Medscape Medical News > Conference News > SLEEP 2022
'Alarming' New Data on Disordered Sleep After COVID
Megan Brooks June 07, 2022
Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.
The "high" prevalence of moderate to severe sleep disturbances is "alarming," study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, told Medscape Medical News.
The findings were presented at SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies.
Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, "which may impair quality of life," Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
"We don't know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions," Pena said.
How long after COVID the fatigue and sleep problems last "remains uncertain," Pena acknowledged. However, she added, in her clinical experience with therapy, patients' sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
"Sleep disturbances and fatigue are part of the sequelae of COVID," Benca, who was not involved in the study, told Medscape Medical News.
"We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there's an actual impact of having the infection itself on worsening sleep," said Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Benca is a consultant for Idorsia Pharmaceuticals.
SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies: Abstract 0735. Presented June 6, 2022.
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Front Neurol . 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. eCollection 2022.
Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain
Gabriela Ioachim 1, Howard J M Warren 1, Jocelyn M Powers 1, Roland Staud 2, Caroline F Pukall 1 3, Patrick W Stroman 1 4 5
PMID: 35599729 PMCID: PMC9120571 DOI: 10.3389/fneur.2022.862976
AbstractChronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord. Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling. The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.
Keywords: brainstem; chronic; fMRI; fibromyalgia; human; pain; spinal cord.
Copyright © 2022 Ioachim, Warren, Powers, Staud, Pukall and Stroman.
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Plos one 2022 Mar 15;17(3):e0265315. doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7, MCAM Study Group
PMID: 35290404 PMCID: PMC8923458
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
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Front. Cell. Neurosci., 09 May 2022 | https://doi.org/10.3389/fncel.2022.888232
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Herbert Renz-Polster1*, Marie-Eve Tremblay2,3,4,5,6,7, Dorothee Bienzle8 and Joachim E. Fischer1
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. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
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BMJ . 2022 Feb 9;376:e068414. doi: 10.1136/bmj-2021-068414.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study
Ken Cohen 1, Sheng Ren 2, Kevin Heath 3, Micah C Dasmariñas 2, Karol Giuseppe Jubilo 2, Yinglong Guo 2, Marc Lipsitch 4, Sarah E Daugherty 2
PMID: 35140117 PMCID: PMC8828141 DOI: 10.1136/bmj-2021-068414
AbstractObjective: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.
Design: Retrospective cohort study.
Setting: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.
Participants: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).
Main outcome measures: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.
Results: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.
Conclusions: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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JACC: Heart Failure Volume 9, Issue 12, December 2021, Pages 927-937
Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease
Author links open overlay panelDonna M.ManciniMDabDanielle L.BrunjesPHDaAnuradhaLalaMDabMaria GiovannaTrivieriMD, PHDaJohanna P.ContrerasMD, MScaBenjamin H.NatelsonMDc
https://doi.org/10.1016/j.jchf.2021.10.002Get rights and content
Robert Naeije, Sergio Caravita
JACC: Heart Failure, Volume 10, Issue 3, March 2022, Pages 214-215
Abstract
ObjectivesThe authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
BackgroundApproximately 20% of patients who recover from coronavirus disease (COVID) remain symptomatic. This syndrome is named PASC. Its etiology is unclear. Dyspnea is a frequent symptom.
MethodsThe authors performed CPET and symptom assessment for ME/CFS in 41 patients with PASC 8.9 ± 3.3 months after COVID. All patients had normal pulmonary function tests, chest X-ray, and chest computed tomography scans. Peak oxygen consumption (peak VO2), slope of minute ventilation to CO2 production (VE/VCO2 slope), and end tidal pressure of CO2 (PetCO2) were measured. Ventilatory patterns were reviewed with dysfunctional breathing defined as rapid erratic breathing.
ResultsEighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO2 averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO2). VE/VCO2 slope was 30 ± 7. PetCO2 at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n = 3) or dysfunctional breathing (n = 12). For the whole cohort, 88% of patients (n = 36) had ventilatory abnormalities with dysfunctional breathing (n = 26), increased VE/VCO2 (n = 17), and/or hypocapnia PetCO2 <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS.
ConclusionsCirculatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.
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Nearly 1 in 5 Adults Who Had COVID Have Lingering Symptoms: US StudyBy Reuters Staff June 24, 2022
(Reuters) - Nearly 1 in 5 American adults in a survey who reported having COVID-19 in the past are still having symptoms of long COVID, according to data collected in the first two weeks of June, U.S. health officials said on Wednesday.
