Resonant breathing improves self-reported symptoms and wellbeing in people with Long COVID (preprint)

Introduction: Long COVID involves debilitating symptoms, many of which mirror those observed with dysautonomia, and care must be taken with traditional autonomic rehabilitation to avoid post-exertional malaise/post-exertional symptom exacerbation. Resonant breathing exercises require less exertion and can potentially improve autonomic function. The objective of this work was to report on the impact of a resonant breathing program on self-reported symptoms and wellbeing in people with Long COVID. Methods: A retrospective analysis of de-identified data was completed in a convenience sample of people with Long Covid, who participated in the Meo Health (formerly known as Stasis HP) resonant breathing program. Participants completed baseline and follow up surveys. Results: Data were available for 99 participants. Most measures of symptoms and wellbeing improved at follow up, with the largest differences per participant seen in sense of wellness (47.3%, p<0.0001), ability to focus (57.5%, p<0.0001), ability to breathe (47.5%, p<0.0001), ability to control stress (61.8%, p<0.0001) and sleep quality (34.9%, p=0.0002). Most (92%) participants reported improvement at follow up on the Patient Global Impression of Change Scale. Conclusion: Self-reported symptoms and wellbeing improved in people with Long COVID completing resonant breathing. Resonant breathing can be considered as an option within the broader treatment plan of people with Long COVID.

Racial/Ethnic Differences in Long-COVID-Associated Symptoms among Pediatrics Population: Findings from Difference-in-differences Analyses in RECOVER Program (preprint)

Racial/ethnic differences are associated with the potential symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study for children and adolescents under the age of 21 from the thirteen institutions in the RECOVER Initiative. The cohort is 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis and 677,448 patients without SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minor racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among specific PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

CLUSTER ANALYSIS IDENTIFIES LONG COVID SUBTYPES IN BELGIAN PATIENTS (preprint)

SARS CoV-2 infection presents complications known as long Covid, a multisystemic organ disease which allow multidimensional analysis. ObjectivesThis study aims to identify Long Covid clusters and to relate them to the clinical classification devised at the Clinical Research Unit of Brugmann University Hospital, Brussels. MethodA two-stage multidimensional exploratory analysis was performed on a cohort of 205 long Covid patients, involving a Factorial Analysis of Mixed Data (FAMD), and then Hierarchical Clustering Post Component Analysis (HCPC). ResultsThe studys sample comprised 76% women, with an average age of 44.5 years. Three clinical forms were identified: long, persistent, and post-viral syndrome. Multidimensional analysis identified three clusters: cluster 1 (myalgia-like pain) associated with the persistent clinical form; cluster 2 (neurocognitive disorders) linked to the long clinical form; cluster 3 (neurocognitive disorders, anxio-depressive syndrome, joint pain and myalgia, peripheral nervous system disorders with dysautonomia, including Postural Orthostatic Tachycardia Syndrome, along with digestive system disorders). However, biological data did not provide sufficient differentiation between the clusters. ConclusionLong Covid phenotypes, as well as clinical forms, appear to be associated with distinct pathophysiological mechanisms or genetic predisposition, warranting further investigation.

HEART rate variability biofeedback breathing programme for LOng Covid dysautonomia (HEARTLOC): results of a feasibility study (preprint)

