Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM.
Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
Source: Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, et al. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. International Journal of Molecular Sciences. 2023; 24(12):10255. https://doi.org/10.3390/ijms241210255 https://www.mdpi.com/1422-0067/24/12/10255 (Full text)

Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study

Abstract:

This observational study aimed to determine whether individuals with fibromyalgia (FM) exhibit higher levels of neuroinflammation than healthy controls (HCs), as measured with positron emission tomography using [18F]DPA-714, a second-generation radioligand for the translocator protein (TSPO).
Fifteen women with FM and 10 HCs underwent neuroimaging. Distribution volume (VT) was calculated for in 28 regions of interest (ROIs) using Logan graphical analysis and compared between groups using multiple linear regressions. Group (FM vs HC) was the main predictor of interest and TSPO binding status (high- vs mixed-affinity) was added as a covariate. The FM group had higher VT in the right postcentral gyrus (b = 0.477, P = 0.033), right occipital gray matter (GM; b = 0.438, P = 0.039), and the right temporal GM (b = 0.466, P = 0.042). The FM group also had lower VT than HCs in the left isthmus of the cingulate gyrus (b = −0.553, P = 0.014).
In the subgroup of high-affinity binders, the FM group had higher VT in the bilateral precuneus, postcentral gyrus, parietal GM, occipital GM, and supramarginal gyrus. Group differences in the right parietal GM were associated with decreased quality of life, higher pain severity and interference, and cognitive problems.
In support of our hypothesis, we found increased radioligand binding (VT) in the FM group compared with HCs in several brain regions regardless of participants’ TSPO binding status. The ROIs overlapped with prior reports of increased TSPO binding in FM. Overall, increasing evidence supports the hypothesis that FM involves microglia-mediated neuroinflammation in the brain.
Source: Mueller C, Fang YD, Jones C, McConathy JE, Raman F, Lapi SE, Younger JW. Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study. Pain. 2023 Jun 15. doi: 10.1097/j.pain.0000000000002927. Epub ahead of print. PMID: 37326674. https://pubmed.ncbi.nlm.nih.gov/37326674/

A Unique Circular RNA Expression Pattern in the Peripheral Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.

In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS.

Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.

Source: Yuning Cheng, Si-Mei Xu, Konii Takenaka, Grace Lindner, Ashton Curry-Hyde, Michael Janitz. A Unique Circular RNA Expression Pattern in the Peripheral Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Gene. Available online 15 June 2023, 147568. https://doi.org/10.1016/j.gene.2023.147568 https://www.sciencedirect.com/science/article/abs/pii/S0378111923004092

Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis

Abstract:

Aims: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with endothelial dysfunction. We aimed to determine the effects of prior coronavirus disease 2019 (COVID-19) on the coronary microvasculature accounting for time from COVID-19, disease severity, SARS-CoV-2 variants, and in subgroups of patients with diabetes and those with no known coronary artery disease.

Methods and results: Cases consisted of patients with previous COVID-19 who had clinically indicated positron emission tomography (PET) imaging and were matched 1:3 on clinical and cardiovascular risk factors to controls having no prior infection. Myocardial flow reserve (MFR) was calculated as the ratio of stress to rest myocardial blood flow (MBF) in mL/min/g of the left ventricle. Comparisons between cases and controls were made for the odds and prevalence of impaired MFR (MFR < 2). We included 271 cases matched to 815 controls (mean ± SD age 65 ± 12 years, 52% men). The median (inter-quartile range) number of days between COVID-19 infection and PET imaging was 174 (58-338) days. Patients with prior COVID-19 had a statistically significant higher odds of MFR <2 (adjusted odds ratio 3.1, 95% confidence interval 2.8-4.25 P < 0.001). Results were similar in clinically meaningful subgroups. The proportion of cases with MFR <2 peaked 6-9 months from imaging with a statistically non-significant downtrend afterwards and was comparable across SARS-CoV-2 variants but increased with increasing severity of infection.

Conclusion: The prevalence of impaired MFR is similar by duration of time from infection up to 1 year and SARS-CoV-2 variants, but significantly differs by severity of infection.

Source: Ahmed AI, Al Rifai M, Alahdab F, Saad JM, Han Y, Alfawara MS, Nayfeh M, Malahfji M, Nabi F, Mahmarian JJ, Cooke JP, Zoghbi WA, Al-Mallah MH. Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis. Eur Heart J Cardiovasc Imaging. 2023 May 31:jead118. doi: 10.1093/ehjci/jead118. Epub ahead of print. PMID: 37254693. https://pubmed.ncbi.nlm.nih.gov/37254693/

Clinical Features of Post-Covid Syndrome

Abstract:

There is no common understanding of the clinical picture of post-covid syndrome. The US regulator CDC proposes to highlight:

(A) persistent symptoms and conditions that begin during acute COVID-19 illness;

B) new onset late complications after asymptomatic disease or a period of acute symptomatic relief or remission;

(C) the evolution of symptoms and conditions that include some persistent symptoms (eg, shortness of breath) with the addition of new symptoms or conditions over time (eg, cognitive difficulties).

