Post Covid-19 Syndrome Dysautonomia: A Tertiary Referral Centre Experience

Post-coronavirus disease 19 (COVID-19) syndrome has substantial health and economic implications. It is multi-systemic, with prevalent autonomic symptoms. Understanding presentations and potential autonomic causes may help guide treatment strategies and recovery. All patients with a suspected or confirmed history of COVID-19 infection who underwent autonomic testing between May 2020 and October 2021 were reviewed retrospectively. We evaluated 62 patients (20 male, 42 female, mean age of 41.38 +/-11.52). COVID-19 was PCR confirmed in 15 patients (26%), and five (8%) required acute hospital intervention. Most common symptoms included palpitations (81%), lightheadedness/ dizziness (62%), dyspnoea (48%), fatigue (46%), or cognitive symptoms (33%) Autonomic testing showed normal blood pressure responses to pressor stimuli, a mean respiratory sinus arrhythmia of 18.89b/m, and Valsalva ratio of 2.09. Postural tachycardia syndrome (PoTS) was diagnosed in 12 patients, autonomically mediated syncope (AMS) in 11, neurogenic orthostatic hypotension (NOH) in two, and initial orthostatic hypotension (IOH) in seven. Normal supine and upright plasma noradrenaline levels were measured in 34 patients (mean 283.38 pg/ml supine;472.43pg/ml tilted). Autonomic testing was reassuring (PoTS and syncope) in the majority with abnormal testing (n=32, or 52%). Further phenotyping of PoTS to exclude neuropathic pathology may be needed. IOH and OH are important considerations.

Long COVID: Rapid Evidence Review

Postacute sequelae of COVID-19, also known as long COVID, affects approximately 10% to 30% of the hundreds of millions of people who have had acute COVID-19. The Centers for Disease Control and Prevention defines long COVID as the presence of new, returning, or ongoing symptoms associated with acute COVID-19 that persist beyond 28 days. The diagnosis of long COVID can be based on a previous clinical diagnosis of COVID-19 and does not require a prior positive polymerase chain reaction or antigen test result to confirm infection. Patients with long COVID report a broad range of symptoms, including abdominal pain, anosmia, chest pain, cognitive impairment (brain fog), dizziness, dyspnea, fatigue, headache, insomnia, mood changes, palpitations, paresthesias, and postexertional malaise. The presentation is variable, and symptoms can fluctuate or persist and relapse and remit. The diagnostic approach is to differentiate long COVID from acute sequelae of COVID-19, previous comorbidities, unmasking of preexisting health conditions, reinfections, new acute concerns, and complications of prolonged illness, hospitalization, or isolation. Many presenting symptoms of long COVID are commonly seen in a primary care practice, and management can be improved by using established treatment paradigms and supportive care. Although several medications have been suggested for the treatment of fatigue related to long COVID, the evidence for their use is currently lacking. Holistic treatment strategies for long COVID include discussion of pacing and energy conservation;individualized, symptom-guided, phased return to activity programs;maintaining adequate hydration and a healthy diet;and treatment of underlying medical conditions.Copyright © 2022 American Academy of Family Physicians.

Impact of the COVID-19 pandemic on clinical autonomic practice in Europe A survey of the European Academy of Neurology (EAN) and the European Federation of Autonomic Societies (EFAS).

OBJECTIVE: To investigate the impact of the coronavirus-disease-2019 (COVID-19) pandemic on European clinical autonomic practice. METHODS: Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021. RESULTS: Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every-third center reported major adverse events due to postponed examinations or visits. The most frequent newly-diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and recurrent vasovagal syncope, deemed likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new-onset of orthostatic intolerance, but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly-diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently POTS and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50-100% recovery rates at follow-up. CONCLUSIONS: Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, while the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints.

Postural orthostatic tachycardia syndrome and orthostatic hypotension post COVID-19.

