WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
Ping-yuan Wang, Jin Ma, Young-Chae Kim https://orcid.org/0000-0002-5130-4413, +10, and Paul M. Hwang
Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT; received February 17, 2023; accepted June 27, 2023
August 14, 2023 120 (34) e2302738120 https://doi.org/10.1073/pnas.2302738120
Vol. 120 | No. 34 Significance
Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance. Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
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The plasma metabolome of long COVID patients two years after infection
Yamilé López-Hernández, Joel Monárrez-Espino, David Alejandro, García López, Jiamin Zheng, Juan Carlos Borrego, Claudia Torres-Calzada, José Pedro Elizalde-Díaz, Rupasri Mandal, Mark Berjanskii, Eduardo Martínez-Martínez, Jesús Adrián López & David S. Wishart
Scientific Reports volume 13, Article number: 12420 (2023) Cite this article
Abstract
One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.
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MEDICAL NEWS (UNIVADIS)
New Treatment Option for Long-term InsomniaRob Hicks | 18 September 2023
The National Institute for Health and Care Excellence (NICE) has recommended daridorexant (QUVIVIQ, Idorsia) as a new treatment option for long-term insomnia but underscored the importance of keeping the duration of treatment as brief as possible.
Long-term insomnia — also known as chronic insomnia or insomnia disorder — is defined as dissatisfaction with quantity or quality of sleep for 3 nights or more per week for at least 3 months with an effect on daytime functioning. The condition — thought to affect around 7% of the UK adult population —has both night-time symptoms as well as a negative impact on physical health, daytime functioning, and overall wellbeing. Furthermore, suboptimal management of the condition is associated with decreased workplace productivity, and an increased risk of workplace accidents, falls, and costly workplace errors.
Lisa Artis, deputy CEO of The Sleep Charity UK, said: "While we all may experience short periods of sleeplessness, people living with chronic insomnia are persistently deprived of the restorative sleep they need, which can have a major impact on their overall health and wellbeing."
The standard first treatment for insomnia is sleep hygiene advice plus cognitive behavioural therapy for insomnia (CBTi). However, access to CBTi varies across England, and there are difficulties accessing CBTi, NICE alerted. "Even when CBTi was available, people with insomnia were often not aware of it," the regulator pointed out.
_______________________________________________________________________________Tackling Overactive WakefulnessA key component of the wake and sleep signalling process is the orexin system — made up of orexin A and orexin B neuropeptides, and receptors OX1R and OX2R — which helps promote wakefulness.
This system stimulates targeted neurons in the wake system leading to the release of several chemicals — serotonin, histamine, acetylcholine, norepinephrine — to promote wakefulness. Under normal circumstances, orexin levels rise throughout the day as wakefulness is promoted, and then fall at night.
Overactivity of the wake system is an important driver of insomnia. Daridorexant works by selectively blocking only the activation of orexin receptors, thereby decreasing the brain's "overactive wakefulness".
Daridorexant is taken orally once a night, around half an hour before bed. The list price per pack for the 50mg or the 25mg dose is £1.40 per day.
Evidence presented to an appraisal committee showed a reduction in insomnia with daridorexant compared with placebo over a 12-month period, and that the drug was effective in improving symptoms related to long-term insomnia, reducing the total number of minutes that a person was awake after initially falling asleep, and the time it took for the person to fall asleep after going to bed. After 12 months' treatment, daridorexant was not associated with physical signs of dependency, tolerance, or rebound insomnia after its discontinuation.
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Daridorexant Recommended as Second LineIn final draft guidance, NICE said that daridorexant would be offered as a second-line treatment option for long-term insomnia, but only if CBTi had been tried but had not worked, or if CBTi was not available or was unsuitable. It is estimated that just over 20,000 people in England could receive the treatment in the next year.
"There is some uncertainty about its longer-term benefit compared with placebo beyond 12 months, and [about] cost-effectiveness modelling assumptions," cautioned NICE. However, it emphasised that "even accounting for this uncertainty", the cost-effectiveness estimates for daridorexant compared with 'no treatment' was within the range it normally considered to be an acceptable use of NHS resources.
Dr David O'Regan, consultant in psychiatry and sleep medicine, said that the decision by the regulator represented a "significant breakthrough" for chronic insomnia patients. "While other treatment options for insomnia are available, these may not be suitable for long-term use, effective for all patients, or specifically licensed for the treatment of chronic insomnia," he explained.
The regulator stressed that the "length of treatment should be as short as possible", and that treatment with the drug should be assessed within 3 months of starting and should be stopped in people whose long-term insomnia had not responded adequately. If treatment was continued, assessment of whether it was still working should be made at regular intervals.