Overall, an estimated 1 in 13 adults in the United States have long COVID symptoms lasting for three months or more after first contracting the disease, and which they did not have before the infection, the data suggests.
The data was collected using an online questionnaire from June 1-13 by the U.S. Census Bureau's Household Pulse Survey, and analyzed by the U.S. Centers for Disease Control and Prevention (CDC).
Long COVID symptoms range from fatigue, rapid heartbeat, shortness of breath, cognitive difficulties, chronic pain, sensory abnormalities and muscle weakness. They can be debilitating and last for weeks or months after recovery from the initial infection.
The CDC analysis also found that younger adults were more likely to report persistent symptoms than older adults.
Women were also more likely to report long COVID than men, according to the study, with 9.4% of U.S. adult women reporting long COVID symptoms compared to 5.5% of men.
The survey found nearly 9% of Hispanic adults reported long COVID, higher than non-Hispanic white and Black adults, and more than twice the percentage of non-Hispanic Asian adults.
There were also differences based on U.S states, with the highest percentage of adults reporting long COVID symptoms in Kentucky and Alabama, while Hawaii, Maryland and Virginia had the lowest.
Among the experimental survey's limitations, the CDC cautions in technical notes, is that the percentage of adults who self-report ever having had COVID-19 is lower than estimates based on national seroprevalence studies. The survey also relies on online responses, and had a low (6.2%) response rate.
SOURCE: https://bit.ly/3NdZjyQ Household Pulse Survey Dashboard, online June 22, 2022.
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Cardiovasc Diabetol . 2021 Aug 23;20(1):172. doi: 10.1186/s12933-021-01359-7.
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Etheresia Pretorius 1, Mare Vlok 2, Chantelle Venter 3, Johannes A Bezuidenhout 3, Gert Jacobus Laubscher 4, Janami Steenkamp 3 5, Douglas B Kell 6 7 8
PMID: 34425843 PMCID: PMC8381139 DOI: 10.1186/s12933-021-01359-7
AbstractBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis.
Methods: We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.
Results: We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.
Conclusions: Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.
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J Clin Sleep Med . 2020 Dec 15;16(12):2009-2019. doi: 10.5664/jcsm.8740.
Effects of trazodone versus cognitive behavioral therapy in the insomnia with short sleep duration phenotype: a preliminary study
Alexandros N Vgontzas 1, Kristina Puzino 1, Julio Fernandez-Mendoza 1, Venkatesh Basappa Krishnamurthy 1, Maria Basta 2, Edward O Bixler 1
PMID: 32780015 PMCID: PMC7848933
AbstractStudy objectives: The insomnia with objective short sleep duration phenotype is associated with increased risk for adverse health outcomes, physiological hyperarousal, and a blunted response to cognitive behavioral therapy for insomnia (CBT-I). Whether insomnia with objective short sleep duration responds better to pharmacological treatment compared to CBT-I has not been examined.
Methods: Participants included 15 patients with chronic insomnia (86.7% female), aged 45.3 ± 8.1 years. Eight patients were randomized to CBT-I and 7 to trazodone. Patients were examined with 2 weeks of actigraphy, salivary cortisol, and the insomnia severity index at 3 time points (pretreatment, 3-month posttreatment, and 6-month follow-up). Mixed between-within-subjects analysis of variance and univariate analysis of covariance were conducted to assess the impact of trazodone and CBT-I on patients' total sleep time, salivary cortisol, and insomnia severity index scores across the 3 time points.
Results: Trazodone, but not CBT-I, significantly lengthened total sleep time (when measured with actigraphy) both at posttreatment (51.01 minutes vs -11.73 minutes; P = .051; Cohen's d = 1.383) and at follow-up (50.35 minutes vs -7.56 minutes; P = .012; Cohen's d = 1.725), respectively. In addition, trazodone, but not CBT-I, showed a clinically meaningful decrease in salivary cortisol from pretreatment to posttreatment (-36.07% vs -11.70%; Cohen's d = 0.793) and from pretreatment to follow-up (-21.37% vs -5.79%; Cohen's d = 0.284), respectively. Finally, there were no differences on insomnia severity index scores between the trazodone and the CBT-I groups.
Conclusions: The current preliminary, open-label, randomized trial suggests that trazodone, but not CBT-I, significantly improves objective sleep duration and reduces hypothalamic-pituitary-adrenal axis activation, suggesting a differential treatment response in the insomnia with objective short sleep duration phenotype.
Clinical trial registration: Registry: ClinicalTrials.gov; Name: Study of Trazodone & Cognitive Behavioral Therapy to Treat Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01348542; Identifier: NCT01348542.