BACKGROUND: Novel coronavirus causes coronavirus disease -19 (COVID-19). The hallmark is acute respiratory distress syndrome, but other system's involvement is less illustrated. Our goal was to evaluate the manifestation of COVID-19 on one of the overlaps of the cardiovascular and nervous system, namely: Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic Hypotension (OH). METHODS: This single-center cross-sectional observational study encompassed 60 consecutive patients that were hospitalized and recovered from severe or critical COVID-19. At the time of discharge, Blood Pressure (BP), Heart Rate (HR) in the supine and upright position (1st, 3rd, 5th and 10th minutes) were measured. Symptomatic patients were reevaluated 2 months later. RESULTS: The mean age of patients was 56.6 (±16.2) years and 42 patients were male (70%). The most frequent cardiovascular risk factor was hypertension (35%). OH and POTS were detected in 29(48.3%) and 10(16.7%) of the patients respectively at the time of hospital discharge. The mean age of patients with OH was higher than POTS and POTS was frequent in the elderly. Two months later among 10 patients with POTS, the sign and symptoms were resolved in 8(80%). Two (20%) patients who still had positive signs and symptoms of POTS were older than 65 years. Among 29 patients with OH, the signs and symptoms were resolved in 26(89.7%). CONCLUSION: In our study 65% of patients had OH or POTs on the day of hospital discharge, Complete recovery is gradual and needs several additional weeks. This is one of the aspects of the entity recently named "Long COVID".

A prospective study to evaluate the efficacy and adverse effects of alpha-blockers in the management of benign prostatic hyperplasia

Conclusion: The obtained results showed that both silodosin and tamsulosin produced significant improvement in IPSS and quality of Life in BPH patients. BPH is a nonemergency medical condition, during COVID pandemic situation outpatient visit to hospitals were postponed or cancelled, even if they struggle with troublesome urinary symptoms and unavoidable impact on quality of life. [...]the need for medical management for symptomatic relief of BPH increased. Exclusion Criteria The following criteria were excluded from the study: * Prostate carcinoma. * Concomitant HIV, HBV or HCV infection. * Renal failure. * Liver disease. * Recent cataract surgery. * Psychiatry disorders.

Clinical presentation and management strategies of cardiovascular autonomic dysfunction following a COVID-19 infection - A systematic review.

BACKGROUND: Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus-disease-2019 (COVID-19) infection, but the available evidence is scattered. Here we sought to understand the acute and mid-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiovascular autonomic function. METHODS: We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS-CoV-2 infection or post-COVID-19 condition. The clinical-demographic characteristics of individuals in the acute versus post-COVID-19 phase were compared. RESULTS: We screened 6470 titles and abstracts. Fifty-four full-length articles were included in the data synthesis. One-hundred and thirty-four cases were identified: 81 during the acute SARS-CoV-2 infection (24 thereof diagnosed by history) and 53 in the post-COVID-19 phase. Post-COVID-19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS-CoV-2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post-COVID-19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post-COVID-19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002). CONCLUSIONS: There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID-19. More data about the prevalence of autonomic disorders associated with a SARS-CoV-2 infection are needed to quantify its impact on human health.

A case of dysautonomia after COVID-19 infection in a patient with poorly controlled type I diabetes.

COVID-19 has been linked to dysautonomia in the current literature, as has uncontrolled diabetes. Here, we present a case report of severe dysautonomia following a COVID-19 infection in a patient with pre-existing poorly controlled type-1 diabetes. This patient exhibited symptoms consistent with both postural orthostatic tachycardia syndrome (POTS), as well as orthostatic hypotension. His symptoms became so severe that he was unable to come to a standing position without experiencing syncope. Extensive workup was completed to identify an alternative cause of his dysautonomia with inconclusive results. Dysautonomia can have devastating consequences in regard to physical, social, and psychological health. Counseling individuals with poorly controlled diabetes about the importance of maintaining tight blood glucose control and avoiding COVID-19 infection should be primary interventions when treating patients with this DM1. Early detection and management of diabetes mellitus, COVID-19, and of possible resultant dysautonomia through medical interventions, as well as lifestyle changes, are extremely important measures to avoid development of dangerous and potentially life-threatening consequences.

