Low-Cost Recruitment Approach: Utilizing Facebook Groups to Recruit COVID-19 Long-Haulers (preprint)

Introduction: The accessibility of social media (e.g., Facebook groups) presents long-haulers with the ability to connect with others with similar experiences and symptomology that are likely outside of their physical social networks. Social media sites may serve as promising platforms for research recruitment, public health campaigns, or interventions. The present study aims to assess, and comprehensively present, the effectiveness of a low-cost approach to recruitment through groups on Facebook within the context of a broader study of COVID-19 long-haulers. Methods: Facebook groups were searched using a variety of COVID-related terminology and included if they were in English, COVID-19 specific, public, and have or were approaching 1,000 or more members. Group administrators were either contacted for permission to post recruitment materials or posts were made and left pending administrator approval, depending on group settings. Group members were able to follow a link to the online survey platform (i.e., RedCap) where they provided informed consent and completed an online assessment of their COVID-19 experiences and psychosocial wellbeing. Upon survey completion participants were able to opt-in to a raffle-based incentive. The characteristics of the Facebook groups and demographic background of participants were assessed. Findings: Contacting administrators and posts made between January and March of 2022 within 17 COVID-19 specific groups yielded a sample size of 460 long-haulers. The groups relied upon for recruitment had a mean size of 21,022 (SD=45,645.3), most had three or more administrators (43%), and a majority were state specific (60%). The long-hauler participants enrolled from the posts had an average age of 32 years (SD=6.19), approximately split between men (48.91%) and women (50.22%), a majority white (70%), having earned a bachelor’s or postgraduate degree (63.48%), and reporting an annual income between $50,000 and $100,000 (56.09%). Discussion: The present study presents strengths and recommendations for survey recruitment through Facebook groups as a low-cost recruitment strategy that is easily targeted to populations with a specific health condition and allows users to complete online psycho-behavioral assessments off-site on a HIPPA compliant survey platform.

Cross-Sectional Survey of Acupuncturists in the United States Who Prescribed Chinese Herbal Medicine for Patients with Symptoms Likely Related to COVID-19.

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 that they were licensed acupuncturists who 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 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 that <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 United States 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 health care provider. Information disseminated from China through collegial networks, along with published sources including scientific studies, informed the approach to treatment. This study provides insight into an unusual circumstance in which clinicians needed to establish evidence-based approaches to the treatment of a new disease during a public health emergency.

COVID-19 Pandemic and Its Impact on Sleep Health: A Rapid Review

This rapid review aims to elucidate the impact of coronavirus 2 (SARS-CoV-2) (COVID) disease-both in the acute phase and the "long-hauler" syndrome-on sleep health. Literature regarding the direct physiologic impact of COVID disease on sleep is sparse but has illuminated a toxic synergy between the immune response to COVID disease and the proinflammatory state brought on by obstructive sleep apnea (OSA). Primary care physicians and sleep medicine specialists should aggressively screen for OSA in COVID patients.

The serum of COVID-19 asymptomatic patients up-regulates proteins related to endothelial dysfunction and viral response in circulating angiogenic cells ex-vivo.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused 6 million deaths worldwide. While asymptomatic individuals are responsible of many potential transmissions, the difficulty to identify and isolate them at the high peak of infection constitutes still a real challenge. Moreover, SARS-CoV-2 provokes severe vascular damage and thromboembolic events in critical COVID-19 patients, deriving in many related deaths and long-hauler symptoms. Understanding how these processes are triggered as well as the potential long-term sequelae, even in asymptomatic individuals, becomes essential. METHODS: We have evaluated, by application of a proteomics-based quantitative approach, the effect of serum from COVID-19 asymptomatic individuals over circulating angiogenic cells (CACs). Healthy CACs were incubated ex-vivo with the serum of either COVID-19 negative (PCR -/IgG -, n:8) or COVID-19 positive asymptomatic donors, at different infective stages: PCR +/IgG - (n:8) and PCR -/IgG + (n:8). Also, a label free quantitative approach was applied to identify and quantify protein differences between these serums. Finally, machine learning algorithms were applied to validate the differential protein patterns in CACs. RESULTS: Our results confirmed that SARS-CoV-2 promotes changes at the protein level in the serum of infected asymptomatic individuals, mainly correlated with altered coagulation and inflammatory processes (Fibrinogen, Von Willebrand Factor, Thrombospondin-1). At the cellular level, proteins like ICAM-1, TLR2 or Ezrin/Radixin were only up-regulated in CACs treated with the serum of asymptomatic patients at the highest peak of infection (PCR + /IgG -), but not with the serum of PCR -/IgG + individuals. Several proteins stood out as significantly discriminating markers in CACs in response to PCR or IgG + serums. Many of these proteins particiArticle title: Kindly check and confirm the edit made in the article title.pate in the initial endothelial response against the virus. CONCLUSIONS: The ex vivo incubation of CACs with the serum of asymptomatic COVID-19 donors at different stages of infection promoted protein changes representative of the endothelial dysfunction and inflammatory response after viral infection, together with activation of the coagulation process. The current approach constitutes an optimal model to study the response of vascular cells to SARS-CoV-2 infection, and an alternative platform to test potential inhibitors targeting either the virus entry pathway or the immune responses following SARS-CoV-2 infection.

COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler Looking for Clarity in the Haze of the Pandemic.

Post-acute sequelae of SARS-CoV-2 (PASC) is defined as persistent symptoms after apparent recovery from acute COVID-19 infection, also known as COVID-19 long-haul. We performed a retrospective review of electronic health records (EHR) from the University of California COvid Research Data Set (UC CORDS), a de-identified EHR of PCR-confirmed SARS-CoV-2-positive patients in California. The purposes were to (1) describe the prevalence of PASC, (2) describe COVID-19 symptoms and symptom clusters, and (3) identify risk factors for PASC. Data were subjected to non-negative matrix factorization to identify symptom clusters, and a predictive model of PASC was developed. PASC prevalence was 11% (277/2,153), and of these patients, 66% (183/277) were considered asymptomatic at days 0-30. Five PASC symptom clusters emerged and specific symptoms at days 0-30 were associated with PASC. Women were more likely than men to develop PASC, with all age groups and ethnicities represented. PASC is a public health priority.

The "Heart" of COVID-19: Brugada Syndrome and Post-SARS-CoV-2 Virus Cardiac Nursing Care.

Coronavirus disease (COVID-19) is an illness that was sudden, unexpected, and global. Primarily a disease of the vascular endothelium, the virus threatens all of core systems, as well as behavioral and mental health, during the acute and long-term phases. Attention is now being given to the identification and care of post-acute sequelae of COVID-19. This article presents the case of a "long hauler" who presented post-cardiac arrest with a history of COVID-19. Diagnosed with Brugada syndrome, his assessment, diagnosis, and care are discussed. In addition, the need for early identification and care for patients with post-COVID-19 symptoms is addressed.

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.

Cortical Grey Matter Volume Loss links to Neurological Sequelae in post COVID-19 “Long Haulers” (preprint)

Objective COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for more than 4 weeks define “long haulers”. There is limited information regarding damage to grey matter structures occurring in COVID-19 “long haulers”. Detecting possible anatomic changes related to COVID-19 is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) accurately analyzes, segments and quantifies brain volumes which allows for comparisons between infected COVID-19 “long haulers” and normative data from age and sex-matched healthy controls to obtain values based on their percentage of intracranial volume.Methods This study involved 19 consecutive post COVID-19 surviving “long haulers” who experienced neurologic symptoms. Each patient had Brain MRI with 3D VBM at median time of 72 days following laboratory confirmation. All patients had relatively mild respiratory symptoms which did not require oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain, forebrain parenchyma, cortical grey matter, hippocampus, and thalamus.Results The key finding is a statistically significant loss of cortical grey matter (CGM) volume in each COVID-19 “long hauler”. The loss of CGM volume likely contributes to long term neurological sequelae resulting from COVID-19 infection.Conclusion This study provides evidence for selective loss of volume in CGM as documented by 3D VBM in 19 COVID-19 “long haulers”. Damage to the CGM provides linkage to neurologic symptoms which can affect their quality of life.

ECMO Long Haulers: A Distinct Phenotype of COVID-19-Associated ARDS With Implications for Lung Transplant Candidacy.

BACKGROUND: Studies indicate that the recovery from coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome may be slower than other viral pneumonia. There are limited data to guide decisions among patients who need extracorporeal membrane oxygenation (ECMO) support, especially the expected time of recovery and considering lung transplantation (LT). METHODS: This was a retrospective chart review of patients with COVID-19-associated acute respiratory distress syndrome placed on ECMO between March 1, 2020, and September 15, 2021 (n = 20; median age, 44 y; range, 22-62 y; male:female, 15:5). We contrasted the baseline variables and clinical course of patients with and without the need for ECMO support >30 d (ECMO long haulers, n = 10). RESULTS: Ten patients met the criteria for ECMO long haulers (median duration of ECMO, 86 d; range, 42-201 d). The long haulers were healthier at baseline with fewer comorbidities but had worse pulmonary compliance and higher partial pressure of CO2. They had a significantly higher number of membrane oxygenator failures, changes to their cannulation sites, and suffer more complications on ECMO. One of the long hauler was bridged to LT while another 6 patients recovered and were discharged. Overall survival was better among the ECMO long haulers (70% versus 20%; 9.3, 1.2-73; P = 0.03). CONCLUSIONS: Despite worse pulmonary physiology, frequent complications, and a tortuous hospital course that may appear to portend a poor prognosis, ECMO long haulers have the potential to recover and be weaned off ECMO without the need for LT. A customized approach comprising a more conservative timeline for the consideration of LT may be prudent among these patients.

Impaired systemic oxygen extraction relates to reduced exercise capacity in post-covid-19 long hauler syndrome

Introduction: Following acute coronavirus 2019 (COVID-19) disease, at least 10% of patients report some form of residual limitation, most commonly dyspnea and fatigue. These COVID-19 “long haulers” experience symptoms that are largely unexplained by pulmonary function testing (PFT), echocardiogram and chest computed tomography (CT). Using invasive cardiopulmonary exercise testing, this pilot study characterized exercise limitation in 5 patients with persistent symptoms 1 year following mild COVID-19 illness. Methods: Following written informed consent, data were obtained in accordance with an IRBapproved protocol entailing placement of radial and pulmonary arterial catheters for pressure monitoring and blood sampling prior to and during maximum upright incremental exercise. Rest and exercise pulmonary hemodynamics, ventilation and gas exchange were recorded. Aerobic exercise capacity was estimated by peak O2 consumption (VO2 ). Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance <3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO2 <80% predicted). Reduced peak VO2 was associated with impaired systemic O2 extraction as indicated by an arterial-venous O2 content difference (adjusted for hemoglobin) of <80% (Figure 1). Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.

Inspiratory Muscle Training in ME/CFS and COVID-19 Survivors

Role of Nutritents for COVID-19 recovery: an integrative approach

Introduction: Many patients (“long-haulers”) suffer lingering illness following COVID-19. The aim of this presentation is to evaluate the evidence of nutrient deficiencies affecting immune function and chronic symptoms from covid19 infection in a subgroup of patients. We will discuss the potential benefit of supplementing with multi-nutrients as an integrative approach to reducing long-hauler symptoms. Methods: A narrative review followed a search of Medline/Pubmed, CINAHL, Google Scholar for studies published between January 2000 and March 2021, using key terms “coronavirus”, “COVID-19”, “immune system”, “inflammation”, “microbiome”, “oxidative stress”, “mitochondrial function”, “micronutrients”, “vitamin”, “minerals”, and “antioxidants”. Six reviews were selected which examined on the role of nutrients in immune and neurological function, including inflammatory processes, microbiome homeostasis, and mitochondrial function. Results: Symptoms of long-haulers may be similar to myalgic encephalomyelitis/chronic fatigue syndrome associated with mitochondria dysfunction due to oxidative stress. Similar findings of chronic inflammation and microbiome dysbiosis associated with mood disorders also suggest the association between nutrient deficiencies and immuno-neurological functions. Nutrients required for optimal immune function included: antioxidants such as CoQ10 is required for mitochondrial function and is depleted quickly during acute immune response. Vitamins C and E and selenium also have antioxidant properties that can decrease proinflammatory cytokines and increase leukocyte and NK cell function. The B vitamins are involved in decrease pro-inflammatory cytokines and increase NK cell activities. Similarly, these nutrients are required for optimal neurological functioning in the CNS. Conclusion: Initial evidence suggests chronic inflammatory processes in the CNS may contribute to the symptoms of covid-19 long-haulers. Given the complementary roles of different nutrient in immune response and CNS pathways, integrating multiple nutrients as treatment for long-haulers warrants further study. Keywords: post-covid syndrome, long hauler, micronutrient treatment;narrative review

Study to Assess the Safety and Pharmacokinetics of WP1122 in Healthy Volunteers

Comparison of SARS-CoV-2 Receptors Expression in Primary Endothelial Cells and Retinoic Acid-Differentiated Human Neuronal Cells.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is primarily responsible for coronavirus disease (COVID-19) and it is characterized by respiratory illness with fever and dyspnea. Severe vascular problems and several other manifestations, including neurological ones, have also been frequently reported, particularly in the great majority of "long hauler" patients. SARS-CoV-2 infects and replicates in lung epithelial cells, while dysfunction of endothelial and neuronal brain cells has been observed in the absence of productive infection. It has been shown that the Spike protein can interact with specific cellular receptors, supporting both viral entry and cellular dysfunction. It is thus clear that understanding how and when these receptors are regulated, as well as how much they are expressed would help in unveiling the multifaceted aspects of this disease. Here, we show that SH-SY5Y neuroblastoma cells express three important cellular surface molecules that interact with the Spike protein, namely ACE2, TMPRSS2, and NRP1. Their levels increase when cells are treated with retinoic acid (RA), a commonly used agent known to promote differentiation. This increase matched the higher levels of receptors observed on HUVEC (primary human umbilical vein endothelial cells). We also show by confocal imaging that replication-defective pseudoviruses carrying the SARS-CoV-2 Spike protein can infect differentiated and undifferentiated SH-SY5Y, and HUVEC cells, although with different efficiencies. Neuronal cells and endothelial cells are potential targets for SARS-CoV-2 infection and the interaction of the Spike viral protein with these cells may cause their dysregulation. Characterizing RNA and protein expression tempo, mode, and levels of different SARS-CoV-2 receptors on both cell subpopulations may have clinical relevance for the diagnosis and treatment of COVID-19-infected subjects, including long hauler patients with neurological manifestations.

Role of senescence in the chronic health consequences of COVID-19.

While the full impact of COVID-19 is not yet clear, early studies have indicated that upwards of 10% of patients experience COVID-19 symptoms longer than 3 weeks, known as Long-Hauler's Syndrome or PACS (postacute sequelae of SARS-CoV-2 infection). There is little known about risk factors or predictors of susceptibility for Long-Hauler's Syndrome, but older adults are at greater risk for severe outcomes and mortality from COVID-19. The pillars of aging (including cellular senescence, telomere dysfunction, impaired proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, genomic instability, progenitor cell exhaustion, altered intercellular communication, and epigenetic alterations) that contribute to age-related dysfunction and chronic diseases (the "Geroscience Hypothesis") may interfere with defenses against viral infection and consequences of these infections. Heightening of the low-grade inflammation that is associated with aging may generate an exaggerated response to an acute COVID-19 infection. Innate immune system dysfunction that leads to decreased senescent cell removal and/or increased senescent cell formation could contribute to accumulation of senescent cells with both aging and viral infections. These processes may contribute to increased risk for long-term COVID-19 sequelae in older or chronically ill patients. Hence, senolytics and other geroscience interventions that may prolong healthspan and alleviate chronic diseases and multimorbidity linked to fundamental aging processes might be an option for delaying, preventing, or alleviating Long-Hauler's Syndrome.

Cellular Senescence and COVID-19 Long-Hauler Syndrome

Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers.

As the numbers of acute severe acute respiratory syndrome coronavirus 2 infections continue to rise, we are learning that symptoms do not resolve quickly in all patients. Although why some patients experience persistent symptoms is not clear, these individuals suffer. Long-hauler is the term that is associated with these persistent symptoms, and this review of the literature provides information to nurse practitioners working in primary care about symptoms, risk factors, and resources for disease management.

Why We Should Treat COVID-19 Long Hauler Syndromes with Convalescent Plasma; Contained Suppressive Exosomes are Likely COVID Antigen-Specific (preprint)

There have been numerous very disappointing results of Convalescent Plasma Therapy (CPT) in active infections with COVID-19 virus, raises a question of how to account for this, given the huge history of seeming benefit of CPT in a variety of infectious diseases over more than the past 100 years. We propose the following as a possible explanation, based on our experimental evidence. In CPT there is a collision between developed desirable viral resistance promoting hyper-immune antibodies and undesirable convalescent exosomes antigen (Ag)-specifically suppressing cellular immune responses stimulated by the prior now recovered acute viral disease. These inhibiting exosomes, that act to suppress Ag presenting cells and anti-COVID-19-Ag-specific effector T cells, are appropriate to convalescence, but when given early in infection may interfere with endogenous early developing profitable cellular immune anti-viral responses.To account for the high incidence of the Long Haulers post COVID patients, we postulate that these are due to immune reactivity to Ag remnants of the virus and not residual infection. These are postulated to held by and augmented by remnants of highly pathogenetic neutrophil extracellular traps (NETs). We propose that CPT with its content of potential broadly COVID Ag-specific suppressive exosomes be considered for possible effective treatment of the COVID-19 Long Hauler Syndromes. This certainly is so compared to the purported value of therapy with vaccines, as the diverse Ag-specific extracellular vesicles in the convalescent plasma would be an inhibitory influence on multiple COVID Ag-specific responses, beyond just to the spike protein of the virus.

COVID-19 Symptoms Over Time: Comparing Long-Haulers to ME/CFS.

INTRODUCTION: Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group. 278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences from an average of 21.7 weeks prior. METHODS: We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms. RESULTS: Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas. CONCLUSIONS: These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.