Hi everyone,
In this issue, we explore recent research articles shedding light on various aspects of Long Covid, from the impact of metabolic disruption and inflammation on cognitive function to the potential links between pre-existing conditions like hypertension and long-term COVID sequelae. We also delve into the role of immune responses, iron dysregulation, and viral load kinetics in the development and persistence of Long Covid symptoms.
As previously requested by our reader Michael S, the CURE-ID survey is still up and running! Enroll here. This important collaboration between the FDA, NIH, and the National Center for Advancing Translational Science is looking to get information from at least 1000 people with Long Covid, as well as their providers. Results will help tell researchers what off-label and repurposed medications are working (or not working, or are harmful) for people with Long Covid. Data is kept anonymous for researchers. Read more about the initiative in The Sick Times.
Also, something else that I think is worth highlighting is the possible connection between Mast cells and Cholesterol. I was in a Twitter thread last week, and another user highlighted that their doctor had brought up the connection. As a result of that conversation I began digging and stumbled on this article: Mast Cells as Potential Accelerators of Human Atherosclerosis—From Early to Late Lesions. Within the article were some interesting tidbits:
"Provided the blood-derived high-density lipoproteins (HDL) particles are able to efficiently carry cholesterol from the foam cells back to the circulation, the early lesions may stay stable or even disappear. However, the modified LDL particles also trigger a permanent local inflammatory reaction characterized by the presence of activated macrophages, T cells, and mast cells, which drive lesion progression."
"Then, the HDL particles become modified and unable to remove cholesterol from the foam cells. Ultimately, the aging foam cells die and form a necrotic lipid core."
This would perhaps explain why many people post-covid have skyrocketing cholesterol. Curious what others think of this theory?
Media
Article: The medical gaslighting of long COVID patients could be nearing its end | The Hill
SUMMARY
Sen. Bernie Sanders chaired a Senate Committee hearing on the challenges faced by long COVID patients, including inadequate research funding, access to quality care, and lack of medical recognition of their symptoms.
The dismissal of long COVID symptoms mirrors the historical skepticism towards myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), often labeled as a psychological issue despite its severe physical impact.
Recent NIH research identified biological markers for ME/CFS, challenging it's psychosomatic framing and suggesting immune dysfunction as a potential cause, offering hope for both ME/CFS and long COVID patients.
The bipartisan Senate hearing underscored the recognition of long COVID as a legitimate medical condition, signaling a shift towards increased research funding and a better understanding of such chronic illnesses.
Article: SARS-CoV-2 viral load and shedding kinetics | Nature Reviews Microbiology
DEFINITIONS:
SARS-CoV-2 viral load: The amount of virus present in a sample, like respiratory secretions, as determined by quantitative measures.
Infectious virus: Virus particles capable of causing infection and replication in host cells.
Real-time PCR (RT-PCR): A diagnostic technique that detects and amplifies specific segments of viral genetic material for identification.
Cycle threshold (Ct): The number of PCR cycles required for the fluorescent signal to exceed background noise, indicative of viral genetic material presence.
Antigen-detecting rapid diagnostic tests (Ag-RDTs): Tests that detect specific viral proteins, like nucleocapsid proteins, as a proxy for infectious virus.
SUMMARY:
The ability to shed infectious SARS-CoV-2, not just detect viral RNA, is crucial for transmission. Factors such as viral characteristics, host immune status, and variants influence shedding patterns and infectiousness.
Standard diagnostics like RT-PCR can't distinguish between infectious virus and non-infectious RNA. Alternatives like Ag-RDTs and viral culture serve as proxies but have limitations, underscoring the need for direct infectious virus detection methods.
SARS-CoV-2 variants and population immunity levels (from vaccination or previous infection) have significantly altered viral load dynamics, shedding patterns, and transmission risks.
Higher viral loads are associated with increased transmission risk. Understanding individual and variant-specific shedding dynamics is essential for public health strategies and interventions.
