Autonomic dysfunction post-acute COVID-19 infection

Abstract

Introduction SARS-CoV-2 infection which causes the disease COVID-19 is most known for its severe respiratory complications. However, a variety of extrapulmonary effects have since been described, with cardiovascular complications being amongst the most common[ 1 ]. Those who recover from the acute phase of COVID-19 may be left with residual symptoms such as chest pain and dyspnea, resulting in a decreased quality of life and a syndrome sometimes described as “long COVID”[ 2 ]. Recent evidence suggests that survivors with some of these chronic symptoms may have autonomic dysfunction with features of postural orthostatic tachycardia syndrome (POTS) and/or inappropriate sinus tachycardia (IST) 3 , 4 . POTS is characterized by symptoms that occur with standing, an increase in heart rate of ≥30 beats per minute (or heart rate >120 bpm) when moving from a supine to a standing position, and the absence of orthostatic hypotension[ 5 ]. IST is defined as a sinus heart rate >100 beats per minute at rest without an identifiable cause of sinus tachycardia[ 6 ]. Cardiac manifestations of autonomic dysfunction lie on a wide spectrum and can therefore be classified as either POTS, IST, or other unspecified symptoms such as tachycardia and palpitations without a clear, single underlying pathological mechanism.[ 7 ] The treatment of these arrhythmias includes nonpharmacologic management, such as increasing salt and fluid intake, as well as the use of oral medications. Beta-blockers or off label use of ivabradine have used reported to be used in both syndromes with the goal of controlling heart rate to reduce the symptoms 8 , 9 . Other therapies more common in POTS include fludrocortisone, midodrine, pyridostigmine, and alpha-2 agonists[ 8 ]. There is a need to understand the patient characteristics and risk factors for developing AD as a sequela of COVID-19. Furthermore, there is limited management information specific to patients suffering from AD following COVID-19. It is unclear how treatment of these patients and their prognoses may differ from other cases of POTS or IST. In this study, we investigated a small cohort of patients diagnosed with suspected AD post SARS-CoV-2 infection to elucidate possible risk factors and treatment strategies in this population. Case Presentation We identified patients ≥18-years-old with a reported history of COVID-19 who were referred to outpatient cardiology at Columbia University Medical Center (NY, NY) and Kansas City Heart Rhythm Institute (Overland Park, KS) for evaluation of unexplained tachycardia, palpitations, chest pain, or orthostatic intolerance. Included patients must have met the definition of POTS, IST, or other cardiac autonomic dysfunction on evaluation by their cardiologist to be included in the study. Patients were considered to have confirmed COVID-19 if polymerase chain reaction (PCR) testing detected SARS-CoV-2 on nasopharyngeal swabs, or if they had symptoms suspicious for COVID-19 without available PCR testing and were later found to have detectable SARS-CoV-2 antibodies on serologic testing. The date of COVID-19 diagnosis was defined as the date of positive PCR testing, or when unavailable, the date of initial symptom onset. Baseline symptoms were obtained from a combination of chart review and self-report via a phone-administered survey to which patients consented. We collected diagnostic information from laboratory reports as well as reports of any available imaging, including computed tomography (CT) scans, cardiac magnetic resonance imaging (MRI), and echocardiograms. Information on prescribed treatments was obtained from chart review, whereas data regarding symptomatic improvement following initiation of these treatments were obtained from the survey mentioned above. Of 17 patients presenting with autonomic dysfunction in this time period suspected of having a history of COVID-19, 11 (64.7%) were confirmed to have contracted COVID-19 infection by the methods previously mentioned. In our Case series of 11 patients (Table 1 ), the mean age was 46.0 years old ± 18.0. A majority of these patients were women (81.8%) without significant medical comorbidities. A minority of patients had hypertension and/or hyperlipidemia, but none had a history of prior autonomic dysfunction, arrhythmia, or other cardiovascular disease. The most common persistent symptoms following COVID-19 diagnoses were palpitations and fatigue (81.8% each), and most patients experienced chest discomfort (63.6%) and/or dyspnea (72.7%). The mean time from COVID-19 diagnosis to onset of these symptoms was 39.5 days ± 57.3. The mean time from COVID-19 diagnosis to the first cardiology visit was 171.5 days ± 119.0, and the mean time from diagnosis to the last cardiology follow up was 260.5 days ± 100.2. Serological evaluation was overall unremarkable and without signs of infection, anemia, thyroid disease, or systemic inflammation. A majority of patients (63.6%) had pulmonary embolism formally ruled out with either a normal D-dimer or a normal chest computed tomography with intravenous contrast, and the remaining patients did not have a formal evaluation for pulmonary embolism. All patients with available data had normal left ventricular ejection fractions, troponins, and brain natriuretic peptide levels. Eight (72.7%) of patients underwent