Annemarie Dedek, Jian Xu, Louis-Étienne Lorenzo, Antoine G Godin, Chaya M Kandegedara, Geneviève Glavina, Jeffrey A Landrigan, Paul J Lombroso, Yves De Koninck, Eve C Tsai ... Show more
Brain, awab408, https://doi.org/10.1093/brain/awab408
Published: 23 March 2022
The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.
Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females.
This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
Fatigue: Biomedicine, Health & Behavior Volume 9, 2021 - Issue 2COVID-19 symptoms over time: comparing long-haulers to ME/CFSLeonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson. https://doi.org/10.1080/21641846.2021.1922140
IntroductionOur objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
ResultsOver time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
ConclusionsThese types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue SyndromeKlaus J Wirth 1, Carmen Scheibenbogen 2, Friedemann Paul 3
J Transl Med. 2021 Nov 22;19(1):471.
PMID: 34809664 PMCID: PMC8607226 DOI: 10.1186/s12967-021-03143-3
Erratum in· Correction to: An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Wirth KJ, Scheibenbogen C, Paul F.J Transl Med. 2022 Jan 11;20(1):25. doi: 10.1186/s12967-021-03216-3.PMID: 35016692
AbstractThere is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.
Keywords: Brain fog; Chronic Fatigue Syndrome; Cognitive impairment; Dysautonomia; Headache; Hypersensitivity; Myalgic Encephalomyelitis; Neurological symptoms; Post-Covid-19 syndrome; Sleep disturbance.
© 2021. The Author(s).
Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis
Felicia Ceban a,b , Susan Ling a,d , Leanna M.W. Lui a , Yena Lee a,c , Hartej Gill a , Kayla M. Teopiz a , Nelson B. Rodrigues a , Mehala Subramaniapillai a , Joshua D. Di Vincenzo a,d , Bing Cao e , Kangguang Lin f,g , Rodrigo B. Mansur a,h , Roger C. Ho i,j , Joshua D. Rosenblat a,d,h , Kamilla W. Miskowiak k,l , Maj Vinberg m,n , Vladimir Maletic o , Roger S.
Brain Behavior and Immunity journal homepage: www.elsevier.com/locate/ybrbi
ABSTRACT Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.
Data sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. Study selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. Data extraction & synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.
Main outcomes & measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome.
Abbreviation: PCS, Post-COVID-19 syndrome. * Corresponding author at: University Health Network, 399 Bathurst S
Does pre-infection stress increase the risk of long COVID? Longitudinal associations between adversity worries and experiences in the month prior to COVID-19 infection and the development of long COVID and specific long COVID symptoms
View ORCID ProfileElise Paul, View ORCID ProfileDaisy Fancourt
Background Long COVID is increasingly recognised as public health burden. Demographic and infection-related characteristics have been identified as risk factors, but less research has focused on psychosocial predictors such as stress immediately preceding the index infection. Research on whether stressors predict the development of specific long COVID symptoms is also lacking.
Methods Data from 1,966 UK adults who had previously been infected with COVID-19 and who took part in the UCL COVID-19 Social Study were analysed. The number of adversity experiences (e.g., job loss) and the number of worries about adversity experiences within the month prior to COVID-19 infection were used to predict the development of self-reported long COVID and the presence of three specific long COVID symptoms (difficulty with mobility, cognition, and self-care). The interaction between a three-level index of socio-economic position (SEP; with higher values indicating lower SEP) and the exposure variables in relation to long COVID status was also examined. Analyses controlled for a range of COVID-19 infection characteristics, socio-demographics, and health-related factors.
Findings Odds of self-reported long COVID increased by 1.25 (95% confidence interval [CI]: 1.04 to 1.51) for each additional worry about adversity in the month prior to COVID-19 infection. Although there was no evidence for an interaction between SEP and either exposure variable, individuals in the lowest SEP group were nearly twice as likely to have developed long COVID as those in the highest SEP group (OR: 1.95; 95% CI: 1.19 to 3.19) and worries about adversity experiences remained a predictor of long COVID (OR: 1.43; 95% CI: 1.04 to 1.98). The number of worries about adversity experiences also corresponded with increased odds of certain long COVID symptoms such as difficulty with cognition (e.g., difficulty remembering or concentrating) by 1.46 (95% CI: 1.02 to 2.09) but not with mobility (e.g., walking or climbing steps) or self-care (e.g., washing all over or dressing).