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Neuropsychopharmacology
2020 Jan;45(1):205-216. doi: 10.1038/s41386-019-0439-z. Epub 2019 Jun 17.
Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications
Monika Haack 1 2, Norah Simpson 3, Navil Sethna 4 5, Satvinder Kaur 6 4, Janet Mullington 6 4
PMID: 31207606 PMCID: PMC6879497
Abstract
Pain can be both a cause and a consequence of sleep deficiency. This bidirectional relationship between sleep and pain has important implications for clinical management of patients, but also for chronic pain prevention and public health more broadly. The review that follows will provide an overview of the neurobiological evidence of mechanisms thought to be involved in the modulation of pain by sleep deficiency, including the opioid, monoaminergic, orexinergic, immune, melatonin, and endocannabinoid systems; the hypothalamus-pituitary-adrenal axis; and adenosine and nitric oxide signaling. In addition, it will provide a broad overview of pharmacological and non-pharmacological approaches for the management of chronic pain comorbid with sleep disturbances and for the management of postoperative pain, as well as discuss the effects of sleep-disturbing medications on pain amplification.
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Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
Jennifer A. Frontera, MD1; Naomi M. Simon, MD, MSc2
JAMA Psychiatry. Published online June 29, 2022. doi:10.1001/jamapsychiatry.2022.1616
COVID-19 Resource Center
Abstract
Importance Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.
Observations Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.
Conclusions and Relevance Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.
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Long covid patients travel abroad for expensive and experimental “blood washing”
BMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o1671 (Published 12 July 2022)Cite this as: BMJ 2022;378:o1671
Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports
Gitte Boumeester, a trainee psychiatrist in Almelo, the Netherlands, was infected with SARS-CoV-2 in November 2020. She was tired for weeks afterwards but chalked it up to the virus. Soon, she was experiencing such extreme fatigue that it took her two hours to walk to the kitchen to make breakfast. She had brain fog and heart palpitations, was short of breath, often felt sick, and woke up in the night with chest pain. A battery of tests found nothing wrong with her heart or lungs, and she was sent back to her GP. She left her job in November 2021, after two failed attempts to go back to work.
She joined a Facebook group for patients with long covid, many of whom discussed travel to Germany for apheresis, what some of them call a “blood washing” treatment. Apheresis, in which large needles are inserted into the veins and the blood is filtered, removing lipids and inflammatory proteins, is recommended by the German Society of Nephrology as a standard last resort in the country for lipid disorders. A new clinic offering apheresis for long covid patients, called the Long Covid Center, was opening in Cyprus, and she could be treated there in March. “I thought, what’s the worst thing I’ve got to lose?” she said. “Money was the only thing. I thought, OK, well, why not give it a try?”
Two months later she was back home in the Netherlands, having spent nearly all her savings—more than €15 000 (£12 700; $15 000)—with no improvement in her symptoms.
Thousands of patients like Boumeester, frustrated at the lack of treatment available for long covid, are travelling to Cyprus, Germany, and Switzerland for apheresis, an investigation by The BMJ and ITV News can reveal. Many are also prescribed anticlotting drugs, including clopidogrel, apixaban, and heparin, on a hypothesis that the symptoms of long covid are caused by small clots in the blood that are blocking the flow of oxygen through capillaries. Although some doctors and researchers believe that apheresis and anticoagulation drugs may be promising treatments for long covid, others worry that desperate patients are spending life changing sums on invasive, unproved treatments.
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THE LANCET: ARTICLES| VOLUME 400, ISSUE 10347, P170-184, JULY 16, 2022
Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis
Franco De Crescenzo, MD Gian Loreto D'Alò, MD † Edoardo G Ostinelli, MD † Marco Ciabattini, MD et al Published:July 16, 2022DOI:https://doi.org/10.1016/S0140-6736(22)00878-9
BackgroundBehavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.
MethodsIn this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ.
FindingsWe included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]).
InterpretationOverall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.
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Cell . 2022 Jul 7;185(14):2452-2468.e16. doi: 10.1016/j.cell.2022.06.008. Epub 2022 Jun 13.
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Anthony Fernández-Castañeda 1, et al PMID: 35768006 PMCID: PMC9189143
Abstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
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Front Neurol . 2022 Apr 11;13:841310. doi: 10.3389/fneur.2022.841310. eCollection 2022.
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review
Shin-Ichi Hirano 1, Yusuke Ichikawa 1 2, Bunpei Sato 1 2, Yoshiyasu Takefuji 3 4, Fumitake Satoh 1 2 PMID: 35493814 PMCID: PMC9042428
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.