SUMMARY:
Three articles this week in the prestigious New England Journal of Medicine discuss cognitive deficits following infection with COVID-19.
This editorial discusses the study by Hampshire et al. (first up under Research below) on COVID-19 and impaired cognition. The study examined cognitive function in over 100,000 adults in England infected with COVID-19. The study’sey points:
Those with mild COVID-19 still had modest cognitive decline equivalent to 3 IQ point loss. Those with persistent symptoms had 6 IQ point loss. ICU admission was associated with 9 IQ point loss.
Deficits were greatest for the original virus strain and early variants compared to later ones. Longer illness and hospitalizations also predicted greater deficits.
Memory, reasoning and executive functions were most affected. Scores correlated with patient-reported brain fog.
Vaccination provided a small cognitive advantage. Reinfection contributed an additional 2 IQ point loss.
The editorial discusses implications such as effects on functional abilities and risks of subsequent dementia. It notes limitations including potential biases and lack of diversity. Overall, it emphasizes the concerning cognitive impact of COVID-19 found by the study.
Research
SUMMARY:
The study examined cognitive function in over 100,000 adults in England who had COVID-19.
It compared performance on 8 cognitive tasks across 6 groups: those with no COVID-19, asymptomatic cases, resolved short-term illness (<4 or 4-12 weeks), resolved long-COVID (>12 weeks), and unresolved long-COVID symptoms (>12 weeks).
Those infected early in the pandemic and with more severe illness showed greater cognitive deficits compared to later milder infections.
Participants with persistent symptoms (>12 weeks) had the largest cognitive deficits (0.42 SD below the no-COVID group).
ICU admission was associated with the greatest deficits (0.63 SD below no-COVID), with a 3.6 times higher likelihood of at least moderate impairment.
Deficits attenuated over time - it was smaller for delta/omicron variants compared to original/alpha variants.
Vaccination (2+ doses) was associated with slightly better cognition.
Memory, reasoning and executive functions were most affected. These related weakly to patient-reported brain fog/poor memory.
SUMMARY:
In another study on cognition published in the New England Journal of Medicine, authors analyzed self-reported memory problems in over 100,000 Norwegians who tested positive for COVID-19. Study findings were presented in the form of a letter. Key findings:
Those testing positive for COVID-19 had numerically worse everyday memory questionnaire (EMQ) scores at timepoints up to 36 months after infection compared to those testing negative.
EMQ scores were generally lowest in younger participants and those with lower BMI. Women had higher scores than men.
Scores increased with longer duration of being bedridden during acute COVID-19 illness.
Limitations include possible response bias and reliance on participant self-report.
DEFINITIONS:
Bifidobacteria: A group of bacteria commonly found in the intestines, known for their beneficial effects on human health, including support for the immune system.
Clostridia: A class of bacteria, some members of which are important for the production of butyrate, a short-chain fatty acid beneficial for gut health. They can be transmitted between hosts (horizontal transmission).
Skin Prick Testing (SPT): A test used to identify immediate allergic reactions to specific allergens by introducing small amounts of the allergens into the skin.
Atopic Dermatitis (AD): A type of eczema characterized by itchy, inflamed skin.
Microbial exposure index: An index created to assess the level of microbial exposure based on various factors, such as the presence of siblings, pets, and daycare attendance.
Vertical transmission: The transmission of bacteria from mother to infant, especially during birth and breastfeeding.
Butyrate producers: Bacteria that metabolize dietary fibers to produce butyrate, a short-chain fatty acid with various beneficial effects on gut health and immune function.
SUMMARY:
Infants' gut microbiota composition is significantly influenced by environmental exposures and dietary factors.
During the COVID-19 pandemic, social distancing measures led to differences in microbiota development compared to pre-pandemic cohorts.
Specifically, infants had higher levels of bifidobacteria and lower levels of Clostridia.
The study highlights the importance of vertically transmitted bacteria (from mother to infant) and dietary supports, suggesting they may play a more crucial role than exposure to environmental microbes alone in protecting against allergic diseases in infancy.
