Detecting Orthostatic Intolerance in Long COVID in a Clinic Setting.

INTRODUCTION: A likely mechanism of Long COVID (LC) is dysautonomia, manifesting as orthostatic intolerance (OI). In our LC service, all patients underwent a National Aeronautics and Space Administration (NASA) Lean Test (NLT), which can detect OI syndromes of Postural Tachycardia Syndrome (PoTS) or Orthostatic Hypotension (OH) in a clinic setting. Patients also completed the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS), a validated LC outcome measure. Our objectives in this retrospective study were (1) to report on the findings of the NLT; and (2) to compare findings from the NLT with LC symptoms reported on the C19-YRS. METHODS: NLT data, including maximum heart rate increase, blood pressure decrease, number of minutes completed and symptoms experienced during the NLT were extracted retrospectively, together with palpitation and dizziness scores from the C19-YRS. Mann-Witney U tests were used to examine for statistical difference in palpitation or dizziness scores between patients with normal NLT and those with abnormal NLT. Spearman's rank was used to examine the correlation between the degree of postural HR and BP change with C19-YRS symptom severity score. RESULTS: Of the 100 patients with LC recruited, 38 experienced symptoms of OI during the NLT; 13 met the haemodynamic screening criteria for PoTS and 9 for OH. On the C19-YRS, 81 reported dizziness as at least a mild problem, and 68 for palpitations being at least a mild problem. There was no significant statistical difference between reported dizziness or palpitation scores in those with normal NLT and those with abnormal NLT. The correlation between symptom severity score and NLT findings was <0.16 (poor). CONCLUSIONS: We have found evidence of OI, both symptomatically and haemodynamically in patients with LC. The severity of palpitations and dizziness reported on the C19-YRS does not appear to correlate with NLT findings. We would recommend using the NLT in all LC patients in a clinic setting, regardless of presenting LC symptoms, due to this inconsistency.

Neural dysregulation in post-COVID fatigue.

Following infection with SARS-CoV-2, a substantial minority of people develop lingering after-effects known as 'long COVID'. Fatigue is a common complaint with a substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison with age- and sex-matched volunteers without fatigue (n = 52), we show underactivity in specific cortical circuits, dysregulation of autonomic function and myopathic change in skeletal muscle. Cluster analysis revealed no subgroupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis, we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control. These abnormalities on objective tests may aid in the development of novel approaches for disease monitoring.

Corona With Lyme: A Long COVID Case Study.

The longevity of the coronavirus disease 2019 (COVID-19) pandemic has necessitated continued discussion about the long-term impacts of SARS-CoV-2 infection. Many who develop an acute COVID-19 infection will later face a constellation of enduring symptoms of varying severity, otherwise known as long COVID. As the pandemic reaches its inevitable endemicity, the long COVID patient population will undoubtedly grow and require improved recognition and management. The case presented describes the three-year arc of a previously healthy 26-year-old female medical student from initial infection and induction of long COVID symptomology to near-total remission of the disease. In doing so, the course of this unique post-viral illness and the trials and errors of myriad treatment options will be chronologized, thereby contributing to the continued demand for understanding this mystifying disease.

Clinical surrogates of dysautonomia predict lethal outcome in COVID-19 on intensive care unit.

BACKGROUND: Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown. METHODS: We retrospectively analyzed data collected during a single-center observational study (March 2020-November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity. RESULTS: Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors. CONCLUSIONS: Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future.

Short Communication: Stellate Ganglion Blockade for Persistent Olfactory and Gustatory Symptoms Post-COVID-19.

One hundred ninety-five patients presenting with post-COVID symptomology, including parosmia and dysgeusia, underwent reversible stellate ganglion blockade. Stellate ganglion blockade was performed at an outpatient facility, and patients were evaluated via survey at seven days post-injection. Of the 195 participants, ages ranged from 18-69 years of age with the breakdown of sexes being females n = 157 and males n = 38. The most significant finding was a reported improvement in olfaction post-injection in 87.4% of subjects. The effectiveness of this novel treatment for post-COVID is promising and warrants further investigation.

Cardiorespiratory dysautonomia in post-COVID-19 condition: Manifestations, mechanisms and management.

A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately 1 out of 10 COVID-19 convalescents reports persistent health issues more than 3 months after initial recovery. This 'post-COVID-19 condition' may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults - particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome or airway disorders - and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms - such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components - are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented.

