SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19.

BACKGROUND: SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown. OBJECTIVE: To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator. RESULTS: Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large "tsunami"-like waves, and increased calcium transient amplitude. After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal. CONCLUSION: The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte's repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.

Prevalence and Characterization of Long Covid-19 Symptoms in Health Care Professionals- A Need of the Hour (preprint)

Background: With the global advent of Covid-19, Healthcare workers (HCW) were under a lot of physical and psychological pressure. Information on persistent symptoms post Covid-19 Infection in HCWs is lacking.  Objectives: This Study is aimed at assessing the impact of the post Covid-19 syndrome in HCWs.  Materials and Methods: A Questionnaire was prepared as google form and shared with the HCWs through WhatsApp enquiring regarding the health conditions that are still persistent post recovery from Covid-19 infection.  Results: A total of 328 Health Care Professionals participated in the present survey (18-65 yrs). The gender distribution revealed 67.7% were females and 32.3% were males. 60.3% of the participants were infected with COVID-19 before taking the first dose of vaccination which is reduced to 17.5% after vaccination. The post COVID complications observed from the study were hair loss (35.4%), easy fatigability (25%), mood swings (22.9%), anxiety (18.8%), insomnia/sleeplessness (13.9%), depression (12.5%) and joint pains/arthritis (11.8%). The other complications observed were loss of taste (9%), lightheadedness/postural hypotension (8.3%), amnesia/loss of memory and anosmia/loss of smell (7.6%), gastritis (6.3%), palpitations, hypersomnia and pulmonary complications (5.6%) and chest pain (4.9%). Unpaired t-test and One-Way ANNOVA resulted in a significant value (p values of >0.05).  Discussion: Despite the fact that females experienced more post-Covid-19 symptoms (15 out of 17), males experienced more chest pain and anxiety symptoms. According to our findings, 57 of 100 Covid-19 health care workers have post-Covid complications. The participants presented with non-specific symptoms such as easy fatigability, mood swings, light headedness, anxiety but most of the participants quoted more specific symptoms such as depression, pulmonary complications, hair loss, joint pains, gastritis, chest pain, palpitations, loss of taste, amnesia, hyperglycemia, insomnia, hypersomnia and anosmia. However, non-specific symptoms such as fatigue, mood swings, lightheadedness, and anxiety were also mentioned. The symptoms of post-acute COVID-19 syndrome vary greatly. Early detection requires a unified definition of long COVID and characterization of its manifestation. Furthermore, more research should be conducted to identify risk factors and the precise mechanisms that lead to the development of long COVID syndrome. Such knowledge may aid future research aimed at preventing such a complication.

Dynamics of upper respiratory tract infections before, during, and after the COVID-19 pandemic in Germany: a cross-sectional study of 2,167,453 outpatients (preprint)

Background Although the burden of the COVID-19 pandemic on global healthcare systems is declining, long-term sequelae such as long COVID syndrome and other disease dynamics not primarily associated with COVID-19 remain a challenge. Recent data suggest that the incidence of non-COVID upper respiratory tract infections (URTI) is increasing sharply in the post-pandemic period, but there is a lack of real-world data from Germany in this respect.Methods This cross-sectional study evaluated the number of patients with a diagnosis of URTI from the Disease Analyzer database (IQVIA) between January 2019 and December 2022. The number of UTRI diagnoses per practice and the duration of sick leave per patient were compared over time.Results A total of 1,872,935 individuals (1,403,907 patients from general practices (GP) and 469,028 patients from pediatric offices) were included, 48% of whom were female. The number of URTI patients per practice was significantly higher in 2022 than in 2019 (732 vs. 464, 58%, p < 0.001) and this was observed for both women (56%, p < 0.001) and men (60%, p < 0.001). The post-pandemic increase in the number of URTI diagnoses correlated with age and was highest in the age group between 18–30 years (22%, p < 0.001) and lowest in older patients > 70 years (3%). In pediatric patients (< 18 years), the increase was highest in the age group ≤ 5 years (89%). Both the number of patients per practice on sick leave due to URTI (184 vs. 92) and the average duration of sick leave (+ 2 days) increased from 2019 to 2022.Conclusion Our data suggest a dramatic increase in the incidence of URTI among all demographic subgroups in Germany between 2019 and 2022, which was associated with a tremendous impact on socioeconomic variables such as the frequency or duration of sick leave. These data could be of great importance in current pandemic management and the management of future pandemics.

