This week, we explore the latest findings, including the potential benefits of medications like metformin, the challenges faced in rehabilitation, and emerging research that connects COVID-19’s impact to myalgic encephalomyelitis/chronic fatigue syndrome.
Important to note, our friends at the Sick Times are covering the RECOVER-TLC meeting which started yesterday. RECOVER-TLC is ‘utilizing an additional $515 million in funding allocated to the program earlier this year’ to support a new round of trials.
Our article of the week, "Impact of COVID-19 on myalgic encephalomyelitis/chronic fatigue syndrome-like illness prevalence: A cross-sectional survey," published in PLOS ONE, investigates the prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like illness in the context of the COVID-19 pandemic. This significant study, conducted within Kaiser Permanente Northern California, assessed nearly 10,000 adults to understand how COVID-19 interacts with the manifestation of ME/CFS.
A couple of key findings highlighted in the study:
"Among those with ME/CFS-like illness, an estimated 14.12% (CI 3.64%, 24.60%) developed the illness after COVID-19."
The data reveal,"COVID-19 vaccination was associated with reduced prevalence of ME/CFS-like illness after COVID-19."
Media
For people with severe Long COVID, medical care is out of reach - The Sick Times
SUMMARY:
People with long COVID who are bedridden struggle to access doctors and treatments.
Tightening restrictions on telehealth and insurance for in-home services limit medical care for bed bound patients.
Many patients face challenges as the medical system remains unprepared to treat severe cases of long COVID or myalgic encephalomyelitis (ME/CFS).
Severe long COVID patients often encounter physicians who lack understanding, resulting in dismissive treatment and inadequate care.
With the end of the public health emergency, many states have rolled back telehealth access, complicating remote care for severely ill patients.
My Take:
As medical options shift away from flexible remote care, it’s crucial to recognize and address the disproportionate impact on marginalized patients.
Article: Use of metformin in adults with diabetes linked to lower risk of long COVID - Florida Hospital News and Healthcare Report
DEFINITIONS:
Metformin: A prescription medication commonly used to manage type 2 diabetes by lowering blood sugar levels, with potential benefits for other health conditions being explored.
SUMMARY:
A recent NIH-funded study indicates that adults using metformin for type 2 diabetes have a reduced risk of developing long COVID or dying post-infection compared to those on other diabetes medications.
The study utilized health data from nearly 38 million Americans to compare outcomes between metformin users and those on alternative treatments.
Results showed a 13% to 21% lower incidence of long COVID or death in metformin users within six months following a COVID-19 infection.
Potential mechanisms through which metformin may provide protection against long COVID include reducing inflammation and viral levels.
Despite its advantages, metformin can have side effects, and its use should be guided by a doctor's prescription.
Article: R&D for long COVID is collapsing | Chemical and Engineering News
SUMMARY:
Research and development for long COVID treatments are struggling due to inadequate funding, leaving affected individuals with limited options.
The NIH’s RECOVER initiative has prioritized observational studies over the development of new compounds.
Private investors and major pharmaceutical companies perceive long COVID treatment development as too risky, complicating research efforts.
The overlapping symptoms of long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have led biotech firms like Aim ImmunoTech to explore existing drugs as potential treatments, yet funding remains elusive.
Many companies attempting to advance long COVID therapies have closed, highlighting the unsustainable nature of self-funded efforts.
As COVID-19 becomes endemic, the long-term presence of long COVID emphasizes the need for innovative treatments that prioritize public health over profit.
Research
Article: Impact of COVID-19 on myalgic encephalomyelitis/chronic fatigue syndrome-like illness prevalence: A cross-sectional survey | PLOS ONE
DEFINITIONS:
Post-Acute Infection Syndrome: A condition following an acute infection, where individuals experience prolonged symptoms that significantly impair daily activities and quality of life.
SUMMARY:
This study estimates that approximately 1.67% of adults in the Kaiser Permanente Northern California population have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like illness.
Among individuals with ME/CFS-like illness, approximately 14.12% developed the condition after COVID-19.
Notably, those who developed ME/CFS-like illness post-COVID-19 reported higher physical functioning compared to those without a prior COVID-19 infection.
While the COVID-19 pandemic did not significantly increase the prevalence of ME/CFS-like illness, it adds an additional burden to affected individuals, highlighting the need for specific diagnoses, awareness, and treatment options.
Article: Long COVID is not the same for everyone: a hierarchical cluster analysis of Long COVID symptoms 9 and 12 months after SARS-CoV-2 test | BMC Infectious Diseases | Full Text
DEFINITIONS:
Hierarchical Cluster Analysis: A statistical method used to group similar cases into clusters based on their characteristics, identifying patterns within data.
Neurocognitive Symptoms: Cognitive impairments related to memory, concentration, and overall cognitive function that arise after neurological events, such as infections like SARS-CoV-2.
