Long Covid Weekly #75: Milestone Paper on PEM, T-Cell Dysfunction and More

Hi everyone,

A really, really important piece of research dropped this week highlighting muscle abnormalities (the first piece highlighted in the ‘research’ section) in Long Covid after exercising. The authors also highlighted and outlined their paper in a Twitter Thread. The same author also mentioned that colleagues are studying PEM after mental exertion. Having more research into the biological mechanisms of PEM is imperative as it further validates the illness.

Also, in this edition we explore the impact of the post-Covid condition on children, shedding light on the long-lasting effects they may experience. Furthermore, we'll explore various aspects of Long Covid, immune system perturbations, reproductive health implications, and neurological complications. 

Something else I wanted to highlight as I did not know the answer. Michael, a reader of the newsletter, left a comment in last week’s newsletter mentioning how he sadly got reinfected. (With his permission) I am asking the community if they have had an experience with the after-effects of a second infection? Can someone develop a second bout of LC? Any help would be much appreciated.

Also, unrelated but curious if anyone with LC or ME/CFS has gotten the PNEUMOVAX vaccine? If so, did you have an adverse reaction?

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Media

Article: Long COVID Has Caused Thousands of US Deaths: New CDC Data

SUMMARY:

• While COVID has now claimed more than 1 million lives in the United States alone, these aren't the only fatalities caused at least in part by the virus.

• A small but growing number of Americans are surviving acute infections only to succumb months later to the lingering health problems caused by long COVID.

• More than 5000 Americans have died from long COVID since the start of the pandemic, according to new estimates from the CDC.

• The death certificate figures indicate that COVID-19 was the third leading cause of American deaths in 2020 and 2021, and the fourth leading cause of death in the United States in 2023.

Article: Paxlovid doesn’t reduce risk of Long Covid

SUMMARY:

• The COVID-19 treatment Paxlovid does not reduce the risk of long COVID for vaccinated people who’ve tested positive for the virus for the first time, according to a new study by UCSF researchers.

• The study also found that a higher share than previously reported experienced rebound symptoms and tested positive for COVID after taking the antiviral medication.

• The new study suggests that other COVID-19 prevention strategies, like vaccination, masking, and social distancing, "are still relevant," said one study author, Dr. Matthew Durstenfeld, a cardiologist and UCSF assistant professor of medicine.

• From a group of individuals who reported feeling better while taking Paxlovid treatment, 21% reported rebound symptoms — 10.8% of whom reported one or more long COVID symptoms compared with 8.3% of individuals without rebound symptoms, the study found.

My Take:

• These findings are generally surprising and contradict some prior findings that have been reported in this newsletter.

Article: Anthony Fauci and unlocking the biggest mystery in medicine

SUMMARY:

• Between 1-2 million people in the U.S. are estimated to have ME/CFS. The COVID-19 pandemic threatens to significantly increase these numbers as many COVID long-haulers develop persistent symptoms meeting ME/CFS diagnostic criteria.

• Dr. Anthony Fauci lays out recommendations for studying ME/CFS in COVID long-haulers: focus only on post-COVID patients meeting strict diagnostic criteria over at least 6 months with documented disability. Analyze a wide range of biological markers over time in these patients.

• Early studies show COVID-19 impacts many organs beyond the lungs, with viral particles persisting for months. Other studies point to mitochondrial dysfunction, low neurotransmitters, etc. as potentially playing a role.

• Treatment trials of various interventions are underway but currently no FDA approved medications exist for ME/CFS or long COVID. Avoiding COVID-19 infection via public health measures, vaccines, and boosters can lower long COVID risks.

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Research

Article: Post–COVID-19 Condition in Children 6 and 12 Months After Infection | Pediatrics | JAMA Network Open | JAMA Network

DEFINITIONS:

• Pediatric Emergency Research Canada (PERC) is a network of Canadian tertiary pediatric emergency departments that conducted this study.

SUMMARY:

• This is a prospective cohort study that aimed to understand the prevalence of post-COVID-19 condition (PCC) among children tested for SARS-CoV-2 infection in pediatric emergency departments.

• The study collected data from 14 Canadian tertiary pediatric EDs and followed up with children at 6 and 12 months after their index visit.

• The study found that while children infected with SARS-CoV-2 reported increased chronic symptoms, few developed PCC according to the WHO definition, and overall quality of life did not differ from children with negative SARS-CoV-2 tests.

My Take:

• This study shows that while some children may experience chronic symptoms following infection, the majority do not meet the criteria for PCC according to the WHO definition.