Cardiovascular Safety of Hydroxychloroquine-Azithromycin in 424 COVID-19 Patients (preprint)

Background Hydroxychloroquine (HCQ) combined with azithromycin (AZM) has been widely administered to patients with COVID-19 despite scientific controversies. In particular the potential to prolong cardiac repolarisation by using this combination has been discussed. Materials and methods We report a pragmatic and simple safety approach which we implemented in the first patients treated for COVID-19 in our center early 2020. Treatment contraindications were the presence of severe structural or electrical heart disease, baseline corrected QT interval (QTc) >500 ms, hypokalaemia, or other drugs prolonging QTc that could not be interrupted. Electrocardiogram and QTc was evaluated at admission and re-evaluated after 48 hours of the initial prescription. Results Among 424 consecutive adults (mean age 46.3 ± 16.1 years; 216 women). Patients were followed in conventional wards (21.5%) or in a day-care unit (78.5%). A total of 11 patients (2.6%) had contraindications to HCQ-AZ combination. In the remaining 413 treated patients, there were no arrhythmic events in any patient during the 10-day treatment regimen. QTc was slightly but statistically significantly prolonged by 3.75 ± 25.4 ms after two days (p=0.003). Ten patients (2.4%) developed QTc prolongation >60 ms, and none had QTc >500 ms. Conclusions This report do not aim to contribute to knowledge of the efficacy of treating COVID-19 with HCQ-AZ. However, a simple initial assessment of patient medical history, ECG and kalaemia identifies contraindicated patients and enables the safe treatment by HCQ-AZ of COVID-19 patients. QT-prolonging anti-infective drugs can be used safely in acute life-threatening infections, provided that a strict protocol and close collaboration between infectious disease specialists and rhythmologists are followed.

Interruption of viral interference by anti-SARS-CoV-2 vaccination (preprint)

Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms. Here we evaluated reactivation of parvovirus B19 and several viruses of the herpes family in patients with long-COVID syndrome, how vaccination affected viral interference, and how virus reactivation influenced clinical conditions. Clinical and laboratory data on 252 consecutive patients (97 vaccinated and 155 non-vaccinated) were recorded between April 2021–May 2022 (median 243 days post-COVID-19 infection). Viral IgG and IgM titers were compared between vaccinated or non-vaccinated patients, and age and sex-matched healthy controls. Vaccination was associated with significantly less frequent fatigue and multiorgan symptoms (P < 0.001), significantly less cumulative IgM positivity of the investigated viruses, significantly lower plasma levels of IgG subfractions 2 and 4, and significantly lower quantitative Cytomegalovirus (CMV) IgG, CMV IgM, and EBV IgM titers. These results indicate that anti-SARS-CoV2 vaccination interrupts viral crosstalk in patients with long-COVID syndrome. (ClinicalTrials.gov Identifier: NCT05398952)

Prospective QTc interval monitoring avoids cardiac toxicity of hydroxychloroquine and azithromycin in critically ill SARS-CoV-2 patients: a cohort study (preprint)

Purpose During the first wave of the SARS-Cov2 pandemic, the use of hydroxychloroquine and azithromycin raised safety concerns in terms of arrhythmias related to QT segment prolongation. The aim of this observational, prospective, single-center study was to describe cardiovascular events in critically ill patients who were mechanically ventilated for SARS-Cov2 pneumonia. Methods Patients included were prospectively monitored for QTc segment prolongation when treated with the association of hydroxychloroquine alone or in combination with azithromycin for Covid-19 pneumonia and treatment had to be stopped before QTc ≤ 500ms. Results 23 patients were prospectively included. Treatment had to be interrupted in 43.5% of patients and more often in the combination group. None of the patients displayed torsade de pointes or sudden cardiac arrest. Forty percent of patients in the combination group experienced atrial fibrillation. Cardiac Troponin I was elevated in 70% of all patients without electric signs of ischemia. Conclusion The association of hydroxychloroquine and azithromycin for treatment of Covid-19 pneumonia mandates the need for prospective evaluation of QTc especially in the presence of biological myocardial injury. The Institutional Review Board waived the need for consent to use prospectively collected clinical data and the study was appointed the serial number 2020-214.

