Long Covid Weekly #76: Long Covid Senate Hearing, T Cell Dysregulation
Hi everyone,
Some BIG LC news this week, the US Senate is holding a hearing on Long Covid on Thursday. This is likely the best opportunity LC has to increase exposure and (try to) get more funding. As we all know, ReCOVer is going to run out of funding at some point, so we need back up options ready to go. If you are going in person to the meeting, the people behind the Moonshot initiative are printing out free T-Shirts!
Also, I want to thank everyone who either commented or emailed me about repeat infections. I got a lot more responses (~40!!) than I initially anticipated. If I have not responded to you yet I will do it soon, but just wanted to let everyone know I appreciate your sharing your stories. Some people had asked me to summarize my learnings. From just the people who responded there appears to be quite a bit of heterogeneity but I would say for most people a second infection made already existing symptoms worse. This of course is anecdotal, I learned from one of my readers that Patient Led is looking into an analysis on repeat infections!
In this issue, we bring you a collection of informative articles that delve into the complexities and emerging knowledge surrounding post-Covid dysautonomias, the long-term implications of hyperbaric oxygen therapy for Long Covid treatment, the prevalence of long Covid in a Korean SARS-CoV-2 cohort at the two-year mark, and the fascinating connection between long Covid symptoms and the diagnosis of hEDS (hypermobile Ehlers-Danlos Syndrome). Additionally, we explore the role of T cell dysregulation and inflammation in the manifestation of Long Covid, the impact of acute Covid-19 on the development of post-acute sequelae, the assessment of cellular immunity against SARS-CoV-2, the potential risk of functional neurological disorders following Covid-19 vaccination, the composition and dynamics of the gut microbiome in post-acute Covid-19 patients, and the predictive value of NT-proBNP (N-terminal pro B-Type Natriuretic Peptide) levels in Covid-19 prognosis.
Media
DEFINITIONS:
Autonomic nervous system (ANS): The part of the peripheral nervous system responsible for regulating involuntary bodily functions, such as heart rate, blood pressure, digestion, and temperature control.
Dysautonomias: Disorders or dysfunctions of the autonomic nervous system.
SUMMARY:
Post-COVID syndrome, can manifest as dysautonomias, which affect the autonomic nervous system (ANS) and result in various symptoms.
Studies of ANS dysregulation in people with post-COVID syndrome have been primarily observational and descriptive, focusing on symptom inventories and indirect measures of cardiovascular function, while neglecting the hormonal and enteric components of the ANS.
Understanding the pathophysiology of post-COVID dysautonomias requires considering the syndromic nature of autonomic dysfunction and the involvement of the extended autonomic system, which includes neuroendocrine, immune, and inflammatory systems.
There is a need to shift towards studying the feedback-regulated, plastic networks that determine homeostasis and allostasis in order to better understand and manage post-COVID dysautonomias.
DEFINITIONS:
HBOT: hyperbaric oxygen therapy, a treatment involving the use of pressurized air and 100% oxygen in a metal chamber.
SUMMARY:
In a recent interview with NeurologyLive®, Hadanny, a neurosurgeon and the chief medical research officer and head of research at Aviv Clinics, discussed the challenges that researchers face in conducting long-term evaluations of COVID treatments, and how they are addressing these issues.
Amir Hadanny, MD, PhD, and colleagues, assessed the impact of HBOT in 73 post-COVID-19 patients for at least 3 months.
Hyperbaric oxygen therapy shows promise in improving cognitive function in post-COVID-19 patients who have experienced long-term symptoms.
In addition, he spoke about the ways the unique combination of pressurized air and 100% oxygen in a metal chamber helps to contribute to the healing process for brain injuries.
Article: Long COVID symptoms lead to hEDS diagnosis in small study
DEFINITIONS:
hEDS: hypermobile Ehlers-Danlos syndrome HSD: hypermobility spectrum disorders
SUMMARY:
Clinicians should test for hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD) if their patients continue to show persistent symptoms after infection with SARS-CoV-2, the virus that causes COVID-19, according to a small report.