Interpretation Results suggest a key role of stress in the time preceding the acute COVID-19 infection for the development of long COVID and for difficulty with cognition specifically. These findings point to the importance of mitigating worries and experiences of adversities during pandemics both to reduce their psychological impact but also help reduce the societal burden of longer-term illness.
Funding The Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].
Front. Neurol., 11 April 2022 | https://doi.org/10.3389/fneur.2022.841310
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature ReviewShin-ichi Hirano1*, Yusuke Ichikawa1,2, Bunpei Sato1,2, Yoshiyasu Takefuji3,4 and Fumitake Satoh1,2
- 1Department of Research and Development, MiZ Company Limited, Kamakura, Japan
Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunctionFriedberg, Fred PhD1; Adamowicz, Jenna L. MA2; Bruckenthal, Patricia PhD, APRN-BC, FAAN3; Milazzo, Maria PhD, RN3; Ramjan, Sameera MA4; Quintana, Daniel PhD5
Psychosomatic Medicine: April 15, 2022 - Volume - Issue - 10.1097/PSY.0000000000001082
AbstractObjective To test a model of non-improvement in chronic fatigue syndrome (CFS) utilizing self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined.
Methods This prospective study in CFS collected all data remotely, including six months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, six months of weekly heart monitoring and three months of daily waking actigraphy data were collected. Improvement or non-improvement status was assessed using semi-structured interviews at 6 months follow-up.
Results 148 individuals (87.2% female) were enrolled and 12.2% were lost to follow-up. Participants reporting non-improvement (n = 92), as compared to improvement (n = 38) showed greater autonomic dysfunction (lower heart rate variability [HRV], group difference = 5.93 (SE = 2.73) ms; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 (SE = 0.16); p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing.
Conclusions This study provided evidence for linking patient-reported non-improvement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS.
Trial Registration: ClinicalTrials.gov ID: NCT02948556
Copyright © 2022 by the American Psychosomatic Society
Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFSby
Yoshiaki Soejima Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Ko Harada. Kenta Nakamoto, Naruhiko Sunada, Yasue Sakurada, Kou Hasegawa, Hideharu Hagiya,Keigo Ueda, and Fumio Otsuka
*Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Medicina 2022, 58(4), 536; https://doi.org/10.3390/medicina58040536
Received: 18 March 2022 / Revised: 7 April 2022 / Accepted: 11 April 2022 / Published: 13 April 2022
(This article belongs to the Special Issue Advances in ME/CFS Research and Clinical Care)
After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).
Keywords: general fatigue; free testosterone; late-onset hypogonadism; long COVID; post-COVID condition
Frontiers in Neuroendocrinology Available online 11 April 2022, 100995The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue SyndromeAuthor links open overlay panel NatalieThomasaCarolineGurvichbKatherineHuangaPaul RGooleyaChristopher WArmstronga
https://doi.org/10.1016/j.yfrne.2022.100995Get rights and content
IntroductionMyalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem disease characterised by severe and disabling new-onset symptoms of post-exertional malaise (PEM), fatigue, brain fog, and sleep dysfunction that lasts for at least six months. Accumulating evidence suggests that sex and endocrine events have a significant influence on symptom onset and moderation of ME/CFS, with female sex being one of the most consistent and credible predictive risk factors associated with diagnosis. Such sex differences suggest sex chromosomes and sex steroids may play a part in the development of the condition or moderation of symptoms, although this has yet to be explored in detail.
Methods/AimsThis narrative review outlines sex differences in ME/CFS in terms of vulnerability factors and clinical phenotype and explores the known sex differences in neuroendocrine systems affected in ME/CFS and how this may relate to disease risk, onset, pathophysiology, and potential treatment avenues.