Glial fibrillary acidic protein astrocytopathy in a patient with recent mRNA SARS-CoV-2 vaccination: COVERSHEET

Background: Literature describing triggers of GFAP astrocytopathy (GFAP-A) is limited. We report a case of GFAP-A in a patient with recent messenger ribonucleic acid (mRNA) severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) vaccination and discuss the possible pathogenesis. Case description: A 45-year-old gentleman presented with features of meningoencephalitis 31 days after the first dose and 4 days after the second dose of mRNA SARS-CoV-2 vaccination. He sequentially developed brainstem/cerebellar, autonomic and cord dysfunction. Cerebrospinal fluid was positive for GFAP autoantibody. Clinical improvement occurred after intravenous methylprednisolone and immunoglobulins. Conclusion(s): Although we are uncertain of a causal link of GFAP-A to mRNA vaccine, indirect activation of an underlying dysregulated immune milieu is plausible.Copyright © 2021 The Author(s)

Exercise intolerance associated with impaired oxygen extraction in patients with long COVID.

OBJECTIVE: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. RESULTS: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

A review of cytokine-based pathophysiology of Long COVID symptoms.

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

COVID-19 and Cardiac Arrhythmias: a Contemporary Review.

Purpose of Review: A significant proportion of patients infected by the severe acute respiratory syndrome-coronavirus (SARS-CoV2) (COVID-19) also have disorders affecting the cardiac rhythm. In this review, we provide an in-depth review of the pathophysiological mechanisms underlying the associated arrhythmic complications of COVID-19 infection and provide pragmatic, evidence-based recommendations for the clinical management of these conditions. Recent Findings: Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death. Summary: Arrhythmic complications from acute COVID-19 infection are commonly encountered in clinical practice, and COVID-19 patients with cardiac complications tend to have worse clinical outcomes than those without. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. Some manifestations, such as the long COVID syndrome, may lead to residual symptoms several months after acute infection. As the pandemic evolves with the discovery of new SARS-CoV2 variants, development and use of newer anti-viral and immuno-modulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.

Long-term assessment of autoantibodies in post-COVID syndrome

Novel coronavirus infection remains to be one of the most serious issues of the modern health care, mainly, due to its prevalence and insufficient knowledge of the pathogenesis of this disease and its complications. The autoimmune hypothesis of the post-COVID-19 syndrome is being described in various studies that evaluate autoantibodies to human tissues, many of which have a direct correlation with the COVID-19 symptoms. Among the most promising laboratory findings, the antinuclear, antiphospholipid antibodies, rheumatoid factor, as well as the autoantibodies to the autonomic nervous system are described. Many studies have been tackling the role of the novel coronavirus infection as a trigger for classic autoimmune diseases, but the extent of the virus's influence on rheumatic diseases is still a matter of debate. The identification of autoantibodies and the development of the evidence-based knowledge about their role in the post-COVID-19 syndrome will allow the elaboration of the new recommendations for the diagnosis and treatment of these patients. © 2023 Elsevier Inc. All rights reserved.

Long COVID prevalence and physiology-centered risks: population-based study in Ukraine.

AIM: Multifaceted long COVID caused by SARS-COV-2 affects all populations in the World and takes priority over any other research topics for health care. The purpose of study is to identify physiology-centered risks, prevalence, symptoms and laboratory findings in patients with long COVID in Ukraine. METHODS: A prospective, cohort study was carried out on 332 patients with long COVID after 4 weeks and more after acute infection COVID-19 from Jul 1, 2021, to Jul 1, 2022. Physiology-centered risks related to age, gender, body mass index (BMI), marital status and educational capacity, smoking, lifestyle, physical activity, and laboratory findings (before disease), and symptom distribution were analyzed. RESULTS: The cohort for the study consisted of 166 females and 107 males (mean age = 42; including young 18 (5.4%) and middle- and old-aged adults 314 (96.4%)). Increased BMI was in 61%, and less physical activity-65%. There were 4 clusters of symptoms related to physical, neurocognitive, pulmonary, and pain conditions. 95% of participants had ≥ 3 symptoms. The most common symptoms were fatigue (90%), muscular pain (85%), anosmia (70%), hair loss (70%), sleep disorders (70%), dyspnea (30%), and brain fog (25%). Among laboratory finding increased CRP (92.6%) and fibrinogen (82.7%) dominated. There are no differences between hospitalized and non-hospitalized patients in distribution symptoms. CONCLUSIONS: The prevalence of long COVID is 23%, and its physiology-centered risk factors are related to age more 38 years, female sex, unhealthy lifestyle, increased BMI, and increased inflammatory markers during COVID-19. The most common symptoms are associated with neurocognitive and pain clusters.

Reduced cardiovagal baroreflex sensitivity is associated with postural orthostatic tachycardia syndrome (POTS) and pain chronification in patients with headache.

