Long Covid Weekly #86: Predicting Long COVID through Plasma Proteins, The Untold Career Costs for Scientists with LC
Hi everyone,
This week's newsletter features a lot of interesting stories! Scientists and individuals battling long COVID continue to face career and health obstacles, with a call for more supportive workplace practices and universal design in academia. Studies reveal the virus's impact on placental health and potential treatments for post-COVID cognitive deficits. We see advances in understanding long COVID's pathophysiology, including its role in cardiovascular complications and lower urinary tract symptoms. Also evidence for repurposing old drugs to treat acute Covid and lower the symptom burden of Long Covid.
The article I want to highlight this week is Article: Frontiers | Beyond acute infection: molecular mechanisms underpinning cardiovascular complications in long COVID. As the title states, the authors review what the underpinnings of the cardiovascular issues in LC are.
Here are some interesting excerpts:
"Among the cardiovascular complications linked to COVID-19 are arrhythmia, myocarditis, acute coronary syndrome, myocardial infarction, and venous thrombosis embolisms, which are detectable through methods such as echocardiography, MRI, electrocardiogram (ECG), coronary angiography, and cardiac autopsies in COVID-19 patients."
"Cardiovascular injury is common among SARS-CoV-2-infected patients, with damage to the myocytes varying from initial injury with elevated troponins to eventual heart failure, indicated by increased levels of the N-terminal-prohormone brain natriuretic peptide BNP (NT-proBNP)."
"In the Netherlands, patients were followed for three months post-infection and showed evidence of elevated inflammatory cytokines and endothelial dysfunction. This is in line with the elevated plasma levels of endothelin-1 (ET-1) that correlate with contact activation factors, hence suggesting endothelial activation and the coagulation process."
Media
Article: Four years on: the career costs for scientists battling long COVID | Nature
SUMMARY:
People with long COVID, including researchers, often face challenges in getting sufficient support in the workplace despite experiencing ongoing health issues.
The condition can impact academic careers and require adjustments and accommodations to manage the illness effectively.
Symptoms can lead to extra administrative burdens and financial pressures on affected researchers.
The academic culture, focused on productivity and competition, may pose additional barriers for individuals with chronic health conditions.
Researchers with long COVID have found ways to adapt and thrive, emphasizing the importance of supportive supervisors and flexible working arrangements.
Advocates call for a shift towards universal design and inclusive practices in academia to better support individuals with long-term health concerns.
Article: How long COVID is still affecting Coloradans - Axios Denver
SUMMARY:
Long COVID affects a significant number of Coloradans, with an estimated 240,000 residents experiencing symptoms.
Patients with long COVID face challenges in accessing care, with some waiting one to six months for treatment.
Individuals with lower incomes and resources are disproportionately affected by long COVID symptoms.
Article: Severe lung infection during COVID-19 can cause dmage to the heart | NIH News Releases
SUMMARY:
A National Institutes of Health-supported study has found that SARS-CoV-2 can damage the heart even without directly infecting the heart tissue.
The study specifically looked at damaged hearts of people who suffered from SARS-CoV2-associated acute respiratory distress syndrome (ARDS), a serious lung condition that can be fatal.
The researchers analyzed heart tissue specimens from 21 patients who died from SARS-CoV-2-associated ARDS and compared them with specimens from 33 patients who died from non-COVID-19 causes. They also infected mice with SARS-CoV-2 to follow what happened to the macrophages after infection.
In both humans and mice, they found the SARS-CoV-2 infection increased the total number of cardiac macrophages and also caused them to shift from their normal routine and become inflammatory.
Researchers said the findings could have relevance to organs beyond the heart and also to viruses other than SARS-CoV-2. “...after a COVID infection, the immune system can inflict remote damage on other organs by triggering serious inflammation throughout the body …in addition to damage the virus itself has directly inflicted on the lung tissue,” said Matthias Nahrendorf, M.D., Ph.D., professor of Radiology at Harvard Medical School and senior author on the study. “These findings can also be applied more generally, as our results suggest that any severe infection can send shockwaves through the whole body.”
Research
DEFINITIONS:
Trophoblast Apoptosis: Apoptosis is the process of programmed cell death. In the context of this study, trophoblast apoptosis refers to the death of cells that form part of the outer layer of the placenta, which is crucial for the exchange of nutrients and gases between the mother and fetus. Increased apoptosis in trophoblasts suggests damage to the placenta.
Immunohistochemistry (IHC): A laboratory method used to visualize specific proteins and antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues.
Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) Assay: A method used to detect DNA fragmentation resulting from apoptotic signaling cascades by labeling the terminal end of nucleic acids.
Interferon-γ (IFN-γ): A cytokine that plays a critical role in innate and adaptive immunity against viral and some bacterial infections. It is produced predominantly by natural killer and natural killer T cells as part of the immune response.
Transmembrane Protease Serine-2 (TMPRSS2): A protein involved in the priming of spike proteins of coronaviruses, including SARS-CoV-2, facilitating viral entry into host cells.
SUMMARY:
The study demonstrates an increase in transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), and trophoblast apoptosis rate in the COVID-19 group compared to the control, while angiotensin converting enzyme-2 (ACE-2) and interleukin-6 (IL-6) expressions did not show significant differences.
SARS-CoV-2 spike protein was detected in 25% of placental samples from COVID-19 positive pregnancies, suggesting the virus's ability to infect placental tissue.
Increased Placental Inflammation and Apoptosis: COVID-19 positive placentas showed increased levels of IFN-γ and higher rates of apoptosis in trophoblast and stromal cells, indicating placental inflammation and damage.
The study found no correlation between the severity of maternal COVID-19 infection and the level of placental inflammation or apoptosis.
DEFINITION:
Methylprednisolone: A glucocorticoid with anti-inflammatory properties, used in various immune-mediated diseases.
SUMMARY:
The ongoing PoCoVIT (post-coronavirus immune treatment) trial investigates the effects of methylprednisolone on cognitive deficits in patients with PCS (Post-COVID-19 Syndrome).
Patients with PCS often experience neurological symptoms such as fatigue and cognitive deficits, impacting their quality of life.
The trial design involves a randomized, double-blind, placebo-controlled study focusing on the hypothesized autoimmune pathogenesis underlying cognitive impairments in PCS.
DEFINITIONS:
Coagulation Profile: A set of tests that evaluate the blood’s ability to clot properly. Key indicators include prothrombin time (PT), activated partial thromboplastin time (aPTT), and D-dimer levels.
Activated Partial Thromboplastin Time (aPTT): Measures the efficiency of the blood’s intrinsic clotting pathway. Prolonged aPTT can indicate clotting disorders.
Prothrombin Time (PT): Assesses the blood’s extrinsic clotting pathway, with prolonged PT suggesting potential bleeding disorders or liver disease.
D-dimer: A fragment produced during the breakdown of a blood clot. Elevated levels can indicate active blood clotting and are used to assess thrombotic conditions.
SUMMARY:
The majority of children with COVID-19 exhibited abnormalities in their coagulation profile (94.5%), with significant age dependency observed. These changes included increased activated partial thromboplastin time (69.1%), prothrombin time (39.8%), and D-dimer levels (45.0%).
Out of 157 participants followed after hospital discharge, 62 patients (39.5%) displayed long COVID symptoms according to WHO criteria. The study identified a statistically significant higher percentage of abnormal prothrombin time values among children with long COVID symptoms.
Besides coagulation abnormalities, factors such as female gender and comorbidities (notably allergic pathology and nutritional disorders, including obesity) were associated with an increased likelihood of developing long COVID.
Between patients with long COVID symptoms and those fully recovered, there was no significant difference in median platelet levels and most coagulation profile indicators.
SUMMARY:
The study analyzed financial data from 45,833 nursing home-year observations between 2018 and 2021, finding a significant deterioration in financial performance during the COVID-19 pandemic. Operating margins decreased by 4.3%, operating costs per resident day increased by $26.51, and operating revenue per resident day increased by about $17, indicating substantial financial strain.
The pandemic's impact on nursing homes was multifaceted, affecting operating costs and revenues. Factors such as occupancy rates, payer mix, staffing intensity, and government aid played roles in shaping financial outcomes.
Costs rose significantly due to increased demands for personal protective equipment (PPE) and staffing challenges. Occupancy rates fell due to reluctance in accepting new residents and a higher mortality rate, adversely affecting revenue.
DEFINITIONS:
Olink Target 96 immune response panel: A technology used to measure the presence and concentration of specific proteins in the blood, useful for studying immune responses.
FDR-adjustment (False Discovery Rate): A statistical method used to correct for multiple comparisons in data analysis, reducing the likelihood of falsely identifying an effect.
SRPK2 and ITGA6: Specific plasma proteins investigated in this study. SRPK2 is involved in mRNA splicing and cell activity regulation, while ITGA6 is a transmembrane protein important in cell adhesion and signal transduction.
