Long Covid Weekly: #141 16,000 Patients, 1 Gene, 1.63× Risk: Inside Long COVID’s Multi-System Siege
FOXP4’s surprising role in lingering symptoms, plus the latest on mitochondrial “rescue missions,” brain-fog biology, and silent cardiac risks.
🗞️ Ever wonder what lingering COVID might be doing deep inside our cells and brains? This week, fresh insights reveal how long COVID reshapes everything—from our genetic blueprint to mitochondrial rescue missions and even unexpected cognitive challenges.
🗞️ Article of the week: This week's article of the week, "Genome-wide association study of long COVID," published in Nature Genetics, explores the genetic factors that may influence an individual’s susceptibility to long COVID. The study draws on a large dataset comprising nearly 16,000 long COVID patients and over 1.8 million controls, highlighting the importance of genetic predispositions in post-viral conditions.
A couple of key findings highlighted in the study:
The FOXP4 risk allele was associated with an increased risk of long COVID with an odds ratio of 1.63, indicating notable genetic vulnerability.
A causal relationship was established between severe COVID-19 and the risk of long COVID, underscoring the complex interplay between acute infection severity and long-term health outcomes.
Research
Article: Genome-wide association study of long COVID | Nature Genetics
Alternative title: Genetic Variants Linked to Long COVID Risk
🗞️ Definitions
FOXP4: A transcription factor gene implicated in lung physiology and potentially in long COVID due to its association with respiratory health.
Odds Ratio (OR): A statistic indicating how much more likely an outcome is to occur in one group compared to another.
🗞️ Summary
The study identifies significant associations between variants in the FOXP4 locus and the risk of developing long COVID, independent of COVID-19 severity.
The FOXP4 risk allele was associated with an increased risk of long COVID with an odds ratio of 1.63, indicating notable genetic vulnerability.
The research included a comprehensive analysis of up to 15,950 individuals with long COVID and 1,892,830 population controls across 24 studies and 16 countries.
A causal relationship was established between severe COVID-19 and the risk of long COVID, underscoring the complex interplay between acute infection severity and long-term health outcomes.
🗞️ Stats/trends
The GWAS meta-analysis included 15,950 long COVID cases and over 1.8 million controls, providing a robust dataset for investigating genetic links.
Variants at the FOXP4 locus showed significant associations with long COVID.
Higher FOXP4 expression levels in blood were linked to a 2.31-fold increased risk of developing long COVID
Article: Assessing a multicomponent intervention to improve quality of life in individuals with Long COVID (COVIDL/MIQoL): study protocol for a randomized controlled trial | Frontiers in Public Health
Study Examines Efficacy of Holistic Intervention to Enhance Quality of Life for Long COVID Patients
🗞️ Definitions
Multicomponent Intervention: A therapeutic approach that combines multiple treatment methods to address various aspects of a disease.
Randomized Controlled Trial (RCT): A study design that randomly assigns participants to an intervention or control group to assess effectiveness.
Cohen's d: A statistical measure used to express the size of an effect or the difference between two groups.
🗞️ Summary
The study protocol aims to assess the effectiveness of a multicomponent intervention to improve quality of life in individuals diagnosed with Long COVID.
A total of 108 participants will be recruited for a randomized controlled trial, comparing outcomes between an intervention and a control group.
The intervention will include 18 sessions of psycho-education and physical rehabilitation over 9 weeks, focusing on various aspects of recovery.
Outcomes will be assessed at baseline, post-intervention, and during follow-up, measuring mental well-being, resilience, and fatigue levels
🗞️ Stats/trends
The sample size of 108 participants will consist of 54 individuals per group, ensuring power to detect significant differences in outcomes.
The intervention will be conducted by trained psychologists and physiotherapists from January to March 2025.
Outcome measures will include the EuroQol5D-5L for quality of life, Warwick-Edinburgh Mental Well-Being Scale for mental well-being, and Hospital Anxiety and Depression Scale for anxiety and depression assessment.
Article: How pandemics reshape our brain: Common links and targets between long‐haul COVID‐19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration | Neuroprotection
Study Links Long-Haul COVID-19 and ME/CFS, Urging Increased Research on Shared Causes
🗞️ Definitions
Oxidative Stress: An imbalance between free radicals and antioxidants in the body that can lead to cellular damage and contribute to various diseases.
Neuroinflammation: Inflammation of nervous tissue implicated in ME/CFS and long-haul COVID-19.