Keywords: chronic fatigue syndrome (CFS); hydroxyl radicals; long COVID; mitochondrial dysfunction; molecular hydrogen; myalgic encephalomyelitis (ME); oxidative stress; post COVID.
Copyright © 2022 Hirano, Ichikawa, Sato, Takefuji and Satoh.
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Original Investigation Pediatrics July 22, 2022
Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection
Anna L. Funk, PhD, MSc1; et al for the Pediatric Emergency Research Network–COVID-19 Study Team
JAMA Netw Open. 2022;5(7):e2223253. doi:10.1001/jamanetworkopen.2022.23253
COVID-19 Resource Center
Key Points
Question What proportion of children infected with SARS-CoV-2 who were tested in emergency departments (EDs) reported post–COVID-19 conditions (PCCs) 90 days after their ED visits?
Findings In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older.
Meaning This study suggests that, given the prevalence of PCCs, appropriate guidance and follow-up are required for children testing positive for SARS-CoV-2.
Abstract
Importance Little is known about the risk factors for, and the risk of, developing post–COVID-19 conditions (PCCs) among children.
Objectives To estimate the proportion of SARS-CoV-2–positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2–negative children, and to assess factors associated with PCCs.
Design, Setting, and Participants This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls.
Exposure SARS-CoV-2 detected via nucleic acid testing.
Main Outcomes and Measures Post–COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey.
Results Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2–positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2–positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2–positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]).
Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.
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Eur Respir J. 2022 Mar 2 : 2103101. doi: 10.1183/13993003.03101-2021
[Epub ahead of print] PMCID: PMC8900538 PMID: 35236727
Inspiratory Muscle Training Enhances Recovery Post COVID-19: A Randomised Controlled Trial
Melitta A McNarry, 1 Ronan M G Berg,2 James Shelley,1 Joanne Hudson,1 Zoe L Saynor,3 Jamie Duckers,4 Keir Lewis,5,6 Gwyneth A Davies,6 and Kelly A Mackintosh1
Abstract: Background
Many people recovering from COVID-19 experience prolonged symptoms, particularly breathlessness. We urgently need to identify safe and effective COVID-19 rehabilitative strategies. The aim of the current study was to investigate the potential rehabilitative role of inspiratory muscle training (IMT).
Methods: 281 adults (46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” wait list control arm. Health-related quality of life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary endpoint was KBILD total score, with the KBILD subdomains and TDI being key secondary outcomes.Results: According to intention to treat (ITT), there was no difference between groups in KBILD total score post-intervention (Control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the KBILD subdomains of breathlessness (Control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (Control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (Control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness.Conclusions: IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long-COVID, further research is warranted on the individual responses to rehabilitation - the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.
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Respiration . 2022;101(6):593-601.doi: 10.1159/000522118. Epub 2022 Feb 24.
Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life
Stephan Nopp 1, Florian Moik 1, Frederikus A Klok 2, Dietlinde Gattinger 3, Milos Petrovic 3, Karin Vonbank 4, Andreas R Koczulla 5 6, Cihan Ay 1, Ralf Harun Zwick 3 7
nPMID: 35203084 PMCID: PMC9059007
Abstract
Background: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking.
Methods: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored.
Results: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation.
Conclusion: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.
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MEDICAL NEWS – UNIVADIS (MEDSCAPE)Long COVID substantially less common in children than adultsDawn O'Shea | 27 July 2022
Almost 6 per cent of children who presented to the emergency department (ED) with COVID-19 develop long COVID, according to a large international study published by JAMA Network Open.
The prospective cohort study was conducted in 36 EDs in eight countries between March 7, 2020, and January 20, 2021, and included 1884 children with COVID-19 who completed 90 days of follow-up. Of these, 1686 were matched by hospitalisation status, country, and recruitment date with 1701 SARS-CoV-2-negative controls.
Long COVID was defined as any persistent, new, or recurrent health problems over a 90-day period.
Among the participants, 5.8 per cent reported symptoms of long COVID. The rate increased to 9.8 per cent of hospitalised children and 4.6 per cent among discharged children. Characteristics associated with long COVID included being hospitalised for 48 hours or more, having four or more symptoms at the index ED visit, and being 14 years of age or older.
,
“Reported rates of long COVID in adults are substantially higher than what we found in children,” said co-principal investigator Nathan Kuppermann, from the University of California. “Our findings can inform public health policy decisions regarding COVID-19 mitigation strategies for children and screening approaches for long COVID among those with severe infections.”
