Long Covid Weekly #96: Biggest LC research week ever! Upcoming hiatus
Hi everyone,
This is arguably the most jam-packed week in the history of the newsletter! Nature has clearly taken a keen interest in publishing on LC with several large papers published this week.
As mentioned last week, we are planning to try and have our research database done by the 100th edition (Early July). As a result of this, we will likely need to go on break in the upcoming weeks for at least one week.
This week’s highlighted article, “Three-year outcomes of post-acute sequelae of COVID-19” published in Nature Medicine. This study, leveraging data from 135,161 COVID-19 patients and 5,206,835 controls from the US Department of Veterans Affairs, extends the follow-up period to three years.
The research reveals that while the risk of death for non-hospitalized individuals diminishes after the first year, a notable residual risk for PASC remains, contributing to 9.6 disability-adjusted life years (DALYs) per 1,000 persons in the third year. Among hospitalized patients, the risk of death decreases but remains significantly elevated even in the third year, with a substantial residual risk for PASC, resulting in 90.0 DALYs per 1,000 persons.
Key Findings from the Study
“Among non-hospitalized individuals, the increased risk of death was no longer present after the first year of infection, and risk of incident PASC declined over the 3 years but still contributed 9.6 (95% confidence interval (CI): 0.4–18.7) disability-adjusted life years (DALYs) per 1,000 persons in the third year.”
“Among hospitalized individuals, risk of death declined but remained significantly elevated in the third year after infection (incidence rate ratio: 1.29 (95% CI: 1.19–1.40)).”
“The cumulative number of post-acute sequelae over the 3 years was 378.7 (95% CI: 356.6–401.1) per 1,000 persons, including 212.3 (197.5–227.0), 125.0 (107.2–142.7) and 41.2 (20.2–62.3) in the first, second and third year, respectively.”
“The 3-year cumulative burden of DALYs due to PASC was 91.2 (95% CI: 81.6–101.0) per 1,000 persons, including 54.3 (47.9–60.7), 27.3 (19.5–35.0) and 9.6 (0.4–18.7) in the first, second and third year, respectively.”
“In the third year, the risks of post-acute sequelae for three organ systems—neurologic, pulmonary, and gastrointestinal disorders—remained elevated, contributing to 14.2 (95% CI: 8.4–20.0), 11.1 (6.3–15.8) and 7.4 (0.8–13.9) sequelae per 1,000 persons, respectively.”
“The 3-year cumulative burden of DALYs for hospitalized individuals was 766.2 (95% CI: 731.7–803.3) per 1,000 persons, reflecting the sizable toll of health loss in this group.”
Media
Article: Bad Blood? The Uncertainty Around Microclots and Long Covid | Undark
SUMMARY:
The debate surrounds whether microscopic blood clots, referred to as microclots, are responsible for the wide variety of symptoms seen in long Covid patients.
Researchers like Resia Pretorius and Douglas Kell have suggested that microclots may contribute to persistent symptoms through clotting mechanisms in the body.
In light of this, various treatments have been proposed, such as antiplatelet drugs, anticoagulants, and apheresis to remove microclots and potentially improve symptoms.
However, the scientific community remains divided on the validity and efficacy of these treatments, citing the need for additional clinical trials and peer-reviewed evidence.
The complexity of diagnosing and treating long Covid underscores the need for further research to understand the role of microclots in the disease and to determine the most effective therapeutic approaches.
Article: Long Covid at 3 Years - by Eric Topol and Ziyad Al-Aly | Ground Truths Substack post
!MUST READ
SUMMARY:
The post summarizes multiple recent key studies, giving us a clearer picture of Long Covid after 3 years of research on these patients. Several of the studies discussed are highlighted in our Research section below.
The VA study, published in Nature Medicine, provided a 3-year follow-up on over 135,000 individuals with COVID-19, showing persistent risks of death, multi-system sequelae, and disability, especially in those initially hospitalized.
Non-hospitalized individuals showed a significant, but smaller, elevation in pulmonary, neurologic, and gastrointestinal sequelae.
The COMEGEN Italy study reported a significant increase in major cardiovascular and cerebrovascular events over three years in nearly 32,000 COVID-19 participants compared to pre-COVID controls, indicating a 70% higher risk of these events.