ConclusionsThere is clear evidence of a sex dimorphism with regards to prevalence (3:1 female preponderance), clinical phenotypes, and aetiological triggers prior to symptom onset of ME/CFS. Endocrinological events, particularly those throughout the female lifespan, are associated with ME/CFS and include reproductive menstrual cycle fluctuations, pregnancy, post-partum and perimenopause. Further, there is evidence for gonadal sex, adrenal stress and renal neuroendocrine systems as implicated in ME/CFS, including changes in estrogen, progesterone compounds, aldosterone, and cortisol levels, of which there are established sex differences. The broad effects of steroid hormones on the physiological systems may also speak to the diversity of ME/CFS symptomatology observed in patients. Further attention must be paid to sex, age, and steroid biology in ME/CFS.
Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis
Similä, Wenche Ann Doctoral thesis URI https://hdl.handle.net/11250/2991015 Date 2022
Institutt for klinisk og molekylær medisin 
Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a disease that affects people of all ages. CFS/ME significantly limits the activity level of those affected, including in relation to physical activity, schooling, occupational life and social life. High levels of school absence among young people with CFS/ME result in loss of important learning and social development among peers. As such, there is increasing uncertainty about their future, and personal and socio-economic consequences could put them at risk of becoming disabled at a young age. Measurements of health-related quality of life (HRQoL), including being able to function in school, have shown that young people with CFS/ME score lower than their counterparts without CFS/ME.
The overall aim of this project was to explore HRQoL among young people with CFS/ME, including the factors associated with HRQoL in relation to school and everyday life. More specifically, the aim was to firstly (Study1) examine HRQoL, including factors that are positively or negatively associated with HRQoL, in a cohort of young people with CFS/ME. Study 1, along with the previous literature, provided the basis for an in-depth study (Study 2) to investigate the positive and negative factors that young people with CFS/ME experience in school and everyday life. Based on the findings from Study 1 and Study 2, a third study (Study 3) was planned to explore teachers’, counsellors’ and school nurses’ experiences with educational and social adaptation at school for young people with CFS/ME.
To explore HRQoL and the factors associated with HRQoL among young people with CFS/ME (Studies 1 & 2), a cross-sectional survey- and interview-based study was conducted. The participants of the cross-sectional study were recruited to participate in the interview study. To explore the experiences of teachers, counsellors and school nurses with education and social adaptions at school for young people with CFS/ME (Study 3), an interview study was conducted with participants recruited among school personnel and school nurses in secondary school (educating students aged 13-16), high school (educating students aged 16-19) and educational psychological services (EPS).
A total of 63 participants were included in the cross-sectional study, 18 of whom participated in the interview study. A total of 12 participants were included in the interview study with the teachers, counsellors and school nurses. In the cross-sectional study (Study 1), young people with CFS/ME scored lower on HRQoL than their counterparts who were healthy or had other chronic diseases. Contact with school and teachers was associated with a higher HRQoL among young people with CFS/ME. This association could be due to that more contact resulted from adaptations of education and social life at school, or that fewer health problems due to CFS/ME had abled the young people to maintain the contact with school and teachers. In Study 2, it was found that an adapted plan for education and social life at school for young people with CFS/ME could increase the possibility of continuing schooling with peers. The lack of an adapted plan for education and social life at school could lead to increased school absence as well as loss of education, social contact and development among peers. Subsequently, this could lead to depressive thoughts and worry about the future. The school personnel and school nurses in Study 3 experienced that young people with CFS/ME lost confidence in school. The challenges experienced by school personnel included (1) understanding students’ needs before they received a diagnosis and before school personnel received information from healthcare providers and (2) maintaining the teacher–student relationship and (3) the continuity of teaching. In terms of measures for better management, early problematization of school absence, interdisciplinary collaboration on early measures, ensuring the maintenance of the teacher–student relationship and increasing CFS/ME-related competence in schools were proposed. These measures could contribute to prevent loss of function and school absence among young people with CFS/ME.
HRQoL among young people with CFS/ME was associated with contact with school and teachers, but a causal relationship could not be proven. Interviews with young people with CFS/ME and school personnel suggested that interdisciplinary strategies for early adaptations to education and social life at school for young people with CFS/ME may benefit education and social development among peers for young people with CFS/ME. Lack of educational and social adaptations at school might lead to loss of education, social life and development among peers.
