key: cord-0694282-l7zlby4y
authors: Jamal, Sameer M.; Landers, David B.; Hollenberg, Steven M.; Turi, Zoltan G.; Glotzer, Taya V.; Tancredi, Jana; Parrillo, Joseph E.
title: Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19
date: 2022-04-02
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2022.03.357
sha: fcf89ff1350bc25de206d3648e0bb583b7bf5bb3
doc_id: 694282
cord_uid: l7zlby4y

Background Patients with PASC often report symptoms of orthostatic intolerance and autonomic dysfunction. Numerous case reports link Postural Orthostatic Tachycardia Syndrome (POTS) to PASC. No prospective analysis has been performed. Objective We performed head-up tilt table (HUTT) testing in symptomatic Post-Acute Sequela of COVID-19 (PASC) patients to evaluate for orthostatic intolerance suggestive of autonomic dysfunction. Methods We performed a prospective, observational evaluation of patients with PASC complaining of poor exertional tolerance, tachycardia with minimal activity or positional change, and palpitations. Exclusion criteria included pregnancy, pre-PASC autonomic dysfunction or syncope, or another potential explanation of PASC symptoms. All subjects underwent HUTT. Results Twenty-four patients with the described PASC symptoms were included. HUTT was performed a mean of 5.8 ± 3.5 months after symptom onset. Twenty-three of the 24 had orthostatic intolerance on HUTT, with 4 demonstrating POTS, 15 provoked orthostatic intolerance (POI) after nitroglycerin, 3 neurocardiogenic syncope, and one orthostatic hypotension. Compared to those with POTS, patients with POI described significantly earlier improvement of symptoms. Conclusions This prospective evaluation of HUTT in PASC patients revealed orthostatic intolerance on HUTT suggestive of autonomic dysfunction in nearly all subjects. Those with POI may be further along the path of clinical recovery than those demonstrating POTS.

PASC patients often report symptoms suggestive of orthostatic intolerance and autonomic dysfunction. We report a prospective analysis. Twenty-four subjects underwent HUTT.

Twenty-three of 24 exhibited orthostatic intolerance on HUTT with the following patterns: four demonstrated POTS, 15 provoked orthostatic intolerance (POI) after sublingual nitroglycerine, 3 neurocardiogenic syncope, and one orthostatic hypotension. Compared with POTS subjects, POI patients described significantly earlier improvement of symptoms. Orthostatic intolerance on HUTT is suggestive of autonomic dysfunction and was seen in nearly all patients. Those with POI may be further along the path of clinical recovery than those demonstrating POTS.

Head-up Tilt Table ( Relatively little is known about the potential lasting impact of COVID-19. There is recognition of a debilitating post COVID-19 syndrome referred to as Post-Acute Sequela of COVID-19 (PASC), defined as the presence of at least one clinical sequela at least 4 weeks after acute COVID-19 infection [1] [2] [3] . While current PASC literature describes fatigue as a primary symptom, palpitations and orthostatic intolerance (OI) have also been reported, albeit less frequently 4, 5 . The etiology of these symptoms is unknown, and a purported mechanism is dysregulation of the autonomic nervous system. Autonomic dysfunction associated with OI, including new onset postural orthostatic tachycardia syndrome (POTS) in PASC patients, has been described in case reports [6] [7] [8] [9] [10] . We identified patients with specific PASC symptoms described below following COVID-19 infection and report a prospective evaluation of orthostatic intolerance in these patients.

The study is a prospective, longitudinal, observational evaluation of patients between the ages of 18 and 70 with PASC symptoms of poor exertional tolerance, tachycardia with minimal activity or positional change, and palpitations. Diagnosis of acute COVID-19 illness required a positive polymerase chain reaction test. The period of acute infection was defined as the time between onset of COVID-19 symptoms, regardless of severity or need for medical attention, and abnormal thyroid-stimulating hormone levels. Patients were also excluded for pregnancy, pre-COVID-19 history of syncope, or pre-COVID-19 autonomic dysfunction by symptoms or diagnosis. Patients taking betablockers initiated for PASC symptoms were not excluded from the study.

After enrollment, demographic data were collected and patients underwent head-up tilt table (HUTT) testing. HUTT was performed as per the Italian protocol on all patients after an overnight fast 11 . After a minimum 5-minute supine position, subjects were tilted to 70 degrees with an initial 21-minute pharmacology-free passive component and, if a normal response was demonstrated, administration of a 0.4mg sublingual nitroglycerin (NTG) tablet with continuation of a 15-minute observation component. Blood pressure was recorded in the right arm with an automated BP cuff at three-minute intervals and additional recordings were performed as guided by development of patient symptoms. Heart rate, electrocardiogram, and pulse oximetry were continuously recorded. HUTT testing was performed by a single research team member (SMJ).