A 3-year follow-up study from Wuhan, China, revealed that 54% of 1,359 survivors had at least one persistent Long COVID symptom, with those who had reinfections being more affected. Lung function metrics mainly resolved to control levels.
Recent findings highlighted SARS-CoV-2 as a potential risk factor for Alzheimer’s disease, with inflammation and neuro-inflammation contributing to cognitive decline and dementia.
Other studies discussed the importance of antiviral therapy, brain inflammation and cognitive symptoms, and the need for standardized definitions and best practice care models for Long COVID, emphasizing multidisciplinary and patient-centered approaches.
Reports indicated a small summer wavelet of COVID-19 in the US due to FLiRT variants, stressing the importance of continued vigilance, potential new booster recommendations, and the development of pan-coronavirus and nasal vaccines.
SUMMARY:
The NIH's $1 billion initiative called RECOVER aimed to study Long Covid but has faced criticism for not meeting its goals, failing to prioritize expert researchers in post-infectious diseases, and running underwhelming clinical trials.
Evidence indicates that RECOVER's clinical trials have not tested drugs addressing the root causes of Long Covid, leading to concerns about the program's ability to identify effective treatments.
Patient representatives involved in RECOVER have expressed frustration at the lack of meaningful engagement in research directions and decision-making processes, pointing to a disconnect between the program's original goals and its current practices.
Despite disappointment in RECOVER's performance, some experts and advocates believe aspects of the program, such as pathobiology studies and pediatric research, hold promise and should receive continued support and funding.
My Take (Amy):
This is an excellent piece of investigative reporting - a must read! Way to go, Sick Times!
SUMMARY:
Kate Grace, a professional athlete, faced challenges such as Long COVID, giving birth, and injuries but has made a comeback aimed at securing an Olympic berth in the 800m event.
Despite setbacks, Kate Grace maintained a positive mindset and approached training with a beginner's attitude, emphasizing growth and learning in her journey.
The challenges she faced, including long COVID and pregnancy, led her to reevaluate her identity as an athlete and the importance of balance in life and sport.
Through reframing obstacles and setting realistic goals, Kate Grace navigated her comeback, focusing on incremental progress and qualifying for the Olympic Trials.
My Take:
Inspiring story!
SUMMARY:
Between 2019 and 2021, global life expectancy dropped by 1.8 years to 71.4 years, returning to the level of life expectancy in 2012.
Similarly, global healthy life expectancy dropped by 1.5 years to 61.9 years in 2021, also returning to the level of 2012.
The 2024 WHO report also highlights how the effects have been felt unequally across the world. The WHO regions for the Americas and South-East Asia were hit hardest, with life expectancy dropping by approximately 3 years and healthy life expectancy by 2.5 years between 2019 and 2021.
COVID-19 rapidly emerged as a leading cause of death, ranking as the third highest cause of mortality globally in 2020 and the second in 2021. Nearly 13 million lives were lost during this period.
The latest estimates reveal that except in the African and Western Pacific regions, COVID-19 was among the top five causes of deaths, notably becoming the leading cause of death in the Americas for both years.
The report also highlights the significant health challenges faced by persons with disabilities, refugees and migrants.
In 2021, about 1.3 billion people, or 16% of the global population, had disability. This group is disproportionately affected by health inequities resulting from avoidable, unjust and unfair conditions.
Access to healthcare for refugees and migrants remains limited, with only half of the 84 countries surveyed between 2018 and 2021 providing government-funded health services to these groups at levels comparable to their citizens.
Universal Health Coverage expanded to 585 million more people, falling short of the goal for one billion. Additionally, only 777 million more people are likely to be adequately protected during health emergencies by 2025, falling short of the one billion target set in WHO’s 13th General Programme of Work.
This protection is increasingly important as the effects of climate change and other global crises increasingly threaten health security.
Research
Article: Long COVID Definitions and Models of Care: A Scoping Review: Annals of Internal Medicine
DEFINITIONS:
Practice-Based Models: Care models implemented within individual clinics or health systems.
Systems-Based Models: Care models implemented across multiple levels of the healthcare system, often involving a network or region.
