Long Covid Weekly #115 : Antiviral Agents, immune exhaustion, off-label treatments?
This newsletter features pivotal studies exploring treatments, healthcare accessibility, and the implications of Long COVID on cognitive health, including exciting new investigations into immune responses and the use of off-label drugs. With research initiatives gaining momentum and significant funding allocated for further studies, we aim to highlight the critical advancements and ongoing challenges faced by patients and healthcare providers alike.
This week's article of the week, titled "Long Covid: a global health issue – a prospective cohort study set in four continents," explores the long-term effects of COVID-19 across various economic regions, emphasizing disparities between high-income countries (HICs) and low- to middle-income countries (LMICs). The study assesses symptoms and health impacts on a large cohort, revealing critical insights into the prevalence and nature of Long COVID.
Key findings from the study include:
"The proportion identified with Long Covid was significantly higher in HICs vs LMICs at both assessment time points (69.0% vs 45.3%, p<0.001; 69.7% vs 42.4%, p<0.001)." This statistic underscores the high burden of long-term symptoms encountered by those in wealthier nations compared to their counterparts in resource-constrained settings.
"Although the prevalence was higher in HICs versus LMICs, the impact of Long COVID may be greater in LMICs if there is a lack of support systems available.”
These findings call for increased attention to the disparities in healthcare access and treatment related to Long COVID globally and suggest a need for more targeted support and resources in LMICs.
Media
Article: Long Covid patients deserve to try off-label drugs | STAT
DEFINITIONS:
Off-label prescribing: The practice of prescribing drugs for conditions or populations not specifically approved by regulatory agencies like the FDA. This is a very common practice throughout the medical field.
Microclots: Tiny blood clots that may disrupt normal blood flow and are proposed contributors to certain symptoms experienced by Long COVID patients.
SUMMARY:
Almost five years into the pandemic, there is still no FDA-approved treatment for long Covid, affecting over 400 million people worldwide.
Authors Julia Moore Vogel and Charlie McCone highlight the slow pace of research and the potential for decades-long waits for effective treatments.
While off-label medications like Plavix may relieve symptoms for some, access is hindered by physicians’ concerns about side effects.
Many individuals with Long COVID face substantial barriers to treatment, including economic inequality and racial medical bias.
The authors argue the healthcare system fails patients by forcing them to navigate treatment options alone, often leading to inadequate care.
They emphasize that “Do no harm” should mean providing access to potentially beneficial treatments rather than withholding them for fear of risks.
Article: USF Health receives $3.75 million NIH research award to advance Long COVID research and its link to Alzheimer’s disease and dementia
DEFINITION:
Tauopathy: A neurodegenerative disorder characterized by the abnormal accumulation of tau protein in the brain, often linked to diseases like Alzheimer’s and associated with cognitive decline and memory loss.
SUMMARY:
The National Institutes of Health has awarded a $3.75 million research grant to USF Health to study the potential link between Long COVID and neurological impacts, including Alzheimer’s disease and dementia.
Long COVID is marked by symptoms such as fatigue and cognitive disturbances, which may also involve tau protein biomarkers associated with Alzheimer’s disease.
The research team aims to uncover the cellular and molecular mechanisms behind COVID-induced tauopathy and identify potential drug targets to intervene and slow its progression.
Dr. Subhra Mohapatra noted that increasing age correlates with the accumulation of neurotoxic tau molecules, exacerbating neuro-inflammatory responses in the brain.
This grant is significant for providing insights into the long-term neurological consequences of COVID-19 and developing effective interventions for affected individuals.
Article: Long Covid health workers pushing for trial date | Nursing Times
DEFINITION:
Personal Protective Equipment (PPE): Gear that healthcare workers use to protect themselves from health hazards, including infectious diseases like Covid-19. This includes masks, gloves, gowns, and face shields.
SUMMARY:
A group of over 290 healthcare workers is taking legal action against several NHS trusts and Welsh health boards, claiming they developed Long COVID due to negligence regarding personal protective equipment during the pandemic.
This case represents one of the most significant collective legal challenges related to Long COVID in the UK.
Lawyers are urging the court to set trial dates, arguing that the prolonged wait is worsening the claimants’ health and financial situations.
Many claimants report severe health issues and are unable to return to work, underscoring the devastating impact of Long COVID.