🗞️ Summary
This study highlights the intricate relationship between long-haul COVID-19 and ME/CFS, emphasizing their shared pathophysiological features.
The prevalence of ME/CFS may surge post-COVID-19, as approximately half of long-haul COVID-19 patients meet the criteria for this syndrome.
Oxidative stress is proposed as a central contributor to both conditions, driving neuroinflammation and impairing cellular functions.
Increased funding and research surrounding long-haul COVID-19 provide an unprecedented opportunity to investigate ME/CFS further.
🗞️ Stats/trends
Following COVID-19 infections, the rate of ME/CFS could rise to between 5 and 9 million in the U.S.
Long-haul COVID-19 has been reported in 8% to 18% of adults infected with the virus, with severe cases linked to increased risks of autoimmune disorders.
Article: Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics | Frontiers in Immunology
Study Links Mitochondrial Dysfunction to Ongoing Fatigue in Post-COVID-19 Patients, Urges More Research
🗞️ Definitions
Mitochondrial Dysfunction: Impairment of mitochondrial function, leading to decreased ATP synthesis, increased oxidative stress, and metabolic abnormalities.
Magnetic Resonance Spectroscopy (MRS): A non-invasive imaging technique to assess metabolic processes in vivo, particularly mitochondrial function.
🗞️ Summary
The review identifies mitochondrial dysfunction as a central mechanism in Post-COVID-19 Condition (PCC), contributing to persistent symptoms such as fatigue and metabolic derangements.
Magnetic resonance spectroscopy (MRS) emerges as a promising tool for evaluating mitochondrial function and guiding nutritional interventions in PCC patients.
Nutrients like Coenzyme Q10, N-acetylcysteine, and creatine have shown potential in restoring energy metabolism and alleviating oxidative stress among affected individuals.
The study highlights significant gaps in the understanding of nutritional strategies, including the need for standardization of MRS methodologies and long-term efficacy data.
🗞️ Stats/trends
MRS techniques revealed correlations between elevated resting phosphocreatine levels and reduced oxidative flux in post-COVID-19 patients.
Nutritional deficiencies significantly increase the risk of PCC, particularly among vulnerable populations, such as cancer patients.
The Molecular Mechanisms of Cognitive Dysfunction in Long COVID: A Narrative Review | International Journal of Molecular Sciences
Long COVID Linked to Neuroinflammation and Potential Similarities to Alzheimer’s Disease
🗞️ Definitions
Neuroinflammation: An inflammatory response within the brain or spinal cord, potentially contributing to neurological symptoms in long COVID.
Amyloid-beta: A protein that accumulates in the brains of Alzheimer’s disease patients, possibly linking long COVID to neurodegenerative processes.
🗞️ Summary
The review suggests that cognitive dysfunction in long COVID may stem from neuroinflammation, oxidative stress, and altered blood-brain barrier permeability.
Shared pathogenic mechanisms between long COVID and Alzheimer’s disease indicate a possible link between viral infection and neurodegenerative processes.
Molecular markers such as inflammatory cytokines and amyloid-beta levels may serve as potential therapeutic targets for managing cognitive symptoms in long COVID patients.
Neurological and cognitive manifestations were reported in up to 80% of individuals recovering from COVID-19, highlighting the urgent need for further research.
The review emphasizes the importance of multi-disciplinary approaches to address the complex symptomatology of long COVID, including cognitive impairment.
🗞️ Stats/trends
Up to 80% of COVID-19 survivors experience neurological or cognitive symptoms during their recovery.
The review analyzed data from over 200 articles focusing on neurological manifestations associated with long COVID.
Elevated levels of inflammatory cytokines were found in the cerebrospinal fluid of long COVID patients compared to healthy controls, indicating significant neuroinflammatory activity.
Article: Intrinsic factors behind long COVID: exploring the role of nucleocapsid protein in thrombosis | PeerJ
SARS-CoV-2 Nucleocapsid Protein Contributes to Severe COVID-19 Complications
🗞️ Definitions
Nucleocapsid Protein (NP): A structural protein of SARS-CoV-2 essential for viral replication and assembly, known to interact with host immune pathways and contribute to disease severity.
Endothelial Dysfunction: A condition where the endothelium fails to maintain normal vascular function, leading to increased inflammation and thrombosis.
Cytokine Storm: An overactive immune response characterized by high levels of pro-inflammatory cytokines, contributing to tissue damage.
🗞️ Summary
This review elucidates the roles of the SARS-CoV-2 nucleocapsid protein (NP) in COVID-19 pathogenesis, particularly its contributions to hyperinflammation and thrombosis.