SUMMARY:
The study identified six key definitions of long COVID from various organizations, highlighting differences in the timing of symptom onset and duration required for diagnosis. A standardized, reliable definition is necessary for better clinical care and research.
Five key principles were identified for effective long COVID care models: a core lead team with expertise, broad multidisciplinary expertise, comprehensive access to services, patient-centered care, and capacity to meet demand.
Seven characteristics were used to distinguish care models: home department/clinical setting, clinical lead, collocation of other specialties, primary care role, population managed, use of teleservices, and whether the model was practice- or systems-based.
The review identified ten practice-based and three systems-based models of care, illustrating various approaches to managing long COVID, such as specialty-based, primary care-led, multidisciplinary, and virtual models.
Article: Three-year outcomes of post-acute sequelae of COVID-19 | Nature Medicine
DEFINITIONS:
Disability-adjusted life years (DALYs): DALYs for a disease or health condition are the sum of the years of life lost to due to premature mortality (YLLs) and the years lived with a disability (YLDs) due to prevalent cases of the disease or health condition in a population. One DALY represents the loss of the equivalent of one year of full health.
Incident rate ratio (IRR): The incidence rate in the exposed group divided by the incidence rate in the unexposed group. For instance, the rate of death in the hospitalized COVID-19 group divided by the rate of death in the control group.
SUMMARY:
This was a longitudinal cohort study of 135,161 people with SARS-CoV-2 infection and 5,206,835 controls with no infection from the US Department of Veterans Affairs.
Participants were followed for 3 years to estimate risks of death and PASC. This totaled 344,592 person-years of follow-up in the non-hospitalized COVID-19 group, 60,891 person-years of follow-up in the hospitalized COVID-19 group, and 15,620,505 person-years of follow-up in the control groups. Altogether, this corresponded to 16,025,988 person-years of follow-up.
Among 114,864 non-hospitalized individuals (88% males and 12 % females), they were at an increased risk of death (incidence rate ratio (IRR): 1.58) during the first year after SARS-CoV-2 infection but not in the second year and third year.
Risk of incident PASC declined over the 3 years but still contributed 9.6 disability-adjusted life years (DALYs) per 1,000 persons in the third year.
Among 20,297 hospitalized individuals (94.2% males and 5.8% females), risk of death declined but remained significantly elevated in the third year after infection (incidence rate ratio (IRR): 1.29).
Risk of incident PASC declined over the 3 years, but substantial residual risk remained in the third year, leading to 90.0 DALYs per 1,000 persons.
The risks of post-acute sequelae for three organ systems in the third year remained elevated, contributing to 14.2 for neurologic sequelae, 11.1 for pulmonary sequelae and 7.4 for gastrointestinal sequelae per 1,000 persons.
The 3-year cumulative burden of DALYs for hospitalized individuals was 766.2 per 1,000 persons, reflecting the sizable toll of health loss in this group.
DEFINITIONS:
CGRP (Calcitonin Gene-Related Peptide): A neuropeptide involved in the transmission of pain and the regulation of inflammatory responses.
IL-6 (Interleukin 6): A cytokine that plays a role in inflammation and is often elevated during infections, including COVID-19.
MA-10 SARS-CoV-2: A mouse-adapted strain of the SARS-CoV-2 virus, which allows it to infect wild-type mice more efficiently.
Gepant: A class of drugs that block the CGRP receptor, used primarily for treating migraines.
SUMMARY:
The study investigated whether olcegepant, a CGRP receptor antagonist used in migraine treatment, could mitigate neurological and inflammatory symptoms of SARS-CoV-2 infection in older mice.
The study used two wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S αCGRP-null line infected with a mouse-adapted SARS-CoV-2 virus.
Infection with SARS-CoV-2 in the tested mice resulted in neurological symptoms such as fever, dizziness, and nausea. These symptoms were consistent across all mouse strains used in the study.
Treatment with olcegepant reduced long-term weight loss and decreased levels of interleukin 6 (IL-6), an important inflammatory cytokine, in the infected mice. The reduction in IL-6 was significant in 129/SvEv mice and similar to levels in αCGRP-null mice.
