Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses’ infection of endothelial cells (ECs) may underlie ME/CFS symptomatology.
We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation.
We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients.
This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.
Source: Nunes, J.M.; Kell, D.B.; Pretorius, E. Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2024, 2024011486. https://doi.org/10.20944/preprints202401.1486.v1 https://www.preprints.org/manuscript/202401.1486/v1 (Full text available as PDF file)

Vaccine Effectiveness Against Long COVID in Children

Abstract:

Objective: Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5-17 years.

Methods: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits after vaccine availability. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5-11, 12-17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination.

Results: The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 – 44.5) against probable long COVID and 41.7% (15.0 – 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 – 61.0]) than children aged 5-11 (23.8% [4.9 – 39.0]). VE was higher at 6 months (61.4% [51.0 – 69.6]) but decreased to 10.6% (-26.8 – 37.0%) at 18-months.

Discussion: This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data.

Source: Razzaghi H, Forrest CB, Hirabayashi K, Wu Q, Allen A, Rao S, Chen Y, Bunnell HT, Chrischilles EA, Cowell LG, Cummins MR, Hanauer DA, Higginbotham M, Horne BD, Horowitz CR, Jhaveri R, Kim S, Mishkin A, Muszynski JA, Naggie S, Pajor NM, Paranjape A, Schwenk HT, Sills MR, Tedla YG, Williams DA, Bailey C. Vaccine Effectiveness Against Long COVID in Children. Pediatrics. 2024 Jan 16. doi: 10.1542/peds.2023-064446. Epub ahead of print. PMID: 38225804. https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2023-064446/196419 (Full text available as PDF file)

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

Abstract:

Background: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.

Materials and methods: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.

Results: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.

Conclusion: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Source: Di Ciaula A, Liberale L, Portincasa P, Khalil M, Galerati I, Farella I, Noto A, JohnBritto S, Moriero M, Michelauz C, Frè F, Olivero C, Bertolotto M, Montecucco F, Carbone F, Bonfrate L. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024 Jan 16:e14155. doi: 10.1111/eci.14155. Epub ahead of print. PMID: 38226472. https://pubmed.ncbi.nlm.nih.gov/38226472/

THE ROLE OF α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN POST-ACUTE SEQUELAE OF COVID-19

Abstract:

Post-Acute Sequelae of COVID-19 or Long COVID becomes evident some weeks to months following acute COVID-19. Symptoms include cognitive impairment and varying degrees of memory loss with no definitive etiologies or efficacious therapies forthcoming even after four years of the SARS-Cov2 pandemic virus. The aim of this review is to demonstrate the important role of α7 nicotinic acetylcholine receptors in both acute COVID-19 and Long COVID.

Evidence presented implicates immune mechanisms stimulated by SARS-Cov-2 S-protein fragment 674-685 that possesses homology with α7-specific ligands. Cognitive dysfunctions observed in Long COVID patients may be derived from anti-idiotypic α7-specific antibodies stimulated by (674-685)-specific antibodies. Therapeutic interventions capable of neutralizing these antibodies and restoring full functions of α7 nicotinic acetylcholine receptors appear to be of paramount importance in post-acute sequelae of COVID-19.

Source: Skok M. THE ROLE OF α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN POST-ACUTE SEQUELAE OF COVID-19. Int J Biochem Cell Biol. 2024 Jan 11:106519. doi: 10.1016/j.biocel.2024.106519. Epub ahead of print. PMID: 38218363. https://www.sciencedirect.com/science/article/abs/pii/S1357272524000104

Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19

Abstract:

Although some studies have shown neuroimaging and neuropsychological alterations in post-COVID-19 patients, fewer combined neuroimaging and neuropsychology evaluations of individuals who presented a mild acute infection. Here we investigated cognitive dysfunction and brain changes in a group of mildly infected individuals.

We conducted a cross-sectional study of 97 consecutive subjects (median age of 41 years) without current or history of psychiatric symptoms (including anxiety and depression) after a mild infection, with a median of 79 days (and mean of 97 days) after diagnosis of COVID-19. We performed semi-structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. For MRI analyses, we included a group of non-infected 77 controls. The MRI study included white matter (WM) investigation with diffusion tensor images (DTI) and functional connectivity with resting-state functional MRI (RS-fMRI).