Rachel Hext, a nurse involved, expressed frustration, stating, “Despite calls for support and compensation… we continue to catch Covid and develop Long COVID, for which there is little treatment and no cure.”
Research
Article: Long Covid: a global health issue – a prospective, cohort study set in four continents | BMJ Global Health
DEFINITIONS:
High-Income Countries (HICs): Nations with a high gross national income (GNI) per capita, typically characterized by developed infrastructure and healthcare systems.
Low-Income and Middle-Income Countries (LMICs): Countries with lower GNI per capita, often facing challenges related to healthcare access and socioeconomic resources.
Quality of Life (QoL): A subjective measure of overall well-being, encompassing physical health, psychological state, social relationships, and environment.
SUMMARY:
The study reveals that Long COVID impacts populations globally, with similar symptoms observed across regions.
Participants from high-income countries (HICs) reported a significantly higher prevalence of Long COVID (69.0%) compared to those in low-income and middle-income countries (LMICs) (45.3%).
Symptoms such as fatigue, not feeling fully recovered, and anxiety/depression were markedly more prevalent in HICs, highlighting disparities in healthcare access and reporting.
Despite a lower observed prevalence in LMICs, the potential impact on functioning might be greater due to fewer support systems.
Neurocognitive symptoms were the most frequently reported in both HICs and LMICs, raising concerns over the long-term cognitive health of COVID-19 survivors.
The findings underscore a pressing need for more extensive research and resource allocation for Long COVID management, especially in under-resourced settings.
My Take:
Recognizing Long COVID as a universal health issue not only necessitates clinical interventions but also emphasizes the need for comprehensive support systems for affected individuals, particularly in resource-limited settings.
Article: Emerging small-molecule antiviral agents in long COVID prevention | Frontiers in Pharmacology
DEFINITIONS:
Neuroinflammation: Inflammation of the nervous tissue, contributing to cognitive symptoms such as "brain fog" commonly reported in Long COVID patients.
Small-molecule agents: Low molecular weight compounds that modulate biological processes and are used in treating diseases, including viral infections.
SUMMARY:
Research into small-molecule antiviral agents shows promise in preventing Long COVID (Post-Acute Sequelae of COVID-19, or PASC).
Notable compounds such as Metformin, Ensitrelvir, Molnupiravir, and Nirmatrelvir have demonstrated efficacy in early intervention to reduce the incidence of Long COVID.
Recent studies indicate that administering antiviral agents shortly after COVID-19 symptoms begin may significantly decrease the likelihood of developing Long COVID.
There is a pressing need for rigorous definitions of Long COVID to effectively validate treatment strategies and optimize patient care.
Article: Immune exhaustion in ME/CFS and long COVID | JCI Insight
DEFINITIONS:
Immune exhaustion: A state where immune cells lose their ability to respond effectively due to continuous exposure to antigens or inflammatory mediators.
Cytokine storm: An excessive immune response, resulting in the release of pro-inflammatory cytokines, often leading to tissue damage and severe complications.
SUMMARY:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share overlapping clinical features, including immune dysregulation and persistent fatigue that significantly impair quality of life.
The study investigates immune exhaustion gene expression among participants with ME/CFS, Long COVID, and healthy controls, revealing downregulation of key immune signaling pathways.
Both conditions displayed downregulated interferon signaling, suggesting a state of immune suppression that could hinder effective immune responses.
Shared molecular pathways involved in immune dysfunction were identified, indicating potentially overlapping etiologies between ME/CFS and Long COVID.
Dysregulated immune responses in Long COVID are characterized by persistent inflammation and elevated pro-inflammatory cytokines, resembling profiles observed in ME/CFS.
My Take:
The overlap in immune responses could redefine our approach to chronic post-viral syndromes, emphasizing integrated care strategies.
Article: The persistence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis | Journal of Infection
SUMMARY:
This article is a systematic review and meta-analysis to determine the proportion of Long COVID (LC) patients that satisfy ME/CFS diagnostic criteria.
The review identified 13 eligible studies that reported a total of 1,973 LC patients. The meta-analysis indicated that 51% of LC patients satisfied ME/CFS diagnostic criteria with fatigue, sleep disruption, and muscle/joint pain being the most common symptoms. Importantly, LC patients also experienced the ME/CFS hallmark symptom, post-exertional malaise.
The study demonstrated that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS.
Findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardized diagnosis, management and the recruitment for clinical studies in the future.