NICE said that as a new medicinal product containing a new active substance, daridorexant was subject to additional monitoring, and it was therefore important to report on the Yellow Card system any suspected adverse events.
Final NICE guidance is due to be published on 18 October, 2023.
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References Disclaimer
Daridorexant for treating long-term insomnia
National Institute for Health and Care Excellence
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Infectious Diseases October 6, 2023
Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19Sung Ha Lim, MD1; Hyun Jeong Ju, MD, PhD2; Ju Hee Han, MD3; et alJi Hae Lee, MD, PhD2; Won-Soo Lee, MD, PhD1; Jung Min Bae, MD, PhD2; Solam Lee, MD, PhD1,4
JAMA Netw Open. 2023;6(10):e2336120. doi:10.1001/jamanetworkopen.2023.36120
Key Points
Question Is COVID-19 associated with an increased risk of autoimmune and autoinflammatory disorders?
Findings This cohort study including 354 527 individuals with COVID-19 and 6 134 940 controls identified a significant elevation in the risk of multiple incident autoimmune and autoinflammatory disorders subsequent to COVID-19. Notably, certain disease risks exhibited a positive association with the severity of COVID-19.
Meaning These findings suggest that autoimmune and autoinflammatory connective tissue disorders may manifest as post–COVID-19 sequelae, highlighting the potential long-term health ramifications associated with COVID-19; long-term management should include evaluating the development of such disorders in patients who had COVID-19.
Abstract
Importance Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified.
Objective To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19.
Design, Setting, and Participants This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023.
Exposures Receipt of diagnosis of COVID-19.
Main Outcomes and Measures The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following
COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses.
Results A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody–associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19.
Conclusions and Relevance In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.
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Autoimmunity Reviews Volume 19, Issue 6, June 2020, 102527
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
Klaus Wirth a, Carmen Scheibenbogen b
https://doi.org/10.1016/j.autrev.2020.102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
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Distinguishing features of long COVID identified through immune profilingJon Klein, Jamie Wood, Jillian R. Jaycox, Rahul M. Dhodapkar, Peiwen Lu, Jeff R. Gehlhausen, Alexandra Tabachnikova, Kerrie Greene, Laura Tabacof, Valter Silva Monteiro, Julio Silva, Kathy Kamath, Minlu Zhang, Abhilash Dhal, Isabel M. Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki
Abstract
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2,3,4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
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Serotonin reduction in post-acute sequelae of viral infectionArticle in Cell Andrea C. Wong, Ashwarya S. Devason, Iboro C. Umana,Sara Cherry,Christoph A. Thaiss,Maayan Levy Published:October 16, 2023DOI:https://doi.org/10.1016/j.cell.2023.09.013
HighlightsLong COVID is associated with reduced circulating serotonin levels
Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
Peripheral serotonin deficiency impairs cognition via reduced vagal signaling
SummaryPost-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
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Long COVID Linked With Viral Persistence, Serotonin DeclineEmily Harris
JAMA. Published online November 1, 2023. doi:10.1001/jama.2023.21170
A study linking viral infection with reduced levels of serotonin, a neurotransmitter involved in learning, memory, and mood, has proposed a new potential mechanism underlying post–COVID-19 condition. Also known as long COVID, the condition involves symptoms such as fatigue, memory loss, and cognitive impairment.
Using results from human participants, mice, and organoid cultures, the researchers found that long COVID was tied with a decline in serotonin. A viral reservoir in the gut appeared to trigger inflammation that decreased intestinal absorption of tryptophan, serotonin’s precursor molecule.
Serotonin activity supports vagus nerve function, among other roles. In the study, serotonin loss was associated with lower nerve activity. Dysfunction in the vagus nerve was linked with characteristic long COVID symptoms such as memory loss and hippocampal dysfunction.
“Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving,” Sara Cherry, PhD, an author of the study published in Cell, said in a statement. “Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials.”
Published Online: November 1, 2023. doi:10.1001/jama.2023.21170
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Brain Behav Immun Health . 2023 Apr 27:30:100627. doi: 10.1016/j.bbih.2023.100627. 2023 Jul.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde 1, Alyssa C Indart 1, Peter H R Green 1 2, Robert H Yolken 3, Dane B Cook 4, Sanjay K Shukla 5, Suzanne D Vernon 6, Armin Alaedini 1 7 2 8
PMID: 37396339 PMCID: PMC10308215 DOI: 10.1016/j.bbih.2023.100627
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.
© 2023 Published by Elsevier Inc.
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Medscape Medical News
Nirmatrelvir-Ritonavir Ineffective at Reducing Most Post-COVID Condition Becky Ellis October 30, 2023
TOPLINE:
Nirmatrelvir-ritonavir doesn't reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
METHODOLOGYA retrospective study of 9593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post-COVID-19 conditions (PCCs).Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
The incidence of PCCs was analyzed 31 to 180 days after treatment.