Beta-blockers were not held prior to HUTT. Five response types were defined for the study and are delineated in Table 1 : POTS, provoked orthostatic intolerance (POI) seen after NTG, neurocardiogenic syncope, orthostatic hypotension and normal. The first four responses were evidence of OI. Both POTS and POI diagnoses required reproduction of a patient's exact clinical symptoms during HUTT with rapid improvement upon return to a supine position.

Dedicated follow up of PASC symptoms was performed at 3 and 6 months after subject enrollment.

Descriptive statistics were calculated for the sample. The Shapiro-Wilk test and Q-Q plots were used in conjunction to assess the normality of continuous variables. Continuous J o u r n a l P r e -p r o o f variables were reported as mean plus minus standard deviation (SD) while categorical variables were reported as number (%). Comparisons between groups were performed using unpaired Ttest for continuous variables and Fisher's exact test for categorical variables due to small sample sizes. All tests were two-sided and a p-value less than 0.05 was used to indicate statistical significance. Analyses were performed in SAS version 9.4 (SAS Institute Inc., Cary, NC).

The study was approved by the Institutional Review Board at Hackensack University Medical Center at Hackensack Meridian School of Medicine.

Thirty-two patients with the described PASC symptoms were referred for this study from a dedicated Post Covid-19 recovery clinic or from other clinics within our hospital network.

Three referred patients chose not to participate in the study, two were excluded for anemia, one was excluded for pregnancy, one was excluded for pre-existing syncope, and one did not wish to have HUTT performed. The remaining 24 patients underwent HUTT. The majority of the subjects (83.3 %) were female with a mean age of 43.1 ± 11.3 years. Only 2 patients had required hospitalization for acute COVID-19 infection, one of whom was managed in the intensive care unit. All patients continued to describe PASC symptoms at the time of HUTT which was performed 5.8 ± 3.5 months from PASC symptom onset. We performed initial follow up of PASC symptoms on all patients at 9.1±3.6 and final follow-up at 11.9±3.7 months from PASC symptom onset. Table 2 describes patient characteristics of all enrolled subjects. Compared to patients with POTS, those with POI trended older in age, had significantly higher BMIs, and were significantly more likely to describe improvement of their PASC symptoms by the time of HUTT testing and at initial follow up ( Table 3 ). None of the 4 patients diagnosed with POTS was taking betablockers.

We performed a prospective evaluation of orthostatic intolerance by HUTT in PASC. All but one of our patients exhibited OI on HUTT suggestive of autonomic dysfunction. Given that only 2 of our patients required hospitalization, our study suggests that even mild cases of COVID-19 illness can lead to PASC symptoms. While nearly one-third of our subjects demonstrated either POTS or neurocardiogenic syncope by classic definitions [12] [13] [14] , nearly all others had a normal passive HUTT response but went on to exhibit OI with reproduction of their PASC symptoms provoked by NTG administration. The pattern of OI provoked by NTG is similar to the triad seen in classic POTS; reproduction of exact clinical symptoms, significant heart rate increase, and minimal blood pressure reduction. As POTS is traditionally diagnosed in the absence of provocative agents 15 we categorized this observation as Provoked Orthostatic Intolerance or POI. Previous investigation of HUTT response after sublingual NTG administration in control subjects demonstrated relatively little impact on blood pressure, heart rate, or symptom reproduction [16] [17] [18] . We believe the POI response seen in these subjects is significant and may suggest underlying autonomic dysfunction after COVID. This dysfunction J o u r n a l P r e -p r o o f is presumably PASC related as no patients reported history suggestive of OI or autonomic disease prior to their illness.

We investigated differences between those demonstrating POTS and POI responses, understanding the inherent limitation of small group sizes. Despite this, subjects with POI response trended older with significantly higher BMI, and all reported significantly greater improvement in PASC symptoms by the time of HUTT performance with symptom improvement or resolution at first follow up, an average of 9 months from the time of PASC symptom onset. One potential explanation of these findings is that compared to the older POI subjects, younger individuals afflicted with PASC may manifest more substantial forms of PASC-related OI that in turn takes longer to improve or resolve. Another possibility is that those with improvement in PASC symptoms require a greater degree of provocation to elicit the OI suggestive of autonomic dysfunction. We speculate that those with POI would potentially have demonstrated a true POTS pattern during the non-pharmacologic phase had HUTT been performed earlier in the course of disease and prior to PASC symptom improvement.