• It’s also important to point out that 80% of the study participants were under 8 years old, and the mean age was 2.

Article: Muscle abnormalities worsen after post-exertional malaise in long COVID | Nature Communications

DEFINITIONS:

• Post-exertional malaise refers to the exacerbation of symptoms, such as fatigue and pain, after physical or mental exertion.

• Amyloid-containing deposits are abnormal protein aggregates that can accumulate in tissues and potentially contribute to disease pathology.

• Exercise-induced myopathy refers to muscle damage and inflammation caused by exercise.

SUMMARY:

• The study aimed to understand the pathophysiology behind post-exertional malaise (PEM), a key symptom of long COVID marked by worsening of symptoms after physical or mental exertion.

• 25 patients with long COVID and 21 controls who recovered from mild COVID were included. All long Covid patients had PEM, fatigue for >6 months, and met other inclusion criteria.

• Long COVID patients showed substantially lower exercise capacity and peripheral muscle impairments compared to controls.

• After maximal exercise to induce PEM, long COVID patients displayed acute drops in muscle mitochondrial enzymes, increased muscle damage/necrosis, greater accumulation of amyloid deposits, and a blunted muscle inflammatory response.

• Metabolomics analysis revealed disturbances in energy metabolism pathways in muscle and blood in long COVID patients at rest. Glycolysis metabolites were higher and TCA cycle metabolites were lower compared to controls.

• The study concludes PEM pathophysiology includes the exercise-induced muscle alterations above. These help explain PEM symptoms but the underlying mechanisms causing these remain unclear.

• Overall, the study provides novel insights into biological factors and pathways associated with PEM in long COVID, though further research is still needed to uncover direct mechanisms.

My Take:

• This is likely one of the most important studies that has ever been highlighted in this Newsletter. A Must READ.

Article: Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series ScienceDirect

DEFINITIONS:

• CD8 T-cells - type of white blood cell that kills virus-infected cells and cancer cells

• T-cell exhaustion - progressive loss of T-cell function due to chronic antigen exposure

SUMMARY:

• Both ME/CFS and Long COVID patients showed dysfunction of CD8 T-cells, with severe deficiencies in ability to produce cytokines IFNγ and TNFα which are important for immune response. This is reminiscent of T-cell exhaustion seen in chronic infections.

• A test measuring CD8 T-cell dysfunction could assist diagnosis and tracking outcomes during therapy for ME/CFS and Long COVID.

• In a retrospective case series, some ME/CFS and Long COVID patients treated with a nebulized antioxidant and anti-pathogen agent showed improved CD8 T-cell function and self-reported symptoms over months of therapy.

• The nebulized agent contains ingredients to relieve oxidative stress, attenuate inflammatory signaling, and inhibit pathogens - mechanisms implicated in ME/CFS and Long COVID pathogenesis.

• Results provide preliminary evidence that the CD8 T-cell dysfunction test could be a useful biomarker to track disease and response to this potential new therapy for ME/CFS and Long COVID.

• More research is needed, but reversing CD8 T-cell dysfunction may be key to resolving aberrant immune responses in these disorders. The earlier therapy is started, the better chances of recovery, especially for Long COVID patients.

Article: Immune system perturbations in patients with long COVID: Trends in Molecular Medicine

DEFINITIONS:

• Peripheral blood mononuclear cells (PBMCs): a type of white blood cell that includes lymphocytes and monocytes.

  • They play a critical role in the immune response.

• MHC class II (HLA-DR): major histocompatibility complex (MHC) class II molecules are involved in antigen presentation and help activate the immune system.

• Hypothalamic–pituitary–adrenal (HPA) axis: a complex network of interactions between the hypothalamus, pituitary gland, and adrenal glands that controls the body's response to stress and regulates various physiological processes, including immune function.

SUMMARY:

• Klein et al. report multimodal analyses of immune cells, proteins, and physiological parameters in patients with long COVID (LC).

• At the group level, LC subjects exhibited elevated antibody responses to SARS-CoV-2, but also to herpes viruses, pointing to a general suppression of viral control mechanisms in LC.

• Participants with LC exhibited significantly higher intensities of reported symptoms, leading to the creation of a Long COVID Propensity Score (LCPS) with diagnostic potential.

• Immunophenotyping of peripheral blood mononuclear cells (PBMCs) uncovered significantly elevated nonconventional monocytes in individuals with LC, along with increased expression of MHC class II (HLA-DR), pointing towards activation.