SUMMARY:
The study identifies four distinct symptom clusters of Long COVID, nine and twelve months after a positive SARS-CoV-2 test, demonstrating its heterogeneous nature.
The clusters include: no or minor symptoms, multi-symptoms, joint pain, and neurocognitive-related symptoms, with memory loss and fatigue being the most common across both time points.
Symptom frequencies remained stable, although the prevalence of memory loss and concentration issues increased over time.
Factors such as age, sex, and pre-existing health conditions significantly differentiated the clusters, with older individuals and those with more pre-existing conditions gravitating towards the joint pain cluster.
The findings highlight the necessity for tailored treatment approaches for Long COVID, as different clusters may require distinct interventions.
My Take:
This study reveals vital insights into the individuality of Long COVID, suggesting that a standardized treatment approach may be ineffective.
Article: Effectiveness of an online multimodal rehabilitation program in long COVID patients: a randomized clinical trial | Archives of Public Health | Full Text
DEFINITIONS:
Telerehabilitation: A method of delivering rehabilitation services through digital platforms, allowing remote engagement between practitioners and patients.
Multimodal rehabilitation: An approach that employs various therapeutic methods (such as physical exercise, cognitive therapy, and nutritional counseling) to address health conditions holistically.
SUMMARY:
This randomized clinical trial assesses the effectiveness of an online multimodal rehabilitation program for Long COVID patients, predicting that digital interventions can significantly improve outcomes.
The study involved 134 participants, randomized into a control group receiving standard primary care and an intervention group receiving additional online rehabilitation.
Results indicated a significant improvement in mental health-related quality of life for the intervention group, with a mean increase of 1.98 points (p < 0.05).
Linear regression analyses identified both receipt of the intervention and enhanced self-efficacy as predictors of greater mental health improvements.
However, no significant differences were found in any of the secondary variables of the study, which included physical functioning, cognitive status, and the number of persistent symptoms.
The findings suggest that telerehabilitation can not only improve the quality of life of people with Long COVID, but also enhances psychological well-being.
Article: SARS-CoV-2 infection induces hyaluronan production in vitro and hyaluronan levels in COVID-19 patients relate to morbidity and long-term lung impairment: a prospective cohort study | mBio
DEFINITIONS:
Hyaluronan (HA): A glycosaminoglycan that acts as a major component of the extracellular matrix, involved in tissue hydration, inflammation, and cellular signaling. It exists in both high molecular weight (anti-inflammatory) and low molecular weight (pro-inflammatory) forms.
Extracellular matrix: A network of proteins and carbohydrates surrounding cells, providing structural and biochemical support.
SUMMARY:
This prospective cohort study reveals that SARS-CoV-2 infection significantly increases hyaluronan (HA) production, which is associated with lung impairment in COVID-19 patients.
Elevated systemic levels of HA correlate with disease severity, particularly during the acute phase of COVID-19, and remain persistently high during convalescence.
The research highlights fragmented, pro-inflammatory HA in lung tissues of deceased COVID-19 patients, suggesting its role in exacerbating respiratory failure.
Advanced light-sheet fluorescence microscopy reveals a substantial reduction in the alveolar surface area in COVID-19 patients compared to healthy individuals.
The study proposes that targeting HA metabolism could provide new therapeutic strategies for managing COVID-19 and potentially prevent long-term lung impairment.
Article: Increased luminal area of large conducting airways in patients with COVID-19 and post-acute sequelae of COVID-19 A retrospective case-control study | medRxiv
DEFINITION:
Luminal Area: The internal cross-sectional area of a tubular structure, such as an airway, which can affect airflow and respiratory function.
SUMMARY:
The study investigates differences in airway luminal areas among patients with post-acute sequelae of COVID-19 (PASC), those experiencing acute COVID-19, and healthy controls.
Using three-dimensional digital reconstruction from computed tomography imaging, researchers measured luminal areas of seven large conducting airways.
Results indicated that airway luminal areas were 12% to 39% larger in PASC patients compared to healthy controls in five out of seven measured airways.
No significant differences were found in luminal area between COVID-19 patients and those with PASC, suggesting possible persistence of airway changes post-infection.
Understanding these airway changes is crucial for addressing long-term respiratory complications faced by patients.
Article: Classification Accuracy and Description of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Integrated Health Care System, 2006–2017 - The Permanente Journal
DEFINITIONS:
International Classification of Diseases (ICD): A standardized system for classifying diseases and health-related issues, aiding in health management and billing.
Cohort Study: An observational study that follows a group over time to determine health outcomes influenced by various factors.
SUMMARY:
The study examined electronic health records to identify cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in individuals aged 9 to 39 between 2006 and 2017.
Only 15% of reviewed cases met the diagnostic criteria for ME/CFS, revealing limitations in historical ICD coding practices.
There was a significant increase in the annual rate of ME/CFS coding, particularly among women aged 30 to 39.