'Alarming' New Data on Disordered Sleep After COVID
Megan Brooks June 07, 2022
Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.
The "high" prevalence of moderate to severe sleep disturbances is "alarming," study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, told Medscape Medical News.
The findings were presented at SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies.
Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, "which may impair quality of life," Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
"We don't know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions," Pena said.
How long after COVID the fatigue and sleep problems last "remains uncertain," Pena acknowledged. However, she added, in her clinical experience with therapy, patients' sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
"Sleep disturbances and fatigue are part of the sequelae of COVID," Benca, who was not involved in the study, told Medscape Medical News.
"We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there's an actual impact of having the infection itself on worsening sleep," said Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Benca is a consultant for Idorsia Pharmaceuticals.
SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies: Abstract 0735. Presented June 6, 2022.
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Front Neurol . 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. eCollection 2022.
Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain
Gabriela Ioachim 1, Howard J M Warren 1, Jocelyn M Powers 1, Roland Staud 2, Caroline F Pukall 1 3, Patrick W Stroman 1 4 5
PMID: 35599729 PMCID: PMC9120571 DOI: 10.3389/fneur.2022.862976
AbstractChronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord. Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling. The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.
Keywords: brainstem; chronic; fMRI; fibromyalgia; human; pain; spinal cord.
Copyright © 2022 Ioachim, Warren, Powers, Staud, Pukall and Stroman.
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Plos one 2022 Mar 15;17(3):e0265315. doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7, MCAM Study Group
PMID: 35290404 PMCID: PMC8923458
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
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Front. Cell. Neurosci., 09 May 2022 | https://doi.org/10.3389/fncel.2022.888232
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Herbert Renz-Polster1*, Marie-Eve Tremblay2,3,4,5,6,7, Dorothee Bienzle8 and Joachim E. Fischer1
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. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
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BMJ . 2022 Feb 9;376:e068414. doi: 10.1136/bmj-2021-068414.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study
Ken Cohen 1, Sheng Ren 2, Kevin Heath 3, Micah C Dasmariñas 2, Karol Giuseppe Jubilo 2, Yinglong Guo 2, Marc Lipsitch 4, Sarah E Daugherty 2
PMID: 35140117 PMCID: PMC8828141 DOI: 10.1136/bmj-2021-068414
AbstractObjective: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.
Design: Retrospective cohort study.
Setting: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.
Participants: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).
Main outcome measures: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.
Results: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.
Conclusions: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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JACC: Heart Failure Volume 9, Issue 12, December 2021, Pages 927-937
Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease
Author links open overlay panelDonna M.ManciniMDabDanielle L.BrunjesPHDaAnuradhaLalaMDabMaria GiovannaTrivieriMD, PHDaJohanna P.ContrerasMD, MScaBenjamin H.NatelsonMDc
https://doi.org/10.1016/j.jchf.2021.10.002Get rights and content
Robert Naeije, Sergio Caravita
JACC: Heart Failure, Volume 10, Issue 3, March 2022, Pages 214-215
Abstract
ObjectivesThe authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
BackgroundApproximately 20% of patients who recover from coronavirus disease (COVID) remain symptomatic. This syndrome is named PASC. Its etiology is unclear. Dyspnea is a frequent symptom.
MethodsThe authors performed CPET and symptom assessment for ME/CFS in 41 patients with PASC 8.9 ± 3.3 months after COVID. All patients had normal pulmonary function tests, chest X-ray, and chest computed tomography scans. Peak oxygen consumption (peak VO2), slope of minute ventilation to CO2 production (VE/VCO2 slope), and end tidal pressure of CO2 (PetCO2) were measured. Ventilatory patterns were reviewed with dysfunctional breathing defined as rapid erratic breathing.
ResultsEighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO2 averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO2). VE/VCO2 slope was 30 ± 7. PetCO2 at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n = 3) or dysfunctional breathing (n = 12). For the whole cohort, 88% of patients (n = 36) had ventilatory abnormalities with dysfunctional breathing (n = 26), increased VE/VCO2 (n = 17), and/or hypocapnia PetCO2 <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS.
ConclusionsCirculatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.
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Nearly 1 in 5 Adults Who Had COVID Have Lingering Symptoms: US StudyBy Reuters Staff June 24, 2022
(Reuters) - Nearly 1 in 5 American adults in a survey who reported having COVID-19 in the past are still having symptoms of long COVID, according to data collected in the first two weeks of June, U.S. health officials said on Wednesday.