TIME TO SLOW DOWN: A DEEPER LOOK INTO REMDESIVIR-ASSOCIATED BRADYCARDIA

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: The use of remdesivir in critical care setting has been utilized treatment of covid, but not without risk. Many cases have reported severe cardiac effects with bradycardia being the most common. CASE PRESENTATION: The patient was a 15-year-old female with a history of asthma, hyperinsulinemia who required hospitalization for acute hypoxic respiratory failure secondary to COVID-19 pneumonia. She received ceftriaxone, azithromycin, and a 10-day course of remdesivir (RDV). On her third day of admission, the patient developed significant sinus bradycardic with heart rate nadir of 30-40 bpm but denied any symptoms. She completed her remdesivir course on day five of hospitalization and was discharged on day nine with a heart rate of 47 bpm. She later presented to ED the night of discharge following acute onset of lightheadedness and blurry vision at home secondary to orthostatic hypotension and bradycardia. Her pulse was 48 bpm, temperature 36.1 C, respirations 24/min, blood pressure 119/50 mmHg and SpO2 99% on room air. Her physical exam was unremarkable. EKG showed sinus bradycardia with a PR interval of 124 ms and QTc of 406 ms. Echocardiogram showed normal cardiac anatomy and function. Patient was diagnosed with persistent RDV-associated bradycardia and discharged home with a Holter monitor and cardiology follow-up. Bradycardia resolved by her follow-up visit two weeks later. DISCUSSION: According to the WHO pharmacovigilance database, bradycardia is a relatively new adverse effect and 3.6% of the 2,603 adverse effects reported since the onset of the pandemic, with 2 million RDV doses administered during this time [1]. The mechanism of RDV-associated bradycardia is proposed to be an effect of adenosine triphosphate, an active metabolite, which reduces SA node automaticity via stimulation of vagal nerve, as well as RDV cross-reactivity with mRNA polymerase, leading to cardiotoxicity that usually resolves within 24 hours of medication discontinuation. In our patient's case bradycardia did not resolve until eight days after discontinuation of medication [2]. Review of previously case reports does not identify any association with patient age but could be related to timing of when medication reaches therapeutic window, as many patients had onset of bradycardia on day 3 of treatment [3]. We report a pediatric case of severe acute COVID-19 who developed sinus bradycardia on day 3 of RDV treatment as previously described, but the bradycardia persisted long after the discontinuation of RDV. CONCLUSIONS: With over 50 thousand pediatric COVID-19 hospitalizations to date, this case serves as a timely reminder that medication side effects should be monitored closely, and that more research needs to be done into the effects of RDV on cardiac function in pediatric patients. Reference #1: Jung SY, Kim MS, Li H, Lee KH, Koyanagi A, Solmi M, Kronbichler A, Dragioti E, Tizaoui K, Cargnin S, Terrazzino S, Hong SH, Abou Ghayda R, Kim NK, Chung SK, Jacob L, Salem JE, Yon DK, Lee SW, Kostev K, Kim AY, Jung JW, Choi JY, Shin JS, Park SJ, Choi SW, Ban K, Moon SH, Go YY, Shin JI, Smith L. Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database. Clin Transl Sci. 2022 Feb;15(2):501-513. doi: 10.1111/cts.13168. Epub 2021 Oct 31. PMID: 34719115;PMCID: PMC8841455. Reference #2: Touafchia A, Bagheri H, Carrié D, Durrieu G, Sommet A, Chouchana L, Montastruc F. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infect. 2021 Feb 27;27(5):791.e5–8. doi: 10.1016/j.cmi.2021.02.013. Epub ahead of print. PMID: 33647441;PMCID: PMC7910147. Reference #3: Rau, Cornelius MPhil;Apostolidou, Sofia MD;Singer, Dominique MD, PhD;Avataneo, Valeria PhD;Kobbe, Robin MD Remdesivir, Sinus Bradycardia and Therapeutic Drug Monitoring in Children With Severe CO

