Long Covid Weekly #101: Long Covid risk decreased? ME/CFS drug worth $3 billion?
Hi everyone,
This week’s edition brings several new studies exploring the mechanisms behind Long COVID, including the roles of the immune response, genetic predispositions, and potential therapeutic interventions.
This week's highlighted article looks into the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It focuses on the dysregulated coagulation system and endothelial dysfunction in ME/CFS patients. The study utilizes Data-Independent Acquisition (DIA) LC-MS/MS to provide an analysis of protein expression in platelet-poor plasma samples.
A key passage from the results section emphasizes biological discrepancies: "We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated." This stark contrast in protein expression highlights the significant impact ME/CFS has on patients' physiological functions. From the discussion, another compelling point notes, "Significant increases in TSP-1 and PF4 suggest that the coagulation system is dysregulated in the present ME/CFS cohort." These findings underscore the abnormal coagulation and immune response in ME/CFS.
Off-topic, but next week we will be dropping a new tutorial video on how to navigate the research database. As always, if you want to submit an article to the database please fill this out.
Media
Article: Long COVID lung damage linked to immune system response | Nature
DEFINITIONS:
Interferon gamma (IFN-γ): A signaling molecule produced by immune cells that directs inflammation and immune responses but can lead to chronic inflammation and tissue damage if excessively released.
SUMMARY:
A study published on July 17, 2024, identifies a signaling molecule, interferon gamma (IFN-γ), as a potential contributor to lung damage in individuals experiencing long COVID.
The research analyzed lung samples from long COVID patients and revealed elevated levels of IFN-γ-producing T cells compared to controls.
By inhibiting IFN-γ in mice infected with SARS-CoV-2, researchers observed improvements in lung health and reduced inflammation.
Chronic inflammation caused by excessive IFN-γ release can lead to tissue damage and contribute to long COVID symptoms such as fatigue and breathlessness.
Targeting the IFN-γ pathway could offer a new approach for treating long COVID, particularly as there are existing drugs that inhibit this protein.
My Take:
Linking existing medications that inhibit this protein provides hope for more effective management of long COVID outcomes.
DEFINITIONS:
Auto-antibodies: Antibodies produced by the immune system that mistakenly target and attack the body’s own tissues, potentially contributing to chronic health problems in long COVID.
SUMMARY:
Since 2020, long COVID has emerged as a widespread disability, affecting millions and costing economies billions in productivity losses.
The risk of developing long COVID has decreased over the course of the pandemic, attributed to vaccination availability and changes in the virus's characteristics.
Even with a reduced risk of 3.5% among vaccinated adults, millions of new long COVID cases continue to arise, exacerbating an already significant public health issue.
A recent report details more than 200 health effects associated with long COVID, affecting multiple body systems and leading to significant disability in many individuals.
Despite evolving public perceptions, COVID-19 remains a serious threat, leading to more hospitalizations and long-term health issues than influenza.
DEFINITIONS:
Epidemiologist: A public health professional who studies the distribution, patterns, and determinants of health and diseases in populations.
SUMMARY:
The risk of long COVID has significantly declined over the course of the pandemic, primarily due to vaccination.
Researchers attribute approximately 70% of this risk reduction to vaccination, while 30% can be attributed to changes in the virus's characteristics and improved management of COVID-19.
Although long COVID continues to pose a risk, the overall decline in cases is viewed positively by researchers.
The study indicates that unvaccinated individuals are at a higher risk for developing long COVID compared to vaccinated individuals during both the delta and omicron variants.
The latest findings distinguish the different health risks associated with various COVID-19 variants, noting a shift in the types of health problems encountered.
Experts emphasize the need for continued vaccination efforts to further reduce risks associated with long COVID and to understand the long-term effects of the virus.
Article: 1 in 10 people infected during pregnancy develop long covid, study finds | Washington Post
SUMMARY:
According to a study published Thursday in the journal Obstetrics and Gynecology, nearly 1 in 10 people infected with the coronavirus during pregnancy developed long COVID. The virus can present a particular threat to pregnant people, who are already a vulnerable population.
As part of this 1,500-person NIH RECOVER study, researchers analyzed individuals infected with the coronavirus during pregnancy; half of the participants, who were mainly in their 30s, were fully vaccinated when they were enrolled.
Researchers wanted to be sure the commonly reported symptoms of malaise, fatigue, and GI issues were associated with COVID rather than being due to pregnancy or the postpartum period. So they evaluated participants 10 months after the initial infection--they found that the effects persisted. This indicated that the study participants’ symptoms, such as fatigue and aches, did not stem from pregnancy but were instead the hallmarks of long Covid.
