms were at their worst or when they were at their least only indicate individual severity scores at any time over a patient's clinical course. In contrast, the severity from the previous month is more of an accurate indicator of the combination of and the severity of the patents' symptoms at one time.

Clinical outcomes of patients with POTS have been reported in at least 6 prior studies. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ The study in 1999 by Sandroni et al from the Mayo Clinic was the first to look at long‐term outcomes. ¹⁹ This was a survey study of 40 patients, in which 60% of patients were “functionally back to normal” after a follow‐up period of at least 18 months. However, 73% of patients continued to require fluid supplementation or medications, and up to 77% of patients had worsening orthostatic symptoms when exposed to a stressor, such as ambient heat, exercise, or meals. This study emphasized that previously symptomatic patients clinically improved in their functional levels over time, although most required supplemental therapy. Another long‐term study, a Portuguese study by Sousa et al, used a 40‐minute tilt table test in the diagnosis of POTS, which they acknowledge may have reduced the specificity of the diagnosis. ²⁰ It was unclear in that study at what time of day follow‐up tilt table testing was performed, which is important to consider as significant diurnal variability of heart rate response to upright posture may occur. ³³ In their relatively small follow‐up portion of the study, 5 out of 16 patients (31%) were reported to be asymptomatic after a follow‐up period up to 123 months, with 10/16 continuing to require medications to help suppress symptoms; it was unclear whether asymptomatic patients were asymptomatic as a result of continued medication use. Kimpinski and his team at the Mayo Clinic performed a prospective study in 58 adults with POTS after 12 months of follow‐up, including tilt table testing and autonomic survey. ²¹ As many as 38% of patients no longer met the heart rate criteria for POTS in follow‐up during tilt testing. The specificity of these test results remain unclear, also due to diurnal variability of heart rate response to upright posture and uncertainty regarding how many total patients remained on medication therapy at the 1‐year follow‐up period. Further, although that study specifically looked at objective testing metrics, such as autonomic testing and autonomic scoring tests, it did not query patients about their functionality or their perceived symptom persistence. The study by Bhatia et al, also performed by the Mayo Clinic, specifically looked at patients whose POTS symptoms began in adolescence and included a survey similar to the one used in the current LT‐POTS study. ²² The follow‐up period ranged from 2 to almost 10 years, with 172, or 34%, of the invited patients responding. In that study, 19% of patients reported “resolution of symptoms,” although 33% of those patients reported experiencing at least 1 persistent symptom.

A study from Kang in South Korea of 45 patients showed improvement in the COMPASS‐31 total score as well as in the orthostatic intolerance domain. ²³ Based on analyses of the COMPASS‐31, 12 patients were reportedly asymptomatic. The Kang study also reported 14 patients no longer meeting orthostatic heart rate criteria for POTS on follow‐up, although, as discussed previously, this does not account for diurnal variation in heart rate. Lastly, a study from China assessed 115 children and adolescents approximately 1.5 years after initial evaluation with a median age of 12 years. ²⁴ They also used upright heart rate response as an indicator of presence or absence of symptoms, claiming that >85% of patients were symptom free by 6 years. However, in either study, it was not clear whether persistent nonpharmacologic support was required to be “symptom free.”

Similar to previously published studies, ¹⁷ , ²⁹ the median age of onset of symptoms of POTS was 13 years (Table 3). Mode of onset was split, with approximately half of patients having a specific putative trigger within 3 months, and about half not having a trigger. Of those without a trigger, nearly one third felt that their symptoms had a gradual onset or were persistent since childhood, as compared with 63% of patients in the Shaw study ¹⁷ and 41% in the Kang study. ²³ However, of those with a trigger, infection was the most frequent cause in just less than half of patients, a higher percentage as compared with what we initially reported in 2018. ²⁹ Interestingly, the combination of concussion, surgery, and accident/nonconcussion trauma was nearly as frequently recognized to be a possible trigger as infection was, with 52 of respondents, or over one third, acknowledging these events. Also, adolescent changes, including hormonal changes and rapid growth, made up >13% of presumed causes for POTS. Immunization, especially with the human papillomavirus vaccine, for which an association with onset of POTS has been previously reported, ³⁴ , ³⁵ , ³⁶ and about which there has been significant discussion over the veracity of these reported associations, ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ comprised nearly 10% of the attributed presumed triggers of onset of POTS in this study. As with any of these potential triggers, these are a list of recalled events occurring proximate to the onset of POTS. In the absence of fully understanding the underlying pathophysiology of POTS, the mechanism for any specific trigger remains debatable. It also does not exclude other more subtle events that may have occurred, or events occurring in combination, that could have triggered the onset of POTS symptoms.