The study suggests that olcegepant's effectiveness in reducing IL-6 levels is due to its inhibition of CGRP signaling. CGRP is a neuropeptide involved in inflammation and migraine, and its inhibition may help mitigate some of the inflammatory responses associated with SARS-CoV-2 infection.
The findings highlight the potential of using CGRP receptor antagonists to manage acute neurological symptoms and inflammatory responses in COVID-19 patients. This is particularly relevant for older adults, who are at higher risk of severe COVID-19 symptoms and related complications.
The study suggests further research into the use of CGRP receptor antagonists for treating long COVID symptoms and other coronaviral diseases. It also highlights the need to compare the effectiveness of different CGRP-targeting treatments, such as monoclonal antibodies and gepants, in managing COVID-19 symptoms.
DEFINITIONS:
T Cells (CD4+ and CD8+): Types of white blood cells that play a crucial role in the immune response. CD4+ T cells help activate other immune cells, while CD8+ T cells are primarily responsible for killing virus-infected cells.
Nab (Neutralizing Antibody): An antibody that can neutralize pathogens, preventing them from infecting cells.
Memory T Cells: Long-lived T cells that can quickly expand and respond to previously encountered antigens.
SUMMARY:
The study longitudinally analyzed SARS-CoV-2-specific immune responses during the acute and convalescent phases in 165 COVID-19 patients categorized by disease severity to understand the relationship between initial severity, T-cell memory, and reinfection risk.
Early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses were associated with milder disease progression and shorter hospital stays. In contrast, delayed and weakened CD8+ T cell responses were characteristic of severe COVID-19 cases.
Delayed production of antiviral antibodies, rather than the absolute titer levels, correlated with severe COVID-19 outcomes. Patients with severe disease showed more sustained antibody levels during the recovery phase compared to those with mild/moderate disease.
Initial COVID-19 severity influenced long-term maintenance of virus-specific adaptive immunity. Severe cases exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate cases.
SUMMARY:
This retrospective cohort study examined the association between COVID-19 vaccination and the development of post-COVID conditions (PCC) in individuals with SARS-CoV-2 infection across eight large healthcare systems in the United States.
The study included 161,531 vaccinated and 161,531 matched unvaccinated COVID-19 cases, focusing on new-onset PCC diagnoses within 30 days to 6 months following a positive SARS-CoV-2 test.
Vaccinated individuals had a lower risk of several PCC categories, including sensory, circulatory, blood and hematologic, skin and subcutaneous, and non-specific COVID-19 related disorders, with reductions in relative risk ranging from 10% to 47%.
Vaccination was associated with a slightly increased risk of mental health disorders (anxiety, psychotic disorder, depression/mood disorders) compared to unvaccinated individuals, particularly among adolescents.
The protective effect of vaccination against PCC was consistent across age groups and persisted regardless of the SARS-CoV-2 variant period (pre-Omicron vs. Omicron), the number of vaccine doses received, or the time since vaccination.
Article: Long-COVID symptoms improved after MDMA and psilocybin therapy: A case report
DEFINITIONS:
Psilocybin: A naturally occurring psychedelic compound found in certain mushrooms, known for altering perception, mood, and cognition.
MDMA (3,4-Methylenedioxymethamphetamine): A synthetic drug that alters mood and perception.
Default Mode Network (DMN): A network of brain regions that is active when a person is not focused on the outside world, often linked to self-referential thoughts and memory.
Neuroplasticity: The brain's ability to reorganize itself by forming new neural connections throughout life.
SUMMARY:
This case report describes a 41-year-old fully vaccinated woman with Long COVID who found significant relief from her symptoms after self-medicating with psilocybin and MDMA.
Post-COVID symptoms included severe anxiety, depression, insomnia, joint pain, cognitive issues, headaches, and decreased libido. Traditional treatments like medications, physical therapy, and alternative treatments provided minimal relief.
The patient tried psilocybin and MDMA under a therapist's guidance. Her first session with psilocybin led to a 20% improvement in symptoms. A subsequent session combining MDMA and psilocybin resulted in significant symptom relief, including reduced pain, improved cognitive function, and decreased headache frequency.
The patient experienced significant improvement in her symptoms, allowing her to return to work and resume her PhD studies. After relapses, additional sessions with psilocybin provided further relief.