Cognitive sequelae of long COVID may not be permanent: A prospective studyOscar H. Del Brutto,Denisse A. Rumbea,Bettsy Y. Recalde,Robertino M. Mera
First published: 16 December 2021 https://doi.org/10.1111/ene.15215
AbstractBackground and purposeCognitive decline is a recognized manifestation of long COVID, even among patients who experience mild disease. However, there is no evidence regarding the length of cognitive decline in these patients. This study aimed to assess whether COVID-19-related cognitive decline is a permanent deficit or if it improves over time.
MethodsCognitive performance was evaluated by means of the Montreal Cognitive Assessment (MoCA) in COVID-19 survivors and noninfected individuals. All study participants had four cognitive evaluations, two of them before the pandemic and the other two, 6 and 18 months after the initial SARS-CoV-2 outbreak infection in the village. Linear mixed effects models for longitudinal data were fitted to assess differences in cognitive performance across COVID-19 survivors and noninfected individuals.
ResultsThe study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant—likely age-related—decline in MoCA scores between the two prepandemic tests (β = −1.53, 95% confidence interval [CI] = −2.14 to −0.92, p < 0.001), which did not differ across individuals who later developed COVID-19 when compared to noninfected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (β = −1.37, 95% CI = −2.14 to −0.61, p < 0.001), which reversed after 1 additional year of follow-up (β = 0.66, 95% CI = −0.11 to 1.42, p = 0.092). No differences were noticed among noninfected individuals when both postpandemic MoCA scores were compared.
ConclusionsStudy results suggest that long COVID-related cognitive decline may spontaneously improve over time.
Peripheral muscle fatigue limits post-COVID exercise
20 April 2022 FROM ESC PREVENTIVE CARDIOLOGY 2022
Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.
The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.
To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.
Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.
Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.
Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.
A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.
However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.
The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.
“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.
Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgiaVivek Verma 1, Gillian L Drury, Marc Parisien, Ayşe N Özdağ Acarli, Tho-Alfakar Al-Aubodah, Anastasia Nijnik, Xia Wen, Nicol Tugarinov, Maria Verner, Richie Klares 3rd, Alexander Linton, Emerson Krock, Carlos E Morado Urbina, Bendik Winsvold, Lars G Fritsche, Egil A Fors, Ciriaco Piccirillo, Arkady Khoutorsky, Camilla I Svensson, Mary A Fitzcharles, Pablo M Ingelmo, Nicole F Bernard, Franck P Dupuy, Nurcan Üçeyler, Claudia Sommer, Irah L King, Carolina B Meloto, Luda Diatchenko, HUNT-All In Pain
- PMID: 34913882 PMCID: PMC8942876 (available on 2023-03-24) DOI: 10.1097/j.pain.0000000000002498
Copyright © 2021 International Association for the Study of Pain.
Natelson et al. Journal of Translational Medicine (2022) 20:95 https://doi.org/10.1186/s12967-022-03289-8 RESEARCH
Physiological assessment of orthostatic intolerance in chronic fatigue syndrome Benjamin H. Natelson1*, Jin‑Mann S. Lin2 , Michelle Blate1 , Sarah Khan1 , Yang Chen2 and Elizabeth R. Unger2
Background: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/ CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identifed in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormal‑ ity, followed by postural orthostatic tachycardia.
Objective: Evaluate the physiologic response of patients with ME/CFS to a standardized OC.
Design: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2≤32 mmHg. Orthostatic tachycardia was heart rate increase≥30 beats per minute compared with resting or≥120 BPM. Orthostatic hypotension was decreased sys‑ tolic pressure≥20 mmHg from baseline. Tachypnea was respiratory rate of ≥20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. Patients: 63 consecutive patients fulflling the 1994 case defnition for CFS underwent lean testing at frst visit and then annually at visit 2 (n=48) and 3 (n=29).
Measures: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.
Results: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not difer between those with and without hypocapnia.
Conclusions: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormal‑ ity, hypocapnia, would be missed without capnography.
Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients
- Natalie Eaton-Fitch, Stanley Du Preez, Hélène Cabanas, Katsuhiko Muraki, Donald Staines & Sonya Marshall-Gradisnik
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.
MethodsLive cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined.
ResultsThe amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001).
ConclusionTRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.
Eye movements may be key to chronic fatigue syndrome diagnosis25 March 2022 Monash University
A Monash Central Clinical School scientist has been awarded $180,000 over three years to develop a way to help diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Associate Professor Joanne Fielding, from the Department of Neuroscience, Associate Professor Fielding is working with Dr Scott Kolbe and Dr Meaghan Clough , both from the Department, and co-investigator Dr Chris Armstrong from the University of Melbourne on the project.
An enigmatic disorder, ME/CFS is characterised by extreme tiredness, pain and a range of other symptoms. Remarkably, there is currently no reliable way to diagnose it and to objectively monitor the effect of treatment in people with the disorder.
“You can’t directly measure ME/CFS at the moment. A clinician’s role is to essentially eliminate other potential causes for the constellation of symptoms,” Associate Professor Fielding said. “While there are some suggested diagnostic criteria there are no formal criteria.
“What we’re trying to do is generate a unique ME/CFS signature based on characteristic changes to eye movements, a behaviourial signature that is specific to the disorder that can be used to help diagnose it and monitor the effects of any treatments.”
Associate Professor Fielding and her team will develop the clinically useful test using ocular-motor, machine learning and neuroimaging techniques.
“We’re using video-oculography, which is basically high-powered cameras that record the eye movements in response to a set of simple stimuli on the screen.
“People with ME/CFS are typically extremely fatigued – we need something very quick that gives a snapshot of how they’re performing.”
Participants in the study can be tested in the lab or in their own homes with a portable eye-tracker – helpful to someone with such a disabling disorder.
Associate Professor Fielding said the research might also give the scientists clues about what might be happening neuropathologically in ME/CFS.
“Tentatively, what we’ve found already looks like a set of aberrant eye movements that suggest that something might be going on at the level of the brain stem – but it’s early days and that’s at best, speculative,” she said.
Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeJessica Van Oosterwijck, Uros Marusic, [...], and Jo Nijs
AbstractAlthough autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.
The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)Rahel S. König, Werner C. Albrich, [...], and Sofia K. Forslund
Front Immunol. 2022 March 30; 13: 878196.
AbstractMyalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed. We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients. Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.
medRxiv. Preprint. 2022 Jan 11. doi: 10.1101/2021.06.14.21258895
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeXiaoyu Che,1,2,† Christopher R. Brydges,3,† Yuanzhi Yu,2 Adam Price,1 Shreyas Joshi,1 Ayan Roy,1 Bohyun Lee,1 Dinesh K. Barupal,4 Aaron Cheng,1 Dana March Palmer,5 Susan Levine,6 Daniel L. Peterson,7 Suzanne D. Vernon,8 Lucinda Bateman,8 Mady Hornig,5 Jose G. Montoya,9 Anthony L. Komaroff,10 Oliver Fiehn,3,* and W. Ian Lipkin1,*
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
MethodsUsing regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
ResultsIn ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
ConclusionOur findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
Long-Term Effects of COVID-19 Shreeya Joshee, BS Nikhil Vatti, MD Christopher Chang, MD, PhD, MBA Published:January 11, 2022DOI:https://doi.org/10.1016/j.mayocp.2021.12.017
AbstractCoronavirus disease 2019 (COVID-19) is the third deadly coronavirus infection of the 21st century that has proven to be significantly more lethal than its predecessors, with the number of infected patients and deaths still increasing daily. From December 2019 to July 2021, this virus has infected nearly 200 million people and led to more than 4 million deaths. Our understanding of COVID-19 is constantly progressing, giving better insight into the heterogeneous nature of its acute and long-term effects. Recent literature on the long-term health consequences of COVID-19 discusses the need for a comprehensive understanding of the multisystemic pathophysiology, clinical predictors, and epidemiology to develop and inform an evidence-based, multidisciplinary management approach. A PubMed search was completed using variations on the term post-acute COVID-19. Only peer-reviewed studies in English published by July 17, 2021 were considered for inclusion. All studies discussed in this text are from adult populations unless specified (as with multisystem inflammatory syndrome in children). The preliminary evidence on the pulmonary, cardiovascular, neurological, hematological, multisystem inflammatory, renal, endocrine, gastrointestinal, and integumentary sequelae show that COVID-19 continues after acute infection. Interdisciplinary monitoring with holistic management that considers nutrition, physical therapy, psychological management, meditation, and mindfulness in addition to medication will allow for the early detection of post-acute COVID-19 sequelae symptoms and prevent long-term systemic damage. This review serves as a guideline for effective management based on current evidence, but clinicians should modify recommendations to reflect each patient's unique needs and the most up-to-date evidence. The presence of long-term effects presents another reason for vaccination against COVID-19.
