Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Symptoms of postural orthostatic tachycardia syndrome in pregnancy: a cross-sectional, community-based survey.

OBJECTIVE: To evaluate the relationship between postural orthostatic tachycardia syndrome (POTS) and pregnancy. DESIGN: Cross-sectional survey. SETTING: International. SAMPLE: A total of 8941 female patients with a diagnosis of POTS. METHODS: Data from the survey were analysed using descriptive measures and stratified for comparisons. MAIN OUTCOME MEASURES: Symptom course of POTS during pregnancy. Secondary outcomes included pregnancy loss, POTS onset during pregnancy and the impacts of a comorbid diagnosis of Ehlers-Danlos syndrome or an autoimmune disorder on symptoms during pregnancy. RESULTS: Overall, 40.8% (n = 3652) of participants reported one or more pregnancies. Most participants experienced worsening of symptoms in the first (62.6%) and third (58.9%) trimesters and 3 months after pregnancy (58.7%), and 81.1% experienced worsening symptoms at any point in their pregnancy. Most participants with worsening symptoms in the first trimester also experienced worsening symptoms in the second (61.6%) and third (68.1%) trimesters, but if they improved in the first trimester then this improvement persisted in the second and third trimesters. Of participants who reported that POTS was triggered by a specific event (41.3%), 8.1% reported pregnancy as the trigger for the onset. CONCLUSIONS: Postural orthostatic tachycardia syndrome symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. This novel information may guide clinicians in counselling patients with POTS who are planning pregnancy.

Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults.

Background: Autonomic dysfunction is a known complication of post-acute sequelae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity are unknown. Objective: To assess the frequency, severity, and risk factors of autonomic dysfunction in PASC, and to determine whether severity of acute SARS-CoV-2 infection is associated with severity of autonomic dysfunction. Design: Cross-sectional online survey of adults with PASC recruited through long COVID support groups between October 2020 and August 2021. Participants: 2,413 adults ages 18-64 years with PASC including patients who had a confirmed positive test for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone. Main measures: The main outcome measure was the Composite Autonomic Symptom 31 (COMPASS-31) total score, used to assess global autonomic dysfunction. Test-confirmed hospitalized vs. test-confirmed non-hospitalized participants were compared to determine if the severity of acute SARS-CoV-2 infection was associated with the severity autonomic dysfunction. Key results: Sixty-six percent of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and test-confirmed non-hospitalized participants [28.95 (15.62, 46.60) vs. 26.4 (13.75, 42.10); p = 0.06]. Conclusions: Evidence of moderate to severe autonomic dysfunction was seen in 66% of PASC patients in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and independent of the severity of acute COVID-19 illness.

Preparing for the long-haul: Autonomic complications of COVID-19.

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Postural orthostatic tachycardia syndrome is associated with significant employment and economic loss.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a debilitating form of chronic orthostatic intolerance that primarily affects women and causes substantial impairment in quality of life and function. Yet, there is minimal literature describing the employment and economic consequences of POTS. We explored these aspects of the POTS patient experience through a self-reported study designed using community-based participatory research principles. METHODS AND RESULTS: A comprehensive questionnaire, including employment and economic consequences, was developed in partnership with Dysautonomia International, a patient advocacy organization. The POTS community engaged in all stages of the research design and analysis. Participants were recruited through Dysautonomia International's website and social media channels. The analysis included 5,556 adult (age ≥18 years) participants with a physician-confirmed diagnosis of POTS. The majority of participants were female (95%). Forty-eight per cent of participants reported employment during the three months prior to the survey, and of these participants, 66.8% would work greater hours if not for illness limitations. Over two-thirds (70.5%) of participants have lost income due to POTS symptoms, with 36.0% of the total cohort losing more than $10,000 USD in the 12 months prior to the survey. Almost all (95%) participants reported POTS-related out-of-pocket medical expenses since diagnosis, with 51.1% of participants spending $10,000 USD or more. CONCLUSIONS: This is the largest study reporting the employment and economic challenges experienced by individuals with POTS. Exposure of these challenges emphasizes the need for earlier diagnosis and improved therapeutic strategies to reduce the negative individual and societal consequences of this disorder.

Symptom Presentation and Access to Medical Care in Patients With Postural Orthostatic Tachycardia Syndrome: Role of Sex.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a chronic form of orthostatic intolerance that primarily impacts female patients of childbearing age. The role of sex differences in POTS is not well understood. We sought to identify sex differences in diagnosis, symptoms, comorbidities, and treatments in female and male patients diagnosed with POTS. METHODS: A comprehensive survey was designed in partnership by Dysautonomia International (East Moriches, NY) and Vanderbilt University Medical Center (Nashville, TN). Patients were recruited through Dysautonomia International's website and social media channels. The survey was delivered online through a secure research data capture database. Responses were analyzed according to biological sex. Continuous variables are presented as median (25th percentile-75th percentile), and categorical variables are presented as number and proportion of participants. RESULTS: A total of 8919 patients reported a physician diagnosis of POTS and were included in this analysis. The majority of respondents were female (93.7%). Female and male patients experienced misdiagnosis at similar rates (76.2% vs 74.9%, P = 0.5) and saw a similar number of doctors before diagnosis (5 [3-8] vs 5 [3-8], P = 0.9). Despite these similarities, diagnostic delay was longer for female, compared with male, patients (1.50 [0.25-5.25] years vs 0.92 [0.08-2.91] years, P < 0.001). CONCLUSIONS: Despite the primarily female demographic of POTS patients, female patients experience more challenges with diagnosis than male patients. Increased awareness and recognition of POTS may help to reduce the diagnostic challenges in both female and male patients, and improve treatment and management for individuals living with this debilitating disorder.