Linear and Logistic Regression Models: Statistical methods used to explore the relationship between one (linear regression) or more (logistic regression) independent variables and a dependent variable.
SUMMARY:
The study investigates whether certain immune response plasma proteins can predict Long COVID or fatigue severity post-SARS-CoV-2 infection, analyzing 257 outpatients.
The study measured 92 plasma proteins using the Olink Target 96 immune response panel and assessed Long COVID symptoms and fatigue severity through surveys.
Nine plasma proteins were initially associated with Long COVID, but their significance was lost after adjusting for multiple testing. SRPK2 and ITGA6 remained significantly associated with fatigue severity after adjustment.
The findings suggest that specific immune response proteins play a crucial role in the pathophysiology of Long COVID and fatigue severity.
The study used a longitudinal design, collecting blood samples two years before assessing Long COVID or fatigue severity, and adjusted its analysis for multiple potential confounders.
DEFINITION:
LUTS: Lower urinary tract symptoms, which could include urinary frequency, urgency, incontinence, and nocturia.
Viral cystitis: Inflammation of the bladder caused by a viral infection.
Bacteriophage: A virus that infects and replicates within bacterial cells.
SUMMARY:
COVID-19 has been linked to lower urinary tract symptoms (LUTS), including urinary frequency, urgency, incontinence, and nocturia, both in the acute and chronic phases of the disease.
The bladder can be affected by COVID-19 through mechanisms such as direct viral cystitis, inflammation mediated by pro-inflammatory cytokines, and potential viral persistence or reactivation leading to immune responses and chronic LUTS.
Researchers are investigating the interaction between SARS-CoV-2 infection and the urinary system, considering viral access to urothelial cells, systemic effects triggering a cytokine storm, and long-term bladder dysfunctions post-infection, raising questions about microbial infections and bacteriophages potentially in the bladder.
Various studies have been suggested to explore the correlations between COVID-19 severity and LUTS, the influence of COVID-19 vaccination on LUTS, the role of biomarkers in predicting LUTS severity, the evolution of COVID-LUTS, and the treatment implications of bacterial infections.
SUMMARY:
SARS-CoV-2 has led to significant cardiovascular burdens in infected individuals that persist beyond the acute phase, and even in asymptomatic cases.
The virus enters cells using membrane fusion or endocytosis pathways, triggering immune responses like hyperactive cytokine release leading to systemic inflammation, vasculitis, and blood clot formation.
COVID-19 can directly infect the heart, alter the gut microbiome, cause prolonged immune activation, oxidative stress-related DNA damage, and induce endothelial dysfunction, driving long-term cardiovascular consequences.
The lasting cardiovascular sequelae of COVID-19 include ischemic injuries, organ damage, immune-mediated disorders, arrhythmia, myocarditis, pericarditis, hypertension, heart failure, and thrombotic disorders that persist post-infection.
Genetic, epigenetic, and mitochondrial implications, along with microbial imbalances and intergenerational/transgenerational impacts, underscore the vast array of cardiovascular complications beyond the acute phase of COVID-19.
DEFINITION:
SUMMARY:Anti-S IgG and Anti-NC Antibody Levels: Immunoglobulins (antibodies) in the serum targeting the spike (S) and nucleocapsid (NC) proteins of the SARS-CoV-2 virus, indicative of immune response to infection or vaccination.
This study analyzed SARS-CoV-2 RNA persistence and symptom duration in 102 participants following COVID-19 diagnosis, finding mucosal RNA detectable for a median of 31.5 days.
Obesity (BMI ≥30) significantly correlated with persistent RNA detection but not age, sex, or chronic conditions.
About 47% of participants reported symptoms lasting ≥2-3 months, with persistence ≥3 months associated with obesity and higher peak antibody levels against the virus's spike (S) and nucleocapsid (NC) proteins.
Fifteen cases of likely reinfection were identified, with lower prior serum anti-S IgG levels linked to a higher reinfection risk, suggesting serum but not mucosal antibody levels correlate with protection from reinfection.
The study did not find a significant association between persistent symptoms and viremia or mucosal RNA, challenging the notion that viremia contributes to long-term symptomatology.
Higher body mass index (BMI) and robust peak antibody responses were identified as factors associated with symptom persistence after acute COVID-19 resolution, suggesting a link between host health, immune response, and long COVID.
DEFINITIONS:
Pulmonary Fibrosis (PF): A lung disease that occurs when lung tissue becomes damaged and scarred, making it difficult for the lungs to work properly.