The NP activates the TLR2/NF-κB and MAPK signaling pathways, exacerbating endothelial dysfunction and promoting thrombotic events.
Patients with severe COVID-19 exhibit elevated levels of soluble ICAM-1 and VCAM-1, which correlate with increased endothelial dysfunction and multiorgan damage.
The NP may contribute to long COVID symptoms through mechanisms such as liquid-liquid phase separation, leading to persistent inflammation.
🗞️ Stats/trends
The review analyzed 149 peer-reviewed studies exploring the role of SARS-CoV-2 NP in COVID-19 and its long-term impacts.
Elevated soluble ICAM-1 and VCAM-1 levels were noted in severe cases, indicating significant endothelial activation and increased thrombosis risks.
Long COVID symptoms were observed in approximately 40% of patients, highlighting the need for research into the persistent effects of SARS-CoV-2 NP.
Article: Cardiac risk in recovered Covid-19 patients evaluated by 123I-mIBG | Scientific Reports
Study Finds Long-Term Cardiac Changes in COVID-19 Patients Without Prior Heart Conditions
🗞️ Definitions
HMR: Heart-to-mediastinum ratio, indicating risk for cardiac events based on mIBG imaging.
LVEF: Left ventricular ejection fraction, a measure of cardiac function.
🗞️ Summary
The study revealed increased cardiac sympathetic activity in 67.7% of recovered COVID-19 patients without pre-existing cardiac conditions, suggesting potential autonomic dysfunction.
Follow-up assessments at 6–8 months indicated that 70.4% of these patients still exhibited cardiac sympathetic innervation abnormalities, with only 3 normalizing their HMR values.
At 12–15 months post-diagnosis, all nine patients with initial sympathetic dysfunction continued to show persistently abnormal HMRs, raising concerns about long-term cardiovascular implications.
The findings highlight that even in asymptomatic individuals without known heart disease, COVID-19 can cause significant alterations in cardiac sympathetic regulation.
Enhanced monitoring of patients for potential cardiac complications is warranted, as increased sympathetic activity is a known negative prognostic factor in cardiovascular health.
🗞️ Stats/trends
The study analyzed 33 recovered COVID-19 patients, with a median age of 40 years and a mean body mass index (BMI) of 26.2.
Cardiac mIBG imaging showed that 67.7% of patients had reduced mIBG uptake initially, which persisted in 70.4% after 6–8 months.
Pathologically reduced HMR values (≤ 1.6) were found in 9.1% of patients at initial imaging and increased to 18.5% by follow-up.
Article: Long-term outcomes of patients with pre-existing coronary artery disease after SARS-CoV-2 infection | The Lancet
Patients with coronary artery disease have poorer long-term outcomes after SARS-CoV-2 infection
🗞️ Summary
SARS-CoV-2 can contribute to the destabilization of atherosclerotic plaques. Severe COVID-19 can exploit these plaques, posing a threat long after the acute infection phase.
This retrospective cohort study compared long-term outcomes of patients with pre-existing coronary artery disease (CAD) after SARS-CoV-2 infection.
Compared to COVID-19 negative controls, patients hospitalised with COVID-19, but not patients not hospitalised with COVID-19, had higher future risk of MACE (adjusted HR = 1.58), all-cause mortality, congestive heart failure (CHF), myocardial infarction (MI), and stroke up to four years post-infection (p < 0.05).
This increased risk was independent of age, sex, race, ethnicity, pre-existing comorbidities, and socioeconomic status.
COVID-19 positive patients not hospitalized with COVID-19 were at higher risk of CHF than patients in the COVID negative group.
Study authors conclude that patients with pre-existing CAD who have had a severe COVID-19 disease course should be carefully monitored for adverse cardiovascular events.
Article: Comparison of long COVID, recovered COVID, and non-COVID Post-Acute Infection Syndromes over three years | Plos One
Long COVID Patients Display Distinct Symptoms and Comorbidities Compared to Other Post-Infection Cases
🗞️ Definitions
Charlson Comorbidity Index (CCI): A score predicting mortality and health outcomes based on pre-existing conditions.
Electronic Health Records (EHR): Digital versions of patients' medical history used for clinical decision-making and research.
🗞️ Summary
The study compared long COVID patients with recovered COVID patients and non-COVID post-acute infection syndrome (PAIS) cases, revealing significant differences in clinical characteristics and outcomes.