It is interesting to note that both before, as well as after, receiving a diagnosis of POTS, about half of patients visited the emergency department for management of their symptoms (Table 4), with patients going to the emergency department overall more times after their diagnosis of POTS than before. When we assessed emergency department use by pediatric patients with POTS at CHOP from 2012 to 2014 as part of an internal quality improvement initiative, we determined that 30.0% of patients were seen due to gastrointestinal complaints, 26.6% due to headache, and 12.5% were due to symptoms of orthostatic intolerance or dehydration, comprising nearly 70% of visits. ⁴² This suggests that a large number of patients felt that the emergency department would be beneficial in trying to manage symptoms that had either worsened or were not able to be managed at home. The Shaw study reports that emergency department use after the diagnosis of POTS, although less overall as compared with before their diagnosis, still averaged 8 visits per patient from the time of diagnosis to the time of completing their survey. ¹⁷

Although psychiatric problems and need for clinical management appear to be prevalent in the general population, our study suggested the POTS diagnosis was commonly delayed or misattributed solely to a psychological or psychiatric disorder, and systemic symptoms were dismissed as imaginary, as similarly seen in Big POTS Study ¹⁷ (Figure 5). Comparable findings have been seen in chronic disorders, such as myalgic encephalomyelitis/chronic fatigue syndrome, ⁴³ in which patients' symptoms were incorrectly attributed to psychological disorders or suspected to be fictitious. Although the numbers of patients with diagnoses ascribed to psychiatric disorders or having fabricated symptoms decreased after patients received a clinical diagnosis of POTS, the overall percentage of patients being treated for these disorders increased to 46%. This is in contradistinction by the study by Raj et al, ⁴⁴ in which up to 33.3% of patients were felt to have an actual psychological or psychiatric disorder.

The problem of lack of provider education and familiarity with POTS was widely seen, with nearly three quarters of patients reporting having had a doctor recognize that there was something wrong but being unclear what to do next (Table 4), and the same amount of patients having at least 1 physician stating that they had never heard of POTS. In the Big POTS Survey, 67% of patients had a provider who acknowledged the presence of a physical illness but were not able to progress with evaluation or clinical therapy. ¹⁷ This points out the lack of historical provider awareness of POTS; however, as the patients in this cohort were diagnosed with POTS before 2018, it does not address whether awareness may be improving over time. The lack of a code for POTS in the the International Classification of Diseases, Tenth Revision (ICD‐10) further complicates the ability to assess the knowledge and understanding of providers of this disorder. Within this context, a wide array of incorrect diagnoses was proffered (Figure 5). Over three quarters of patients had at least 1 doctor who they felt did not listen to them when they tried to explain POTS following their clinical diagnosis or whom they perceived as feeling that the information given to them was irrelevant, suggestive of having significant residual clinical bias against this disorder. Similar occurrences have been seen in myalgic encephalomyelitis/chronic fatigue syndrome, where patients were told that their disorder was not real, the patient was not actually ill, the providers were not interested in listening to patients, or the providers has no knowledge of or interest in learning about their disorder. ⁴³ Surprisingly, this is despite the fact that providers recognize the challenge of patients with chronic illness to obtain appropriate symptomatic care. ⁴⁵

Despite the overwhelming majority of patients having been diagnosed with POTS by a cardiologist or neurologist (Figure 6), similarly as has been observed in other studies, ¹⁷ a wide variety of other providers also made the diagnosis in our pediatric cohort, including an infectious disease specialist, nephrologist, geneticist, nutritionist, psychologist, and a school nurse. Anecdotally, we recognized that a number of patients were referred to our clinic for POTS evaluation because school nurses who were familiar with previously diagnosed student‐patients had an increased index of suspicion when new students arrived in their offices with similar symptoms. ⁴⁶