The study analyzed fecal samples from infants at 6 and 12 months using 16S sequencing and compared the data with pre-pandemic cohorts.
Online questionnaires collected information on the home environment, diet, healthcare utilization, and allergic diseases. Skin prick testing (SPT) and assessments for atopic dermatitis (AD) and food allergy were performed at 12 and 24 months.
The study found that breastfeeding and the introduction of diverse foods during weaning significantly impacted microbiota development.
Infants born during the pandemic had a higher relative abundance of beneficial bifidobacteria and lower levels of Clostridia, which are environmentally transmitted.
The abundance of Clostridia was correlated with a microbial exposure index, supporting the hypothesis that reduced exposure to humans and the environment outside the immediate family during COVID-19 restrictions altered infants' gut microbiota development.
The prevalence of allergen sensitization, food allergy, and AD did not increase over pre-pandemic levels, despite changes in microbiota composition.
Levels of bifidobacteria at 6 months and butyrate producers at 12 months were negatively associated with AD and SPT positivity, suggesting that these bacteria may offer protection against allergic diseases.
DEFINITIONS:
Cox regression models: Statistical methods for exploring the relationship between the survival time of subjects and one or more predictor variables.
Hazard ratios (HRs): A measure used in survival analysis to compare the risk of an event occurring at any time point among one group with the risk among another group.
Inverse probability weights (IPTW): A method used to create a synthetic sample in which the treatment assignment is independent of measured baseline covariates, balancing the covariates across groups.
Chronic obstructive pulmonary disease (COPD): A chronic inflammatory lung disease that causes obstructed airflow from the lungs.
Interstitial lung disease (ILD): A group of lung conditions affecting the interstitium, the tissue and space around the air sacs of the lungs.
Pulmonary vascular disease (PVD): Refers to any condition that affects the blood vessels within the lungs, which can lead to high blood pressure in the lungs.
SUMMARY:
This study aimed to investigate the long-term risk of respiratory diseases following COVID-19 infection, leveraging a longitudinal, population-based cohort study utilizing the UK Biobank database.
It involved three cohorts: a COVID-19 group diagnosed between January 30, 2020, and October 30, 2022; a contemporary control group; and a historical control group, with the follow-up period for all groups being approximately 2.7 years.
The study focused on various respiratory outcomes, including asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer, using Cox regression models for analysis.
Patients with COVID-19 showed an increased risk of developing respiratory diseases compared to both contemporary and historical control groups.
This increased risk was associated with the severity of the initial COVID-19 infection and the occurrence of reinfection.
Over a 24-month follow-up, the risks of asthma and bronchiectasis trended upwards, whereas the risk association for lung cancer diminished after the initial 6–12 months.
Reinfected patients exhibited a higher risk for asthma, COPD, ILD, and lung cancer compared to those with a single infection.
The increased risks for various respiratory outcomes were noted before the widespread availability of COVID-19 vaccinations.
DEFINITIONS:
Dyspnea: Difficulty or labored breathing.
Cognitive failures: Lapses in memory, perception, or motor function that are not attributed to a lack of knowledge or inattention.
Health-related quality of life (HRQoL): An individual's or group's perceived physical and mental health over time.
Immunomodulatory treatments: Therapies that modify the immune response or the functioning of the immune system.
SUMMARY:
This study explored the impact of acute COVID-19 treatments on long-term health outcomes in patients hospitalized due to COVID-19.
Conducted in the Netherlands from July 2020 to October 2021, the research focused on patients aged 18 years or older who received various in-hospital treatments, including steroids, anti-inflammatory, and antiviral medications.
The study aimed to understand if these treatments affected the prevalence of long-term health problems such as dyspnea, fatigue, cognitive issues, and overall health-related quality of life.
Patients were assessed 2 years post-hospital discharge using self-reported questionnaires and the 6-minute walk test.
A total of 502 patients were studied, with the majority being male and having a median age of 60 years at the time of hospital admission.