The exact mechanisms by which psychedelics alleviate Long COVID symptoms are unclear. Potential explanations include modulation of neurotransmitter activity, increased neural plasticity, and altered brain connectivity.
DEFINITIONS:
Matrix Metalloproteinases (MMPs): A family of enzymes involved in the breakdown of extracellular matrix components, playing roles in tissue remodeling and immune responses.
Tissue Inhibitors of Metalloproteinases (TIMPs): Proteins that regulate the activity of MMPs, balancing tissue remodeling and degradation.
TNF-a (Tumor Necrosis Factor-alpha): A pro-inflammatory cytokine involved in systemic inflammation and a part of the body's immune response.
Glucocorticoids: A class of corticosteroids that are used to reduce inflammation in various conditions, including COVID-19.
Tocilizumab: An immunosuppressive drug that inhibits interleukin-6 (IL-6) and is used to treat inflammatory diseases.
SUMMARY:
This research investigated differences in serum matrix metalloproteinases (MMPs) profiles between adult and pediatric COVID-19 patients, and the effects of anti-inflammatory treatments on MMP levels. Serum samples from both patient groups and healthy controls were analyzed.
Elevated levels of MMP-1, MMP-7, TIMP-1, and TIMP-2 were observed in both adults and children with COVID-19. Adults exhibited higher concentrations of MMP-3, MMP-8, MMP-9, TNF-a, and TIMP-4 compared to children. Post-treatment reductions in MMP-1, MMP-8, and MMP-9 levels were observed in adults.
Anti-inflammatory treatments, including glucocorticoids, tocilizumab, and convalescent plasma, correlated with a significant reduction in certain MMP levels post-treatment, suggesting therapeutic benefits.
The study highlights distinctive inflammatory responses in adults and children, with potential implications for long-term consequences like lung fibrosis. The persistence of certain elevated MMPs despite treatment raises concerns about chronic respiratory dysfunction.
The small sample size and observational nature of the study limit the generalizability of the findings. Further research with larger cohorts and controlled designs is needed to validate these results.
DEFINITIONS:
Inverse Probability of Treatment Weighting (IPTW): A statistical method used to adjust for baseline differences between groups in observational studies.
ICD-10 Codes: International Classification of Diseases, Tenth Revision, used for coding various diseases and conditions in healthcare.
SUMMARY:
This retrospective cohort RECOVER study evaluated the association between acquiring SARS-CoV-2 infection during pregnancy versus outside of pregnancy and the development of post-acute sequelae of SARS-CoV-2 infection (PASC).
The study used electronic health record data from 19 U.S. health systems, including 83,915 non-pregnant and 5,397 pregnant females aged 18-49 with lab-confirmed SARS-CoV-2 infection.
Acquiring SARS-CoV-2 during pregnancy was associated with a lower incidence of PASC (25.5%) compared to acquiring it outside of pregnancy (33.9%).
However, certain PASC component diagnoses, such as abnormal heartbeat, abdominal pain, and thromboembolism, were more prevalent in pregnant females.
The study hypothesizes that the immune adaptations during pregnancy, which create an immune-tolerant state, may contribute to a lower incidence of PASC by down-regulating the robust immune response that could cause inflammatory damage.
These findings can inform counseling for pregnant individuals and guide future research. Despite the lower overall incidence of PASC, the increased risk for specific conditions such as thromboembolism underscores the need for tailored healthcare strategies during and after pregnancy.
SUMMARY:
In previous studies in children and young people (CYP), 13·3% of 12–17-year-olds with prior symptomatic infection had persistent symptoms for 3-months or more following COVID-19, with one in nine reporting a large impact on their ability to carry out day-to-day activities.
There is less research regarding the prevalence, duration, and characteristics of cognitive impairment in CYP suffering from PCC (post-Covid condition).
This study examined CYP aged 11-17. At 12-months post-testing, 7.0 % (24/345) of first-positives and 7.5 % (27/360) of reinfected CYP experienced cognitive impairment with no difference between infection-status groups (p = 0.78).
Strikingly, for first-positives, most CYP (70.8 %) who were experiencing cognitive impairment at 12-months, were 15–17 years old. But for reinfected patients, most CYP (66.7 %) who were experiencing cognitive impairment at 12-months, were 11–14 year olds (p < 0.01).