Despite the various misdiagnoses given to patients before their actual POTS diagnosis, many of those same diagnoses, along with many others, were eventually found concurrently in numerous patients, with multisystem pathogenesis (Figure 7). The findings of migraine, Ehlers–Danlos syndrome, irritable bowel syndrome, and mast cell activation syndrome seen comorbidly in this cohort have been previously associated with POTS. ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ In fact, migraine, Ehlers–Danlos syndrome, and irritable bowel syndrome were the most common comorbidities seen in the Big POTS Survey. ¹⁷ It is also interesting to note that vitamin D deficiency, although not specifically reported in association with POTS, is associated with orthostatic intolerance. ⁵⁴

Our assessment of QoL and overall autonomic severity measures revealed moderate degrees of intrusion of POTS symptoms into various aspects of these patients' lives, with significant overall negative influence on energy and general health (Table 5). These findings were nearly identical to those seen in an Australian study from 2014. ⁵⁵ In a study published in 2021 that used the SF‐36 to assess QoL in adults with both POTS and vasovagal syncope, ⁵⁶ patients with POTS had reduced QoL measures in physical functioning, role limitations due to physical health, energy and fatigue, social functioning, pain, and general health as compared with patients with syncope. Interestingly, in our pediatric POTS cohort study, our patients' domain scores in physical functioning, social functioning, and pain were closer to that of the reported adult cohort syncope patients (ie, higher score), were higher than both adult POTS and syncope groups in role limitations due to physical health, and were similar in energy, fatigue, and general health. However, the median age of subjects in that study was older at 30.5 years, suggesting persistent symptoms may worsen health‐related QoL proportionate with increasing age. Although the mean age of participants in the Australian study was similarly 30.1 years, it involved a much smaller POTS cohort. ⁵⁴ In the LT‐POTS survey, the COMPASS‐31 assessment revealed that autonomic symptoms were most notable in orthostatic intolerance and gastrointestinal domains. In comparison with other scores of various autoimmune disorders with associated autonomic dysfunction reported in patients with scleroderma, ⁵⁷ fibromyalgia, ⁵⁸ diabetic polyneuropathy, ⁵⁹ and small fiber neuropathy, ⁶⁰ as well as healthy controls, ⁵⁸ our pediatric‐onset patient cohort had domain scores similar to those of the other disorders, except for higher domain scores for orthostatic intolerance (Figure 10). When interpreting results from this study, is important to note that the COMPASS‐31 was designed for use in patients with autonomic neuropathies and synucleinopathies and has not been validated for other autonomic disorders such as POTS. ²⁷ Furthermore, the COMPASS‐31 total score is derived through weighting of domain scores specific to autonomic neuropathy, a condition not associated with POTS.

Figure 10. COMPASS‐31 Domain Score in CHOP pediatric‐onset POTS patient cohort compared with previously reported adult cohorts of patients with Scleroderma (57), Fibromyalgia (58), Diabetic Polyneuropathy (59), Small‐Fiber Neuropathy (60), and Healthy Controls (58).

CHOP indicates Children's Hospital of Philadelphia; and POTS, postural orthostatic tachycardia syndrome.

A wide range of medications was reportedly used for POTS treatment and likely other associated or comorbid symptoms or conditions (Figure 8). At minimum, the use of most medications reflects the practice style of the ordering provider(s). The typical medication usage approach in the CHOP POTS clinic for management of symptoms associated with POTS was published previously. ⁶¹ , ⁶² However, a number of other medications, especially various antidepressant therapies, appear to have been added, targeting psychiatric symptoms, chronic pain, or modulation of autonomic function. The medications that seemed to have the highest reported perceived efficacy by patients in combination with significant use included ondansetron (typically used for nausea), fludrocortisone (intravascular volume expansion), modafinil (fatigue), citalopram (psychiatric/autonomic modulation), and salt supplements (volume expansion). Interestingly, of the medications considered to be most effective, many were not reported as medications currently taken, or taken in a limited manner. Ondansetron, salt supplements, clonidine, metoprolol, melatonin, and fludrocortisone were still felt to be necessary to control symptoms. In our practice, clonidine was indicated for insomnia, and metoprolol was used for headache prophylaxis and management of persistent tachycardia. Interestingly, buspirone, an anxiolytic therapy not used in the CHOP POTS clinic, was reported to have been used in this patient population. In the absence of prospective trials, ¹² assessment of the use of medications in POTS has mostly been either retrospective or by small, nonplacebo controlled trials. As reported by the Mayo Clinic, ⁶³ a small number of published studies with appropriate controls were identified that demonstrated that fludrocortisone, beta adrenergic receptor blockers, midodrine, and selective serotonin reuptake inhibitors appeared to have valid beneficial effects for POTS symptom. This is consistent with our current findings, in which patients reported to either be actively using fludrocortisone, metoprolol, and citalopram or reported that these medications were effective.