Monocytes: A type of white blood cell that plays a vital role in the body's immune response by fighting infections and aiding in the removal of dead or damaged tissue.
HLA-DR Expression: Part of the major histocompatibility complex (MHC) class II, HLA-DR is critical for the immune system to recognize foreign molecules, with its expression on monocytes indicating their role in antigen presentation.
CD8+ T Cells: A subtype of T cells that are primarily responsible for killing infected cells. Their activation is crucial in the body's immune response to pathogens.
SUMMARY:
The study explored immune mechanisms between Early-Resolving (ER) and Late-Resolving (LR) COVID-associated Pulmonary Fibrosis (PF) using single-cell RNA-sequencing and multiplex immunostaining on blood samples, comparing them to idiopathic pulmonary fibrosis (IPF) patients and controls.
LR COVID-PF patients exhibited significantly fewer circulating monocytes and altered monocyte HLA-DR expression, correlating with decreased lung function, differing from ER COVID-PF patients and controls.
CD8+ T cells in LR COVID-PF showed higher activation markers, such as upregulated MHC-II class molecules, suggesting prolonged immune activation distinct from both ER COVID-PF and IPF.
Unlike LR COVID-PF, IPF patients displayed a different pattern of monocyte HLA-DR expression and a varied T cell activation profile, indicating unique underlying immune responses between post-COVID PF and IPF.
LR COVID-PF patients had a more pronounced T cell activation and effector memory phenotype, contrasting with the naïve state observed in controls and IPF patients, implying ongoing inflammation.
DEFINITIONS:
Generalized joint hypermobility (GJH): An excessive range of motion across multiple joints - not necessarily a medical problem by itself.
Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD): Clinical phenotypes of GJH. These are associated with clinically significant issues, including chronic disabling fatigue and dysautonomia.
UK COVID Symptom Study Biobank (CSSB): A collection of plasma, DNA and fecal samples from Covid Symptom Study App participants with specific COVID symptomatology.
SUMMARY:
There is growing interest in how generalized joint hypermobility may represent a common factor predisposing to complex multisystem conditions, such as chronic fatigue, fibromyalgia, and neurological disorders, among others.
The aim of this study was to use the UK COVID Symptom Study Biobank (CSSB) to determine if the presence of GJH is associated with an increased risk of not recovering fully from infection with COVID-19.
Data was extracted from the UK CSSB. Of the 914 participants (32.0%) who reported not having recovered fully from COVID-19 infection, 269 patients (29.4%, 254 female) had GJH. In the fully recovered group, 439 of 1940 patients (22.6%, 400 female) had GJH.
GJH was significantly associated with not having recovered from COVID-19 (p<0.001) with OR 1.43 (95% CI 1.20 to 1.70).
In a model adjusting for all covariates, GJH also significantly predicted higher fatigue levels (p=0.002).
In this large population-based study, an individual with GJH was approximately 30% more likely not to have recovered after initial COVID-19 infection. This observation has potential impact for understanding and identifying sub-phenotypes of long COVID for screening and targeted interventions.
DEFINITIONS:
Fluvoxamine: An SSRI (selective serotonin reuptake inhibitor) typically used to treat obsessive-compulsive disorder, anxiety disorder, and depression.
Bromhexine: A mucolytic medicine - used to break up excessive or thick phlegm associated with a chest cough.
Cyproheptadine: An antihistamine used to relieve allergy symptoms, headaches, and motion sickness.
Niclosamide: A drug used to treat parasitic infections. Recent studies indicate it may have broad clinical applications for treating other types of diseases.
SUMMARY:
The aim of this open-label, randomized, outpatient, controlled trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19. This may be particularly relevant to low-resource countries.
Participants received treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care.
995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen.
In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5%.
All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine-only arm (p < 0.0001).
Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration.
This treatment was also associated with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms.
When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients.
My Take (Amy):
If these data are found to be accurate, and doctors world-wide use these readily available drugs, along with Paxlovid, the rate of hospitalizations and death from Covid would likely approach zero. And usage would likely have a significant impact on Long Covid as well. Wouldn’t that be awesome?
Great newsletter! I was reading one of the December posts and saw the bit about fasting to treat long Covid which is likely correct. However, the article states "current knowledge indicates that CoVs interact with the multiple components of autophagy machinery in order to facilitate viral replication", which suggests that while you have the actual virus you should probably avoid fasting. Intermittent fasters may find this useful. I have possibly missed mention of this somewhere, if so, my apologies.