Overall, an estimated 1 in 13 adults in the United States have long COVID symptoms lasting for three months or more after first contracting the disease, and which they did not have before the infection, the data suggests.
The data was collected using an online questionnaire from June 1-13 by the U.S. Census Bureau's Household Pulse Survey, and analyzed by the U.S. Centers for Disease Control and Prevention (CDC).
Long COVID symptoms range from fatigue, rapid heartbeat, shortness of breath, cognitive difficulties, chronic pain, sensory abnormalities and muscle weakness. They can be debilitating and last for weeks or months after recovery from the initial infection.
The CDC analysis also found that younger adults were more likely to report persistent symptoms than older adults.
Women were also more likely to report long COVID than men, according to the study, with 9.4% of U.S. adult women reporting long COVID symptoms compared to 5.5% of men.
The survey found nearly 9% of Hispanic adults reported long COVID, higher than non-Hispanic white and Black adults, and more than twice the percentage of non-Hispanic Asian adults.
There were also differences based on U.S states, with the highest percentage of adults reporting long COVID symptoms in Kentucky and Alabama, while Hawaii, Maryland and Virginia had the lowest.
Among the experimental survey's limitations, the CDC cautions in technical notes, is that the percentage of adults who self-report ever having had COVID-19 is lower than estimates based on national seroprevalence studies. The survey also relies on online responses, and had a low (6.2%) response rate.
SOURCE: https://bit.ly/3NdZjyQ Household Pulse Survey Dashboard, online June 22, 2022.
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Cardiovasc Diabetol . 2021 Aug 23;20(1):172. doi: 10.1186/s12933-021-01359-7.
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Etheresia Pretorius 1, Mare Vlok 2, Chantelle Venter 3, Johannes A Bezuidenhout 3, Gert Jacobus Laubscher 4, Janami Steenkamp 3 5, Douglas B Kell 6 7 8
PMID: 34425843 PMCID: PMC8381139 DOI: 10.1186/s12933-021-01359-7
AbstractBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis.
Methods: We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.
Results: We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.
Conclusions: Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.
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J Clin Sleep Med . 2020 Dec 15;16(12):2009-2019. doi: 10.5664/jcsm.8740.
Effects of trazodone versus cognitive behavioral therapy in the insomnia with short sleep duration phenotype: a preliminary study
Alexandros N Vgontzas 1, Kristina Puzino 1, Julio Fernandez-Mendoza 1, Venkatesh Basappa Krishnamurthy 1, Maria Basta 2, Edward O Bixler 1
PMID: 32780015 PMCID: PMC7848933
AbstractStudy objectives: The insomnia with objective short sleep duration phenotype is associated with increased risk for adverse health outcomes, physiological hyperarousal, and a blunted response to cognitive behavioral therapy for insomnia (CBT-I). Whether insomnia with objective short sleep duration responds better to pharmacological treatment compared to CBT-I has not been examined.
Methods: Participants included 15 patients with chronic insomnia (86.7% female), aged 45.3 ± 8.1 years. Eight patients were randomized to CBT-I and 7 to trazodone. Patients were examined with 2 weeks of actigraphy, salivary cortisol, and the insomnia severity index at 3 time points (pretreatment, 3-month posttreatment, and 6-month follow-up). Mixed between-within-subjects analysis of variance and univariate analysis of covariance were conducted to assess the impact of trazodone and CBT-I on patients' total sleep time, salivary cortisol, and insomnia severity index scores across the 3 time points.
Results: Trazodone, but not CBT-I, significantly lengthened total sleep time (when measured with actigraphy) both at posttreatment (51.01 minutes vs -11.73 minutes; P = .051; Cohen's d = 1.383) and at follow-up (50.35 minutes vs -7.56 minutes; P = .012; Cohen's d = 1.725), respectively. In addition, trazodone, but not CBT-I, showed a clinically meaningful decrease in salivary cortisol from pretreatment to posttreatment (-36.07% vs -11.70%; Cohen's d = 0.793) and from pretreatment to follow-up (-21.37% vs -5.79%; Cohen's d = 0.284), respectively. Finally, there were no differences on insomnia severity index scores between the trazodone and the CBT-I groups.
Conclusions: The current preliminary, open-label, randomized trial suggests that trazodone, but not CBT-I, significantly improves objective sleep duration and reduces hypothalamic-pituitary-adrenal axis activation, suggesting a differential treatment response in the insomnia with objective short sleep duration phenotype.
Clinical trial registration: Registry: ClinicalTrials.gov; Name: Study of Trazodone & Cognitive Behavioral Therapy to Treat Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01348542; Identifier: NCT01348542.