AFTER VISIT SUMMARY WORKSHOP IN AMBULATORY CLERKSHIP FOR 4TH YEAR MEDICAL STUDENTS

SETTING AND PARTICIPANTS: Online module, Ambulatory Internal Medicine Clerkship, 4th year medical students DESCRIPTION: Due to the COVID pandemic, the structure of the 4th year Advanced Ambulatory Medicine Clerkship at the Geisel School of Medicine at Dartmouth has been divided into two sections, two weeks in the clinical setting and two weeks of virtual cases. We developed an online module to teach students how to complete a high quality after visit summary, linked to one of the virtual cases. The module consists of the following activities: 1. A pre-module questionnaire to gauge student confidence in writing after visit summaries on a scale of 1 to 5 2. A 25 minute recorded lecture on After Visit Summaries. The lecture describes the essential aspects of the AVS for effective communication and patient comprehension, as well as components that meet CMS billing requirements. Information in the lecture was based on a literature review of surveys concerning what patients found the most helpful AVS components. 3. A virtual case from Aquifer concerning a 78 year old female who presents to clinic with falls, found to have orthostatic hypotension. 4. The students complete an AVS using a provided downloadable template that includes space for the following: Encounter Diagnoses, Problem List Diagnoses, Medication list with visit changes, Orders (including tests and referrals), Results, Provider Instructions, Follow-up 5. After submission of the worksheet, the students receive personalized feedback regarding the AVS they completed. The feedback is purely formative, as the assignment is graded as either Complete or Incomplete. 6. The students complete the same questionnaire as in step 1. EVALUATION: Quantitative data is gathered through the pre and postmodule questionnaires assessing student confidence. Preliminary data has been encouraging with improvement in the measured confidence scores. The question gauging student confidence in writing patient instructions showed an improvement from a mean score of 3.57, prior to the module, to 4.29, 95% CI [4.13, 4.45] out of a maximum score of 5 in a sample of 41 students. Students will also provide formative feedback to the program during clerkship evaluations. DISCUSSION / REFLECTION / LESSONS LEARNED: This AVS module is an effective learning exercise that improves the skills of learners in writing after visit summaries, a skill which may not be systematically taught in clinical settings. Utilization of a virtual case with skills practice followed by personalized feedback during the virtual portion of a clerkship, allowed for augmentation of didactic teaching that can be completed at students' own pace. The next steps in expanding the module, will be having students write an AVS for a patient encounter during their clinical weeks of the clerkship, with further feedback from their individual preceptors using a similar rubric utilized in the virtual case. This will allow us to take the next step in evaluating the module's effectiveness, via how well students apply the knowledge from the module in a real-life setting.

ORTHOSTATIC HYPOTENSION IN COVID 19 - CATCH IT IF YOU CAN!