The patients reported memory loss (36%), fatigue (31%) and headache (29%). The quantitative analyses confirmed symptoms of fatigue (83% of participants), excessive somnolence (35%), impaired phonemic verbal fluency (21%), impaired verbal categorical fluency (13%) and impaired logical memory immediate recall (16%). The WM analyses with DTI revealed higher axial diffusivity values in post-infected patients compared to controls.

Compared to controls, there were no significant differences in the functional connectivity of the posterior cingulum cortex. There were no significant correlations between neuropsychological scores and neuroimaging features (including DTI and RS-fMRI).

Our results suggest persistent cognitive impairment and subtle white matter abnormalities in individuals mildly infected without anxiety or depression symptoms. The longitudinal analyses will clarify whether these alterations are temporary or permanent.

Source: Scardua-Silva, L., Amorim da Costa, B., Karmann Aventurato, Í. et al. Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19. Sci Rep 14, 1758 (2024). https://doi.org/10.1038/s41598-024-52005-7  https://www.nature.com/articles/s41598-024-52005-7 (Full text)

Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys

Abstract:

Background Long COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined.

Methods Leveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctor’s diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection.

Results Among the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctor’s diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White.

Conclusions In the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.

Source: Yixuan Wu, Mitsuaki Sawano, Yilun Wu, Rishi M. Shah, Pamela Bishop, Akiko Iwasaki, Harlan M. Krumholz. Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys. medRxiv 2024.01.12.24301170; doi: https://doi.org/10.1101/2024.01.12.24301170 https://www.medrxiv.org/content/10.1101/2024.01.12.24301170v1.full-text (Full text)

Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis

Abstract:

Context: In some patients, symptoms may persist after COVID-19, defined as long COVID. Its pathogenesis is still debated and many hypotheses have been raised.

Objective: Our primary objective was to evaluate the corticotroph and somatotroph functions of patients previously infected with SARS-CoV-2 and experiencing post–COVID-19 syndrome to detect any deficiencies that may explain long COVID.

Methods: A cross-sectional study was conducted including patients who had previously contracted SARS-CoV-2 with a postinfection period of 3 months or less to 15 months, divided into 2 groups. The first group (G1) comprised fully recovered patients, while the second group (G2) included patients experiencing long COVID. The primary outcome was the comparison of corticotroph and somatotroph functions.

Results: A total of 64 patients were divided into 2 groups, each consisting of 32 patients. G2 exhibited more frequently anterior pituitary deficits compared to G1 (P = .045): for the corticotroph axis (G1: 6.3% vs G2: 28.1%) and for the somatotroph axis (G1: 31.3% vs G2: 59.4%). Baseline cortisol level was significantly lower in G2 (G1: 13.37 µg/dL vs G2: 11.59 µg/dL) (P = .045). The peak cortisol level was also lower in G2 (G1: 23.60 µg/dL vs G2: 19.14 µg/dL) (P = .01). For the somatotroph axis, the insulin growth factor-1 level was lower in G2 (G1: 146.03 ng/mL vs G2: 132.25 ng/mL) (P = .369). The peak growth hormone level was also lower in G2 (G1: 4.82 ng/mL vs G2: 2.89 ng/mL) (P = .041).

Conclusion: The results showed that long COVID patients in our cohort were more likely to have anterior pituitary deficiencies. The endocrine hypothesis involving anterior pituitary insufficiency can be considered to explain long COVID.

Source: Taieb Ach, Nassim Ben Haj Slama, Asma Gorchane, Asma Ben Abdelkrim, Meriem Garma, Nadia Ben Lasfar, Foued Bellazreg, Widéd Debbabi, Wissem Hachfi, Molka Chadli Chaieb, Monia Zaouali, Amel Letaief, Koussay Ach, Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis, Journal of the Endocrine Society, Volume 8, Issue 3, March 2024, bvae003, https://doi.org/10.1210/jendso/bvae003 https://academic.oup.com/jes/advancearticle/doi/10.1210/jendso/bvae003/7517018 (Full text)

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID

Abstract:

Background Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology.

Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.

Results Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-β and CNTF, among soluble analytes.

Conclusions Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.

Plain language summary The impact of the COVID-19 vaccine on vaccine-naïve individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.

