Long Covid Weekly #80: Ampligen Clinical trial results, More Evidence of T-Cell Dysfunction & more
Hi everyone,
Seemingly slow news week. Could be a function of the time of year. But I am hopeful this was an anomaly as we have seen a lot of research over the first month of the year.
I did not have time to read this article, but figured I would plug it anyway. It looks like the microneedle research pioneered by Ron Davis’s lab is back on the table. For those who do not remember this work aimed to get a biomarker for ME/CFS.
Also, the Ampligen article covered in this edition reminded me - is anyone in the community actively maintaining a list of clinical trials and the results?
In this edition, we delve into the setbacks in AIM's Ampligen Phase II trial, the reliance on private funding for long COVID research, and the potential breakthroughs in treating long COVID through amino acid deficiencies. We also explore the duration of COVID-19 in the body, predictors of non-recovery from fatigue and cognitive deficits, the effects of pulmonary rehabilitation, and much more.
Media
Article: AIM’s ampligen stumbles in Phase II trial
DEFINITIONS:
Ampligen: A mismatched, double-stranded RNA molecule with immunomodulatory and antiviral properties.
SUMMARY:
AIM’s Ampligen failed to meet its primary endpoint in the Phase II trial in people with post-Covid fatigue.
The US-based company stated that subjects in the Ampligen group had experienced lower levels of fatigue at multiple time points during the treatment phase compared to the placebo group.
My Take:
Although Ampligen did not meet the primary endpoint, the results suggest some potential benefits in reducing post-Covid fatigue.
The future trial design using the six-minute walk test results shows promise in informing further research for treatment.
This is why we need velocity in trials. Likely most won't work but the more we test, the better chance we have at finding something that sticks for most.
Article: Scientists rely on private funding to push long COVID research forward
DEFINITIONS:
Private Funding: financial support for research provided by non-governmental sources.
SUMMARY:
For many patients, progress on solving long COVID seems to be stalled, but scientists are actively working on it.
Private funding is increasingly being used to propel research forward.
A key reason is that federal funding and processes tend to be slow and cumbersome.
The article highlights the work of Amy Proal, a microbiologist who runs a nonprofit called PolyBio Research Foundation.
Her organization has received $30 million from a Russian Canadian billionaire to fund research on the biological causes of long COVID, including whether persistent viral infection drives symptoms.
DEFINITIONS:
Metabolomics: the study of small molecules present in biological samples.
ATP: adenosine triphosphate, a molecule that provides energy in cells.
SUMMARY:
Telltale amino acid deficiencies may provide new treatment options for long COVID patients.
A research team at the University of Alberta is studying the key factors contributing to long COVID.
Analysis of blood samples from long COVID patients showed persistently low levels of the amino acids sarcosine, glutamine and serine.
Deficiencies in these amino acids can impact brain function
The study also found long COVID patients exhibited mitochondrial dysfunction, resulting in insufficient cellular energy (ATP).
This could help explain constant fatigue.
Markers of inflammation and compromised gut integrity were also seen.
Article: How Long Does COVID-19 Stay In Your Body?
DEFINITIONS:
Viral Shedding: The release of virus particles from an infected person.
SUMMARY:
The length of time that COVID-19 stays in the body can vary, but most people who get COVID are no longer contagious after 10 days.
However, there are cases where COVID infections can persist for weeks or even months, especially in immunocompromised individuals.
Evidence suggests COVID may persist in tissues like the intestines even when nasal swabs are negative. 49% of people with mild to moderate COVID infections had virus in their stool and 12.7% kept shedding for 4 months after negative nasal tests.
Viral persistence theory supports the idea that long COVID can occur despite negative tests. Most long-haulers test negative.
Research
DEFINITIONS:
PHQ-8: A questionnaire to evaluate depressive symptoms.
GAD-7: A questionnaire to assess anxiety symptoms.
SUMMARY:
Despite the prevalence and major disability associated with fatigue and cognitive deficits from Long Covid, little is known about long-term trajectories of these symptoms.
This study aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery.
Over 3,000 participants responded to a baseline evaluation, and 80% of those participated in a follow up at 9 months.
At baseline, 21% had fatigue and 23% had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA (clinical tests to measure fatigue and cognitive issues).
Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up and 46% had recovered from fatigue.
Post-COVID fatigue and cognitive deficits improve over time, yet about 50% of patients experience symptoms that persist for up to two years.
Addressing comorbid depression and headache is an important part of fatigue management.
Further research is needed to deepen our understanding of the connection between SARS-CoV-2 infection and lasting cognitive deficits.
DEFINITIONS:
Pulmonary Rehabilitation (PR): a program that aims to improve the physical and psychological condition of people with chronic respiratory diseases.
Dynamic Hyperinflation (DH): a condition in which air gets trapped in the lungs, leading to increased lung volume at the end of expiration.
SUMMARY:
Pulmonary rehabilitation (PR) is recommended in people with post-acute COVID-19 syndrome (PACS), although there is a lack of studies evaluating its benefits via the most commonly used primary endpoint: the six-minute walk test (6MWT).
The main findings of the present study were that PACS patients undergoing pulmonary rehabilitation had better performance on the 6MWT than PACS patients not undergoing PR, with a higher 6MWD and less DH (dynamic hyperinflation).
My Take (Amy):
It's unclear whether physical lung damage is present in some patients with Long Covid, especially those with mild initial infections.