Some manifestations may resemble other postviral syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome, dysautonomia (eg, postural orthostatic tachycardia syndrome), or mast cell activation syndrome.

Source: Sayfulloyevich, P. S. ., & Musayevich, U. R. . (2023). Clinical Features of Post-Covid Syndrome. EUROPEAN JOURNAL OF INNOVATION IN NONFORMAL EDUCATION, 3(6), 34–36. Retrieved from http://inovatus.es/index.php/ejine/article/view/1786 http://inovatus.es/index.php/ejine/article/view/1786/1794 (Full text)

Pre-assessment and management of long COVID patients requiring elective surgery: challenges and guidance

Abstract:

Whilst most patients infected with COVID-19 make a full recovery, around 1 in 33 patients in the UK report ongoing symptoms post-infection, termed ‘long COVID’. Studies have demonstrated that infection with early COVID-19 variants increases postoperative mortality and pulmonary complications for around 7 weeks after acute infection. Furthermore, this increased risk persists for those with ongoing symptoms beyond 7 weeks. Patients with long COVID may therefore also be at increased postoperative risk, and despite the significant prevalence of long COVID, there are minimal guidelines on how best to assess and manage these patients perioperatively.

Long COVID shares several clinical and pathophysiological similarities with conditions such as myalgic encephalitis/chronic fatigue syndrome and postural tachycardia syndrome; however, there are no current guidelines for the preoperative management of these patients to help develop something similar for long COVID patients. Developing guidelines for long COVID patients is further complicated by its heterogenous presentation and pathology. These patients can have persistent abnormalities on pulmonary function tests and echocardiography 3 months after acute infection, correlating with a reduced functional capacity.

Conversely, some long COVID patients can continue to experience symptoms of dyspnoea and fatigue despite normal pulmonary function tests and echocardiography, yet demonstrating significantly reduced aerobic capacity on cardiopulmonary exercise testing even a year after initial infection. How to comprehensively risk assess these patients is therefore challenging.

Existing preoperative guidelines for elective patients with recent COVID-19 generally focus on the timing of surgery and recommendations for pre-assessment if surgery is required before this time interval has elapsed. How long to delay surgery in those with ongoing symptoms and how to manage them perioperatively are less clear.

We suggest that multidisciplinary decision-making is required for these patients, using a systems-based approach to guide discussion with specialists and the need for further preoperative investigations. However, without a better understanding of the postoperative risks for long COVID patients, it is difficult to obtain a multidisciplinary consensus and obtain informed patient consent. Prospective studies of long COVID patients undergoing elective surgery are urgently required to help quantify their postoperative risk and develop comprehensive perioperative guidelines for this complex patient group.

Source: Boles S, Ashok SR. Pre-assessment and management of long COVID patients requiring elective surgery: challenges and guidance. Perioper Med (Lond). 2023 Jun 5;12(1):20. doi: 10.1186/s13741-023-00305-3. PMID: 37277879; PMCID: PMC10241122. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10241122/ (Full text)

Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID

Abstract:

Sustained cognitive deficits are a common and debilitating feature of “long COVID”, but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function.
KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.
Source: Fesharaki Zadeh A, Arnsten AFT, Wang M. Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID. Neurology International. 2023; 15(2):725-742. https://doi.org/10.3390/neurolint15020045 https://www.mdpi.com/2035-8377/15/2/45 (Full text)

Long COVID: Complications, Underlying Mechanisms, and Treatment Strategies

Abstract:

Long Covid is one of the most prevalent and puzzling conditions that arose with the Covid pandemic. Covid-19 infection generally resolves within several weeks but some experience new or lingering symptoms. Though there is no formal definition for such lingering symptoms the CDC boadly describes long Covid as persons having a wide range of new, recurring or sustained health issues four or more weeks after first being infected with SARS-CoV2. The WHO defines long Covid as the manifestation of symptoms from a “probable or confirmed” Covid-19 infection that start approximately 3 months after the onset of the acute infection and last for more than 2 months.

Numerous studies have looked at the implications of long Covid on various organs. Many specific mechanisms have been proposed for such changes. In this article, we provide an overview of some of the main mechanisms by which long Covid induces end-organ damage proposed in recent research studies. We also review various treatment options, current clinical trials, and other potential therapeutic avenues to control long Covid followed by the information about the effect of vaccination on long Covid.

Lastly, we discuss some of the questions and knowledge gaps in the present understanding of long Covid. We believe more studies of the effects long Covid has on quality of life, future health and life expectancy are required to better understand and eventually prevent or treat the disease. We acknowledge the effects of long Covid are not limited to those in this article but as it may affect the health of future offspring and therefore, we deem it important to identify more prognostic and therapeutic targets to control this condition.