Source: Connor B Grady, Bornali Bhattacharjee, Julio Silva, Jillian Jaycox, Lik Wee Lee, Valter Silva Monteiro, Mitsuaki Sawano, Daisy Massey, César Caraballo, Jeff R. Gehlhausen, Alexandra Tabachnikova, Tianyang Mao, Carolina Lucas, Mario A. Peña-Hernandez, Lan Xu, Tiffany J. Tzeng, Takehiro Takahashi, Jeph Herrin, Diana Berrent Güthe, Athena Akrami, Gina Assaf, Hannah Davis, Karen Harris, Lisa McCorkell, Wade L Schulz, Daniel Grffin, Hannah Wei, Aaron M Ring, Leying Guan, Charles Dela Cruz, Akiko Iwasaki, Harlan M Krumholz. Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID. medRxiv 2024.01.11.24300929; doi: https://doi.org/10.1101/2024.01.11.24300929. https://www.medrxiv.org/content/10.1101/2024.01.11.24300929v1.full-text (Full text)

Impact of sleep disruption on cognitive function in patients with post-acute sequelae of SARS-CoV-2 infection: Initial findings from a Neuro-COVID-19 clinic

Abstract:

Introduction: Fatigue, brain fog and sleep disturbance are among the most common symptoms of post-acute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality-of-life in patients with neurologic manifestations of PASC (Neuro-PASC).

Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH toolbox cognitive tests, and 7 days of wrist actigraphy.

Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p<0.001) and later sleep midpoint (p=0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with severity of fatigue (p<0.001), anxiety (p=0.05), and depression (p<0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency and latency were associated with decreased performance in attention and processing speed.

Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

Source: Kathryn J Reid, Louis T Ingram, Millenia Jimenez, Zachary S Orban, Sabra M Abbott, Daniela Grimaldi, Kristen L Knutson, Phyllis C Zee, Igor J Koralnik, Mathew B Maas, Impact of sleep disruption on cognitive function in patients with post-acute sequelae of SARS-CoV-2 infection: Initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, 2024;, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/advance-article/doi/10.1093/sleepadvances/zpae002/7517273 (Full text available as PDF file)

Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms

Abstract:

The flow from transcription of genes through translation and processing of proteins is a common basis for all life. Redox homeostasis is crucial for the defence against oxidative stress. We adapt through hormesis; non-lethal stress regulates redox-sensitive systems to maintain homeostasis. If the stress is chronic or acutely overwhelming, the cells can either go into apoptosis or into senescence to maintain homeostasis. Similar effects have been seen with HBOT as with intermittent oxygen deprivation. Hyperbaric oxygen therapy (HBOT) is delivered in a pressure chamber by breathing 100% oxygen intermittently, several times a week, in an ambient pressure equivalent to 10-20 meters of seawater. The aim of this thesis was to evaluate potential harms of HBOT for novel indications and to explore biomarkers in experimental and clinical trials in order to enable future precision medicine. We used methods evaluated on healthy volunteers in randomised clinical trials (RCTs) conducted in compliance with good clinical practice (ICH-GCP).

In Paper I, we evaluated Electron paramagnetic resonance (EPR) spectroscopy for measuring reactive oxygen species (ROS) in blood and RNA sequencing (RNAseq) of monocytes in peripheral blood (PBMC), and compared HBOT and HIIT in ten healthy volunteers. We could measure ROS in blood in the same physiological range in both interventions. We also discovered pathways involved in adaption to hypoxia and inflammation that were similar in both interventions. In Papers II and III, we evaluated harms and explored RNAseq in PBMC in an open label RCT where 31 patients with severe COVID- 19 were randomised to HBOT or best practice. We observed similar frequencies of adverse events (AEs) in the two groups and could not see any negative effect on vital signs or oxygenation. We discovered a unique transcriptomic signature in the subjects that had received HBOT. The differentially expressed genes were associated with the unfolded protein response, apoptosis, and immune response. In Paper IV, we evaluated harms and described health related quality of life (HRQoL)in an interim analysis of the first 20 subjects froma placebo controlled RCT where 80 patients with Long COIVD were randomised to HBOT or sham treatment. We reported more AEs than expected and severe physical and mental disabilities with a very poor HRQoL. Most AEs were mild, and all were transient.

We have shown that HBOT shares similarities in immune response with HIIT in healthy volunteers. HBOT has a favourable profile of harms and has a potent immunomodulatory effect that is associated with fast recovery for critical COVID-19 patients. HBOT has a favourable profile of harms for patients with post COVID-19 condition. The results provide a base for future clinical trials with HBOT.

Source: Kjellberg, Anders. Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms. Thesis: Karolinska Institute, Dept of Physiology and Pharmacology. https://openarchive.ki.se/xmlui/handle/10616/48928 (Full study available as PDF file)