CONTEXTE: Le syndrome de tachycardie orthostatique posturale (STOP) est une forme chronique d'intolérance orthostatique qui touche principalement les femmes en âge de procréer. L'incidence du sexe sur le STOP n'est pas bien comprise. Nous avons cherché à déterminer les différences entre les sexes en ce qui a trait au diagnostic, aux symptômes, aux comorbidités et aux traitements chez les patients féminins et masculins ayant reçu un diagnostic de STOP. MÉTHODOLOGIE: Une enquête exhaustive a été conçue en partenariat par Dysautonomia International (East Moriches, NY, États-Unis) et le Vanderbilt University Medical Center (Nashville, TN, États-Unis). Les patients ont été recrutés par l'entremise du site Web de Dysautonomia International et des médias sociaux. L'enquête a été réalisée en ligne au moyen d'une base de données sécurisée de saisie de données de recherche. Les réponses ont été analysées en fonction du sexe biologique. Les variables continues sont présentées sous forme de médiane (25e percentile-75e percentile), et les variables nominales sont présentées sous forme de nombre et de proportion de participants. RÉSULTATS: Au total, 8 919 patients ont signalé un diagnostic de STOP établi par un médecin et ont été inclus dans cette analyse. La majorité des répondants étaient des femmes (93,7 %). Les patients de sexe féminin et masculin ont été mal diagnostiqués dans des proportions similaires (76,2 % vs 74,9 %, p = 0,5) et ont vu un nombre similaire de médecins avant le diagnostic (5 [3-8] vs 5 [3-8], p = 0,9). Malgré ces similitudes, le retard de diagnostic était plus long chez les femmes que chez les hommes (1,50 [0,25-5,25] an contre 0,92 [0,08-2,91] an, p < 0,001). CONCLUSIONS: Même si les patients atteints de STOP sont principalement des femmes, ces dernières ont plus de difficultés à recevoir un diagnostic que les hommes. Une meilleure connaissance et reconnaissance du STOP peut contribuer à réduire les problèmes liés au diagnostic chez les patients féminins et masculins, et à améliorer le traitement et la prise en charge des personnes atteintes de ce trouble débilitant.

Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome.

Despite well-established clinical associations between Hypermobile Ehlers-Danlos syndrome (hEDS) and postural orthostatic tachycardia syndrome (POTS), the precise prevalence is unknown. We therefore evaluated for hEDS in 91 POTS participants using the 2017 hEDS diagnostic checklist, which has three major criteria: 1) generalized joint hypermobility (Beighton score), 2) systemic features, family history, and 3) absence of exclusion criteria. Overall, 28 out of 91 POTS participants (31%) met clinical criteria for hEDS. An additional 24% of participants had generalized joint hypermobility without meeting hEDS criteria. Identifying the prevalence of hEDS in POTS is important for understanding possible mechanisms connecting these two syndromes.

The patient perspective: What postural orthostatic tachycardia syndrome patients want physicians to know.

Diagnosing and treating postural orthostatic tachycardia syndrome (POTS) can be a frustrating experience for patients and physicians alike. Experienced patient leaders solicited input from the large online POTS community to identify patient suggestions and concerns, with the goal of improving the patient-physician relationship and outcomes in POTS. This review article offers practical tips to improve POTS patient care and links to credible resources for your patients. The authors emphasize the urgent need for improved physician education, a tailored treatment approach, and expanded research efforts.

Autoimmunity in postural orthostatic tachycardia syndrome: Current understanding.

There is growing interest in the role of autoimmunity in postural orthostatic tachycardia syndrome (POTS). In recent years, investigators have described an increased rate of co-morbid autoimmune disease, and the presence of several neural receptor autoantibodies and non-specific autoimmune markers in POTS. Case reports on the efficacy of immunotherapy in highly selected POTS patients continue to appear in the literature, while no prospective clinical trials have occurred to date. This article summarizes the current state of knowledge on the role of autoimmunity in POTS, the clinical implications of these findings, and prospects for future research.

Special issue for the silver anniversary of Postural Tachycardia Syndrome.

Postural Tachycardia Syndrome (POTS) is a multi-system disorder that can be associated with significant functional disability. Likely due to the multi-system nature of the disorder, it can be difficult for physicians caring for these patients with POTS to know enough about the management of problems that fall within so many different specialties. This special issue was written for these clinicians and their patients. We have brought together experts on POTS with different backgrounds to share their approach to many of the medical issues that confront patients with POTS. The result is this special POTS Issue of Autonomic Neurosciences that can serve as a "User's Guide to POTS".