Given the similarities between ME/CFS and LC, PEM may represent a core domain that is important in the diagnostic identification of LC patients.
Article: Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo: The ACTIV-6 Randomized Clinical Trial | JAMA Network Open - Infectious Diseases
DEFINITIONS:
Montelukast: A medication primarily used for asthma and allergic rhinitis, acting as a leukotriene receptor antagonist to decrease inflammation in the airways.
Sustained recovery: In this study, defined as experiencing three consecutive days without symptoms of COVID-19.
Cox proportional hazards regression: A statistical method used to analyze the time until an event occurs, such as recovery from illness.
SUMMARY:
A randomized clinical trial of montelukast involved 1,250 participants with mild to moderate COVID-19, assessing whether a 14-day course would reduce symptom duration compared to a placebo.
Results showed no significant difference in sustained recovery time between the montelukast group and the placebo group, with a median recovery time of 10 days for both. The adjusted hazard ratio was 1.02, indicating no beneficial effect from montelukast treatment (p = .63 for efficacy).
Adverse events were rare, with only five serious cases reported, suggesting the treatment is generally well tolerated.
The study's findings do not support the use of montelukast in treating mild to moderate COVID-19, contributing to the ongoing evaluation of existing medications for effective COVID-19 management in outpatient settings.
Article: One-year mortality and associated factors in older hospitalized COVID-19 survivors: a Nationwide Cohort Study in Korea | Scientific Reports
DEFINITIONS:
Corticosteroids: A class of anti-inflammatory drugs often used to treat severe infections and diseases by dampening the immune response, potentially leading to adverse effects like infections or organ dysfunction.
Charlson Comorbidity Index (CCI): A method of classifying prognostic comorbidity that predicts ten-year mortality for a patient with various comorbid conditions.
SUMMARY:
The study reveals that the one-year mortality rate among older COVID-19 survivors in Korea is 4.9%, closely matching the in-hospital mortality rate of 4.8%.
Key factors associated with one-year mortality include older age, male sex, COVID-19 severity, cardiovascular disease, and organ dysfunction.
Notably, the use of corticosteroids was linked to poorer long-term outcomes, potentially due to the drug's adverse reactions in severely ill patients.
Vaccination significantly improved survival, with patients receiving two or more doses experiencing better outcomes than those who were unvaccinated or had only one dose.
Survivors reported a decline in quality of life post-COVID-19, with increased job loss and a higher prevalence of disabilities after hospitalization.
Article: Finding Long-COVID: temporal topic modeling of electronic health records from the N3C and RECOVER programs | npj Digital Medicine
DEFINITION:
Topic Modeling: A statistical method used to identify underlying themes associated with a set of texts, commonly applied to analyze electronic health records for clinical outcomes.
SUMMARY:
Researchers analyzed over 600 million diagnoses from 14 million patients through the National COVID Cohort Collaborative (N3C), identifying numerous clinical phenotypes.
The study employed topic modeling techniques to cluster patient data, revealing significantly increased new-onset conditions among COVID-19 patients compared to controls.
Findings showed that certain clinical phenotypes varied based on factors such as patient age, sex, and wave of infection, enhancing our understanding of disease trajectories post-COVID-19.
While the results corroborated many known features of Long COVID, they also pointed to new avenues for diagnostics and treatment.
My Take:
The findings underscore the potential of advanced analytics to deepen our understanding of Long COVID, affecting millions globally. By revealing specific demographic patterns and new clinical phenotypes, this research can help shape targeted intervention strategies and sets a precedent for future studies utilizing big data in addressing complex medical conditions.
Article: The negative effects of long COVID-19 on cardiovascular health and implications for the presurgical examination | Journal of Osteopathic Medicine
SUMMARY:
This literature review of the effects of long COVID on cardiovascular health adds to the body of literature exploring postacute cardiovascular outcomes of COVID-19, with a focus on presurgical cardiac clearance in the adult patient.
Cardiac conditions associated with Long COVID require special attention in the context of the presurgical candidate due to an increased risk of sudden cardiac death, myocarditis, stroke, and myocardial infarction – even in those who were healthy prior to acute COVID-19 infection.
The prevalence of cardiovascular symptoms mentioned in the reviewed literature is as follows: chest pain (83.3%), arrhythmias (88.3%), hypertension (40.0%), hypotension (16.7%), myocarditis (80.0%), pericarditis (51.7%), Heart Failure (HF) (70.0%), cardiomyopathy (55.0%), orthostatic intolerance (56.7%), and thromboembolic events (85.0%).