Introduction Post-covid-19 syndrome, or Long covid (LC) refers to symptoms persisting 12 weeks after Covid-19 infection. LC comprises a wide range of dysautonomia symptoms, including fatigue, breathlessness, palpitations, dizziness, pain and brain fog. This study tested the feasibility and estimated the efficacy, of a Heart Rate Variability Biofeedback (HRV-B) technique via a standardised slow diaphragmatic breathing programme in individuals with LC. Methods and Analysis LC patients underwent a 4-week HRV-B intervention for 10 minutes twice daily for a total of 4 weeks using the Polar H10 ECG (Electrocardiogram) chest strap and Elite HRV phone application. Outcome measures C19-YRSm (Yorkshire Rehabilitation Scale modified), EQ5D- 5L (EuroQol 5 Dimensions), Composite Autonomic Symptom Score (COMPASS-31), WHO Disability Assessment Schedule (WHODAS), and Root Mean Square of Successive Differences between heartbeats (RMSSD) using a Fitbit device were completed before and after the intervention. The study was pre-registered at clinicaltrials.gov NCT05228665. Results 13 participants (54% female, 46% male) completed the study with high levels of data completeness and adherence. There was a statistically significant improvement in C19YRS-m (p=0.001), EQ5D Global Health Score (p=0.009), COMPASS-31 (p=0.007), RMSSD (p=0.047) and EHODAS (p=0.02). Qualitative feedback suggested participants were able to use it independently, were satisfied with the intervention, and reported beneficial effects from the intervention. Conclusion This is the first study in the literature to report that HRV-B is a feasible intervention for LC and seems to be potentially improving symptoms of LC and dysautonomia.

The Role of VSL#3 in the Treatment of Fatigue and Other Symptoms in Long Covid-19 Syndrome: a Randomized, Double-blind, Placebo-controlled Pilot Study (DELong#3) (preprint)

Long COVID, also known as Post-acute COVID-19 Syndrome (PACS), is a chronic condition affecting individuals who have recovered from acute COVID-19. It is currently estimated that around 65 million people worldwide suffer from Long COVID. It is characterized by a range of symptoms, including fatigue, exertion intolerance, neurocognitive and sensory impairment, sleep disturbance, myalgia/arthralgia, and dysautonomia. Among them fatigue has emerged as a burdensome and pervasive issue, significantly impacting the quality of life and daily functioning of Long COVID patients. Alterations in the composition of the intestinal microbiota has been reported in COVID-19 patients. Dysbiosis persists even after several months of recovery from acute SARS-CoV-2 infection. Based on this evidence, we carried out a phase 3, randomized, double-blind, placebo-controlled trial aimed at evaluating the efficacy of VSL#3, a consortium of probiotic bacterial strains, in reducing fatigue and improving various aspects of patients' well-being in patients with Long COVID syndrome.

Vagus nerve inflammation contributes to dysautonomia in COVID-19 (preprint)

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we show that SARS-CoV-2 is detectable in postmortem vagus nerve specimen together with inflammatory cell infiltration derived primarily from monocytes. This is associated with a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction.

Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of "long-COVID" patients.

Several disabling symptoms potentially related to dysautonomia have been reported in "long-COVID" patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests. Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls. Sixteen patients (median age 37 years [31-43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0-16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls. In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population.

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis (preprint)

Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia. Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

Patient-Centered Paradigm for Managing Autonomic Long COVID Symptoms During Sports and Exercise.

ABSTRACT: This report highlights a new, patient-centered paradigm for managing post-COVID-19 dysautonomia symptoms during sports and exercise. The patient was a healthcare worker exposed before vaccination. She experienced postural orthostatic tachycardia plus exertional tachycardia, with postexertional fatigue, beginning a few weeks after testing positive for COVID-19. Stress test, echo, and an extensive dysautonomia evaluation were negative. Recommended nonpharmacological and pharmacological interventions were poorly tolerated. Prescription of a novel regimen of "basal-dose" ivabradine, plus very low-dose metoprolol according to an exertional "sliding scale" managed symptoms to an acceptable level for work and recreation.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background:  Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design:  A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction.  A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction.  Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.