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Neuropsychopharmacology
2020 Jan;45(1):205-216. doi: 10.1038/s41386-019-0439-z. Epub 2019 Jun 17.
Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications
Monika Haack 1 2, Norah Simpson 3, Navil Sethna 4 5, Satvinder Kaur 6 4, Janet Mullington 6 4
PMID: 31207606 PMCID: PMC6879497
Abstract
Pain can be both a cause and a consequence of sleep deficiency. This bidirectional relationship between sleep and pain has important implications for clinical management of patients, but also for chronic pain prevention and public health more broadly. The review that follows will provide an overview of the neurobiological evidence of mechanisms thought to be involved in the modulation of pain by sleep deficiency, including the opioid, monoaminergic, orexinergic, immune, melatonin, and endocannabinoid systems; the hypothalamus-pituitary-adrenal axis; and adenosine and nitric oxide signaling. In addition, it will provide a broad overview of pharmacological and non-pharmacological approaches for the management of chronic pain comorbid with sleep disturbances and for the management of postoperative pain, as well as discuss the effects of sleep-disturbing medications on pain amplification.
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Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
Jennifer A. Frontera, MD1; Naomi M. Simon, MD, MSc2
JAMA Psychiatry. Published online June 29, 2022. doi:10.1001/jamapsychiatry.2022.1616
COVID-19 Resource Center
Abstract
Importance Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.
Observations Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.
Conclusions and Relevance Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.
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Long covid patients travel abroad for expensive and experimental “blood washing”
BMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o1671 (Published 12 July 2022)Cite this as: BMJ 2022;378:o1671
Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports
Gitte Boumeester, a trainee psychiatrist in Almelo, the Netherlands, was infected with SARS-CoV-2 in November 2020. She was tired for weeks afterwards but chalked it up to the virus. Soon, she was experiencing such extreme fatigue that it took her two hours to walk to the kitchen to make breakfast. She had brain fog and heart palpitations, was short of breath, often felt sick, and woke up in the night with chest pain. A battery of tests found nothing wrong with her heart or lungs, and she was sent back to her GP. She left her job in November 2021, after two failed attempts to go back to work.
She joined a Facebook group for patients with long covid, many of whom discussed travel to Germany for apheresis, what some of them call a “blood washing” treatment. Apheresis, in which large needles are inserted into the veins and the blood is filtered, removing lipids and inflammatory proteins, is recommended by the German Society of Nephrology as a standard last resort in the country for lipid disorders. A new clinic offering apheresis for long covid patients, called the Long Covid Center, was opening in Cyprus, and she could be treated there in March. “I thought, what’s the worst thing I’ve got to lose?” she said. “Money was the only thing. I thought, OK, well, why not give it a try?”
Two months later she was back home in the Netherlands, having spent nearly all her savings—more than €15 000 (£12 700; $15 000)—with no improvement in her symptoms.
Thousands of patients like Boumeester, frustrated at the lack of treatment available for long covid, are travelling to Cyprus, Germany, and Switzerland for apheresis, an investigation by The BMJ and ITV News can reveal. Many are also prescribed anticlotting drugs, including clopidogrel, apixaban, and heparin, on a hypothesis that the symptoms of long covid are caused by small clots in the blood that are blocking the flow of oxygen through capillaries. Although some doctors and researchers believe that apheresis and anticoagulation drugs may be promising treatments for long covid, others worry that desperate patients are spending life changing sums on invasive, unproved treatments.
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THE LANCET: ARTICLES| VOLUME 400, ISSUE 10347, P170-184, JULY 16, 2022
Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis
Franco De Crescenzo, MD Gian Loreto D'Alò, MD † Edoardo G Ostinelli, MD † Marco Ciabattini, MD et al Published:July 16, 2022DOI:https://doi.org/10.1016/S0140-6736(22)00878-9
BackgroundBehavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.
MethodsIn this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ.
FindingsWe included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]).
InterpretationOverall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.
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Cell . 2022 Jul 7;185(14):2452-2468.e16. doi: 10.1016/j.cell.2022.06.008. Epub 2022 Jun 13.
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Anthony Fernández-Castañeda 1, et al PMID: 35768006 PMCID: PMC9189143
Abstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
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Front Neurol . 2022 Apr 11;13:841310. doi: 10.3389/fneur.2022.841310. eCollection 2022.
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review
Shin-Ichi Hirano 1, Yusuke Ichikawa 1 2, Bunpei Sato 1 2, Yoshiyasu Takefuji 3 4, Fumitake Satoh 1 2 PMID: 35493814 PMCID: PMC9042428
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.