This review encourages providers to be aware of potential sequelae in the context of the presurgical examination. Clinicians should have a low threshold to pursue more extensive cardiac workup prior to surgery.
My Take (Amy):
We need more studies like this that have practical implications and provide at least some guidance for clinicians.
Article: Telehealth-delivered cognitive rehabilitation for people with cognitive impairment as part of the post-COVID syndrome: protocol for a randomised controlled trial as part of the CICERO (Cognitive Impairment in Long COVID: Phenotyping and Rehabilitation) study | Trials
DEFINITIONS:
Cognitive rehabilitation: A therapeutic approach designed to improve cognitive functioning through various techniques and strategies, often involving training and exercises that support cognitive performance and daily activities.
Telehealth: A method of delivering healthcare services remotely using technology, enhancing convenience and accessibility for patients with mobility or transportation challenges.
SUMMARY:
Cognitive impairment is a significant symptom of Post-Acute Sequelae of SARS-CoV-2 infection (PASC), affecting between 25% and 75% of those infected.
A new cognitive rehabilitation program aims to address issues like impaired attention, processing speed, and overall cognitive functionality stemming from PASC.
This randomized controlled trial (RCT) will evaluate the effectiveness of a ten-session cognitive rehabilitation program delivered via telehealth compared to standard clinical care.
Participants will include 120 non-hospitalized adults aged 30-60 who have experienced cognitive impairment for over three months post-COVID infection.
Expected outcomes include improvements in cognitive function and quality of life, along with potential economic benefits from equipping patients to manage their symptoms.
My Take:
This seems like a waste of time and money…
Article: Barriers and facilitators of healthcare access for long COVID-19 patients in a universal healthcare system: qualitative evidence from Austria | International Journal for Equity in Health
DEFINITIONS:
Health literacy: The ability of individuals to access, understand, and use information related to health to make informed decisions regarding their care.
Multidisciplinary care: A collaborative approach to healthcare where professionals from multiple disciplines work together to provide comprehensive care tailored to a patient's needs.
Complementary health insurance: Additional health insurance that covers services not included in standard public health coverage, often used to access private care or additional treatments.
SUMMARY:
The study identifies critical access barriers faced by Long COVID patients in Austria, including stigma from healthcare professionals, long waiting times, and inadequate insurance coverage, which significantly impact their healthcare experiences.
Patients expressed frustration over a lack of clear information and resources to navigate their treatment pathways, leading to feelings of isolation and helplessness.
Gender and age-related stigmas persist, with women and younger patients often feeling their symptoms are dismissed by medical professionals.
Supportive social environments and telemedicine have emerged as facilitators of care, helping to bypass some accessibility issues.
Experts noted that while some improvements in Long COVID care have been made, significant gaps remain in knowledge and treatment structures, particularly in multidisciplinary approaches.
The findings call for urgent reforms in Austria's healthcare system to enhance access to care, improve awareness of Long COVID, and address socioeconomic disparities affecting health outcomes.
Article: Associations between symptom-based long COVID clusters and long-term quality of life, work and daily activities among individuals testing positive for SARS-CoV-2 at a national retail pharmacy | Journal of Patient-Reported Outcomes
DEFINITIONS:
Health-Related Quality of Life (HRQoL): A measure of how well individuals can perform daily activities and perceive their health in physical, mental, and social domains.
Work Productivity and Activity Impairment (WPAI): A tool used to assess the impact of health on work productivity and daily activities, focusing on absenteeism and presenteeism.
SUMMARY:
The study identifies three distinct clusters of Long COVID symptoms based on symptom co-occurrence: low (<2), moderate (2-6), and high (>6 symptoms).
Participants with a high symptom burden (more than six symptoms) experienced significantly worse Health-Related Quality of Life (HRQoL) and Work Productivity and Activity Impairment (WPAI) scores over a six-month period.
The findings indicate a direct relationship between the number of Long COVID symptoms and the level of impairment in both work productivity and quality of life.
Participants in Cluster 3, who reported the highest number of symptoms, exhibited increased activity impairment and presenteeism compared to those in Cluster 1.