ambulatory cardiac monitoring and 2 (18.2%) of the patients underwent tilt table testing. Based on clinician impressions, 2 (18.2%) patients were diagnosed with IST, 2 (18.2%) were diagnosed with POTS, and the remaining patients (63.6%) were either still undergoing evaluation or did not meet formal criteria for IST or POTS. Table 1 Demographic and clinical characteristics of included patients from chart review. Parameter Overall (N = 11) Age (years), mean (SD) 46.00 (17.98) Female, n (%) 9 (81.8) Hypertension, n (%) 3 (27.3) Hyperlipidemia, n (%) 2 (18.2) Days to symptoms, mean (SD) 39.45 (57.30) Palpitations, n (%) 9 (81.8) Chest discomfort, n (%) 7 (63.6) Dyspnea, n (%) 8 (72.7) Fatigue, n (%) 9 (81.8) Dizziness, n (%) 3 (27.3) Symptoms worse when: Standing 1 (9.1) Sitting 1 (9.1) Same 4 (36.4) N/A 5 (45.5) Days to first cardiology clinic visit, mean (SD) 171.45 (119.02) Left ventricular ejection fraction (%), mean (SD) 57.50 (4.51) White blood cell count (per μL), mean (SD) 7546.25 (2362.41) Hemoglobin (g/dL), mean (SD) 14.12 (1.10) Thyroid stimulating hormone (mIU/L), mean (SD) 2.40 (1.97) Erythrocyte sedimentation rate (mm/hr), mean (SD) 17.00 (2.83) C-reactive protein (mg/L), mean (SD) 0.85 (0.35) Troponin, n (%): Normal 7 (63.6) N/A 4 (36.4) Brain natriuretic peptide, n (%): Normal 8 (72.7) N/A 3 (27.3) Pulmonary embolism formally ruled out, n (%) 7 (63.6) Ambulatory heart rate monitoring, n (%) 8 (72.7) Ambulatory monitor duration, n (%): <7 days 4 (36.4) 7-10 days 2 (18.2) >10 days 2 (18.2) N/A 3 (27.3) Average heart rate (bpm), mean (SD) 86.25 (11.45) Minimum heart rate (bpm), mean (SD) 51.38 (5.34) Maximum heart rate (bpm), mean (SD) 154.25 (25.05) Orthostatic vitals, n (%): Positive 1 (9.1) Negative 4 (36.4) Not Checked 6 (54.5) Tilt table test performed, n (%) 2 (18.2) Diagnosis, n (%): Inappropriate sinus tachycardia 2 (18.2) Postural orthostatic tachycardia syndrome 2 (18.2) Other 7 (63.6) 9 patients (81.8%) were prescribed medications and 2 (22.2%) were treated with lifestyle modification alone, including the use of compression stockings and increasing salt intake. Of these medications, beta-blockers were the most common, with five patients (55.6%) being prescribed beta-blockers. Three patients were prescribed metoprolol succinate, and two patients were prescribed metoprolol tartrate. Two of these patients had intolerance to metoprolol, in one Case resulting in a switch to pindolol, and in another case resulting in a switch to ivabradine. Of the remaining patients prescribed medications, one was prescribed midodrine, one was prescribed colchicine, and two were prescribed ibuprofen. Upon follow-up phone survey of included patients (Table 2 ), 4 out of 5 patients treated with beta-blockers (80.0%) reported improved or resolved symptoms and 1 out of 5 (20.0%) reported unchanged symptoms. The patient receiving midodrine reported improvement in symptoms. The patient receiving colchicine reported unchanged symptoms, while the two patients receiving ibuprofen reported improved or resolved symptoms. Table 2 Results of patients from phone survey. Parameter Frequency (%) COVID-19 + 11 (100.0%) Prescribed medication from cardiologist 9 (81.8%) Medication Received Beta-blocker 5/9 (55.6%) Midodrine 1/9 (11.1%) Anti-inflammatory 3/9 (33.3%) After receiving meds, symptoms ______: Resolved 2/9 (22.2%) Improved 4/9 (44.4%) Unchanged 3/9 (33.3%) Worsened 0/9 (0.0%) COVID-19 Vaccination Status Vaccinated 6 (54.5%) Unvaccinated 0 (0.0%) Unknown 5 (45.5%) Number of doses received One 0 (0.0%) Two 6/6 (100.0%) Vaccine Received Pfizer 4/6 (66.7%) Moderna 1/6 (16.7%) Unknown 1/6 (16.7%) After vaccination, symptoms _________: Resolved 1/6 (16.7%) Improved 2/6 (33.3%) Unchanged 3 (50.0%) Worse 0 (0.0%) From the cohort of patients, 6 (54.5%) patients reported they had received the COVID-19 vaccine. Of these six patients, 4 (66.7%) received the Pfizer vaccine, 1 (16.7%) received the Moderna vaccine, and 1 received an unknown vaccine. All patients received two injections of the vaccine they were administered. After receiving the vaccine, 3/6 patients (50.0%) reported an improvement of symptoms, while 3/6 (50.0%) reported no difference in symptom status. No patients reported a worsening of existing AD symptoms after taking the COVID-19 vaccine. Discussion From this small cohort of patients, several important findings can be derived that may impact the approach to suspected AD following COVID-19 infection. In terms of our study population, the majority of our cohort was young women, aligned with typical population that suffers from POTS, IST, and post-acute COVID-19 autonomic dysfunction 3 , 4 , 10 , 11 . Of patients prescribed medications, a majority received beta-blockers, which improved symptoms in 4 out of 5 patients. Anti-inflammatory medications were the second most common types of treatment and resulted in symptom improvement in 2 out of 3 cases. However, it is important to note that among patients who received medications, a majority still had ongoing symptoms at follow-up without complete resolution. This is consistent with a Case series by Johansson et al. that reported on 3 patients with post-COVID-19 POTS who all remained symptomatic despite pharmacologic management[ 4 ]. Similarly, in Blitshteyn and Whitelaw’s study on post-COVID AD[ 10 ], a vast majority of patients received medications, but 85% of the cohort