2.4% of children and young people experienced persistent cognitive impairment at 3-, 6- and 12-months after SARS-CoV-2 infection.
12 months after SARS-CoV-2 infection, more females, white ethnicities, and older at the time of first infection, children and young people reported cognitive impairment.
Cognitive impairment co-occurs with poorer mental health, fatigue and sleep problems.
DEFINITIONS:
COMPASS-31: A questionnaire used to assess autonomic symptoms across six domains, including orthostatic intolerance and gastrointestinal function.
Work Ability Index (WAI): A tool that measures a worker's ability to perform their job based on physical and mental demands, health status, and job satisfaction.
Orthostatic Intolerance: A condition characterized by dizziness, fainting, and rapid heartbeat upon standing up.
SUMMARY:
This study explored the impact of SARS-CoV-2 on the autonomic nervous system among working-age individuals, identifying that one in three developed chronic autonomic syndrome within six months post-infection.
Those with Long-COVID autonomic syndrome exhibited a significant reduction in their ability to work, highlighting an inverse relationship between the severity of autonomic symptoms and work performance.
Key symptoms included orthostatic intolerance, gastrointestinal, bladder, and pupillo-motor dysfunctions, persisting for six months after the initial infection.
Autonomic dysfunction was assessed using the COMPASS-31 and Work Ability Index (WAI) questionnaires, along with clinical examinations and standing tests.
Early recognition and management of autonomic symptoms could aid in improving patient outcomes, facilitating their return to work, and preventing long-term unemployment.
DEFINITIONS:
Schizophrenia Spectrum and Psychotic Disorders (SSPD): A range of disorders characterized by symptoms such as delusions, hallucinations, and disorganized thinking.
Acute Respiratory Distress Syndrome (ARDS): A severe lung condition causing widespread inflammation and fluid buildup in the lungs, leading to difficulty breathing.
Hazard Ratio (HR): A measure of how often a particular event happens in one group compared to another over time.
Propensity Score Matching: A statistical technique used to create comparable groups in observational studies by matching individuals based on certain characteristics.
Cochran Mantel Haenszel Test: A statistical test used to evaluate the association between an exposure and an outcome while controlling for confounding variables.
Wald Test: A statistical test that assesses the significance of individual predictors in a statistical model.
Log-rank Test: A statistical test used to compare the survival distributions of two samples.
SUMMARY:
The study reveals a significant increase in new diagnoses of Schizophrenia Spectrum and Psychotic Disorders (SSPD) among COVID-19 positive patients compared to those with Acute Respiratory Distress Syndrome (ARDS) and COVID-19 negative patients.
The study analyzed 19,344,698 patients, creating propensity-matched cohorts: ARDS (n = 222,337), COVID-19 positive (n = 219,264), and COVID-19 negative (n = 213,183).
The hazard rate of new-onset SSPD was examined over three time intervals: 0-21 days, 22-90 days, and beyond 90 days post-infection.
COVID-19 positive patients exhibited consistently higher hazard ratios for developing SSPD across all intervals [0-21 days (HR: 4.6; CI: 3.7-5.7), 22-90 days (HR: 2.9; CI: 2.3-3.8), beyond 90 days (HR: 1.7; CI: 1.5-1.9)] compared to ARDS and COVID-19 negative patients.
Despite the reduction in hazard ratios over time, COVID-19 survivors remain at a heightened risk for SSPD well beyond the immediate aftermath of their infection, necessitating vigilant psychiatric assessment and support.
Huge issue and so much to go through! But all valuable information. And this information is the light we use to see our way through the darkness of the ailment. I am now halfway through Year Five of long Covid. How time flies while ones health flutters like a fraying flag in the wind. For me, it went like this:
Yr 1 2020 (diagnosed March/April)
Yr 2 2021 (a bad year, bewilderment, "Why am I still sick? Where are all these symptoms coming from?")
Yr 3 2022 (the worst year for me)
Yr 4 2023 (noticeable improvement- rapid recovery
starts, body self-healing gathering momentum)
Yr 5 2024 (almost back to normal but severely damaged-life expectancy much shortened)