Objective: The relationship between COVID-19 and blood pressure (BP) has raised great concern since the discovery of Angiotensin Convertase Enzyme 2 (ACE 2) - mediated mechanism of action for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2). Hypertension (HTN) itself proved to be a risk factor for more severe Coronavirus Disease 19 (COVID -19). However less studies focus on the trend of blood BP for patients with COVID-19 during the initial phase of disease. Design and method: We present the case of a 71 years old woman with grade 2 HTN previously controlled with diuretic and betablocker therapy that came to our hospital with dyspnea, cough and debilitating fatigue progressively worsened in the last 10 days. The patient also related the first episode of syncope in her life the night before the presentation. Results: The clinical evaluation revealed a conscious, euvolemic, with polypnea and a peripheral saturation in oxygen of 86%, corrected to 95% with 9 liters oxygen/ minute via simple face mask and a BP of 110/70 mmHg with a ventricular rate of 45 beats per minute in supine position. The assessment of BP values while standing showed a value of 78/60 mmHg after 1 minute and 58/40 mmHg after 3 minutes, while the ventricular rate increased overall to 65 beats per minute. ECG was remarkable only for mild bradycardia and computed tomography pulmonary angiogram excluded pulmonary embolism. The patient was admitted with severe COVID-19 accompanied by severe orthostatic hypotension and bradycardia. Continuous telemonitoring showed only mild bradycardia. Under standard COVID 19 treatment, after 10 days, her symptoms had resolved with no residual orthostatic hypotension or bradycardia. Conclusions: In conclusion this case reflects the life-threatening dysautonomia caused by SARS-COV 2 infection. More concern should be placed on this type of fragile patients, taking into account both the macroscopic implications of being confined to bed for a long period of time and the microscopic butterfly effect caused by the binding of the virus on the widespread ACE 2 in the lungs, heart, kidneys and digestive tract.

Demonstrating New-onset orWorsened Sudomotor Function post COVID-19

Objective: Identify if SARS-CoV-2 virus is triggering and/or worsening dysautonomia by reviewing the function of autonomic patients pre-COVID-19 and post-COVID-19 infection, as well as new onset autonomic patients post-COVID-19 infection. Background: Autonomic dysfunction may be part of acute and long COVID-19 infection. Design/Methods: Six participants were enrolled and divided into two groups. The first group of 4 volunteers reported worsened autonomic symptoms post-COVID-19 infection. These individuals had first autonomic test prior to COVID-19 pandemic outbreak (July 2019- December 2019). Autonomic function testing was repeated in these participants, 6 months to 1- year post-COVID-19 infection (June, 2021). The second group of 2 volunteers reported newonset autonomic symptoms post-COVID-19 infection and were tested March-May, 2021. All participants were screened for known causes of autonomic dysfunction and had normal neurophysiological studies (EMG/NCS), no hypertension/hyperlipidemia or thyroid dysfunction, no diabetes/prediabetes, no vitamin deficiencies, no history of HIV, hepatitis, or syphilis, no prior radiation or chemical exposure and no evidence of monoclonal gammopathy, or autoimmune condition. Participants were diagnosed with COVID-19 via PCR testing, and tested again via SARS-CoV-2 capsid-antibody test. Results: All volunteers were female (age: 21-37y) and endorsed orthostatic intolerance. Gastrointestinal symptoms (5/6), new-onset paresthesias, drier skin (3/6), and sexual dysfunction (2/6) were reported. Dysgeusia reported in 50%, but was not demonstrated on neurological examination. Parasympathetic autonomic function remained stable 6-months to 1- year post-COVID-19 infection and not demonstrated in participants with new-onset symptoms. Sympathetic-adrenergic dysfunction as new-onset orthostatic hypotension and abnormalities on blood-pressure response to Valsalva was found in 50% of participants. Sympathetic cholinergic (sudomotor) dysfunction was demonstrated in ALL participants. Worsened, or new-onset, sudomotor dysfunction was demonstrated in those with mild or normal sudomotor function on pre-COVID-19 autonomic testing Conclusions: Sudomotor dysfunction was demonstrated as worsened or new-sequelae to COVID-19 infection. COVID-19 may be responsible for new-onset or worsened small-fiber neuropathy in this sample.

Autonomic dysfunction following COVID-19 infection: an early experience

Objective: We present an early systematic analysis of autonomic dysfunction following COVID19 to provide initial insights into the spectrum of this condition. Background: Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. Design/Methods: We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021. Results: We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%);22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy. Conclusions: Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.

Orthostatic hypotonia as a probably late sequela of SARS-CoV-2 infection in a patient provided with palliative home care: a case report.