had residual symptoms months greater than 6 months after initial COVID-19 diagnosis. These findings suggest that while these medications, especially beta-blockers, certainly may improve symptoms of patients, post-COVID AD is consistent with the general prognosis of IST and POTS, which are both challenging to manage and often require ongoing management to reduce symptoms 6 , 12 . Further larger studies investigating the predominant presenting symptoms of patients and which medications they respond to may help improve our management. Beyond receipt of medication, of six patients receiving the COVID-19 vaccine, three patients noticed improved symptoms and three symptoms noticed unchanged symptoms. Importantly, none of these patients experienced worsening of symptoms, a complication which was originally suspected and feared for patients both with long COVID and previous COVID-infection during initial vaccine rollout[ 13 ]. This small cohort suggests the feasibility of vaccination in the population of patients suffering from suspected post-COVID AD, with no specific worsening of symptoms noted. A study of 6,030 individuals in the UK revealed the odds of long COVID symptoms, including autonomic dysfunction, were nearly halved when receiving both doses of the SARS-CoV-2 vaccine, supporting our findings.[ 14 ] While the exact mechanism for why these symptoms are alleviate following immunization remain unclear, among many hypotheses, one which may be likely is that residual viral particles in tissues may be eliminated following administration of the vaccine, helping to alleviate lingering symptoms for the subset of patients who experience them. Further longitudinal studies comparing vaccinated individuals to those unwilling to take the vaccine should be conducted to evaluate the efficacy of these vaccines to resolve longer-term symptoms of COVID-19, including autonomic dysfunction, in a larger and more controlled setting. There are a few important strengths to note about this study. Unlike previous Case studies of patients with cardiac complications COVID-19, we had 24 hour Holter monitor data, vaccination information, and follow-up phone survey data of patients, months after they had been seen by their cardiologist. This allowed for longitudinal assessment of patients with suspected AD over time, allowing us to understand characteristics of both the condition and syndrome in ways otherwise not possible due to our increased follow-up time. As long-haul COVID-19 syndrome has become more prevalent, this data offers valuable insights into what patients with suspected AD may encounter and benefit from. There are some possible limitations to this study. Given a small overall sample size of 11 patients, despite the majority of patients having received medication or a vaccine, missing data for some patients is a significant limitation. Furthermore, there could have been considerable recall bias since when taking phone surveys of included patients with regard to certain elements of their care (e.g. medication prescribed by the cardiologist). There was also only a handful of patients who underwent tilt testing or had orthostatic vitals confirmed. Both patients who underwent tilt testing had increases in heart rate of over 30 bpm in the first 10 minutes of a 70-degree tilt, with considerable heart rate variability and subtle change in P-wave morphology on slower beats, suggestive of autonomically-driven right atrial or sinus tachycardia originating in the superior and inferior aspect of the sinus node. Further studies can possibly use tilt testing or ambulatory monitoring further as a means of confirming a suspected diagnosis of autonomic dysfunction. Our study also lacked serial routine testing for markers of inflammation or autoimmunity, which prevent us from making comparisons to other cohorts or testing the observation that POTs patients may have underlying autoimmune disease 4 , 15 . One third of Blitshteyn’s cohort had laboratory testing consistent with inflammation or autoimmunity, but a significant minority of patients in this cohort also had pre-existing autonomic symptoms even prior to COVID-19, so they may represent a different population than ours[ 10 ]. Conclusions In this small cohort of patients diagnosed with AD post-SARS-CoV-2 infection, a majority were women, and few had preexisting conditions, suggesting the unpredictability of developing AD after COVID-19 infection. Beta-blockers and vaccines both show efficacy in improving symptoms of suspected post-COVID AD. Further follow-up is necessary to assess efficacy of therapeutics, length of treatment, and time to recovery. Larger prospective studies with longer follow-up are needed to test efficacy of treatments for relief of AD symptoms following COVID-19. Lastly, as novel variants continue to arise, the impact of SARS-CoV-2 reinfection of previously infected individuals, including those with autonomic dysfunction following their first bout of the virus, should be performed to specifically evaluate the impact of reinfection on long-term sequelae like autonomic dysfunction. Key-Points: • AD post-SARS-CoV-2 infection affects primarily female patients without a clear history of pre-existing conditions • AD post-SARS-CoV-2 affects patients showed of a wide age distribution • Beta-blockers and vaccines show strong efficacy in improving symptoms of suspected post-COVID AD