TAKEAWAY:The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
No statistically significant reduction of other conditions was found.
Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.
IN PRACTICE:"Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions," the authors write.
SOURCE:The study was funded by the US Department of Veterans Affairs and was published online in Annals of Internal Medicine on October 30. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.
LIMITATIONS:A large number of outcomes were observed, so it's possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.
Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the International Classification of Diseases, 10th Revision, which was used for diagnosis codes.
Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
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Postacute sequelae of COVID-19 at 2 yearsBenjamin Bowe, Yan Xie & Ziyad Al-Aly
Nature Medicine volume 29, pages2347–2357 (2023)
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6–89.6) and 642.8 (95% CI: 596.9–689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9–31.0%) and 21.3% (18.2–24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.
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Characterising the evolving SARS-CoV-2 seroprevalence in urban and rural Malawi between February 2021 and April 2022: a population-based cohort studyLouis Banda, Antonia Ho,Stephen Kasenda ,Annie Chauma Mwale, AbenaS Amoah,Amelia Crampin * Published:October 27, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.020
HighlightsThis was a longitudinal SARS-CoV-2 serosurvey in an urban & rural cohort in Malawi
Post-Omicron SARS-CoV-2 seroprevalence was very high (rural: 89%; urban: 94%)
Most SARS-CoV-2 infections were subclinical; few required healthcare attendants
Seroconversion risk varied by location & age across the successive infection waves
Hybrid immunity was associated with higher seroprevalence and antibody titresAbstractObjectivesTo investigate the changing SARS-CoV-2 seroprevalence and associated health and sociodemographic factors in Malawi between February 2021 and April 2022.
Methods
Four three-monthly serosurveys were conducted within a longitudinal population-based cohort in rural Karonga District and urban Lilongwe, testing for SARS-CoV-2 S1 IgG antibodies using an enzyme-linked immunosorbent assay. Population seroprevalence was estimated in all and unvaccinated participants. Bayesian mixed effects logistic models estimated the odds of seropositivity in the first survey, and of seroconversion between surveys, adjusting for age, sex, occupation, location, and assay sensitivity/specificity.
Results
Of 2005 participants (Karonga,n=1005;Lilongwe,n=1000), 55.8% were female and median age was 22.7 years. Between Surveys 1-4, population-weighted SARS-CoV-2 seroprevalence increased from 26.3% to 89.2% and 46.4% to 93.9% in Karonga and Lilongwe, respectively. At Survey 4, seroprevalence did not differ by COVID-19 vaccination status in adults, except for those aged 30+ in Karonga (unvaccinated:87.4%,95% credible interval 79.3-93.0%; 2 doses:98.1%,94.8-99.5%). Location and age were associated with seroconversion risk. Individuals with hybrid immunity had higher SARS-CoV-2 seropositivity and antibody titres, than those infected.
Conclusions
High SARS-CoV-2 seroprevalence combined with low morbidity and mortality indicate that universal vaccination is unnecessary at this stage of the pandemic, supporting change in national policy to target at-risk groups.
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Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants
Jane Agergaard, Jesper Damsgaard Gunst, Berit Schiøttz-Christensen, Lars Østergaard, Christian Wejse Published:October 29, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.022
Highlights
Trajectory of long COVID in SARS-CoV-2 wild-type, Alpha, Delta, and Omicron
Similar patterns of symptoms and severity of long COVID across all four variants
No clinically significant decline in median severity up to 1.5 years after infection
More than 50% of long COVID patients failed to improve using any outcome measure
Patients infected with Omicron may experience severe non-improving long COVID
Abstract
Objectives
Knowledge is limited on how changing SARS-CoV-2 variants may translate into different characteristics and affect prognosis of patients with long COVID, especially following Omicron variants. We compared long-term prognosis of patients in a Danish Post COVID Clinic infected with wild-type strain, Alpha, Delta, or Omicron variants as well as the pre-Omicron compared to the Omicron period.
Methods
At enrollment a Post COVID symptom Questionnaire (PCQ), and standard health scores, were registered, and repeated four times until 1.5 years after infection. PCQ was the primary outcome to assess severity of long COVID, and delta PCQ to assess failure to improve.
Results
A total of 806 patients were enrolled. Patients infected with Omicron and Delta variants presented with more severe long COVID (median PCQ 43 in Delta vs 38 in wild-type, P=0.003) and health scores (EQ5D-index was 0.70 in Omicron vs 0.76 in wild-type, P=0.009 and 0.78 pre-Omicron, P=0.006). At 1.5 year after infection patients had no clinically meaningful decline in severity of long COVID, and 57% (245/429) of patients failed to improve 1.5 years after infection, with no differences between variants.