Evaluation of potential drug-drug interactions and polypharmacy in hospitalized COVID-19 patients.

Background: Drugs that are used in COVID-19 infection, may interact with each other, as well as with the drugs for comorbidities, used concomitantly with COVID-19 treatment. Objectives: It is quite important to calculate and present the patients' exposure to clinically important potential drug-drug interactions (pDDIs). We aimed to investigate the pDDIs and the burden of polypharmacy in COVID-19. Methods: The medical records of 126 consecutive inpatients with COVID-19 treatment were retrospectively analyzed. The Lexi-interact database was used to investigate pDDIs. Results: According to the Lexi-interact database, 605 pDDIs were detected. Of these pDDIs, 23 (3.8%) were A risk category interaction, 186 (30.7%) were B risk category interaction, 339 (56%) were C risk category interaction, 54 (8.9%) were D risk category interaction, and 3 (0.5%) were X risk category interaction. Sixty-five-point five percent of pDDIs (n=396) were clinically important pDDIs (C, D, and X categories), and 69 patients (54.8%) had at least one clinically important pDDIs. The most interacting drug was hydroxychloroquine (n=171, 28.3%). Hydroxychloroquine was also the most interacting drug in the C risk category (n=101, 29.8%) and had 19 pDDIs with metformin, 16 pDDIs with beta-blockers, 13 pDDIs with acetylsalicylic acid, and 10 pDDIs with insulin in the C risk category. Enoxaparin was the most interacting drug (n=25, 46.3%) in the D risk category and most of them were with acetylsalicylic acid (n=12). The most common possible clinical manifestations of pDDIs were QT prolongation, hypoglycemia, and hemorrhage. One hundred and eighteen patients (93.6%) used five or more drugs daily. There was a significant positive correlation between the number of drugs prescribed to patients and the number of clinically important pDDIs (r=0.80, p<0.001). Conclusions: Clinically important pDDIs are common among COVID-19 patients and the majority of pDDIs require monitoring of therapy. COVID-19 patients should be closely observed for QT prolongation, hypoglycemia, and hemorrhage due to pDDIs during treatment.

What interventions or best practice are there to support people with Long COVID, or similar post-viral conditions or conditions characterised by fatigue, to return to normal activities: a rapid review (preprint)

Previous research has categorised symptoms of COVID-19 / Long COVID into 12 thematic areas including: fever, myalgia, fatigue, impaired cognitive function, and that COVID-19 survivors had reduced levels of physical function, activities of daily living, and health-related quality of life. Our aim was to review the evidence for interventions or best practice to support people with Long COVID, or similar post-viral conditions characterised by fatigue, to return to normal activities. Evidence was included from guidelines, systematic reviews (SR), and primary studies. The primary studies focussed on Long COVID (LC) indicated that there should be a needs-based focus to care for those with LC. Consideration should be given to individuals living with LC in the same way as people with disabilities are accommodated in terms of workplace adjustment. Two SRs indicated that non-pharmaceutical interventions (NPIs) for patients with LC or chronic fatigue syndrome could help improve function for activities of daily life. However, the third, most recent SR, concluded that there is a lack of robust evidence for NPIs. LC fatigue management methods may be beneficial under certain conditions. One SR reported work capability as an outcome however they did not find any studies which evaluated the impact of interventions on return to work/ normal life. One primary study, on individuals with CFS, described a written self-management programme. Following this intervention there was an 18% increase in the number of patients in employment. Policy and practice implications: Long COVID is still being established as a post-viral condition with many symptoms. Patient-centred treatment options such as occupational therapy, self-management therapy and talking therapy may be considered in the same way as for other debilitating conditions. Return-to-work accommodations are needed for all workers unable to return to full-time employment. Due to the nature of the studies included, there was little reported evidence of effectiveness of getting individuals back into their normal activities.