The patients in this study were all diagnosed with Covid pneumonia, which may have made them better candidates for pulmonary rehabilitation.
But it's possible that pulmonary rehab would also benefit some with no lung damage, just by increasing lung efficiency for those who are persistently short of breath.
SUMMARY:
This was a systematic review of studies on post-viral conditions in children and young adults ages 0-20 years.
The review aimed to describe post-viral conditions and determine if post-COVID symptoms differ from other post-viral syndromes.
The review included 28 studies on post-COVID, 5 on RSV/rhinovirus, 1 on EBV, and 1 on gastrointestinal viruses.
Post-COVID studies had longer follow-up (median 182 days).
Fatigue was common in 84% of post-COVID and 47% of post-EBV patients.
36.8% of post-COVID patients developed chronic symptoms, while 63.2% recovered.
55% of those studied developed chronic diarrhea after gastrointestinal viruses.
Post-viral fatigue is shared by post-COVID and post-EBV patients.
Post-COVID syndrome is unique but shares features of other post-viral syndromes.
Authors pointed to a need for standardized definitions and outcomes measures.
The overall healthcare burden of post-viral conditions warrants further investigation.
My Take:
Again, this highlights details on what a lot of people in the LC community have theorized but it’s good to know this is gaining traction through rigorous research.
DEFINITIONS:
CD8 T-cells: A type of T cell that kills virally infected cells and tumor cells; it is implicated in dysfunctional immune responses.
SUMMARY:
Both ME/CFS and Long COVID patients showed severe deficiencies in the ability of CD8 T-cells to produce the cytokines IFNγ and TNFα upon stimulation, indicating dysfunction.
ME/CFS and Long COVID patients had similar symptom profiles, scoring high on fatigue, post-exertional malaise (PEM), sleep problems, brain fog, etc.
A 69-year old ME/CFS patient and a 61-year old Long COVID patient showed improvements in symptoms and CD8 T-cell function during 15 months of treatment with the nebulized Inspiritol agent.
Retrospective data on 4 ME/CFS and 4 Long COVID patients treated with Inspiritol for 3-15 months showed increases in CD8 T-cell cytokine production, decreased symptom severity scores (54% decrease), and no side effects.
The results suggest the potential utility of tracking CD8 T-cell dysfunction as a biomarker and possible benefit of the nebulized antioxidant/anti-pathogen treatment for ME/CFS and Long COVID. Further clinical trials are warranted.
DEFINITIONS:
Peripheral blood mononuclear cells (PBMCs): Immune cells such as T cells, B cells and monocytes that are isolated from whole blood samples. Used to analyze immune responses.
Flow cytometry: A technique used to detect and quantify cells and cell components by suspending cells in a fluid and passing them through a laser beam. Allows analysis of cell surface and intracellular markers.
T-cell activation markers: Proteins and cytokines expressed by T cells when they become activated to respond to pathogens. Examples are CD38, Granzyme B, Ki67, etc.
Regulatory T cells (CD4+CD25+): A subpopulation of T cells that suppress immune responses to prevent excess inflammation and autoimmunity. They express CD25 surface marker.
Anti-RBD IgG: IgG antibodies produced by the immune system that target the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and neutralize the virus.
SUMMARY:
Participants with persistent symptoms like dyspnea, confusion, forgetfulness, and chest pain had significantly higher levels of proliferating cytotoxic T-cells (CD8+Ki67+) compared to recovered participants, indicating continued immune activation.
Those with dyspnea showed the most pronounced inflammation, with elevated CD8+CD38+, CD8+Granzyme B+, CD8+IL10+ cells. This suggests dyspnea is closely tied to chronic inflammation post-COVID.
Regulatory T-cells (CD4+CD25+) were higher in those with persistent cognitive symptoms, indicating an ongoing attempt to control inflammation.
CD8+Ki67+ cells were elevated during acute infection in patients who later developed persistent dyspnea, suggesting it could help predict PASC development.
Inflammation was most pronounced 15-44 days post-diagnosis but persisted over 180 days in symptomatic patients. Anti-RBD IgG also remained significantly elevated.
DEFINITIONS:
Proprotein convertase subtilisin/kexin type 9 (PCSK9): An enzyme that regulates low-density lipoprotein (LDL) receptors and cholesterol metabolism in the liver.
LDL receptors: Receptors on liver cells that bind to LDL cholesterol particles and remove them from blood circulation.
Immunopathology: Harm inflicted on the host by an aberrant or dysfunctional immune response. Can contribute to tissue/organ damage.
Dyslipidemia: Abnormal blood lipid levels, including high LDL cholesterol or triglycerides. Dyslipidemia is a cardiovascular risk factor.
SUMMARY:
The paper explores the potential role of PCSK9 inhibition in modulating inflammation and immune responses during COVID-19.
PCSK9 is best known for regulating cholesterol metabolism by promoting the degradation of LDL receptors.
However emerging evidence suggests PCSK9 may also influence cytokine production, immune cell function, and thrombosis.
The rationale for targeting PCSK9 in COVID-19 is based on the interconnections between dyslipidemia, inflammation, and cardiovascular complications frequently observed in patients.
COVID-19 can worsen underlying cardiovascular conditions and lead to endothelial dysfunction. As PCSK9 drives pro-inflammatory signaling, its inhibition could help dampen cytokine storm and hyperinflammation in severe cases.
Thanks so much for this info, Brandon!
Clinicaltrials.gov has a list of me/cfs research and their status. I hope that helps!