Conclusions
More than half of patients referred to a Post COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants of SARS-CoV-2.
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Medscape Medical News
Inside a Long COVID Clinic's Fight to Meet Crushing Patient NeedsSolarina Ho November 17, 2023
Janna Friedly was thrilled, hopeful — and relieved — by the email that had landed in her inbox: After years of fighting an uphill battle to treat patients with long COVID, her Seattle clinic, one of the first and longest-running facilities in the US, was finally getting a much-needed financial boost from the US Department of Health and Human Services.
The multimillion-dollar grant, which came through in September, was going to help Friedly and her colleagues at the University of Washington's Post-COVID Rehabilitation and Recovery Care at Harborview Medical Center meet some of the crushing demands of long COVID care.
"This entire year has been really filled with patients that have been trying to get access to the clinic for a year. And they're still struggling," said Friedly, MD, MPH, chair of the Department of Rehabilitation Medicine at the University of Washington School of Medicine and executive director at Harborview.
The tremendous demand and backlog had prompted the clinic in January 2023 to severely limit referrals to King County and the university. It was a hard decision that meant the rest of Washington, Wyoming, Alaska, Montana and Idaho — the five-state "WWAMI" region the clinic served — lost access to critical post-COVID healthcare.
At Harborview, there is now hope. The grant money will allow Friedly and her colleagues to make meaningful headway on their ambitious goals. But they are also realistic about the formidable task ahead.
Their circumstances are hardly unique. Clinics across the country are facing daunting challenges — amid dire patient needs, insufficient funding from state and federal health agencies has led to significant hurdles in patient care, especially for vulnerable and underserved communities, according to interviews and surveys with more than a dozen long COVID clinics, doctors, advocates, and patients. At the same time, a lack of training and education on long COVID within the broader medical community is hurting patients.
The grant announcement of a million dollars a year for up to 5 years per clinic — awarded to nine established multidisciplinary centers across the US through the Agency for Healthcare Research and Quality (AHRQ) of HHS — provides considerable relief.
But how far can $5 million stretch, given that long COVID is so complex, the needs of patients are so great, and the resources clinics have to manage them are so limited?
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SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study View ORCID ProfileEmily Hadley, View ORCID ProfileYun Jae Yoo, View ORCID ProfileSaaya Patel, View ORCID ProfileAndrea Zhou, View ORCID ProfileBryan Laraway, View ORCID ProfileRachel Wong, View ORCID ProfileAlexander Preiss, View ORCID ProfileRob Chew, Hannah Davis, View ORCID ProfileChristopher G Chute, View ORCID ProfileEmily R Pfaff, View ORCID ProfileJohanna Loomba, View ORCID ProfileMelissa Haendel, View ORCID ProfileElaine Hill, View ORCID ProfileRichard Moffitt, the N3C and RECOVER consortia the N3C and RECOVER consortia
doi: https://doi.org/10.1101/2023.01.03.22284042
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. 00001401819.
AbstractAlthough the COVID-19 pandemic has persisted for over 2 years, reinfections with SARS-CoV-2 are not well understood. We use the electronic health record (EHR)-based study cohort from the National COVID Cohort Collaborative (N3C) as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative to characterize reinfection, understand development of Long COVID after reinfection, and compare severity of reinfection with initial infection. We validate previous findings of reinfection incidence (5.9%), the occurrence of most reinfections during the Omicron epoch, and evidence of multiple reinfections. We present novel findings that Long COVID diagnoses occur closer to the index date for infection or reinfection in the Omicron BA epoch. We report lower albumin levels leading up to reinfection and a statistically significant association of severity between first infection and reinfection (chi-squared value: 9446.2, p-value: 0) with a medium effect size (Cramer’s V: 0.18, DoF = 4).
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Complement dysregulation is a predictive and therapeutically amenable feature of long COVID
Kirsten Baillie, Helen E Davies, Samuel B K Keat, Kristin Ladell, Kelly L Miners, Samantha A Jones, Ermioni Mellou, View ORCID ProfileErik J M Toonen, View ORCID ProfileDavid A Price, B Paul Morgan, Wioleta M Zelek
doi: https://doi.org/10.1101/2023.10.26.23297597
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. 003040347
ABSTRACTBackground Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.
Methods We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.
Findings Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.
Conclusions These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.
Funding This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.
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Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2
Topic ImportancePostacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.
Review FindingsEarly studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.
SummaryThis review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.