Common comorbid conditions for those with confirmed or probable ME/CFS included chronic pain, depression, and anxiety.
The study indicated that diagnosis delays could lead to underestimation of ME/CFS incidence, with a median time from symptom onset to diagnosis coding of five years.
Findings highlight the need for improved methods to accurately identify ME/CFS cases in electronic health records.
My Take:
This study reveals a critical gap in the diagnosis and understanding of ME/CFS amid growing awareness, especially post-COVID-19. The significant under-detection of true cases in health records emphasizes the urgent need for enhanced clinician training and better diagnostic practices.
Article: No signs of mast cell involvement in long‐COVID: A case–control study - Lenning - Scandinavian Journal of Immunology - Wiley Online Library
DEFINITIONS:
Mast cells: Innate immune cells involved in allergic reactions and defense against pathogens, known for releasing bioactive molecules such as histamine and proteases during activation.
Beta-tryptase (TPSB2) and carboxypeptidase A3 (CPA3): Specific proteases released from mast cells that serve as biomarkers for mast cell activation.
SUMMARY:
A recent case-control study found no signs of mast cell involvement in patients with long COVID compared to age and sex-matched controls.
Serum levels of beta-tryptase (TPSB2) and carboxypeptidase A3 (CPA3), indicators of mast cell activation, showed no significant differences between the long COVID and control groups.
The long COVID cohort reported symptoms including fatigue, dizziness, and exertional intolerance, prevalent in approximately 10% of individuals post-COVID-19 infection.
Researchers failed to find any correlation between elevated mast cell marker levels and physical exertional intolerance in long COVID patients.
This study suggests that the pathophysiology of long COVID may not involve persistent mast cell activation, challenging previous assumptions about its role in long-term symptoms.
My Take (Amy):
The people out there with MCAS after getting COVID-19 will beg to differ with this study’s findings.
My Take (Brandon):
I definitely at the very least have some level of mast cell sensitivity that was made even worse by Covid, so I am not sure I fully agree here.
Postacute Sequelae of COVID (PASC or Long COVID): An Evidenced-Based Approach | Open Forum Infectious Diseases
SUMMARY:
This lengthy review article draws from discussions that were initially held on the podcast This Week in Virology.
The article was written with the goal of preparing primary care providers to make the diagnosis, provide treatment, and refer as needed.
The review covers long COVID diagnosis, mechanisms driving long COVID, biochemical abnormalities, physiological abnormalities, phenotypes, prevention, and therapeutics for long COVID.
The growing understanding of the mechanisms and improvements with certain therapies may lead to better outcomes for both those with long COVID and other post-infectious diseases.
My Take (Amy):
This review was easy to read with helpful tables. Though the treatments section was short, this may be a good resource for patients and health professionals to gain understanding of the disease.
Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection | Cell: Stem Cell
DEFINITIONS:
Spatial multi-omics: A field of study that integrates and visualizes transcriptomic and proteomic data, enabling a deeper understanding of cellular organizations and interactions within a tissue of interest.
β cell pyroptosis: A type of programmed cell death that occurs in pancreatic beta cells in both type 1 and type 2 diabetes. Loss of these cells leads to diabetes. Pyroptosis is a specific form of cell death that is triggered by proinflammatory signals and associated with inflammation.
Human pluripotent stem cells (hPSCs): A type of stem cell that has the ability to develop into any cell type in the human body. In this study it serves as a model in vitro platform for studying disease mechanisms, developing cell therapy approaches, and drug screening.
SUMMARY:
Previous research has shown there is a strong connection between COVID-19 and diabetes.
This study used a spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples. This revealed an accumulation of proinflammatory macrophages.
The study also showed that virus exposure causes proinflammatory macrophage activation and β cell pyroptosis, which can eventually lead to diabetes.
Study authors also developed a hPSC-derived vascularized macrophage-islet (VMI) organoid model containing hPSC-derived endocrine cells, macrophages, and endothelial cells. The model helped uncover the mechanism of β cell damage during viral exposure, and will be useful in the future for studying macrophage-mediated host damage.
This edition made me feel pretty deflated.
It seems there is little financial investment into finding the causes (which I realise is not simple), therefore they are just focusing on available treatments in the hope it may help but will not really offer insights into the mechanisms of the disease.
There also seems to be little in the way of increasing the medical professions knowledge of long Covid.
I initially believed that long Covid would be the breakthrough for me/cfs treatment/cure. Now I’m thinking long Covid will be put in the ‘I can’t see any issues in your bloods so you are fine, you just need to exercise’ basket.
It’s so sad for the sufferers.
I am so much better thankfully but the uncertainty of whether I’m fully recovered, if I got Covid again, what would be the impact, is my daughters future altered by her long Covid are all very concerning?
The world has moved on from Covid but for some, it’s not that simple.
Amy and Brandon, thank you for your takes on the mast cell study. I think they found all 24 long haulers who don’t have MCAS 🙄