A wide variety of nonpharmacologic and complementary interventions also were reportedly used by this patient cohort (Figure 9). Some were dependent upon patients being seen by specific practitioners, such as providers of massage, osteopathic manipulation, or chiropractic. Others employed external devices such as transcutaneous or vagus nerve stimulation, or used techniques focused on mental or psychological change such as cognitive behavioral therapy, biofeedback, and meditation. However, exercise interventions, such as the Levine protocol ³¹ and other nonspecified exercise activities, as well as dietary changes were used most often, still being used at the time of survey completion, and perceived by patients to be the most effective. Indeed, exercise has been proven to successfully reduce POTS symptoms. ⁶⁴ , ⁶⁵ As per Shibata, ³¹ the combination of isometric and aerobic exercise is typically initiated in a recumbent position and in minimal amounts, with gradual increases and eventual transition to an upright position. Results of our LT‐POTS survey suggest a range of exercises may achieve the same goals.

Gluten‐free and dairy‐free dietary modifications were reported in the LT‐POTS survey to be most frequently made and still being used each by over one third of patients, without significant sex differences in their initial or subsequent usage (Table 6). A British study from 2016 also noted that patients with POTS were independently starting gluten‐free diets, had higher incidence of biopsy‐proven celiac disease than the local population, as well as higher incidence of self‐reported gluten intolerance relative to age‐ and sex‐matched controls. ⁶⁶

In assessment of the various interventions for reducing POTS symptoms, those perceived by patients as most helpful were addition of medications, increased fluid and salt intake, and increased exercise (Table 7). Although dietary changes were among the most frequent changes patients made, this was not felt to be among the most beneficial interventions. Similarly, the Big POTS Survey found that 52% of patients found that nonpharmacologic interventions (eg, increased fluid/salt intake and exercise) were important to reduce symptoms, whereas 29% credited medication therapy as the cause for their symptom improvement. ¹⁷ These findings suggest that the management of POTS is multimodal, requiring a wide array of nonpharmacologic and pharmacologic approaches, depending on the patient's needs. Indeed, nearly 90% of patients still required nonpharmacologic therapies to continue to control their symptoms. It is also notable that although the median fluid intake was 64 ounces daily, there was wide variation of intake, with some patients reporting >128 ounces of fluid intake daily. This presents an opportunity for future research to further explore the relationship between fluid intake and symptom severity. Interestingly, female patients felt that nonpharmacologic interventions were much more necessary for symptomatic management than male patients (P=0.0003). Taken in combination, this finding, the increased female predominance in POTS, the aforementioned greater symptom severity in female patients, and findings from a case series of transgender patients who had significant decrease in their POTS symptoms after receiving exogenous testosterone, ⁵⁴ suggest that male patients with POTS may be less affected by POTS symptoms over time.

Our study offers several advantages over prior studies. The diagnosis of POTS was made by 1 of 2 medical providers through the POTS Program at CHOP between 2007 and 2018, limiting the variability of how the clinical diagnosis was made among pediatric patients. The patients were followed longitudinally across multiple visits; this long‐term symptom management allowed patients to regain functional performance, often allowing return to school, sports, and other exercise, by using an exercise protocol such as that created by Shibata et al (the Levine protocol). ⁶³ Such protocols help to further alleviate POTS symptoms, which allowed us to wean any added therapies as tolerated. Although the patients were diagnosed as children, many were followed into their 20s until the POTS Program closed in February 2018, when the hospital transitioned to a multidisciplinary medical management approach. The mean duration of symptoms in this cohort from onset to June 2021, at the time of survey administration, is nearly 10 years, which is longer than was reported in any previously published studies. Additionally, this is a larger cohort than those of previously published pediatric studies.