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Front. Neurosci., 26 June 2023 Sec. Autonomic Neuroscience
Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1203514
Fatigue: Physiology and Pathology
Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes
Heather Day1 Brayden Yellman2 Sarah Hammer2 Candace Rond2 Jennifer Bell2 Saeed Abbaszadeh2 Greg Stoddard1 Derya Unutmaz3 Lucinda Bateman2 Suzanne D. Vernon2*
Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.
Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.
Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.
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CONCISE REVIEW FOR CLINICIANS| VOLUME 98, ISSUE 10, P1544-1551, OCTOBER 2023
Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Stephanie L. Grach, MD, MS Jaime Seltzer, MS Tony Y. Chon, MD Ravindra Ganesh, MD, MBBS https://doi.org/10.1016/j.mayocp.2023.07.032
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic neurologic disease often preceded by infection. There has been increased interest in ME/CFS recently because of its significant overlap with the post-COVID syndrome (long COVID or post-acute sequelae of COVID), with several studies estimating that half of patients with post-COVID syndrome fulfill ME/CFS criteria. Our concise review describes a generalist approach to ME/CFS, including diagnosis, evaluation, and management strategies.
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Post-acute sequelae of SARS-CoV-2 (PASC) in nursing home residents: A retrospective cohort studySophie E. Clark MD, Liza Bautista MD, Karen Neeb MSN, CNP, Ana Montoya MD, MPH, Kristen E. Gibson MPH, Julia Mantey MPH, MUP, Mohammed Kabeto MS
First published: 10 November 2023 https://doi.org/10.1111/jgs.18678
Presentation: poster presentation at American Geriatric Society, Long Beach CA, May 2023.
AbstractBackgroundPost-acute sequelae of SARS-CoV-2 (PASC) describes a syndrome of physical and cognitive decline that persists after acute symptoms of infection resolve. Few studies have explored PASC among nursing home (NH) residents.
MethodsA retrospective cohort study was conducted at two NHs in Michigan. COVID-positive patients were identified from March 21, 2020 to October 26, 2021. The comparison group were patients who lived at the same NH but who were never infected during the study period. Minimum Data Set was used to examine trajectories of functional dependence (Activity of Daily Living [ADL] composite score) and cognitive function (Brief Interview for Mental Status [BIMS]). Linear mixed-effects models were constructed to estimate short-term change in function and cognition immediately following diagnosis and over time for an additional 12 months, compared to pre-COVID and non-COVID trajectories and adjusting for sex, age, and dementia status.
ResultsWe identified 171 residents (90 COVID-19 positive, 81 non-COVID) with 719 observations for our analyses. Cohort characteristics included: 108 (63%) ≥ 80 yrs.; 121 (71%) female; 160 (94%) non-Hispanic white; median of 3 comorbidities (IQR 2–4), with no significant differences in characteristics between groups. COVID-19 infection affected the trajectory of ADL recovery for the first 9 months following infection, characterized by an immediate post-infection decrease in functional status post-infection (−0.60 points, p = 0.002) followed by improvement toward the expected functional trajectory sans infection (0.04 points per month following infection, p = 0.271).ConclusionsNH residents experienced a significant functional decline that persisted for 9 months following acute infection. Further research is needed to determine whether increased rehabilitation services after COVID-19 may help mitigate this decline.
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Naltrexone 6 mg once daily versus placebo in woNaltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial: a randomised, double-blind, placebo-controlled trialKarin Due Bruun, MD ,Prof Robin Christensen, PhD,Prof Henrik Bjarke Vaegter, PhD,Morten Rune Blichfeldt-Eckhardt, PhD Lars Bye-Møllert al.
https://doi.org/10.1016/S2665-9913(23)00278-3
SummaryBackgroundLow-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia.
MethodsWe did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18–64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30).
FindingsWe screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was –1·3 points (95% CI –1·7 to –0·8) in the low-dose naltrexone group and –0·9 (–1·4 to –0·5) in the placebo group, corresponding to a between-group difference of –0·34 (–0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred.
InterpretationThis study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021–2022
NCHS Data Brief No. 488, December 2023
Anjel Vahratian, Ph.D., M.P.H., Jin-Mann S. Lin, Ph.D., Jeanne Bertolli, Ph.D., M.P.H., and Elizabeth R. Unger, Ph.D., M.D.
Key findings
Data from the National Health Interview Survey
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after activity, and other symptoms (1). It affects all age, sex, and racial and ethnic groups and costs the U.S. economy about $18–$51 billion annually (2–5). This report describes the percentage of adults who had ME/CFS at the time of interview by selected demographic and geographic characteristics based on data from the 2021–2022 National Health Interview Survey (NHIS).