“We conclude that hEDS/HSD should be considered … especially in patients of female gender and when multisystem neurogenic and musculoskeletal pain are major concerns,” researchers wrote.
After physical tests and evaluation of generalized joint hypermobility, all five patients fulfilled criteria for HSD.
The five women had genetic variants in an enzyme (methylenetetrahydrofolate reductase) linked to the development of hEDS and HSD.
Taking into account clinical and lab findings, four women were diagnosed with hEDS and one with HSD.
Research
SUMMARY:
This study analyzed blood samples from 27 people with long COVID (LC) and 16 people who fully recovered (R) from COVID-19. The goal was to understand the lasting effects of COVID-19 on the immune system in those with LC.
People with LC had higher levels of T cells associated with immune memory and regulation. This suggests ongoing immune activation in LC.
SARS-CoV-2 specific CD8+ T cells in people with LC showed higher expression of PD1 and CTLA4. These are markers of T cell exhaustion, indicating persistent viral antigen stimulation.
Antibody levels to SARS-CoV-2 were higher in LC. However, unlike in resolved individuals, antibody levels did not correlate with levels of SARS-CoV-2 specific T cells. This suggests a disconnect between cellular and humoral immunity in LC.
CD4+ T cells in people with LC showed higher expression of homing receptors CXCR4, CXCR5 and CCR6. This implies these cells are poised to migrate to inflamed tissues.
RNA sequencing revealed altered gene expression related to heme synthesis, carbon dioxide transport, and immunoglobulin production in people with LC. This points to dysregulation of immune pathways.
My Take:
These immune features may contribute to the clinical symptoms and debilitation experienced by individuals with LC.
SUMMARY:
A large prospective study followed participants from the time of acute COVID-19 hospitalization and found that more than half of the participants had persistent symptoms lasting 3 or more months after discharge.
Patient-reported outcome surveys identified four clusters of deficits in PASC: minimal, physical, mental/cognitive, and multidomain.
The clusters were associated with distinct clinical presentations, with sub-phenotypes linked to female sex and specific comorbidities.
During the acute phase of the disease, higher viral burden and lower antibody titers were associated with both physical and multidomain deficits.
My Take:
The identification of distinct clusters of deficits in PASC suggests that there may be different underlying mechanisms and clinical manifestations of the condition.
Amy’s Take: I think it’s important to point out that this study only involved patients who were hospitalized with acute Covid, which is a unique cluster of patients in itself.
DEFINITIONS:
IFN-γ: Interferon-gamma, a cytokine involved in the immune response against viral infections.
IL-2: Interleukin-2, a cytokine that stimulates the proliferation of T-cells.
SUMMARY:
The study assessed the measurement of IFN-γ and IL-2 cytokines for the evaluation of cellular immunity against SARS-CoV-2.
The study included blood samples from acute COVID-19 patients, convalescent individuals, and unvaccinated/vaccinated uninfected individuals.
The results showed that IFN-γ and IL-2 detection increased response detection in acute and convalescent individuals.
IFN-γ detection can be a useful biomarker for monitoring severe acute patients.
The study highlighted the importance of assessing both cellular and humoral immune responses in understanding long-term immunity and infection management.
My Take:
Interesting because the majority of cytokine studies highlighted in this newsletter have been focused on IL-6 and TNF-A.
SUMMARY:
The purpose of this study was to evaluate the possible correlation between SARS-CoV-2 vaccines and the onset of neurological syndromes.
The study involved 843 subjects, namely 411 unvaccinated (UVC) and 432 vaccinated cases; these groups were comparable for demographics and clinical diagnosis distribution.
Compared to UVC, subjects hospitalized within the first 30 days from vaccine exhibited higher prevalence of FNDs (Functional Neurological Disorders) (12.3% vs. 3.6%) and headache (10.8% vs. 5%) but no other neurological syndromes.