• An analysis of circulating hormones and immune mediators uncovered significant differences between groups, particularly in serum cortisol levels.

• Participants with LC exhibited lower cortisol levels, without the expected compensatory increase in adrenocorticotropic hormone, suggestive of a dysregulated hypothalamic–pituitary–adrenal (HPA) axis.

My Take:

• Seeing studies like this makes me long for more readily available blood tests.

Article: Menstruation, lower reproductive tract health, COVID-19 | IJWH

SUMMARY:

• This study aimed to evaluate the impact of COVID-19 on menstruation and lower reproductive tract health in women.

• The study found that COVID-19 can cause changes in menstrual flow, period duration, and cycle length, but these changes are temporary and menstruation gradually returns to the pre-infection state after recovery from COVID-19.

• Women with COVID-19 symptoms occurring more than 1 month after their last menstrual period, chest tightness during COVID-19, and COVID-19-related low mood and stress were found to be at higher risk of menstrual changes.

• Abnormal observations of the lower reproductive tract during COVID-19 were reported by 19.7% of women, but these changes were transient and most women reported that their lower reproductive tract health returned to normal after recovery from COVID-19.

My Take (Amy):

• While the study authors conclude that “women’s menstruation gradually returns to their pre-infection menstruation,” their results show this was true for 73% of participants. This means that it was not true for 27% of participants. 

• The study period was limited to 2 months, so more information is needed to determine longer outcomes, and whether there may be a difference between people with long COVID and those without. 

Article: New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross-sectional study | BMC Infectious Diseases | Full Text

DEFINITIONS:

• New daily persistent headache (NDPH): A primary headache characterized by persistent pain, daily from its onset, which is clearly remembered.

• It is typically bilateral, moderate to severe in intensity, and can exhibit features of both migraine and tension-type headache.

SUMMARY:

• Persistent headache is a frequent symptom after coronavirus disease 2019 (COVID-19) and there is limited knowledge about its clinical spectrum and predisposing factors.

• New daily persistent headache (NDPH) is among the most treatment-refractory primary headache syndromes.

• This study aimed to characterize individuals with persistent headache after SARS-CoV-2 infection in Latin America, particularly NDPH, and identify potential factors associated with NDPH.

• One in four participants met the diagnostic criteria for NDPH, with the most predominant clinical characteristics being occipital location, severe/unbearable intensity, burning character, and radiating pain.

Article: Electroencephalographic Abnormalities in a Patient Suffering from Long-Term Neuropsychological Complications following SARS-CoV-2 Infection | Case Reports in Neurology | Karger Publishers

DEFINITIONS:

• Emotional apathy: the ability to associate emotional value with ongoing behavior.

• EEG abnormalities: deviations from normal electrical activity in the brain measured by electroencephalography.

• Delta band activity: slow brainwave activity between 0.5-4 Hz associated with deep sleep, relaxation, and unconscious mental processing.

• Beta band activity: fast brainwave activity between 13-30 Hz associated with alertness, concentration, and active thinking.

• Alpha band activity: brainwave activity between 8-13 Hz associated with relaxation, daydreaming, and the "resting" state of the brain.

SUMMARY:

• A case report describes the neuropsychological complications experienced by a 47-year-old patient with long-term symptoms following SARS-CoV-2 infection.

• The patient exhibited cognitive difficulties, emotional apathy, and EEG abnormalities characterized by increased delta and beta band activity, decreased alpha band activity, and widespread oscillatory abnormalities.

• This case report suggests widespread changes in neural oscillatory patterns in patients with long COVID and neuropsychological symptoms, particularly emotional apathy.

• The findings highlight the need for further research to explore the pathophysiology and long-term consequences of neuropsychological complications in patients with long COVID.

Article: Effects of antivirals on patients with COVID-19 breakthrough | BMC Infectious Diseases | Full Text

SUMMARY:

• Antivirals were not associated with faster resolution of respiratory symptoms or lower risks of long COVID-19.

• There were 34 patients (23.9%) with the primary outcome of symptoms lasting longer than 7 days, with an average duration of 11.1 ± 1.9 days experiencing respiratory symptoms. 

• Antiviral-taking patients had lower incidence of residual respiratory symptoms than those who received standard of care (20.3% vs 27.9%), but the effect was not statistically significant.

• During a median of 21 days of follow-up (interquartile range 12.3–39.8), 14 diagnoses (9.9%) of long COVID-19 were given.