BACKGROUND: The SARS-CoV-2 pandemic has become a challenge for the entire healthcare system. Treatment for COVID-19 includes casual and symptomatic management in the acute phase of the disease and focuses on the treating early complications of the disease. Long-term health consequences of the infection have not yet been fully identified. A special group of patients with comorbidities, including neoplastic disease for whom the interpretation and management of symptoms is a major challenge. CASE PRESENTATION: In this case report, we present a 73-year-old woman with recently diagnosed gastric adenocarcinoma in whom we diagnosed orthostatic hypotonia in the aftermath of SARS-CoV-2 infection. We administered thiethylperazine maleate 6.5 mg daily. Additionally, we advised the patient to slowly lift from the recumbent position, raise the headboard, take meals in small portions, and increase fluid intake. These pharmacological and nonpharmacological measures resulted in sustained relief of dizziness and nausea. CONCLUSIONS: The occurrence of orthostatic hypotonia seems a possible late sequela of SARS-CoV-2 infection, and simple measures appeared sufficient to achieve sustained symptom control.

Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study.

INTRODUCTION: Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection. OBJECTIVE: The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients. METHODS: In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID - group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses. RESULTS: The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31. CONCLUSION: Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection.

Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19.

BACKGROUND: Patients with post-acute sequela of COVID-19 (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. OBJECTIVES: This study performed head-up tilt table (HUTT) testing in symptomatic patients with PASC 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 1 orthostatic hypotension. Compared with those with POTS, patients with POI described significantly earlier improvement of symptoms. CONCLUSIONS: This prospective evaluation of HUTT in patients with PASC 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.

Cardiac Amyloid Reaching for Extended Survival (CARES): Study Design of Two Placebo-Controlled, Double-Blind, Randomized, International Phase 3 Trials Assessing Cael-101 in Patients with Mayo Stage Iiia or Stage IIIb AL Amyloidosis