Keywords: chronic fatigue syndrome (CFS); hydroxyl radicals; long COVID; mitochondrial dysfunction; molecular hydrogen; myalgic encephalomyelitis (ME); oxidative stress; post COVID.
Copyright © 2022 Hirano, Ichikawa, Sato, Takefuji and Satoh.
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Original Investigation Pediatrics July 22, 2022
Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection
Anna L. Funk, PhD, MSc1; et al for the Pediatric Emergency Research Network–COVID-19 Study Team
JAMA Netw Open. 2022;5(7):e2223253. doi:10.1001/jamanetworkopen.2022.23253
COVID-19 Resource Center
Key Points
Question What proportion of children infected with SARS-CoV-2 who were tested in emergency departments (EDs) reported post–COVID-19 conditions (PCCs) 90 days after their ED visits?
Findings In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older.
Meaning This study suggests that, given the prevalence of PCCs, appropriate guidance and follow-up are required for children testing positive for SARS-CoV-2.
Abstract
Importance Little is known about the risk factors for, and the risk of, developing post–COVID-19 conditions (PCCs) among children.
Objectives To estimate the proportion of SARS-CoV-2–positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2–negative children, and to assess factors associated with PCCs.
Design, Setting, and Participants This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls.
Exposure SARS-CoV-2 detected via nucleic acid testing.
Main Outcomes and Measures Post–COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey.
Results Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2–positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2–positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2–positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]).
Conclusions and Relevance In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.
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Eur Respir J. 2022 Mar 2 : 2103101. doi: 10.1183/13993003.03101-2021
[Epub ahead of print] PMCID: PMC8900538 PMID: 35236727
Inspiratory Muscle Training Enhances Recovery Post COVID-19: A Randomised Controlled Trial
Melitta A McNarry, 1 Ronan M G Berg,2 James Shelley,1 Joanne Hudson,1 Zoe L Saynor,3 Jamie Duckers,4 Keir Lewis,5,6 Gwyneth A Davies,6 and Kelly A Mackintosh1
Abstract: Background
Many people recovering from COVID-19 experience prolonged symptoms, particularly breathlessness. We urgently need to identify safe and effective COVID-19 rehabilitative strategies. The aim of the current study was to investigate the potential rehabilitative role of inspiratory muscle training (IMT).
Methods: 281 adults (46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” wait list control arm. Health-related quality of life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary endpoint was KBILD total score, with the KBILD subdomains and TDI being key secondary outcomes.Results: According to intention to treat (ITT), there was no difference between groups in KBILD total score post-intervention (Control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the KBILD subdomains of breathlessness (Control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (Control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (Control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness.Conclusions: IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long-COVID, further research is warranted on the individual responses to rehabilitation - the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.
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Respiration . 2022;101(6):593-601.doi: 10.1159/000522118. Epub 2022 Feb 24.
Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life
Stephan Nopp 1, Florian Moik 1, Frederikus A Klok 2, Dietlinde Gattinger 3, Milos Petrovic 3, Karin Vonbank 4, Andreas R Koczulla 5 6, Cihan Ay 1, Ralf Harun Zwick 3 7
nPMID: 35203084 PMCID: PMC9059007
Abstract
Background: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking.
Methods: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored.
Results: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation.
Conclusion: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.
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MEDICAL NEWS – UNIVADIS (MEDSCAPE)Long COVID substantially less common in children than adultsDawn O'Shea | 27 July 2022
Almost 6 per cent of children who presented to the emergency department (ED) with COVID-19 develop long COVID, according to a large international study published by JAMA Network Open.
The prospective cohort study was conducted in 36 EDs in eight countries between March 7, 2020, and January 20, 2021, and included 1884 children with COVID-19 who completed 90 days of follow-up. Of these, 1686 were matched by hospitalisation status, country, and recruitment date with 1701 SARS-CoV-2-negative controls.
Long COVID was defined as any persistent, new, or recurrent health problems over a 90-day period.
Among the participants, 5.8 per cent reported symptoms of long COVID. The rate increased to 9.8 per cent of hospitalised children and 4.6 per cent among discharged children. Characteristics associated with long COVID included being hospitalised for 48 hours or more, having four or more symptoms at the index ED visit, and being 14 years of age or older.
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“Reported rates of long COVID in adults are substantially higher than what we found in children,” said co-principal investigator Nathan Kuppermann, from the University of California. “Our findings can inform public health policy decisions regarding COVID-19 mitigation strategies for children and screening approaches for long COVID among those with severe infections.”
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