The treatments administered during hospitalization varied, with nearly half of the patients receiving steroids only, and others receiving anti-inflammatory treatments, antivirals, or no specific COVID-19 treatment.
Two years after hospital discharge, a significant proportion of patients continued to experience long-term health issues, regardless of the type of in-hospital COVID-19 treatment received.
The study did not find a significant association between the type of acute COVID-19 treatment and the presence of long-term health problems.
The findings suggest that the acute treatments for COVID-19 administered in the hospital do not significantly impact the long-term health outcomes of patients.
DEFINITIONS:
Vortioxetine: A multimodal antidepressant known for improving cognitive performance in individuals with Major Depressive Disorder (MDD).
DSST: Digit Symbol Substitution Test, a measure of cognitive function assessing processing speed, attention, and visuomotor coordination.
SUMMARY:
This study investigated the efficacy of vortioxetine on cognitive deficits in individuals with post-COVID-19 condition (PCC), considering the role of metabolic dysfunction, elevated inflammation, and body mass index (BMI).
This was a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial among 200 adults in Canada displaying WHO-defined PCC symptoms, with 147 participants randomized to either vortioxetine or placebo.
The analysis demonstrated significant improvement in cognitive function over time with vortioxetine, particularly among participants with baseline metabolic dysfunction, elevated inflammation, and higher BMI, compared to placebo.
The authors suggest vortioxetine could be beneficial for individuals with PCC and specific health markers, highlighting the interconnectedness of metabolic disorders, high BMI, inflammation, and cognitive impairment.
My Take (Amy):
Any new randomized controlled trial for medication treatment that shows an improvement in symptoms is cause for hope for people with Long Covid!
DEFINITIONS:
IL-6: Interleukin-6, a cytokine involved in the body's inflammatory response.
IL-17: Interleukin-17, a cytokine that plays a role in the immune response to infections and autoimmune diseases.
Hypertension: High blood pressure, a common condition in which the force of blood against the artery walls is consistently too high.
SUMMARY:
The study investigates the connection between pre-existing hypertension, interleukins IL-6 and IL-17, and long-term COVID-19 sequelae in patients undergoing hemodialysis.
Patients with uncontrolled blood pressure had a higher prevalence of long-term COVID sequelae, along with elevated levels of IL-6 and IL-17.
IL-6 and IL-17 concentrations were significantly higher in patients with uncontrolled blood pressure and long-term COVID sequelae compared to controlled blood pressure groups.
The study suggests that hypertension and COVID-19 may lead to endothelial dysfunction, impacting IL-6 and IL-17 levels, contributing to long COVID in hemodialysis patients.
My Take:
This study sheds light on the complex interplay between hypertension, inflammatory cytokines, and long-term COVID effects in hemodialysis patients.
Understanding how IL-6 and IL-17 may contribute to elevated risks for long COVID in hypertensive patients undergoing hemodialysis is crucial.
The findings emphasize the importance of monitoring cytokine levels in patients with hypertension to potentially mitigate long-term COVID-19 complications.
DEFINITIONS:
Erythropoiesis: The process of producing red blood cells (erythrocytes) in the body.
Hepcidin: A hormone produced by the liver that regulates iron absorption and distribution in the body.
Reticulocytosis: An increase in the number of reticulocytes (immature red blood cells) in the bloodstream, often a response to anemia.
Iron homeostasis: The regulation of iron levels within the body, ensuring a balance between iron absorption, utilization, and storage.
C-reactive protein (CRP): A substance produced by the liver in response to inflammation.
Transferrin saturation (TSAT): A measure of the amount of iron bound to transferrin (a blood protein that transports iron) relative to the total iron-binding capacity of the blood, indicating the availability of iron for erythropoiesis.
SUMMARY:
This study investigates the relationship between iron dysregulation, inflammatory stress erythropoiesis, and the long-term outcomes of COVID-19, focusing on post-acute sequelae of SARS-CoV-2 infection (PASC).