The Use and Safety Risk of Repurposed Drugs for COVID-19 patients: Lessons Learned Utilizing the Food and Drug Administrations Adverse Event Reporting System (preprint)

Objectives: This study was designed to assess the disproportionality analyses of adverse drug reactions (ADRs) related to hydroxychloroquine and remdesivir and how ADR reporting fluctuated during the COVID-19 pandemic. Methods: A retrospective observational study was conducted utilizing the Food and Drug Administrations Adverse Event Reporting System (FAERS) data between 2019 and 2021. The study was conducted in two phases. In the first phase, all reports associated with the drugs of interest were evaluated to assess all related adverse drug reactions. In the second phase, specific outcomes of interest (i.e., QT prolongation and renal and hepatic events) were determined to study their association with the drugs of interest. A descriptive analysis was conducted for all adverse reactions related to the drugs being studied. In addition, disproportionality analyses were conducted to compute the reporting odds ratio, the proportional reporting ratio, the information component, and the empirical Bayes geometric mean. All analyses were conducted using RStudio. Results: A total of 9,443 ADR reports related to hydroxychloroquine; 6,160 (71.49) patients were female, and higher percentage of patients of both sexes were over the age of 65 years. QT prolongation (1.48%), pain (1.38%), and arthralgia (1.25%) were most frequently reported ADRs during the COVID-19 pandemic. The association of QT prolongation with use of hydroxychloroquine was statistically significant (ROR 47.28 [95% CI 35.95-62.18]; PRR 42.41 [95% CI 32.25-55.78]; EBGM 16.08; IC 4.95) compared with fluoroquinolone. The outcome was serious medical events in 48.01% of ADR reports; 27.42% required hospitalization and 8.61% resulted in death. Of 6,673 ADR reports related to remdesivir, 3,928 (61.13%) patients were male. During 2020, the top three ADR reports were elevated liver function tests (17.26%), acute kidney injury (5.95%) and death (2.84%). Additionally, 42.71% of ADR reports indicated serious medical events; 19.69% resulted in death and 11.71% indicated hospitalization. The ROR and PRR of hepatic and renal events associated with remdesivir were statistically significant, (4.81 [95% CI 4.46-5.19] and 2.96 [95% CI 2.66-3.29], respectively. Conclusion: Our study showed that several serious ADRs were reported with the use of hydroxychloroquine, which resulted in hospitalization and death. Trends with the use of remdesivir were similar, but to a lesser extent. Therefore, this study showed us that off-label use should be based on thorough evidence-based evaluation. Keywords: COVID-19, hydroxychloroquine, remdesivir, QT prolongation, FAERS.

Persistent Myocardial Dysfunction Assessed by Global Myocardial Strain in Covid-19 Recovered Patients with Cardiovascular Comorbidities at 3 Months after Acute Infection (preprint)

Background Previous studies reported the Coronavirus disease (COVID-19) has long implications, which involve multiple organs, including the cardiovascular system. This study aims to assess myocardial dysfunction by echocardiograph myocardial longitudinal strain Left ventricular-Global Longitudinal Strain (LV-GLS) and Right Ventricular-Free Wall Strain (RV-FWS) measurements as a marker for myocardial dysfunction and heart fibrosis. Additionally, we aim to identify admission factors that may serve as a predictor of long COVID syndrome.Methods This cross-sectional study assessed echocardiograph global longitudinal strain (GLS) values measurement done three months after initial hospitalization. Multivariate analysis was done to investigate admission factors associated with differences in GLS values.Results 100 subjects with cardiovascular comorbidities and prior COVID-19 infection were enrolled. Echocardiography examination showed lower GLS values in this group compared to the normal population. Demographic and risk factors-matched subjects without a history of COVID-19 (n = 31, Control 1) and healthy subjects (n-31, Control 2) were included as comparisons to validate GLS results. The case group had significantly lower LV-GLS values compared to other groups (p < 0.05, mean ± SD -16.17 ± 3.379, -19.48 ± 1.141, -21.48 ± 1.777 respectively for case, control one, and control two groups). Upon admission, a history of coronary artery disease was found to be associated with decreased LV GLS values in recovered COVID-19 patients with cardiovascular comorbidity.Conclusion LV GLS values significantly decreased in recovered COVID-19 patients with cardiovascular comorbidities. Upon admission, a history of CAD may predict cardiac long COVID-19 syndrome.

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome.