POTS is thought to be a disorder of the autonomic nervous system associated with OI, and clinically presents as orthostatic tachycardia with varied symptoms of fatigue, palpitations, dizziness and cognitive dysfunction 15 . The precise pathophysiology of POTS is unclear and whether the purported mechanisms are similarly responsible for the OI seen in PASC patients is an area in need of additional investigation. Regardless, the development of POTS after viral and bacterial illness is well established 19 beginning with the earliest description of the disorder 20 .

With the overwhelming number of COVID-19 infections, it seems logical that case studies and retrospective analyses now demonstrate the development of POTS in those recovering from COVID-19 6-10 . Our investigation adds to this emerging body of knowledge, suggesting in a J o u r n a l P r e -p r o o f prospective manner that nearly all individuals with the described PASC symptoms are impacted by OI that suggests autonomic dysfunction.

In our study, patients were excluded for history of syncope before PASC development.

While only one patient described syncope as a symptom of their PASC, neurocardiogenic syncope was observed on HUTT in 9 patients. Neurocardiogenic syncope is known to occur in 10-38% of POTS patients 21-24 . It is theorized that the characteristic findings in POTS are a result of increased sympathetic discharge which may dissipate, resulting in bradycardia, hypotension, and syncope from relative sympathetic withdrawal 25 . Although the mechanism is unclear, we believe POI may have an overlap with neurocardiogenic syncope similar to POTS.

While neurocardiogenic syncope on HUTT may represent a paroxysmal event in other scenarios, we speculate that this finding may be part of a constellation of PASC related disorders of autonomic tone.

Our investigation is limited by both the small overall population of patients and enrollment at a single site with an increased potential for type II error. We do not have an accurate assessment of the total PASC population from which our patients were selected as they were referred from several clinics. The small size of the patient population and the heterogeneity of management did not lend themselves to analysis of the potential effects of therapy on symptom resolution. We evaluated patients by updated criteria of PASC and included those with specific symptoms, but recognize that the definition, symptoms, and timeline of PASC is evolving. Prior to HUTT, betablockers were not held for the subjects taking these medications.

Our objective was to assess patients in their current PASC state, even if on betablocker therapy.

Although beat-to-beat invasive or non-invasive arterial pressure monitoring can be used during J o u r n a l P r e -p r o o f HUTT, we performed fixed interval blood pressure monitoring. In this prospectively gathered but retrospectively analyzed database of COVID-19 patients, we did not systematically collect data regarding other autonomic dysfunction symptoms, hence we acknowledge that these patients had OI that was strongly suggestive but not necessarily diagnostic of autonomic dysfunction. Nevertheless, we feel that the OI is a potentially important, objective element of autonomic dysfunction with limited alternate explanations. Finally, the POI group of patients defined by OI after NTG had identical PASC symptoms and a HUTT response strikingly similar to POTS. Although we recognize that this pattern cannot be categorized as POTS and appreciate that the explanation of the POI pattern has not been clearly established, we believe it is highly suggestive of underlying autonomic dysfunction.

This is a prospective evaluation of HUTT in PASC patients with specific symptoms. We found OI on HUTT in nearly all study patients, and neurocardiogenic syncope in 9 of 24. These 

Significant fall in heart rate or blood pressure with loss of consciousness or inability to maintain posture

Any heart rate increase with a SBP decrease greater than 20 mm Hg or DBP decrease greater than 10 mm Hg

Absence of patterns noted above 

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6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Follow-up of adults with noncritical COVID-19 two months after symptom onset

A case report of postural tachycardia syndrome after COVID-19

Acute hyperhidrosis and postural tachycardia in a COVID-19 patient

New-onset Postural Orthostatic Tachycardia Syndrome Following Coronavirus Disease

Long-Haul Post-COVID-19 Symptoms Presenting as a Variant of a Postural Orthostatic Tachycardia Syndrome: The Swedish Experience. JACC Case Rep

Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients

The Italian Protocol': a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope

Syncope: Mechanisms and Management

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Value of head-up testing potentiated with sublingual nitroglycerine to assess the origin of unexplained syncope

Characteristic Total (n=24)

Months from Positive COVID-19 Test to Onset of PASC Symptoms, Mean (SD) 1.0 ± 0

Months from Onset of PASC Symptoms to Tilt Table Test

Months from Onset of PASC Symptoms to first study follow up, Mean (SD) 9

PASC Symptoms resolved/improving/unchanged at first study follow up 2/17/5

Months from Onset of PASC Symptoms to final study follow up, Mean (SD) 11

PASC Symptoms resolved/improving/unchanged at final study follow up 4