Post-COVID-19 syndrome and related dysautonomia affect patients life and work productivity (preprint)

Background: A significant percentage of COVID-19 patients experience post-COVID-19 symptoms and signs. Post-COVID-19 syndrome affects physical and mental health of patients in several ways. Aim: To investigate the impact of post-COVID-19 syndrome and related dysautonomia on patients life and work productivity. Methods: We conducted a cross-sectional study in Greece using an online questionnaire. Study population included 108 workers over 18 years old that have been diagnosed with post-COVID-19 syndrome. Patients were recruited from the Long COVID Greece patients society. We measured demographic and clinical characteristics of patients, resilience, and social support. Results: Among patients, 68.5% stated that post-COVID-19 syndrome affected their daily life to a great extent, 25% to a moderate level, and 6.5% to a small extent. Moreover, 56.5% stated that post-COVID-19 syndrome affected their work productivity to a great extent, 27.8% to a moderate level, and 15.7% to a small extent. Multivariable analysis identified that females and patients with post-COVID-19 dysautonomia had more problems in their daily life. Moreover, increased duration of COVID-19 symptoms was associated with increased daily problems. Increased resilience was related with fewer problems in daily life. Also, we found that patients with post-COVID-19 dysautonomia had less work productivity. Moreover, increased duration of COVID-19 symptoms was associated with more problems in work. Resilience was related with increased work productivity. Conclusions: Post-COVID-19 syndrome and related dysautonomia affect significantly patients daily and work life. Also, resilience is an important preventive factor improving patients life. Policy makers should develop and implement educational programs to improve patients life. Healthcare professionals should be aware of the post-COVID-19 syndrome and its consequences in order to understand post-COVID-19 patients and their problems.

Post-COVID-19 syndrome and related dysautonomia reduce quality of life, and increase anxiety and depressive symptoms: evidence from Greece (preprint)

Background: Post-COVID-19 syndrome affects a significant number of SARS-CoV-2 infected individuals even asymptomatic cases causing several neurological and neuropsychiatric symptoms and signs. Materials and Methods: An online cross-sectional study with a convenience sample was conducted in Greece from November 2022 to January 2023. We measured demographic and clinical characteristics of patients, post-COVID-19 dysautonomia, quality of life with the EQ-5D-3L, and anxiety and depressive symptoms with the Patient Health Questionnaire-4. Results: Study population included 122 patients with post-COVID-19 syndrome. One out of four patients (27.8%) manifested post-COVID-19 dysautonomia, while mean duration of COVID-19 symptoms was 11.6 months. Anxiety and depressive symptoms were worse after the post-COVID-19 syndrome (p<0.001 in both cases). A statistically significant reduction in quality of life was observed among patients after the post-COVID-19 syndrome (p<0.001 for both EQ-5D-3L index value and EQ-5D-3L VAS). Post-COVID-19 dysautonomia increased depression symptoms after the post-COVID-19 syndrome (p=0.02). We found a negative relationship between duration of COVID-19 symptoms and quality of life (p<0.001). Moreover, our results showed that depressive symptoms were more often among females after the post-COVID-19 syndrome (p=0.01). Also, quality of life was lower among females than males (p=0.004 for EQ-5D-3L index value, and p=0.007 for EQ-5D-3L VAS). Conclusions: Our results suggest that post-COVID-19 syndrome causes a tremendous impact on patients quality of life and mental health. In addition, we found that the groups most psychologically affected were patients with post-COVID-19 dysautonomia, females, and patients with longer duration of symptoms. Policy makers should attach priority to vulnerable groups in future psychiatric planning. Policy measures should focus on mental health of post-COVID-19 patients who seem to be particularly vulnerable.

Central Effects of Ivermectin in Alleviation of Covid-19-induced Dysauto-nomia.