Lancet Discovery Science: Volume 47, May 2022, 101417
Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohortAdamHampshireaDoris A.ChatfieldbAnne ManktelowMPhilbAmyJollyaWilliamTrenderaPeter J.HellyeraMartina DelGiovaneaVirginia F.J.NewcombebJoanne G.OuttrimbBenWarnebJunaidBhattidLindaPointondAnneElmereNyarieSitholebfJohnBradleybghNathalieKingstonlStephen J.SawceriEdward T.Bullmorecdj…David K.Menonbck1
https://doi.org/10.1016/j.eclinm.2022.101417Get rights and content
Summary:BackgroundPreliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
FindingsCOVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
InterpretationCognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.
Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome
Am J Respir Crit Care Med. 2022 Jan 1; 205(1): 126–129.
Published online 2021 Oct 19. doi: 10.1164/rccm.202108-1903LE
Esther de Boer, 1 , 2 Irina Petrache, 1 , 2 ,* Nir M. Goldstein, 1 J. Tod Olin, 1 Rebecca C. Keith, 1 , 2 Brian Modena, 1 Michael P. Mohning, 1 , 2 Zulma X. Yunt, 1 , 2 Inigo San-Millán, 2 , 3 , ‡ and Jeffrey J. Swigris 1 , 2 , ‡
After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (1). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (2). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (3). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (4). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.
In this study, we investigated whether patients with PASC had compromised mitochondrial function during graded exercise. Data were obtained via retrospective review of the electronic medical record from a cohort of 50 subjects with PASC (n = 50, age = 50 ± 15 yr, 35 female) that were consecutively referred to and willing to complete CPET in the Pulmonary Physiology Laboratory at National Jewish Health between June 2020 and April 2021 (Table 1). No subject was excluded. Patients were assessed on a cycle ergometer (Vmax 29; SensorMedics Corp) using a continuous ramp protocol to exhaustion. Cardiovascular, ventilatory, metabolic, and gas exchange data were collected using a metabolic cart (Ultima Cardio2 System; Med graphics) per standard protocol (5). For calculations of total FATox and carbohydrate oxidation (CHOox), we used the stoichiometric equations by Frayn and colleagues: FATox [g/min] = 1.67 × V˙o2 [L/min] – 1.67 × V˙co2 [L/min] and CHOox [g/min] = 4.55 × V˙o2 [L/min] – 3.21 × V˙co2 [L/min] (6). Patient data were compared with results from two published cohorts that included subjects tested with CPET in Denver, Colorado (i.e., the same altitude as our cohort). The characteristics of these cohorts have been previously described (3). Statistical analyses were performed in SPSS Statistics V.27 (IBM) and graphed with Prism V.9.1.0(221) (GraphPad Software). Our study was approved by The Biomedical Research Alliance of New York (BRANY) Institutional Review Board (IRB) study # 20-12-582-528.