Background: Non-cephalgic symptoms including orthostatic intolerance, fatigue, and cognitive impairment, are common in patients with chronic headache disorders and may result from alterations in the autonomic nervous system. However, little is known about the function of autonomic reflexes, which regulate cardiovascular homeostasis and cerebral perfusion in patients with headache. Methods: Autonomic function testing data from patients with headache collected between January 2018 and April 2022 was retrospectively analyzed. Through review of EMR we determined headache pain chronicity and patient self-report of orthostatic intolerance, fatigue, and cognitive impairment. Composite Autonomic Severity Score (CASS), CASS subscale scores, and cardiovagal and adrenergic baroreflex sensitivities were used to quantify autonomic reflex dysfunction. Descriptive analyses (Mann-Whitney-U or χ2, as appropriate) determined associations between autonomic reflex dysfunction and POTS as well as chronic headache. Binomial logistic regression adjusted for age and sex. Spearman's rank correlation determined the association between the total CASS score and the number of painless symptoms reported by each participant. Results: We identified 34 patients meeting inclusion criteria, of whom there were 16 (47.0%) with orthostatic intolerance, 17 (50.0%) with fatigue, 11 (32.4%) with cognitive complaints, and 11 (32.4%) with Postural Orthostatic Tachycardia Syndrome (POTS). The majority of participants had migraine (n = 24, 70.6%), were female (n = 23, 67.6%) and had a chronic (>15 headache days in a month) headache disorder (n = 26, 76.5%). Reduced cardiovagal baroreflex sensitivity (BRS-V) independently predicted chronic headache [aOR: 18.59 (1.16, 297.05), p = 0.039] and POTS [aOR: 5.78 (1.0, 32.5), p = 0.047]. The total CASS was correlated with the total number of non-painful features in the expected direction (r = 0.46, p = 0.007). Conclusion: Abnormal autonomic reflexes may play an important role in pain chronification and the development of POTS in patients with headache.

Suspected COVID-19 mRNA Vaccine-Induced Postural Orthostatic Tachycardia Syndrome.

We present a case of a 15-year-old South Asian male who developed suspected postural orthostatic tachycardia syndrome (POTS) two weeks after receiving the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine booster, which was successfully managed with low-dose fludrocortisone and ivabradine. Clinicians should be aware of the Pfizer-BioNTech COVID-19 vaccine being implicated with the onset of POTS.

An interval of clinically silent gastrointestinal bleed in dysautonomic spinal cord injury: a case report.

BACKGROUND: Gastrointestinal bleed (GIB) has high incidence in traumatic spinal cord injured (tSCI) patients and can frequently be life-threatening, especially early post-injury. Several risk factors often compound bleeding risk, some are unique to this patient population. Normally, clinical suspicion for GIB arises from symptoms like coffee-ground emesis, hematemesis, melena or even hematochezia. A hemoglobin drop may be a late sign. Due to tSCI, however, patients often experience neurogenic bowels and dysautonomia, which may delay symptom presentation and complicate timely diagnosis of GIB. We report a case of an almost clinically silent GI bleed in the context of acute cervical tSCI. CASE PRESENTATION: A 21-year-old female presented with cervical cord transection at C-7 in the setting of motor vehicle rollover, for which surgical decompression was performed. During the acute injury phase, she also received a 10-day course of dexamethasone for symptomatic COVID-19 pneumonia. Two weeks after injury, she underwent percutaneous endoscopic gastrostomy (PEG) placement which demonstrated normal gastric and duodenal anatomy. One week later, a large spike (10x) in blood urea nitrogen: creatinine (BUN: Cr) ratio raised concern for GIB, but hemoglobin remained stable, and stool color remained unchanged. The following day, a gastroenterology consult was requested under increased suspicion of GIB from a sudden 3.5 g/dL hemoglobin drop. The patient received blood transfusion and pantoprazole. An upper endoscopy was performed, revealing three small duodenal ulcers. Melanotic stool ensued afterwards. CONCLUSIONS: Due to dysautonomia, clinical presentation of GIB can be significantly delayed in the tSCI patient population, leaving them vulnerable to succumb to illness. This case illustrates the possibility of an interval in which the patient was bleeding, with the sole indicator being an elevated BUN. Our case calls for closer monitoring of and vigilance for tSCI patients, and possibly employment of different strategies to reduce the incidence and enhance early detection of GIB in tSCI patients to subsequently decrease the morbidity and mortality associated with it.

Autonomic Nerve Involvement in Post-Acute Sequelae of SARS-CoV-2 Syndrome (PASC).

The novel SARS-CoV-2 virus and resulting COVID-19 global pandemic emerged in 2019 and continues into 2022. While mortality from COVID-19 is slowly declining, a subset of patients have developed chronic, debilitating symptoms following complete recovery from acute infection with COVID-19. Termed as post-acute sequelae of SARS-CoV-2 syndrome (PASC), the underlying pathophysiology of PASC is still not well understood. Given the similarity between the clinical phenotypes of PASC and postural orthostatic tachycardia syndrome (POTS), it has been postulated that dysautonomia may play a role in the pathophysiology of PASC. However, there have been only a few studies that have examined autonomic function in PASC. In this retrospective study, we performed an analysis of autonomic nerve function testing in PASC patients and compared the results with those of POTS patients and healthy controls. Our results suggest that a significant number of PASC patients have abnormal autonomic function tests, and their clinical features are indistinguishable from POTS.