Patients with long COVID had a higher Charlson comorbidity index, indicating a greater burden of pre-existing health issues.
During the acute phase, individuals with long COVID reported more severe symptoms, including abnormal heart rhythms and cognitive difficulties.
Many symptoms persisted beyond 30 days post-infection, with the long COVID cohort showing strong associations with malaise, fatigue, and cognitive issues compared to non-COVID PAIS patients.
The findings highlight similarities between long COVID and non-COVID PAIS, suggesting that risk factors may be prevalent regardless of the infectious agent involved.
🗞️ stats/trends
The study analyzed records from 580 long COVID patients, 7,437 recovered COVID patients, and 106 non-COVID PAIS patients from the University of Washington Medicine EHR database.
The long COVID group exhibited a median Charlson comorbidity index of 2, significantly higher than the 1 seen in both recovered COVID and non-COVID PAIS groups.
Severe symptoms such as abnormal heart rhythms and cognitive difficulties were more prevalent in long COVID patients, with odds ratios of 5.31 and 5.14, respectively.
Article: 12-Month trajectories of physical and mental symptom scores after COVID-19 hospitalization and their role in predicting “very long” COVID | Frontiers in Rehabilitation Sciences
Study Reveals High Rates of Long COVID Symptoms Persisting Beyond a Year in Hospitalized Patients
🗞️ Definition
Predictive Model: A framework that forecasts the likelihood of future outcomes, such as the persistence of long COVID symptoms.
🗞️ Summary
The study found that 76% of hospitalized COVID-19 patients reported long COVID symptoms at three months, decreasing to 43% by twelve months.
The EFTER-COVID and PCFS scales effectively differentiated between patients with and without long COVID symptoms, with significantly higher scores in the LCS (Long Covid Syndrome) cohort throughout the follow-up period.
Younger patients (<40 years) recovered more quickly and exhibited lower symptom scores compared to older patients (>60 years), who showed prolonged respiratory and cognitive issues at twelve months.
A machine learning model incorporating survey-based scores at three months achieved 91% predictive accuracy for LCS persistence at twelve months.
The findings advocate for early, survey-based symptom assessments as tools for predicting long-term health outcomes and facilitating targeted rehabilitation for COVID-19 survivors.
🗞️ Stats/trends
The study followed 166 hospitalized COVID-19 survivors, evaluating them pre-discharge and at 1, 3, and 12 months post-discharge.
Persistent LCS symptoms were reported by 88% at one month, decreasing to 76% by three months, and 43% by twelve months.
EFTER-COVID scores showed significant differences, with LCS patients having a cumulative physical symptom score of 25.3 ± 6.7 compared to 16.2 ± 5.5 in recovered patients (P < 0.001).
Article: Elevated adipokines and myokines are associated with fatigue in long COVID patients | Frontiers in Medicine
Study Shows High Rates of Fatigue Among COVID-19 Survivors
🗞️ Definitions
Myokines: Hormones secreted by muscle tissue involved in metabolic regulation
ICU Admission: The requirement for intensive medical care, typically linked to poorer long-term recovery outcomes post-COVID-19.
SF-36 Questionnaire: A widely used survey tool measuring health-related quality of life across various dimensions, including physical and mental health.
🗞️ Summary
The study found that 34% of evaluated COVID-19 patients reported new or worsening fatigue four months post-discharge, highlighting its prevalence among long COVID patients.
ICU admission during acute COVID-19 illness emerged as a significant risk factor for persistent fatigue, with an odds ratio of 2.65.
Elevated serum levels of myostatin and irisin were significantly associated with post-COVID fatigue, suggesting possible myopathic mechanisms.
Patients experiencing fatigue had significantly lower scores across multiple domains of the SF-36 questionnaire, indicating diminished functional capacity and quality of life.
The findings underscore the need for further research to elucidate mechanisms contributing to fatigue in post-COVID patients and develop targeted therapeutic strategies.
🗞️ Stats/trends
A total of 88 patients were evaluated in this study, with fatigue reported by 34% during follow-up assessments conducted at least four months post-discharge.
ICU admission emerged as a significant risk factor for fatigue with an odds ratio of 2.65 (95% CI: 1.03–6.94).
Fatigued patients had significantly elevated mean levels of myostatin (93.0 pg/mg vs. 74.0 pg/mg, P < 0.001) and irisin (789.0 pg/mg vs. 536.5 pg/mg, P = 0.001).