Pulmonary function testing (PFT) showed mostly normal resting airflow and gas transfer capacity. All six patients (12%) with PFT abnormalities had preexisting illnesses, including asthma (n = 3) or interstitial lung disease (n = 1). Resting transthoracic echocardiogram was obtained in 39 patients (78%) within 2 ± 3 months of CPET. Left ventricular systolic function was normal (left ventricular ejection fraction 50–70%) in all patients. Among the 50 patients who underwent CPET, the mean time from COVID-19 diagnosis to the CPET was 6 ± 4 months. V˙o2max was normal (>84% predicted) in 34 (68%; mean peak V˙o2 107 ± 22% predicted) and reduced in 16 patients (32%; mean peak V˙o2 67 ± 13% predicted). Among these 16, none had ventilatory limitation, but 9 (56%) had cardiovascular limitation (heart rate reserve <15 beats per minute at peak exercise), and 10 (63%) had a low O2 pulse value at peak exercise.
Regardless of the presence of comorbidities, among the 39 patients with PASC who had arterial catheters in place, mean lactate was significantly higher (Figures 1A and 1B); and in all 50 patients with PASC, calculated levels of FATox were significantly lower (Figures 1C and 1D) during exercise when compared with historical cohorts of subjects who are moderately active or with metabolic syndrome (3). Calculated levels of CHOox in patients with PASC were not significantly different from these published cohorts (data not shown). Average power output, oxygen consumption, and blood lactate did not differ between patients with PASC with or without comorbidities (data not shown). Correlations between post–COVID-19 symptoms, Borg score for dyspnea and leg fatigue, and time lapse from COVID-19 diagnosis to CPET with the anaerobic threshold and mitochondrial dysfunction (i.e., FATox) did not yield statistically significant relationships.
Our data suggest abnormally low FATox and altered lactate production by skeletal muscle as a putative cause of—or contributor to—the functional limitation of patients with PASC. Normally, as glycolysis increases with exercise intensity, lactate is oxidized for fuel in mitochondria, mainly in adjacent slow-twitch muscle fibers. Like FATox, lactate clearance capacity is a useful surrogate for mitochondrial function. In patients with PASC, even in those with normal pre–COVID-19 physical fitness and free of comorbidities, the metabolic disturbances of the skeletal muscle during exercise may be worse than those reported in moderately active individuals or in individuals with metabolic syndrome (3). Whereas rising blood lactate levels are expected during high exercise intensity (as glycolytic flux exceeds the rate of mitochondrial pyruvate oxidation), a high blood lactate at lower exercise levels indicates mitochondrial dysfunction (7). The inappropriately high arterial lactate levels at relatively low exercise intensity (e.g., >9 mM at 150 W) in patients with PASC indicate that the transition from FATox to CHOox occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.
Dysregulated lipid oxidation and decreased mitochondrial biogenesis have been reported in acute critically ill patients admitted to the ICU (8). However, the long-term weakness in ICU survivors is associated with heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity and not solely by diminished mitochondrial content (9).
Our study has several limitations, including a small cohort size, retrospective methodology, and lack of a contemporaneous control, relying on comparisons with historical cohorts that have distinct demographics. Therefore, our findings may not be generalizable and should be considered hypothesis-generating. They should provide impetus for further investigations into the molecular mechanisms linking COVID-19 to metabolic reprogramming and mitochondrial dysfunction. Our report is consistent with that by Pleguezuelos and colleagues, who also showed that patients with PACS that followed acute COVID-19 requiring admission to the ICU suffered from reduced exercise efficiency (10) and with that of Rinaldo and colleagues showing that disease severity does not impact exercise capacity in COVID-19 survivors; however, the study focused on peak values and cardiorespiratory peak values and not on metabolic/cellular adaptations as we did in our study (11).
To our knowledge, our study provides the first evidence of mitochondrial dysfunction that advances our understanding of the pathogenesis of PACS in patients with preserved pulmonary and cardiac function. Future studies into the mechanisms of mitochondrial dysfunction in individuals with PACS will help accelerate the development of therapies to improve their functional status.
Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for FibromyalgiaA Systematic Review and Network Meta-analysis
Hussein M. Farag, PharmD, MSc, PhD1; Ismaeel Yunusa, PharmD, PhD1,2; Hardik Goswami, BPharm, MSc, PhD1,3; et alIhtisham Sultan, PharmD1,4; Joanne A. Doucette, MSc, MSLIS1; Tewodros Eguale, MD, PhD1,5
JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939 Neurology May 19, 2022
Question What pharmacological treatments for adults with fibromyalgia are associated with the highest efficacy and acceptability?