Covid-19 may be associated with various neurological disorders, including dysautonomia, a dysfunction of the autonomic nervous system (ANS). In Covid-19, hypoxia, immunoinflammatory abnormality, and deregulation of the renin-angiotensin system (RAS) may increase sympathetic discharge with dysautonomia development. Direct SARS-CoV-2 cytopathic effects and associated inflammatory reaction may lead to neuroinflammation, affecting different parts of the central nervous system (CNS), including the autonomic center in the hypothalamus, causing dysautonomia. High circulating AngII, hypoxia, oxidative stress, high pro-inflammatory cytokines, and emotional stress can also provoke autonomic deregulation and high sympathetic outflow with the development of the sympathetic storm. During SARS-CoV-2 infection with neuro-invasion, GABA-ergic neurons and nicotinic acetylcholine receptor (nAChR) are inhibited in the hypothalamic pre-sympathetic neurons leading to sympathetic storm and dysautonomia. Different therapeutic modalities are applied to treat SARS-CoV-2 infection, like antiviral and anti-inflammatory drugs. Ivermectin (IVM) is a robust repurposed drug widely used to prevent and manage mild-moderate Covid-19. IVM activates both GABA-ergic neurons and nAChRs to mitigate SARS-CoV-2 infection- induced dysautonomia. Therefore, in this brief report, we try to identify the potential role of IVM in managing Covid-19-induced dysautonomia.

HEART rate variability biofeedback for LOng Covid symptoms (HEARTLOC): protocol for a feasibility study (preprint)

IntroductionLong covid (LC), also known as Post-COVID-19 syndrome, refers to symptoms persisting 12 weeks after COVID-19 infection. It affects up to 1 in 7 people contracting the illness and causes a wide range of symptoms, including fatigue, breathlessness, palpitations, dizziness, pain and brain fog. Many of these symptoms can be linked to dysautonomia or dysregulation of the autonomic nervous system after SARS-CoV2 infection. This study aims to test the feasibility and estimate the efficacy, of the Heart Rate Variability Biofeedback (HRV-B) technique via a standardised slow diaphragmatic breathing programme in individuals with LC. Methods and Analysis30 adult LC patients with symptoms of palpitations or dizziness and an abnormal NASA Lean Test (NLT) will be selected from a specialist Long COVID rehabilitation service. They will undergo a 4-week HRV-B intervention using a Polar chest strap device linked to the Elite HRV phone application while undertaking the breathing exercise technique for two 10-min periods every day for at least 5 days a week. Quantitative data will be gathered during the study period using: HRV data from the chest strap and wrist-worn Fitbit, the modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), composite autonomic symptom score (COMPASS 31), World Health Organisation Disability Assessment Schedule (WHODAS 2.0) and EQ-5D-5L health related quality of life measures. Qualitative feedback on user experience and feasibility of using the technology in a home setting will also be gathered. Standard statistical tests for correlation and significant difference will be used to analyse the quantitate data. Ethics and DisseminationThe study has received ethical approval from Health Research Authority (HRA) Leicester South Research Ethics Committee (21/EM/0271). Dissemination plans include academic and lay publications. Study RegistrationClinicaltrials.gov No: NCT05228665 Strengths and limitations of the studyO_LITo our knowledge, this is the first study of HRVB in long covid and will provide new information regarding the feasibility of the technology-based intervention in this condition. C_LIO_LIThe estimation of efficacy will determine the scope and sample size for a larger controlled trial in the condition that currently has no definitive treatments C_LIO_LIThe study will provide preliminary evidence on the correlation between long covid symptoms and dysautonomia. C_LIO_LIThe limitation of this study is the small sample size of 30 participants which might not give an accurate estimate of efficacy. C_LIO_LIHRV-B is a technology-based intervention, therefore its take-up could be limited in those with a lack of experience in using digital technology in daily life, particularly those from less privileged backgrounds. C_LI

Impaired Vagal Activity in Long-COVID-19 Patients.

Long-COVID-19 refers to the signs and symptoms that continue or develop after the "acute COVID-19" phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction. To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p < 0.0001; Cohens-d = 1.12) and for the VLF (6.84 ± 0.8 vs. 7.66 ± 0.6; p < 0.0001; Cohens-d = 1.16) and HF (4.65 ± 0.9 vs. 5.33 ± 0.9; p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized ß-coefficient = 0.259), NT-ProBNP (standardized ß-coefficient = 0.281), HF component of spectral analysis (standardized ß-coefficient = 0.696), and LF/HF ratio (standardized ß-coefficient = 0.820). Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention.