Long COVID is a complex, multisystem illness with a poorly understood pathophysiology, absence of specific diagnostic tests or criteria, or evidence-based treatments. With over 200 identified symptoms and approximately 10% of COVID-19 cases resulting in Long COVID, it is a challenge to provide comprehensive treatment at a scale commensurate with the illness burden. The diverse manifestations of Long COVID, encompassing numerous medical specialties, typically place primary care providers (PCPs) at the forefront of management, navigating an evolving landscape of research and lack of evidence-based guidelines. This paper presents a pragmatic, structured framework for Long COVID management in primary care, integrating current knowledge and best practices. The approach is individualized, addressing Long COVID\'s broad symptomatology through a four-step framework. The first step focuses on energy management strategies, emphasizing the prevention of post-exertional malaise, a cardinal feature of Long COVID. The second step, intentional rehabilitation, employs carefully titrated multidisciplinary modalities to address physical, cognitive, and emotional domains. The third step utilizes symptomatic management through both pharmacological and non-pharmacological interventions, targeting debilitating symptoms like fatigue, insomnia, and chronic pain. The fourth step outlines an approach to trialing experimental, targeted therapies that may impact Long COVID\'s underlying pathophysiology. These treatments, while experimental and lacking quality evidence in Long COVID, may be available off-label on an individual basis following a thorough risk-benefit discussion. This stepwise framework can equip PCPs to effectively address the most common and disabling symptoms of Long COVID, individualize care, and remain attuned to the evolving scientific understanding of the condition.

In the wake of the COVID-19 pandemic, millions worldwide are still struggling with persistent or recurring symptoms known as long COVID. Fatigue is one of the most prevalent symptoms associated with long COVID, and for many it can be debilitating. Understanding the potential pathological processes that link fatigue to long COVID is critical to better guide treatment. Challenges with diagnosis and treatment are reviewed, recognizing that post-COVID fatigue does not always present with corroborating clinical evidence, a situation that is frustrating for both patients and healthcare providers. Firefighters are a group of public safety workers who are particularly impacted by long COVID-related fatigue. Firefighters must be able to engage in strenuous physical activity and deal with demanding psychological situations, both of which may be difficult for those suffering from fatigue. Disruption in public safety worker health can potentially impact community welfare. This review creates a framework to explain the clinical-pathological features of fatigue resulting from long COVID, addresses diagnosis and treatment challenges, and explores the unique impact fatigue may pose for public safety workers and their organizations.

There is limited long-term evidence on the effects of COVID-19 on vascular injury between male and female sex. An adult cohort of COVID-19 survivors (COVID+) and confirmed SARS-CoV-2 antibody-negative participants (COVID-) were prospectively enrolled. COVID+ participants who have documented the presence of persistent symptoms four weeks following infection were considered to have post-acute sequelae of COVID-19 (PASC). Non-invasive, FDA-approved EndoPAT (Endo-PAT2000) was used for endothelial assessment. COVID-(n = 94) were 1:1 propensity score matched to COVID+ (n = 151) on baseline covariates including sex. Among COVID+, 66.2% (n = 100) had PASC. Higher levels of coagulation marker, D-dimer (p = 0.001), and gut permeability marker, zonulin (p = 0.001), were associated with female sex. Estimated differences in augmentation index (AI) between COVID- (0.9 ± 17.2) and COVID+ (8.4 ± 15.7; p = 0.001) and between female and male sex (12.9 ± 1.9; p < .0001) were observed. Among COVID+ with PASC, the average AI (10.5 ± 1.6) was 9.7 units higher than COVID- (p < .0001) and 6.2 units higher compared to COVID+ with no PASC (p = 0.03). COVID+ PASC+ female sex had the highest AI (14.3 ± 1.9). The effects of SARS-CoV-2 infection on vascular function varies across strata of sex and female sex in the post-acute phase of COVID-19 have the worse arterial elasticity (highest AI).

Endothelial dysfunction represents a measurable and early manifestation of vascular disease. Emerging evidence suggests cardiovascular risk remains elevated after COVID-19 infection for at least 12 months, regardless of cardiovascular disease status prior to infection. We review the relationship between the severity of endothelial dysfunction and the severity of acute COVID-19 illness, the degree of impairment following recovery in both those with and without postacute sequalae SARS-CoV-2 infection, and current therapeutic efforts targeting endothelial function in patients following COVID-19 infection. We identify gaps in the literature to highlight specific areas where clinical research efforts hold promise for progress in understanding the connections between endothelial function, COVID-19, and clinical outcomes that will lead to beneficial therapeutics.

UNASSIGNED: The long-lasting persistence of autoantibodies stands as one of the hypotheses explaining the multisystemic manifestations seen in individuals with post-COVID-19 condition. The current review offers restricted insights into the persistence of autoantibodies in plasma/serum in people with post-COVID symptoms.
UNASSIGNED: PubMed/MEDLINE, CINAHL, EMBASE, and Web of Science databases, as well as on medRxiv and bioRxiv preprint servers were searched up to January 5th, 2024. Papers investigating the presence of autoantibodies in plasma/serum samples in people with post-COVID symptoms were included. The Newcastle-Ottawa Scale (NOS) was used to assess methodological quality.
UNASSIGNED: From 162 identified records, five articles met all inclusion criteria; four studies included infected controls with no post-COVID symptoms whereas all five studies included non-infected controls (410 COVID-19 survivors with post-COVID symptoms, 223 COVID-19 survivors with no post-COVID symptoms as controls and 266 non-infected healthy controls). Four studies concluded that the presence of autoantibodies had a potential (but small) role in post-COVID-19 condition whereas one study concluded that autoantibodies were not associated. Quality assessment showed all studies had high methodological quality.
UNASSIGNED: Although evidence suggests that persistent autoantibodies can be associated with post-COVID symptoms, the clinical relevance of their presence seems modest at this stage. Current results highlight further research to clarify the role of autoantibodies in the development of post-COVID symptoms, guiding the development of tailored diagnostic and treatment approaches to enhance patient outcomes.
UNASSIGNED: https://osf.io/vqz28.

BACKGROUND: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified.
METHODS: In this single centre prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing. PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity.
RESULTS: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harbouring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.
CONCLUSIONS: Blood DNA methylation levels identify PASC, stratify PASC severity, and suggest that DNA motifs are targeted by circadian rhythm-regulating pathways in PASC.
BACKGROUND: This project has been funded by the following agencies: NIH-AI173035 (A. Jaitovich and R. Alisch); and NIH-AG066179 (R. Alisch).

UNASSIGNED: This study aims to systematically assess physical exercise-related symptoms of post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID) in coronavirus disease 2019 (COVID-19) survivors.
UNASSIGNED: Eight databases were systematically searched on March 03, 2024. Original studies that compared physical exercise-related parameters measured by exercise testing between COVID-19 survivors who recovered from SARS-CoV-2 infection over 3 months and non-COVID-19 controls were included. A random-effects model was utilized to determine the mean differences (MDs) or standardized MDs in the meta-analysis.
UNASSIGNED: A total of 40 studies with 6241 COVID-19 survivors were included. The 6-min walk test, maximal oxygen consumption (VO2max), and anaerobic threshold were impaired in COVID-19 survivors 3 months post-infection compared with non-COVID-19 controls in exercise testing, while VO2 were comparable between the two groups at rest. In contrast, no differences were observed in SpO2, heart rate, blood pressure, fatigue, and dyspnea between COVID-19 survivors and non-COVID-19 controls in exercise testing.
UNASSIGNED: The findings suggest an underestimation of the manifestations of PASC. COVID-19 survivors also harbor physical exercise-related symptoms of PASC that can be determined by the exercise testing and are distinct from those observed at rest. Exercise testing should be included while evaluating the symptoms of PASC in COVID-19 survivors.

Post-acute sequelae of Coronavirus (PASC), or Long COVID, has emerged as a critical health concern. The clinical manifestations of PASC have been described, but studies have not quantified the cardiopulmonary effects. The goal of this study was to quantify PASC cardiopulmonary changes among endurance athletes. Endurance athletes were recruited via social media; 45 met inclusion criteria, 32 had PASC and 13 were asymptomatic at 3 months (control). Comprehensive interviews were conducted to assess: cardiopulmonary symptoms at 3 months; quantitative and qualitative changes in cardiovascular endurance; exercise hours per week at baseline and 3 months; and Modified Oslo, Dyspnea, and EQ-5D-5L scales. All collected data was based on self-reported symptoms. Wilcoxon rank sum compared PASC with control to distinguish the effects of PASC vs effects of COVID infection/lockdown. PASC subjects were more likely to be female (Table). The most common 3-month symptoms in PASC were fatigue and shortness of breath. Based on self-reported data, subjects endorsed a median decrease of 27% in cardiopulmonary endurance levels compared with 0% in controls (p = 0.0019). PASC subjects exercised less hours and had worse self-reported health as compared with controls. PASC subjects also had significantly worse Modified Oslo, Dyspnea, and EQ-5D-5L scores. Of the 32 PASC patients, 10 (31%) reported a complete inability to engage in any cardiovascular endurance exercise at 3 months. PASC leads to a significant, quantifiable decrease in cardiopulmonary health and endurance.

UNASSIGNED: The relationship between SARS-CoV-2 viral dynamics during acute infection and the development of long COVID is largely unknown.
UNASSIGNED: A total of 7361 asymptomatic community-dwelling people enrolled in the Test Us at Home parent study between October 2021 and February 2022. Participants self-collected anterior nasal swabs for SARS-CoV-2 RT-PCR testing every 24-48 hours for 10-14 days, regardless of symptom or infection status. Participants who had no history of COVID-19 at enrollment and who were subsequently found to have ≥1 positive SARS-CoV-2 RT-PCR test during the parent study were recontacted in August 2023 and asked whether they had experienced long COVID, defined as the development of new symptoms lasting 3 months or longer following SARS-CoV-2 infection. Participant\'s cycle threshold values were converted into viral loads, and slopes of viral clearance were modeled using post-nadir viral loads. Using a log binomial model with the modeled slopes as the exposure, we calculated the relative risk of subsequently developing long COVID with 1-2 symptoms, 3-4 symptoms, or 5+ symptoms, adjusting for age, number of symptoms, and SARS-CoV-2 variant. Adjusted relative risk (aRR) of individual long COVID symptoms based on viral clearance was also calculated.
UNASSIGNED: 172 participants were eligible for analyses, and 59 (34.3%) reported experiencing long COVID. The risk of long COVID with 3-4 symptoms and 5+ symptoms increased by 2.44 times (aRR: 2.44; 95% CI: 0.88-6.82) and 4.97 times (aRR: 4.97; 95% CI: 1.90-13.0) per viral load slope-unit increase, respectively. Participants who developed long COVID had significantly longer times from peak viral load to viral clearance during acute disease than those who never developed long COVID (8.65 [95% CI: 8.28-9.01] vs. 10.0 [95% CI: 9.25-10.8]). The slope of viral clearance was significantly positively associated with long COVID symptoms of fatigue (aRR: 2.86; 95% CI: 1.22-6.69), brain fog (aRR: 4.94; 95% CI: 2.21-11.0), shortness of breath (aRR: 5.05; 95% CI: 1.24-20.6), and gastrointestinal symptoms (aRR: 5.46; 95% CI: 1.54-19.3).
UNASSIGNED: We observed that longer time from peak viral load to viral RNA clearance during acute COVID-19 was associated with an increased risk of developing long COVID. Further, slower clearance rates were associated with greater number of symptoms of long COVID. These findings suggest that early viral-host dynamics are mechanistically important in the subsequent development of long COVID.

COVID-19 patients often suffer from post-COVID-19 acute sequelae (PASC). Pulmonary fibrosis has the most significant long-term impact on the respiratory health of patients, known as post-COVID-19 pulmonary fibrosis (PC19-PF). PC19-PF can be caused by acute respiratory distress syndrome (ARDS) or COVID-19-induced pneumonia. Individuals who experience COVID-19 pneumonia symptoms (including cough, shortness of breath, dyspnea on exertion, and desaturation) for at least 12 weeks after diagnosis, almost all develop PC19-PF. Extracellular matrix molecules: laminin (LN), type IV collagen (IV Col), procollagen III N-terminal peptide (PIIINP), and hyaluronic acid (HA) are involved in the development and progression of PC19-PF. This study aimed to investigate the relationship between the progression of PC19-PF and serum levels of laminin, IV COL, PIIINP, and hyaluronic acid. This retrospective study included 162 PC19-PF patients treated and 160 healthy controls who received treatment at Shenzhen Longgang District Third People\'s Hospital, Hebei PetroChina Central Hospital and Changzhi People\'s Hospital from January 2021 to December 2023. Serum levels of LN, IV COL, PIIINP, and HA were detected by chemiluminescence immunoassay using commercial kits. Predicted forced vital capacity percentage (FVC% pred), predicted carbon monoxide lung diffusion capacity percentage (DLCO% pred), high-resolution computed tomography (HRCT) scores were assessed, and patient mortality was compared with healthy controls. Serum levels of LN, IV Col, PIIINP, and HA were significantly higher in PC19-PF or CTD-ILD patients than in healthy controls (all p < 0.05), and they were further elevated in acute exacerbation cases (all p < 0.01). In patients, HA was positively associated with HRCT scores and negatively associated with FVC% pred and DLCO% pred (all p < 0.05). Serum levels of LN, IV COL, PIIINP, and HA were significantly lower in surviving patients than in those who deceased (all p > 0.05). Serum levels of LN, IV C, PIIINP, and HA may affect the progression of PC19-PF and may serve as indicators of PC19-PF severity.