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December 28, 2023 Post–COVID-19 Condition in Children 6 and 12 Months After Infection
Frederick Dun-Dery, PhD, MPhil1; Jianling Xie, MD, MPH2; Kathleen Winston, MSc3; et alBrett Burstein, MDCM, PhD, MPH4,5; Jocelyn Gravel, MD, MSc6; Jason Emsley, MSc, MD, PhD7; Vikram Sabhaney, MD8; Roger Zemek, MD9,10; Simon Berthelot, MD, MSc11; Darcy Beer, MD12; April Kam, MD, MScPH13; Gabrielle Freire, MDCM, MHSc14; Ahmed Mater, MD15; Robert Porter, MD, MSc16; Naveen Poonai, MD, MSc17,18,19; Anne Moffatt, MD20; Andrew Dixon, MD21; Marina I. Salvadori, MD22,23; Stephen B. Freedman, MDCM, MSc24; for the Pediatric Emergency Research Canada (PERC) COVID Study Group
JAMA Netw Open. 2023;6(12):e2349613. doi:10.1001/jamanetworkopen.2023.49613
Key Points
Question What proportion of children meet the post–COVID-19 condition (PCC) symptom definition at 6 and 12 months following SARS-CoV-2 testing in pediatric emergency departments?
Findings In this cohort study, at 6 and 12 months, a statistically greater number of children with SARS-CoV-2 positive tests compared with those with negative tests met the PCC symptom and quality of life change definition. However, the absolute risk differences were very small (0.42% and 0.51% at 6 and 12 months, respectively).
Meaning Although there is an increased prevalence of symptoms consistent with the PCC definition that reduce quality of life among SARS-CoV-2 infected children, very few infected children develop PCC.
Abstract
Importance There is a need to understand the long-term outcomes among children infected with SARS-CoV-2.
Objective To quantify the prevalence of post–COVID-19 condition (PCC) among children tested for SARS-CoV-2 infection in pediatric emergency departments (EDs).
Design, Setting, and Participants Multicenter, prospective cohort study at 14 Canadian tertiary pediatric EDs that are members of the Pediatric Emergency Research Canada network with 90-day, 6-month, and 12-month follow-up. Participants were children younger than 18 years who were tested for SARS-CoV-2 infection between August 2020 and February 2022. Data were analyzed from May to November 2023.
Exposure The presence of SARS-CoV-2 infection at or within 14 days of the index ED visit.
Main Outcomes and Measures Presence of symptoms and QoL reductions that meet the PCC definition. This includes any symptom with onset within 3 months of infection that is ongoing at the time of follow-up and affects everyday functioning. The outcome was quantified at 6 and 12 months following the index ED visit.
Results Among the 5147 children at 6 months (1152 with SARS-CoV-2 positive tests and 3995 with negative tests) and 5563 children at 12 months (1192 with SARS-CoV-2 positive tests and 4371 with negative tests) who had sufficient data regarding the primary outcome to enable PCC classification, the median (IQR) age
was 2.0 (0.9-5.0) years, and 2956 of 5563 (53.1%) were male. At 6-month follow-up, symptoms and QoL changes consistent with the PCC definition were present in 6 of 1152 children with positive SARS-CoV-2 tests (0.52%) and 4 of 3995 children with negative SARS-CoV-2 tests (0.10%; absolute risk difference, 0.42%; 95% CI, 0.02% to 0.94%). The PCC definition was met at 12 months by 8 of 1192 children with positive SARS-CoV-2 tests (0.67%) and 7 of 4371 children with negative SARS-CoV-2 tests (0.16%; absolute risk difference, 0.51%; 95% CI, 0.06 to 1.08%). At 12 months, the median (IQR) PedsQL Generic Core Scale scores were 98.4 (90.0-100) among children with positive SARS-CoV-2 tests and 98.8 (91.7-100) among children with negative SARS-CoV-2 tests (difference, −0.3; 95% CI, −1.5 to 0.8; P = .56). Among the 8 children with SARS-CoV-2 positive tests and PCC at 12-month follow-up, children reported respiratory (7 of 8 patients [88%]), systemic (3 of 8 patients [38%]), and neurologic (1 of 8 patients [13%]) symptoms.
Conclusions and Relevance In this cohort study of children tested for SARS-CoV-2 infection in Canadian pediatric EDs, although children infected with SARS-CoV-2 reported increased chronic symptoms, few of these children developed PCC, and overall QoL did not differ from children with negative SARS-CoV-2 tests.
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Long COVID: New Info on Who Is Most Likely to Get ItSolarina Ho December 27, 2023 Medscape Medical news.
The COVID-10 pandemic may no longer be a global public health emergency, but millions continue to struggle with the aftermath: Long COVID. New research and clinical anecdotes suggest that certain individuals are more likely to be afflicted by the condition, nearly 4 years after the virus emerged.