“I was initially surprised at the prevalence of long covid in this population,” said Torri Metz, one of the study’s lead authors and a maternal-fetal medicine specialist at University of Utah Health. “It really drew my attention to the fact I need to have this on my radar when I am seeing patients.”
Research
Article: Determining the societal value of a prospective drug for ME/CFS in Germany | PLOS ONE
DEFINITIONS:
Quality-Adjusted Life Year (QALY): A measure that combines the quantity and quality of life, used to assess the value of medical interventions; one QALY equates to one year of perfect health.
Societal Value (SV): The combined monetary gains from health improvements and cost savings achieved through reducing direct medical expenses and productivity losses, from a societal perspective.
SUMMARY:
This study aims to ascertain the optimal level of public research and development (R&D) investment in Germany for a prospective drug for targeting ME/CFS.
The anticipated introduction of a prospective drug for ME/CFS is estimated to yield a quality-adjusted life year (QALY) gain of approximately 29,000 and a societal value of about €2.6 billion
The optimal R&D investment in Germany is estimated at €676 million, which represents about a quarter of the total investment required to bring a significant drug to market.
The study concludes that a coordinated international approach is imperative to address funding and market size limitations in developing treatments for ME/CFS.
Factors such as the diverse range of symptoms, the absence of definitive biomarkers, and a significant lag in research funding contribute to the lack of approved treatments for ME/CFS.
My Take:
I have mentioned this before, but I think these ‘opportunity sizing’ estimates are extremely useful. Especially since funding primarily comes from legislators, many of whom want to know the fiscal impact a disease has.
DEFINITIONS:
Endothelial dysfunction: A condition where the endothelium (inner lining of blood vessels) does not function normally, contributing to vascular issues and cardiovascular risk.
Complement system: A part of the immune system that enhances the ability of antibodies and phagocytic cells to clear pathogens, promote inflammation, and attack the pathogen's cell membrane.
Dysregulated coagulation system: An abnormal coagulation response where the balance between bleeding and clotting is disrupted, potentially leading to an increased risk of thrombosis.
SUMMARY:
Analysis of plasma samples using data-independent LC-MS/MS reveals a dysregulated coagulation system and endothelial dysfunction in ME/CFS patients, indicating potential cardiovascular pathology.
A total of 45 proteins showed significant differential expression between ME/CFS patients and controls, highlighting the importance of the coagulation and immune systems in the disease mechanism.
The study identified the upregulation of proteins related to clotting processes, including thrombospondin-1 and platelet factor 4, which suggest a procoagulant state that may contribute to symptoms in ME/CFS.
Complement system components were significantly downregulated, specifically proteins like C9, hinting at possible immune dysregulation and compromised defense mechanisms in individuals with ME/CFS.
The findings suggest that further research into the identified proteins and pathways could lead to potential biomarkers for ME/CFS and improve understanding of its pathophysiology.
My Take:
Fascinating and very insightful study!
DEFINITIONS:
Mast cell activation syndrome (MCAS): A disorder characterized by episodes of severe symptoms caused by the overactivation of mast cells without their proliferation.
Tryptase: An enzyme released by mast cells that serves as a biomarker in diagnosing MCAS.
Angioedema: Swelling of the deeper layers of the skin, often associated with allergic reactions, which can be a symptom of MCAS.
SUMMARY:
Mast cell activation syndrome (MCAS) is characterized by increased mast cell numbers due to decreased cell death, leading to symptoms that affect multiple organ systems.
Common clinical manifestations of MCAS include flushing, hypotension, urticaria, angioedema, headache, vomiting, and diarrhea.
The pathogenesis of MCAS involves chronic abnormal activation of mast cells rather than neoplastic proliferation.
Diagnostic criteria for MCAS require serum tryptase levels exceeding 120% + 2 ng/mL above baseline, clinical reactions to anti-mediator drugs, and exclusion of other mast cell activation diseases.
MCAS is related to conditions like long COVID, where immune dysregulation can lead to persistent inflammatory states and exacerbation of symptoms.
Current treatment strategies for MCAS focus on patient education regarding avoiding triggers, prophylactic anti-mediator therapy, and potentially the use of immunotherapy in cases of secondary MCAS.
DEFINITIONS:
Mendelian randomization (MR): A statistical method that uses genetic variants as instrumental variables to infer causal relationships between exposures (like infections) and diseases.