It is also important to acknowledge the limitations of the current study. It relies upon a diagnosis of POTS based on a 10‐minute standing test, a test that has neither been standardized nor validated in the literature. However, prior literature routinely discussed the use of a standing test to assess heart rate change. ³⁰ Also, Plash and his colleagues at Vanderbilt University performed a comparison of tilt table testing and standing testing in the same adult patients with POTS, demonstrating a significant difference in typical heart rate increase between the 2 methods. ⁶⁷ We also used a 30 beat per minute threshold for the diagnosis of POTS for adolescent patients. Although there are several consensus statements that came along from 2011 and after listing 40 beats per minute as the threshold for patients aged 12 to 19 years, ⁴ , ⁶⁸ the weakness of this concept has been discussed at length in several other publications. ⁴⁸ , ⁶⁹ , ⁷⁰ It is notable that the patients included in this study were diagnosed between 2007 and 2018, with many patients diagnosed and treated before the publication of the multisociety consensus statement in 2011 in which the 40 beat per minute threshold was first stated and whose symptomatology and disabilities were no different before or after its publication.

Of course, the use of an electronically transmitted survey, as with any other survey, is going to receive a much smaller number of respondents as compared with the total number of invitations. Our response rate was only 29.1% for all potential patients who had been diagnosed in our clinic, and 32.1% for those whom we could reach by valid email address. In conversations with parents and facilitators of various POTS support groups, one of many potential reasons that the survey may not have been completed was that the patients' POTS may have clinically improved or resolved, with patients viewing that prior time in their life as stressful, and not wanting to revisit those memories or having moved on in their lives. Conversely, since the survey was lengthy, they may not have had the energy to complete the survey if their POTS symptoms were significant. Either reason would reasonably contribute to a response bias in the reported data.

Lastly, because there were so many varied therapies, therapy combinations, and patients with individualized treatment that changed over time, our numbers to assess efficacy were small, especially among male patients. As well, as a cross‐sectional study, we were not able to assess either specific symptom improvement and exacerbations over time, or their putative triggers. And, due to multiple tests, the statistically significant differences between female and male patients may not be as strong, although for repeated testing, a Bonferroni correction was used.

In summary, a novel LT‐POTS survey instrument was created that highlighted several issues surrounding the diagnosis and management of POTS. POTS leads to a wide variety of associated symptoms across multiple body systems, with some patients having acute onset whereas others had symptoms ostensibly since childhood. Despite various therapeutic approaches that have been developed for patients, the large majority of patients are not completely free of their POTS symptoms more than a decade following their clinical diagnosis. Front‐line providers often continue to be unfamiliar or uncomfortable with POTS as a clinical diagnosis, leading to delays in diagnosis as well as incorrect diagnoses, both psychiatric as well as somatic. A wide variety of comorbid disorders are also seen in this group of patients. POTS leads to modest to severe impairment in multiple aspects of QoL, manifesting mostly in the orthostatic and gastrointestinal domains when assessed by an autonomic survey of symptomatology. The overwhelming majority of patients are not completely free of their POTS symptoms, even after a more than 9‐year period since POTS diagnosis. Use of a combination of fluid and salt supplementation, exercise, and medications is perceived by patients to help control their symptoms and required for long‐term symptom management. A wide variety of medications is used to try to suppress POTS symptoms, with some perceived efficacious by a large percentage of patients with POTS and several being commonly continued as part of long term management. Dietary changes, such as gluten‐free or dairy‐free diets, though widely attempted, seemed helpful to modify POTS symptoms in only one third of patients with POTS. Similarly, the vast majority of nonpharmacologic interventions outside of exercise and dietary changes seem to either have little efficacy or to have been discontinued by patients with POTS over time. At minimum, improved provider education and awareness as well as acceptance of this clinical entity is important to ensure appropriate and timely diagnosis and treatment. It is as important to recognize the accompanying and complicating diagnoses seen with POTS, to further minimize both diagnostic delay and morbidity. However, the most important research required for the future of POTS care is ascertainment of the underlying pathophysiology, such that more specific and targeted diagnostic tools as well as therapies can be developed to effectively treat this clinical syndrome and prevent its myriad downstream effects.

Sources of Funding

Funding for this research came from the CHOP POTS Research Fund, a private, donor‐directed fund supporting research performed by Dr Boris.

Disclosures

Dr. Boris is a paid consultant for CSL Behring, for Argenx, and for the US Department of Health and Human Services Vaccine Injury Compensation Program. He is also an unpaid member of the Medical Advisory Board of Dysautonomia International. The remaining authors have no disclosures to report.