Source: Farigol Hakem Zadeh, Daniel R. Wilson, Devendra K. Agrawal. Long COVID: Complications, Underlying Mechanisms, and Treatment Strategies. Archives of Microbiology and Immunology. 7 (2023): 36-61. http://www.fortunejournals.com/articles/long-covid-complications-underlying-mechanisms-and-treatment-strategies.html (Full text)

Long COVID syndrome after SARS-CoV-2 survival in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Abstract:

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients have a more severe COVID-19 course than the general population. Many patients report different persistent symptoms after SARS-CoV-2 infection. The aim of our study is to analyze the prevalence of long COVID-19 symptoms and assess if COVID-19 affects pulmonary hypertension (PH) prognosis.

PAH/CTEPH patients who survived COVID-19 for at least 3 months before visiting the PH centers were included in the study. The patients were assessed for symptoms in acute phase of SARS-CoV-2 infection and persisting in follow-up visit, WHO functional class, 6-min walk distance, NT-proBNP concentration. The COMPERA 2.0 model was used to calculate 1-year risk of death due to PH at baseline and at follow-up. Sixty-nine patients-54 (77.3%) with PAH and 15 (21.7%) with CTEPH, 68% women, with a median age of 47.5 years (IQR 37-68)-were enrolled in the study.

About 17.1% of patients were hospitalized due to COVID-19 but none in an ICU. At follow-up (median: 155 days after onset of SARS-CoV-2 symptoms), 62% of patients reported at least 1 COVID-19-related symptom and 20% at least 5 symptoms. The most frequently reported symptoms were: fatigue (30%), joint pain (23%), muscle pain (17%), nasal congestion (17%), anosmia (13%), insomnia (13%), and dyspnea (12%).

Seventy-two percent of PH patients had a low or intermediate-low risk of 1-year death due to PH at baseline, and 68% after COVID-19 at follow-up. Over 60% of PAH/CTEPH patients who survived COVID-19 suffered from long COVID-19 syndrome, but the calculated 1-year risk of death due to PH did not change significantly after surviving mild or moderate COVID-19.

Source: Wieteska-Miłek M, Kuśmierczyk-Droszcz B, Betkier-Lipińska K, Szmit S, Florczyk M, Zieliński P, Hoffman P, Krzesińki P, Kurzyna M. Long COVID syndrome after SARS-CoV-2 survival in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Pulm Circ. 2023 May 31;13(2):e12244. doi: 10.1002/pul2.12244. PMID: 37266140; PMCID: PMC10232226. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232226/ (Full text)

Case Report of Improvement in Long-COVID Symptoms in an Air Force Medic Treated With Transcranial Magnetic Stimulation Using Electro-Magnetic Brain Pulse Technique

Abstract:

Long-coronavirus disease (COVID) is an ill-defined set of symptoms persisting in patients following infection with COVID-19 that range from any combination of persistent breathing difficulties to anosmia, impaired attention, memory, fatigue, or pain. Recently, noninvasive transcutaneous electrical brain stimulation techniques have been showing early signs of success in addressing some of these complaints. We postulate that the use of a stimulation technique with transcranial magnetic stimulation may also similarly be effective.

A 36-year-old male suffering from symptoms of dyspnea, anosmia, and “brain fog” for 2 years following coronavirus infection was treated with 10 sessions of Electro-Magnetic Brain Pulse (EMBP®), a personalized transcranial magnetic stimulation protocol guided by the patient’s electroencephalograph (EEG). At the conclusion of the treatment, the patient had improvements in mood, sense of smell, and brain fogging. Dyspnea also decreased with a gain of 11% forced expiratory volume 1/forced vital capacity.

A high-sensitivity athletic training cognitive test showed an overall 27% increase in aggregate score. A significant portion of this was attributed to changes in visual clarity and decision-making speed. Post-treatment EEG showed a shift from predominantly delta waves to more synchronized alpha wave patterns during the resting state. Brain stimulation techniques appear to be showing early signs of success with long-COVID symptoms.

This is the first case describing the use of a magnetic stimulation technique with quantitative test results and recorded EEG changes. Given the early success in this patient with cognition, dyspnea, and anosmia, this noninvasive treatment modality warrants further research.

Source: Zhang JX, Zhang JJ. Case Report of Improvement in Long-COVID Symptoms in an Air Force Medic Treated With Transcranial Magnetic Stimulation Using Electro-Magnetic Brain Pulse Technique. Mil Med. 2023 Jun 2:usad182. doi: 10.1093/milmed/usad182. Epub ahead of print. PMID: 37267198. https://academic.oup.com/milmed/advance-article/doi/10.1093/milmed/usad182/7189756 (Full text)