Findings In this systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia), duloxetine (120 mg) was associated with higher efficacy in treating pain and depression, while amitriptyline was associated with higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes.
Meaning These findings suggest that with the heterogeneity of fibromyalgia symptoms, pharmacological treatments should be tailored to individual symptoms, including pain, sleep problems, depressed mood, fatigue, and health-related quality of life.
Importance Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
Objective To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.
Data Sources Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.
Study Selection Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.
Data Extraction and Synthesis This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.
Main Outcomes and Measures Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.
Results A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD, −0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI, −0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
Conclusions and Relevance These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.
Environ Health Perspect . 2022 May;130(5):57001. doi: 10.1289/EHP9009. Epub 2022 May 11.
Evaluation of a Gene-Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case-Control Study Drawn from the U.S. Military Health Survey's National Population SampleRobert W Haley 1, Gerald Kramer 1, Junhui Xiao 1, Jill A Dever 2, John F Teiber 1
PMID: 35543525 PMCID: PMC9093163 DOI: 10.1289/EHP9009
Background: Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias.
Objectives: We investigated a prestated hypothesis of the association of GWI with a gene-environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure.
Methods: A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment.
Results: The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18controls=1.18; 95% CI: 0.81, 1.73; p=0.35p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine.
Discussion: Given gene-environment independence and monotonicity, the unconfounded aRERI>0aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009
Decreased NO production in endothelial cells exposed to plasma from ME/CFS patientsRominaBertinataRobertoVillalobos-LabrabLidijaHofmanncJenniferBlauensteinercNunoSepúlvedadeFranciscoWestermeiercf
https://doi.org/10.1016/j.vph.2022.106953Get rights and content
ME/CFS-plasma reduced the ability of ECs to produce NO.
Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
We provide new methodological approaches to study in vitro ED in ME/CFS.
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of plasma from either ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence and presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.
Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndromeArnaud Germain,1 Ludovic Giloteaux,1 Geoffrey E. Moore,2 Susan M. Levine,1 John K. Chia,3 Betsy A. Keller,2 Jared Stevens,4 Carl J. Franconi,1 Xiangling Mao,5 Dikoma C. Shungu,5 Andrew Grimson,1 and Maureen R. Hanson1
Published March 31, 2022 - Open Access | 10.1172/jci.insight.157621
Post-exertional malaise (PEM) is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We monitored the evolution of 1157 plasma metabolites in 60 ME/CFS (45 female, 15 male) and 45 matched healthy control participants (30 female, 15 male) before and after 2 maximal cardiopulmonary exercise test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four time points allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of participants with ME/CFS compared with the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.
Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)Joanne Hunt , Charlotte Blease , Keith J Geraghty
First Published March 27, 22 Research Article https://doi.org/10.1177/13591053221084494
AbstractWhilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.
Published:May 05, 2022DOI:https://doi.org/10.1016/j.chest.2022.04.146
ABSTRACTBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.
Research QuestionDoes neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?
MethodsForty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.
ResultsTwenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.
InterpretationPyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Front Cell Neurosci. 2022; 16: 888232. Published online 2022 May 9. doi: 10.3389/fncel.
Herbert Renz-Polster, Marie-Eve Tremblay, Dorothee Bienzl , Joachim E Fischer
Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking.
Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated.
Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes).
We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.
HYPOTHESIS AND THEORY published: 25 May 2022 doi: 10.3389/fneur.2022.877772
Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to SustainDisease and Promote Relapses
Warren Tate 1,2*, Max Walker 1, Eiren Sweetman 1,3, Amber Helliwell 1, Katie Peppercorn 1,2, Christina Edgar 1, Anna Blair 4 and Aniruddha Chatterjee 5
1 Department of Biochemistry, University of Otago, Dunedin, New Zealand, 2 Brain Health Research Centre, University of Otago, Dunedin, New Zealand, 3 School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand,
4 Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia, 5 Department of Pathology, University of Otago, Dunedin, New Zealand
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented ashaving arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, withbrain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctionalblood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effectsof Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with someunique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are verysimilar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.