Exacerbation of motor symptoms: Worsening of physical symptoms related to movement, common in conditions like Parkinson’s disease.
Bradykinesia: A condition characterized by slow movement, often observed in Parkinson’s disease patients.
SUMMARY:
The study investigates the association between COVID-19 and Parkinson’s disease (PD) through both a single-center study and Mendelian randomization (MR) analysis.
A questionnaire survey revealed that 65.7% of PD patients experienced COVID-19 infection, and 35.3% had exacerbated motor symptoms post-infection.
Long disease duration (≥ 10 years) and a long time since the last vaccination (> 12 months) were identified as significant risk factors for COVID-19 infection in PD patients.
The MR analysis indicated that PD is associated with increased susceptibility to COVID-19, but COVID-19 did not significantly affect the severity or hospitalization rates for PD.
Over one-third of PD patients reported exacerbated motor symptoms, particularly bradykinesia, following COVID-19 infection, raising concerns about symptom management.
DEFINITIONS:
Endothelial cell senescence: A state in which endothelial cells lose their ability to proliferate and function properly, contributing to vascular aging and cardiovascular diseases.
NLRP3 inflammasome: A multi-protein complex within cells that plays a critical role in mediating the innate immune response, often activated by cellular stress and inflammation.
Cytoprotective proteins: Proteins that help protect cells from damage, promote cell survival, and maintain cellular functions, critical in the context of aging and disease.
SUMMARY:
SARS-CoV-2's spike (S) protein has been found to reduce cytoprotective defenses and prompt premature senescence in human endothelial cells, which are critical for vascular health.
The study demonstrated that exposure to the S protein leads to increases in senescence markers and DNA damage response, negatively impacting endothelial function.
Inhibiting the NLRP3 inflammasome with MCC950 mitigated the senescence and detrimental effects induced by the S protein, suggesting a potential therapeutic avenue.
Supplementation with recombinant klotho or angiotensin-(1-7) was shown to protect against the pro-senescence effects of the S protein and improve endothelial cell functionality.
The findings underscore the significant vascular complications associated with both acute and long COVID, highlighting the enduring impact of endothelial dysfunction.
By elucidating the mechanisms underlying S protein-induced endothelial dysfunction, this research points to potential strategies for developing therapeutic interventions to prevent vascular sequelae in COVID-19 patients.
DEFINITIONS:
Cytokines: Small proteins that are important in cell signaling and play a crucial role in the immune response.
CRP (C-reactive protein): A substance produced by the liver in response to inflammation, often used as a marker for inflammatory conditions.
SUMMARY:
After initial COVID-19, immune dysregulation may persist and drive post-acute sequelae of COVID-19 (PASC).
This study describes longitudinal trajectories of cytokines in adults up to 6 months following SARS-CoV-2 infection.
The study includes data from 186 participants with laboratory-confirmed SARS-CoV-2 infection, revealing that 54% reported PASC at 12 weeks.
Findings indicate that raised CRP levels and abnormal diffusion capacity were associated with PASC and elevated levels of specific cytokines at 24 weeks.
Significant predictors of PASC included early IL-1β levels and body mass index (BMI) at COVID-19 onset.
The study emphasizes that chronic inflammation appears to play a critical role in the pathogenesis of PASC, particularly for individuals with decreased pulmonary function.
DEFINITIONS:
Bayesian model averaging (BMA): A statistical technique that averages over multiple models to account for model uncertainty, providing more robust predictions about likely causal relationships.
Autoimmune diseases (AIDs): Conditions where the immune system mistakenly attacks the body’s own tissues, leading to inflammation and damage; examples include inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC).
SUMMARY:
The study employs Mendelian randomization and Bayesian model averaging to investigate the causal relationships between autoimmune diseases (AIDs) and Long COVID.
The analysis suggests that inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) have significant causal effects on Long COVID.
Among these diseases, UC was identified as the highest-ranked causal factor associated with Long COVID, followed by IBD and CD.
Approximately 31%–69% of COVID-19 patients are reported to experience symptoms of Long COVID, indicating the considerable prevalence of this condition.
The findings also highlight the necessity of screening high-risk populations, particularly those with a history of AIDs, for potential Long COVID symptoms.
My husband has long COVID and I've had ME/CFS since 1990, so I was thrilled to find this informative newsletter--with links to real research! Thank you for the work you do. I've got my fingers crossed that there even IS a possible drug for ME/CFS, and my husband forwarded the article about existing drugs that might help with long COVID to his doctor.
Thanks Again. You are providing a significant service to the public.