Article: In Utero Exposure to Maternal COVID-19 and Offspring Neurodevelopment Through Age 24 Months | JAMA Network Open - Pediatrics
DEFINITION:
Ages & Stages Questionnaires, Third Edition (ASQ-3): A validated developmental screening tool that pinpoints developmental progress in children between the ages of one month to 5 ½ years.
SUMMARY:
In utero exposure to maternal infections has been associated with abnormal neurodevelopment among offspring. SARS-CoV-2 infection warrants investigation of developmental implications for exposed offspring.
Two previous retrospective electronic medical record studies showed increased susceptibility to neurodevelopmental diagnoses, specifically among male offspring exposed to maternal COVID-19. Different studies have also shown discordant results, so study authors initiated a larger-scale prospective study of whether in utero exposure to maternal COVID-19 was associated with abnormal neurodevelopmental screening results.
In this prospective cohort study of 2003 pregnant individuals and their children, the adjusted prevalence of abnormal scores on the ASQ-3 of children through age 24 months did not differ between offspring exposed and unexposed to maternal SARS-CoV-2 infection in utero.
Authors conclude that their findings suggest that individuals infected with SARS-CoV-2 during pregnancy can be reassured that there is no association with abnormal neurodevelopmental scores through 24 months.
Article: Circadian re-set repairs long-COVID in a prodromal Parkinson’s parallel: a case series | Journal of Medical Case Reports
DEFINITIONS:
Bright light therapy (LT): A treatment method involving exposure to intense light to reset circadian rhythms and improve sleep, often used for conditions like Seasonal Affective Disorder and sleep disorders.
Circadian rhythm: The natural internal process that regulates the sleep-wake cycle and other physiological processes in a roughly 24-hour cycle, responding to external cues like light.
Prodromal Parkinson’s disease: Early symptoms that may indicate the onset of Parkinson's disease, such as sleep disturbances, depression, and cognitive impairments.
SUMMARY:
This case series reports the effects of bright light therapy (LT) on Long COVID symptoms, closely resembling those of prodromal Parkinson's disease.
The study highlights improvements in sleep, depression, anxiety, and cognitive dysfunction among five patients with long COVID symptoms lasting between 12 weeks and over 139 weeks post-infection.
LT treatment restored sleep patterns within a week, leading to lasting symptom relief for many patients and suggesting a potential non-invasive solution for Long COVID.
Patients who underwent LT reported significant enhancements in sleep quality, with marked reductions in insomnia and fatigue.
The findings indicate that a compromised circadian mechanism may interfere with patient recovery, opening a promising new direction for treating Long COVID through the modulation of circadian rhythms.
Article: Possible mechanisms of SARS-CoV-2-associated myocardial fibrosis: reflections in the post-pandemic era | Frontiers in Microbiology
DEFINITION:
Myocardial fibrosis: Scarring of the heart muscles due to a sudden or chronic heart injury. It is a progressive pathological process elicited by the activation and excessive proliferation of myocardial fibroblasts and the deposition of extracellular matrix (ECM).
SUMMARY:
Emerging evidence reveals that COVID-19 could generate myocardial fibrosis, termed “COVID-19-associated myocardial fibrosis.”
COVID-19-associated myocardial fibrosis can result from the activation of fibroblasts via the renin-angiotensin-aldosterone system (RAAS), transforming growth factor-β1 (TGF-β1), microRNAs, and other pathways, and can also occur in other cellular interactions with SARS-CoV-2, such as immunocytes and endothelial cells.
This review summarizes the potential mechanisms of COVID-19-associated myocardial fibrosis at the molecular and cellular levels. It describes the underlying mechanisms contributing to COVID-19-associated myocardial fibrosis while also examining the antifibrotic potential of current COVID-19 treatments, offering guidance for future clinical trials of these medications.
The review suggests several drugs that may be effective in treating COVID-19-associated myocardial fibrosis: Remdesivir, Lisinopril, Captopril, Telmisartan, Candesartan, Spironolacton, Toclizumab, Anakinra, and Colchicine.
The authors recommend that relevant tests be added to the follow-up of COVID-19 patients to detect myocardial fibrosis promptly.
It’s nice to have some articles about actual treatments and preventive treatments, even if it’s a nes that don’t work. It advances the field and gets us closer to answers!
https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-024-04812-9
I did the treatment discussed in this article with the author it set me back significantly and was a time waster. He only wanted people for his research rather than actually caring about helping them . Three people does not prove anything.