Scores on the SF-36 for fatigued patients were significantly lower in multiple domains, including physical functioning and vitality (P < 0.05).
Article: Long COVID’s Hidden Complexity: Machine Learning Reveals Why Personalized Care Remains Essential | Journal of Clinical Medicine
Machine Learning Shows Need for Personalized Care for Long COVID
🗞️ Definitions
Machine Learning: A branch of artificial intelligence that utilizes algorithms to analyze and interpret complex data, enabling predictive analytics and personalized treatment options.
Predictive Models: Statistical tools used to forecast outcomes based on historical and current data, often employing machine learning techniques.
🗞️ Summary
The study utilizes machine learning to identify distinct symptom clusters in Long COVID patients, revealing significant variability in individual experiences and recovery trajectories.
Through predictive modeling, researchers established that demographic factors and symptom severity play critical roles in determining patient outcomes.
Patients with a fatigue-dominant cluster showed poorer recovery prospects than those with transient symptoms, highlighting the need for personalized care strategies.
The findings advocate for tailored interventions based on individual symptom profiles, suggesting a shift towards more nuanced healthcare approaches for Long COVID management.
Machine learning models improved accuracy in predicting recovery timelines by over 30%, demonstrating the potential utility of advanced analytics in clinical settings.
Article: Predicting Long-Term Health-Related Quality of Life in Individuals with Prior Sars-CoV-2 Infection: A 12-Month Prospective Study | Journal of Primary Care & Community Health
Shortness of Breath and Lower BMI Predict Lower Quality of Life After Sars-CoV-2 Infection
🗞️ Summary
This was a longitudinal, prospective, cohort study examining health-related quality of life (HRQoL) over a 12 month time frame of 82 participants with SARS-CoV-2 infection.
The study found that shortness of breath, a diagnosis of COPD, lower BMI, and a history of anxiety at the initial visit were all significantly associated with clinically meaningful worsening of HRQoL at 12 months. Specifically, individuals with these factors experienced more pronounced declines in HRQoL compared to those without.
Although the association with COPD is less reliable due to sample size limitations, these findings highlight the need for targeted interventions and continued support for patients exhibiting these risk factors to improve long-term HRQoL outcomes.
Future research with larger samples is needed to confirm these results and further investigate the role of these factors in post-COVID HRQoL declines.
Article: SARS-CoV-2 Spike Protein and Long COVID--Part 1: Impact of Spike Protein in Pathophysiological Mechanisms of Long COVID Syndrome | Viruses
The Spike Protein’s Role in Long COVID--Part 1 of a 2 Part Series
(Part 2 under Quicklinks)
🗞️ Summary
This review discusses the role of the SARS-CoV-2 spike protein (S protein) in the pathophysiology of Long COVID. It is broken into several parts.
Viral component or spike protein persistence:
Symptoms in Long COVID (LC) are modulated by a SARS-CoV-2 reservoir persistence, mainly by the spike protein (S), spike subunit S1, and nucleocapsid [N] proteins found in tissues and in circulation.
Long COVID could be driven by two underlying mechanisms: continuing viral replication and the presence of viral components even in the absence of active replication.
Epithelial and endothelial dysfunction:
Independent of infection and replication, epithelial and endothelial dysfunction has been linked to interaction between the S protein and cellular receptors. The S protein induces barrier dysfunction, vascular leak, and vascular inflammation.
The S protein and S1 subunit may play a vital role in the development of vascular long COVID across multiple systems.
Immune system dysregulation leading to increased levels of pro-inflammatory cytokines and autoantibodies:
SARS-CoV-2 infection can induce cross-reactive antibodies with host proteins through molecular mimicry, potentially sustained by the presence of a SARS-CoV-2 reservoir.
Damage to the Blood–Brain Barrier (BBB), mediated by the S protein, has been shown as a key factor in the brain damage and neurological symptoms associated with LC. Ongoing circulation of the S protein may be a risk factor directly related to the pathogenesis of Neuro-PASC.
Pathophysiological effects related to spike protein-based vaccines:
Concerns regarding the adverse effects of vaccines (AEVs) have come up after findings in assays and animal models using the S protein and its S1/S2 subunits, showing cell injury and pro-inflammatory responses in several cell types.
🔗 Quick Links
Gastrointestinal Barrier Disruption in Post-COVID Fatigue Syndrome Fatigue Patients | Allergy
Long-term Clinical Outcomes of Adults Hospitalized for COVID-19 Pneumonia
So much research! The one on Alzheimer’s is particularly interesting…and alarming.