Background: Light-chain amyloidosis (AL-A) is a rare, severe, progressive, systemic disorder with high mortality caused by immunoglobulin (Ig) light chains that misfold and aggregate into amyloid fibrils that deposit in multiple organs, leading to progressive organ dysfunction/damage and death. Prognosis is poor for patients with cardiac involvement (characterized by high levels of cardiac troponin T and N-terminal brain natriuretic peptide). Median survival is 24 and 4 months for Mayo Stage IIIa and IIIb AL-A, respectively, based on the 2013 European Modification of the 2004 Mayo Staging system. For most patients, standard of care (SOC) is anti-plasma cell dyscrasia (PCD) therapy to suppress plasma cell proliferation, halt generation of amyloidogenic free light chains, and stop deposition of new amyloid fibrils and further organ decline. However, a critical need exists for therapies that accelerate the removal of deposited fibrils. CAEL-101 is a monoclonal antibody that binds to misfolded Ig light chains in amyloid fibrils. In Phase 1 and 2, CAEL-101 (with and without concurrent PCD SOC) was well tolerated up to 1000 mg/m 2. Preliminary Phase 2 data (NCT04304144) suggest improvements in cardiac and renal biomarkers in some patients. Objective: To evaluate the efficacy and safety of CAEL-101 versus placebo when administered concurrently with SOC anti-PCD therapy in treatment-naïve patients with cardiac AL-A, Mayo Stages IIIb (NCT04504825;Study 1) or IIIa (NCT04512235;Study 2). Methods: These international, multicenter, double-blind, randomized, phase 3 trials, initiated in 2020, are enrolling patients at over 70 sites in 14 countries. Newly diagnosed adults with AL-A stage IIIb or IIIa based on the 2013 European Modification of 2004 Mayo Staging (Wechalekar AD et al. Blood 2013;121:3420. Dispenzieri A, et al. J Clin Oncol. 2004;22:3751), measurable hematologic disease, and histopathological diagnosis of amyloidosis with cardiac involvement are eligible. Patients cannot have any other form of amyloidosis, symptomatic orthostatic hypotension, or supine systolic blood pressure <90 mmHg. Patients in Mayo Stages IIIb (N=111) and IIIa (N=267) are randomized 2:1 to receive once-weekly intravenous infusions of CAEL-101 (1000 mg/m 2) or placebo for 4 weeks, followed by maintenance dosing every 2 weeks. In these event-driven studies, treatment will continue to a minimum of 54 deaths for Study 1 and 77 deaths for Study 2 (a minimum treatment duration of 12 months is expected). Patients will receive concurrent anti-PCD therapy per the institutional protocol for SOC and will be followed to death from any cause or until end of study (Figure). The primary endpoint is overall survival (defined as the time from first dose of study drug to date of death, with censoring at last known living date), and will be analyzed via time-to-event log-rank statistics. Functional, quality of life, and echocardiography measures are targeted secondary endpoints. Results: Patient baseline characteristics and demographics are presented (Table). As of July 17, 2021, 9/13 (69.2%) patients in Study 1 and 23/39 (59%) patients in Study 2 have received at least 4 doses of CAEL-101 concurrently with anti-PCD therapy. Discussion: These ongoing trials will evaluate the efficacy and safety of CAEL-101 as first-in-class treatment to reduce amyloid burden in patients with cardiac AL-A. Notably, Study 1 (Mayo Stage IIIb) is the first randomized, placebo-controlled efficacy clinical trial to formally assess the effects of a pharmacological in this severely ill population. Because the median expected survival for Mayo Stage IIIb patients is far shorter than for Mayo Stage IIIa patients, the resulting sample size required for the Mayo Stage IIIB study is less (111 patients) than for the Mayo Stage IIIA study (267 patients). Importantly, these studies include patients identified as Stage III and IV based on the 2012 Mayo staging system (Kumar S. et al. J Clin Oncol. 2012;30:989). These trials are ongoing in a challenging environment. The approval of daratumumab i 2021 changed the landscape and modified the SOC, requiring appropriate protocol amendments. While the COVID pandemic affected all people, it had a greater impact on patients with AL amyloidosis, a rare disease that can only be treated effectively by a coordinated team of experts at centers of excellence. [Formula presented] Disclosures: Wechalekar: Alexion, AstraZeneca Rare Disease: Consultancy;Caelum Biosciences: Other: Clinical Trial Funding;Janssen: Consultancy;Celgene: Honoraria;Takeda: Honoraria;Amgen: Research Funding. Silowsky: Caelum Biosciences: Current Employment. Daniel: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment. Quarta: Alexion, AstraZeneca Rare Disease: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Tulchinskiy: Caelum Biosciences: Consultancy. Bhattacharyya: Alexion, AstraZeneca Rare Disease: Current Employment. Liedtke: Karyopharm: Membership on an entity's Board of Directors or advisory committees;Kite: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Kura Oncology: Membership on an entity's Board of Directors or advisory committees;Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Alnylam: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding.

COVID-19 Dysautonomia.

Objective: To report a case series of dysautonomia associated with COVID-19 infection. Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing. Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia. Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.

COVID-19-Associated Dysautonomia.

Orthostatic hypotension (OH) refers to a significant reduction in blood pressure (BP) that occurs on standing. It mainly results when autonomic reflexes are impaired or when the intravascular volume is depleted. Symptoms can range from syncope, dizziness, even angina or stroke. Major mechanisms causing OH are autonomic dysfunction affecting the baroreflex, severe volume depletion, and adverse medication effects. Case reports have described neurologic symptom association with coronavirus disease 2019 (COVID-19) including dysautonomia. Although most common symptoms of COVID have been primarily respiratory including fever, cough, shortness of breath, myriad other presentations including neurological, gastrointestinal, cardiac, and thromboembolic presentations have also been described. We describe a patient who was found to have OH and recurrent falls secondary to underlying COVID-19 infection and associated dysautonomia who was successfully treated with midodrine and fludrocortisone.