Sudden death is defined as the unexpected death of a healthy person that occurs within the first hour of the onset of symptoms or within 24 h of the victim being last seen alive. In some of these cases, rare deleterious variants of genes associated with inherited cardiac disorders can provide a highly probable explanation for the fatal event. We report the case of a 21-year-old obese woman who lost consciousness suddenly in a public place and was pronounced dead after hospital admission. Clinical autopsy showed an inconclusive gross examination, while in the histopathological analysis an eosinophilic inflammatory focus and interstitial fibrosis in the sino-atrial node were found. Molecular autopsy revealed an intronic variant in the KCNQ1 gene (c.683 + 5G > A), classified as likely pathogenic for long QT syndrome according to the guidelines provided by the American College of Medical Genetics and Genomics. Therefore, there were many anomalies that could have played a role in the causation of the sudden death, such as the extreme obesity, the cardiac anomalies and the KNCQ1 variant. This case depicts the difficult interpretation of rare cardiac structural abnormalities in subjects carrying rare variants responsible for inherited arrhythmic disorders and the challenge for the forensic pathologist to make causal inferences in the determinism of the unexpected decease.

Remdesivir (VEKLURY) for Treating COVID-19: Guinea Pig Ex Vivo and In Vivo Cardiac Electrophysiological Effects.

ABSTRACT: Bradycardia and QTc interval prolongation on the ECG have been reported with remdesivir (Veklury), an antiviral drug recently approved for treating severely ill patients with COVID-19. The objective was to evaluate the effects of remdesivir on cardiac electrophysiology ex vivo and in vivo. Ex vivo: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 23, total) exposed to either remdesivir 3, 10, or 30 µmol/L to assess drug-induced prolongation of the monophasic action potential duration measured at 90% repolarization (MAPD 90 ). In vivo: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 6) treated with daily i.p. doses of remdesivir 5 mg/kg on day 1 and 2.5 mg/kg on days 2-10. Ex vivo remdesivir (3, 10, and 30 µmol/L) had no statistically significant effect on MAPD 90 , while pacing the hearts at basic stimulation cycle lengths of 200 or 250 milliseconds, or when the hearts were not paced and beating at their intrinsic heart rate. In a second set of similar ex vivo experiments, remdesivir 10 µmol/L did not potentiate the MAPD 90 -prolonging effects of dofetilide 20 nmol/L (n = 4) hearts. In vivo remdesivir caused small but statistically significant prolongations of the RR and QTc F intervals at day 1 (5 mg/kg) and at day 10 (2.5 mg/kg). No ventricular arrhythmias were ever observed under the effect of remdesivir. Remdesivir causes bradycardia, and mild QTc prolongation, which nonetheless, could be of clinical relevance in many hospitalized patients with COVID-19 concomitantly treated with multiple drugs.

The emotional well-being of Long COVID patients, widening social support and stigmatization in health and social services: a qualitative study (preprint)

Introduction: Long COVID patients have experienced a decline in their quality of life caused, in part but not wholly, by its negative emotional impact. Some of the most prevalent mental symptoms presented by Long COVID patients are anxiety, depression, and sleep disorders. Therefore, the need has arisen to establish the personal experiences of these patients to understand how they are managing in their daily lives while dealing with the condition. Objective: To increase understanding of the emotional well-being of people diagnosed with Long COVID. Methodology: A qualitative design was created and carried out using 35 patients, with 17 subjects being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study themes were emotional well-being, social support networks and experience of discrimination. All analyzes were performed iteratively using NVivo software. Results: The Long COVID patients demonstrated a very low state of mind due to their symptoms and limitations that had been persistent for many months in their daily life. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most identified discriminatory situations in health care. Conclusion: It is necessary to continue delving into the impact that Long COVID has had on mental health, and to provide entities with the necessary resources to solve these problems.