People with a history of allergies, anxiety or depression, arthritis, and autoimmune diseases and women are among those who appear more vulnerable to developing long COVID, said doctors who specialize in treating the condition.
Many patients with long COVID struggle with debilitating fatigue, brain fog, and cognitive impairment. The condition is also characterized by a catalog of other symptoms that may be difficult to recognize as long COVID, experts said. That's especially true when patients may not mention seemingly unrelated information, such as underlying health conditions that might make them more vulnerable. This makes screening for certain conditions and investigating every symptom especially important.
The severity of a patient's initial infection is not the only determining factor for developing long COVID, experts said.
"Don't judge the person based on how sick they were initially," said Mark Bayley, MD, medical director of the Toronto Rehabilitation Institute at University Health Network and a professor with the Temerty Faculty of Medicine at the University of Toronto. "You have to evaluate every symptom as best you can to make sure you're not missing anything else."
Someone who only had a bad cough or felt really unwell for just a few days and recovered but started feeling rotten again later — "that's the person that we are seeing for long COVID," said Bayley.
While patients who become severely sick and require hospitalization have a higher risk of developing long COVID, this group size is small compared with the much larger number of people infected overall. As a result, despite the lower risk, those who only become mild to moderately sick make up the vast majority of patients in long COVID clinics.
A small Northwestern Medicine study found that 41% of patients with long COVID never tested positive for COVID-19 but were found to have antibodies that indicated exposure to the virus.
Doctors treating patients with long COVID should consider several risk factors, specialists said. They include:
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Long COVID in Nursing Home Residents Manifests as Functional DeclineEmily Harris
JAMA. 2024;331(1):15. doi:10.1001/jama.2023.24682
People living in nursing homes tended to need more help with activities of daily living, such as bathing and dressing, for months following infection with SARS-CoV-2 compared with their peers who were not infected, a retrospective cohort study found. Nursing home residents also experienced modest declines in cognition after COVID-19 infection.
The findings were based on data from 171 residents, most of whom were aged 80 years or older. About 94% of participants were White individuals. In addition, all participants had multiple comorbidities, with more than half living with dementia.
The nursing home residents who had COVID-19 experienced improvements in both their functional status and cognition within 1 year after their illness. Moreover, most residents were unvaccinated at the time of their diagnoses, which occurred between March 2020 and October 2021. The results might therefore reflect the highest rates of long COVID early in the pandemic before widespread vaccination, the researchers wrote in the Journal of the American Geriatrics Society.
Published Online: December 13, 2023. doi:10.1001/jama.2023.24682
Ping-yuan Wang, Jin Ma, Young-Chae Kim https://orcid.org/0000-0002-5130-4413, +10, and Paul M. Hwang
Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT; received February 17, 2023; accepted June 27, 2023
August 14, 2023 120 (34) e2302738120 https://doi.org/10.1073/pnas.2302738120
Vol. 120 | No. 34 Significance
Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance. Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
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The plasma metabolome of long COVID patients two years after infection
Yamilé López-Hernández, Joel Monárrez-Espino, David Alejandro, García López, Jiamin Zheng, Juan Carlos Borrego, Claudia Torres-Calzada, José Pedro Elizalde-Díaz, Rupasri Mandal, Mark Berjanskii, Eduardo Martínez-Martínez, Jesús Adrián López & David S. Wishart
Scientific Reports volume 13, Article number: 12420 (2023) Cite this article
Abstract
One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.
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MEDICAL NEWS (UNIVADIS)
New Treatment Option for Long-term InsomniaRob Hicks | 18 September 2023
The National Institute for Health and Care Excellence (NICE) has recommended daridorexant (QUVIVIQ, Idorsia) as a new treatment option for long-term insomnia but underscored the importance of keeping the duration of treatment as brief as possible.
Long-term insomnia — also known as chronic insomnia or insomnia disorder — is defined as dissatisfaction with quantity or quality of sleep for 3 nights or more per week for at least 3 months with an effect on daytime functioning. The condition — thought to affect around 7% of the UK adult population —has both night-time symptoms as well as a negative impact on physical health, daytime functioning, and overall wellbeing. Furthermore, suboptimal management of the condition is associated with decreased workplace productivity, and an increased risk of workplace accidents, falls, and costly workplace errors.
Lisa Artis, deputy CEO of The Sleep Charity UK, said: "While we all may experience short periods of sleeplessness, people living with chronic insomnia are persistently deprived of the restorative sleep they need, which can have a major impact on their overall health and wellbeing."