Persistent symptoms of COVID-19 (PASC) were assessed in 214 individuals over a year. A signature of unresolved inflammation, anemia, low serum iron, altered gene expression related to iron homeostasis, and stress erythropoiesis identified individuals who later reported PASC, regardless of initial COVID-19 severity.
Inflammation-driven iron dysregulation was observed, with increased levels of C-reactive protein (CRP) and cytokines, elevated hepcidin (an iron-regulating hormone), and low serum iron and transferrin saturation.
This suggests a state of inflammatory anemia and disrupted iron homeostasis.
Reticulocytosis with iron deficiency was noted, indicating a stress response to anemia that might be ineffective due to low iron availability for hemoglobin synthesis.
Analysis of blood samples showed prolonged immune-cell abnormalities and iron metabolism disruption in those with PASC. Specific immune cell types, such as monocytes, showed signs of iron loading, while lymphocytes indicated increased iron demand.
Early markers of iron dysregulation and inflammation were predictive of PASC, suggesting that interventions targeting iron homeostasis might reduce long-term COVID-19 sequelae.
DEFINITIONS:
STING: Stimulator of interferon genes, an adapter protein involved in the innate immune response to viral infections.
cGAS: Cyclic GMP-AMP synthase, an enzyme that detects viral DNA and activates the cGAS-STING pathway.
IFN-α: Interferon-alpha, a type I interferon involved in antiviral immunity.
SUMMARY:
Severe COVID-19 and long COVID are associated with high expression of STING, cGAS, and IFN-α, indicating immune dysregulation in these conditions.
The study found that patients with severe COVID-19 had elevated levels of cGAS, STING, IFN-α, TNF-α, and IL-6 compared to those with nonsevere disease.
In long COVID, higher expression of cGAS, STING, and IFN-α was observed even after resolution of the acute infection, suggesting ongoing inflammation and immune dysregulation.
SUMMARY:
Abstract only. This prospective, multicenter, observational cohort study from RECOVER estimated the prevalence of post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID) after infection with SARS-Cov-2 during pregnancy. Another study goal was to characterize associated risk factors.
Over 1,500 participants were included in the study. The prevalence of PASC at the first study visit 6 months or more after infection was 9.3%. The most common defining symptoms among individuals with PASC were post-exertional malaise (82%), fatigue (75%) and dizziness (62%).
Several factors were associated with increased odds of developing PASC, including obesity (aOR-adjusted odds ratio=1.63), preexisting depression or anxiety disorder (aOR=2.64), economic hardship (self-reported difficulty covering expenses) (aOR=1.66), and treatment with oxygen during infection (aOR=1.88).
At 9.3%, the prevalence of long Covid after Covid infection during pregnancy was lower than the previously published RECOVER adult cohort estimates of 23%. This may reflect differential immune responses in pregnancy, differences in sampling strategies, or lower rates of pre-existing comorbidities.
SUMMARY:
This prospective, longitudinal cohort study from Wuhan, China, with 728 participants, aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulations, and fibrotic-like changes) and pulmonary function, three years following COVID-19.
Follow-up assessments were conducted at 6 months, 12 months, 2 years, and 3 years post-discharge, and included pulmonary function tests, 6-minute walk distance (6MWD), chest CT scans, and symptom questionnaires.
Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%, p<0.001), a lower 6MWD (494 m versus 510 m, p=0.003), and abnormal DLCO (carbon monoxide diffusion capacity) (57% versus 27%, p<0.001) compared to those with complete resolution.
Compared to the controls, the proportion of DLCO impairment (38% versus 17%, p<0.001) and respiratory symptoms (23% versus 2.2%, p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up.
Two-thirds of patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than one-third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.
The iron dysregulation particularly fascinates me. I was formally diagnosed with iron deficiency anemia in 2021, before I got Covid, but it's still present, despite the iron supplement I was taking. This might explain a few things!
Also noting, just to throw a monkey wrench into the works, my cholesterol levels were excellent with my last blood panel, but I will definitely keep an eye on them moving forward.
So many articles this week!