An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Hydroxychloroquine (HCQ)-associated cardiovascular adverse events (CVAEs) have been increasingly reported. AIM: This study aimed to present an observational, retrospective, and comprehensive pharmacovigilance analysis of CVAE associated with HCQ in patients with and without COVID-19 using the US Food and Drug Administration Adverse Events Reporting System (FAERS) data from January 2020 to December 2020. METHOD: We identified 3302 adverse event reports from the FAERS database in the year 2020 and divided them into COVID-19 and non-COVID-19 groups, respectively. Then we analyzed whether there were differences in CVAEs between the two groups. RESULTS: We found that CVAE was higher in cases with COVID-19 compared to those without COVID-19, odds ratio (OR) of 1.26 and a 95% confidence interval (95% CI) of 1.02-1.54. Cases with COVID-19 treated with HCQ exhibited relatively higher proportions of torsade de points (TdP) and QT prolongation (OR 3.10, 95% CI 2.24-4.30), shock-associated TdP (OR 2.93, 95% CI 2.13-4.04), cardiac arrhythmias (OR 2.07, 95% CI 1.60-2.69), cardiac arrhythmia terms (including bradyarrhythmias and tachyarrhythmias) (OR 2.15, 95% CI 1.65-2.80), bradyarrhythmias (including conduction defects and disorders of sinus node function) (OR 2.56, 95% CI 1.86-3.54), and conduction defects (OR 2.56, 95% CI 1.86-3.54). CONCLUSION: Our retrospective observational analysis suggested that the proportion of CVAE associated with HCQ, especially TdP and QT prolongation, was higher in patients with COVID-19. Understanding the effects of COVID-19 on the cardiovascular system is essential to providing comprehensive medical care to patients receiving HCQ treatment.

Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study (preprint)

Despite the increasing prevalence of patients with Long Covid Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization. To address these issues, we performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long Covid Syndrome (LCS) patients. Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS). Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups. Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients. The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients. In summary, here we present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.

Sonographic Diaphragm Dysfunction is an Unexpectedly Frequent Feature of Long COVID with Non-Specific Dyspnea and Fatigue (preprint)

Introduction/Aims The primary aim of this study is to define the sonographic diaphragm phenotype of Long COVID patients with non-specific dyspnea and fatigue. We analyzed patients referred from a pulmonary medicine COVID clinic without any intrinsic cardiopulmonary explanation for their new symptoms. Additionally, we report the functional outcomes of patients who completed an outpatient cardiopulmonary physical therapy program. Methods This was a retrospective cohort study (n = 37) of consecutive patients referred for neuromuscular assessment centered on B-mode ultrasound of the diaphragm muscle. Patients were recruited from a single academic hospital between February 25, 2021 and October 7, 2021. Results Sonographic abnormalities were identified in 65% (24/37) of patients, and in the vast majority of cases (23/24) was defined by low diaphragm muscle thickness. Thinner diaphragm muscles positively correlated with lower serum creatinine and creatine kinase values, but there was no association with markers of systemic inflammation. Eighteen patients participated in outpatient cardiopulmonary physical therapy that included respiratory muscle training, and 77.8% (n=14) had documented improvement. Discussion In the outpatient rehabilitation setting, patients with Long COVID frequently display low diaphragm muscle thickness, but intact muscle contractility on sonographic studies. We speculate this represents a form of disuse atrophy, which has a good response rate to cardiopulmonary physical therapy.

Use of Chinese herbs to treat symptoms likely related to COVID-19: Survey analysis of licensed acupuncturists in the United States (preprint)

Objective: The objective of this study was to examine the prescribing of Chinese herbal medicine (CHM) by licensed acupuncturists in the United States during the COVID-19 pandemic. Methods: A 28-question survey with nine branching questions was disseminated through collegial networks, paid advertisements, and a study website in April-July 2021. Participants indicated they were licensed acupuncturists that treated more than five patients for symptoms likely related to COVID-19 to gain entry to the full survey. Surveys were undertaken electronically through the Research Electronic Data Capture (REDCap) system. Results: The survey was undertaken by 103 participants representing all US geographic regions, and had an average of 17 years in practice. Sixty-five percent received or intended to receive the COVID-19 vaccine. Phone and videoconference were the predominant methods of patient contact; granules and pill forms of CHM were the most commonly prescribed. A wide variety of information sources were used in devising patient treatments inclusive of anecdotal, observational, and scientific sources. Most patients were not receiving biomedical treatment. Ninety-seven percent of participants reported that they had no patients die of COVID-19, and the majority reported less than 25% of their patients developed long hauler syndrome (post-acute sequelae SARS-CoV-2 infection). Conclusions: This study demonstrates that licensed acupuncturists were treating COVID-19 infected individuals in the US during the early stages of the pandemic, and for many such patients this was the only therapeutic intervention they had access to from a licensed healthcare provider. Information disseminated from China through collegial networks, along with published sources including scientific studies, informed the approach to treatment for the vast majority of the acupuncturists surveyed. This study provides insight into an unusual circumstance in which clinicians needed to establish evidence-based approaches to the treatment of a new disease in the midst of a public health emergency.