SARS-CoV-2 vaccination is associated with a significant short-term increased risk of FND and headache requiring hospitalization in an acute neurological setting.
DEFINITIONS:
Gut microbiome: refers to the collection of microorganisms, including bacteria, fungi, viruses, and other microbes, that live in the digestive tract.
Alpha diversity: a measure of species richness and diversity within a specific environment or sample.
Beta diversity: a measure of the differences in species composition between different environments or samples.
SUMMARY:
The gut microbiome plays a pivotal role in the modulation of host responses during viral infections, including COVID-19.
There is a widely accepted consensus about the significant decline in alpha diversity of the gut microbiome of COVID-19 patients compared to healthy individuals.
The gut microbiome compositions in individuals with COVID-19 and healthy individuals are entirely distinct according to beta diversity analyses.
COVID-19 patients have a higher abundance of opportunistic pathogens and a lower abundance of beneficial bacteria compared to healthy individuals.
The composition of the gut microbiome may take up to six months to restore in patients who fully recover from COVID-19, while dysbiosis may persist for even longer in patients with post-acute COVID-19 syndrome.
My Take:
It feels like until we know how certain strains causally affect LC symptoms this seems like an interesting but unactionable article.
DEFINITIONS:
N-terminal pro B-type natriuretic peptide (NT-proBNP): a biomarker of hemodynamic myocardial stress and heart failure.
Emergency Use Authorization (EUA): a mechanism to facilitate the availability and use of medical countermeasures.
SUMMARY:
Elevated cardiac biomarkers, such as hs-cTnT (high-sensitivity cardiac troponin T)and NT-proBNP, have been related to worse short-term prognosis in COVID-19 patients.
High age-adjusted NT-proBNP levels at the time of hospital admission for COVID-19 are associated with poor short and long-term prognosis.
14% of patients had high adjusted NT-proBNP
High levels were associated with older age, more comorbidities, higher inflammation
60% with high levels died in hospital vs 10% with low
High NT-proBNP independently predicted higher in-hospital and 1-year mortality
Among 1-year survivors, high NT-proBNP patients had higher mortality despite no difference in readmissions
High NT-proBNP seems also to be related to worse prognosis in survivors of the acute phase of COVID-19.
DEFINITIONS:
Endoscopy: a medical procedure used to examine the inside of a person's body using an endoscope, a long, flexible tube with a light and camera attached.
Nucleocapsid proteins: Viral proteins that encapsulate the viral genome
Immunohistochemistry: A method using antibodies to detect specific proteins in tissue samples
SUMMARY:
The study analyzed biopsies from 249 patients with a history of COVID-19 who underwent endoscopy.
Using immunohistochemistry, SARS-CoV-2 nucleocapsid proteins were detected in 30.5% of biopsies, indicating persistent gut infection.
Persistent infection was more common in upper GI tract biopsies (37.3%) compared to lower GI tract (16.9%).
Smokers and diabetic patients showed higher rates of persistent infection, suggesting they may be at increased risk for long COVID syndrome.
No differences were seen in persistent infection related to number of prior infections, time since last infection, symptoms, or vaccination status.
Although persistent viral particles were detected, no infectious virions could be isolated, posing minimal infection risk during endoscopy.
The study confirms the gut can be a reservoir for SARS-CoV-2 months after initial infection, which may be linked to development of long COVID syndrome.
My Take:
This is a really interesting piece that went under the radar.
Hi Brandon, this is a week late....I had Covid again in December with a Paxlovid rebound. It felt like a cold and I have fully recovered. I did not have any LC set backs. Thank you for all of the amazing work you do.
Great post as usual. The gut research is particularly interesting to me because dysbiosis is my most intractable symptom. Literally nothing I’ve tried - several different diets, pre- pro- and post-biotics, intermittent fasting, longer fasting - moves the needle on this. Either I have persistent viral infection in my gut or several key species have just been wiped out.