The standard first treatment for insomnia is sleep hygiene advice plus cognitive behavioural therapy for insomnia (CBTi). However, access to CBTi varies across England, and there are difficulties accessing CBTi, NICE alerted. "Even when CBTi was available, people with insomnia were often not aware of it," the regulator pointed out.
_______________________________________________________________________________Tackling Overactive WakefulnessA key component of the wake and sleep signalling process is the orexin system — made up of orexin A and orexin B neuropeptides, and receptors OX1R and OX2R — which helps promote wakefulness.
This system stimulates targeted neurons in the wake system leading to the release of several chemicals — serotonin, histamine, acetylcholine, norepinephrine — to promote wakefulness. Under normal circumstances, orexin levels rise throughout the day as wakefulness is promoted, and then fall at night.
Overactivity of the wake system is an important driver of insomnia. Daridorexant works by selectively blocking only the activation of orexin receptors, thereby decreasing the brain's "overactive wakefulness".
Daridorexant is taken orally once a night, around half an hour before bed. The list price per pack for the 50mg or the 25mg dose is £1.40 per day.
Evidence presented to an appraisal committee showed a reduction in insomnia with daridorexant compared with placebo over a 12-month period, and that the drug was effective in improving symptoms related to long-term insomnia, reducing the total number of minutes that a person was awake after initially falling asleep, and the time it took for the person to fall asleep after going to bed. After 12 months' treatment, daridorexant was not associated with physical signs of dependency, tolerance, or rebound insomnia after its discontinuation.
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Daridorexant Recommended as Second LineIn final draft guidance, NICE said that daridorexant would be offered as a second-line treatment option for long-term insomnia, but only if CBTi had been tried but had not worked, or if CBTi was not available or was unsuitable. It is estimated that just over 20,000 people in England could receive the treatment in the next year.
"There is some uncertainty about its longer-term benefit compared with placebo beyond 12 months, and [about] cost-effectiveness modelling assumptions," cautioned NICE. However, it emphasised that "even accounting for this uncertainty", the cost-effectiveness estimates for daridorexant compared with 'no treatment' was within the range it normally considered to be an acceptable use of NHS resources.
Dr David O'Regan, consultant in psychiatry and sleep medicine, said that the decision by the regulator represented a "significant breakthrough" for chronic insomnia patients. "While other treatment options for insomnia are available, these may not be suitable for long-term use, effective for all patients, or specifically licensed for the treatment of chronic insomnia," he explained.
The regulator stressed that the "length of treatment should be as short as possible", and that treatment with the drug should be assessed within 3 months of starting and should be stopped in people whose long-term insomnia had not responded adequately. If treatment was continued, assessment of whether it was still working should be made at regular intervals.
NICE said that as a new medicinal product containing a new active substance, daridorexant was subject to additional monitoring, and it was therefore important to report on the Yellow Card system any suspected adverse events.
Final NICE guidance is due to be published on 18 October, 2023.
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References Disclaimer
Daridorexant for treating long-term insomnia
National Institute for Health and Care Excellence
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Infectious Diseases October 6, 2023
Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19Sung Ha Lim, MD1; Hyun Jeong Ju, MD, PhD2; Ju Hee Han, MD3; et alJi Hae Lee, MD, PhD2; Won-Soo Lee, MD, PhD1; Jung Min Bae, MD, PhD2; Solam Lee, MD, PhD1,4
JAMA Netw Open. 2023;6(10):e2336120. doi:10.1001/jamanetworkopen.2023.36120
Key Points
Question Is COVID-19 associated with an increased risk of autoimmune and autoinflammatory disorders?
Findings This cohort study including 354 527 individuals with COVID-19 and 6 134 940 controls identified a significant elevation in the risk of multiple incident autoimmune and autoinflammatory disorders subsequent to COVID-19. Notably, certain disease risks exhibited a positive association with the severity of COVID-19.
Meaning These findings suggest that autoimmune and autoinflammatory connective tissue disorders may manifest as post–COVID-19 sequelae, highlighting the potential long-term health ramifications associated with COVID-19; long-term management should include evaluating the development of such disorders in patients who had COVID-19.
Abstract
Importance Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified.
Objective To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19.
Design, Setting, and Participants This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023.
Exposures Receipt of diagnosis of COVID-19.
Main Outcomes and Measures The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following
COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses.
Results A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody–associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19.
Conclusions and Relevance In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.
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Autoimmunity Reviews Volume 19, Issue 6, June 2020, 102527
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
Klaus Wirth a, Carmen Scheibenbogen b
https://doi.org/10.1016/j.autrev.2020.102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
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Distinguishing features of long COVID identified through immune profilingJon Klein, Jamie Wood, Jillian R. Jaycox, Rahul M. Dhodapkar, Peiwen Lu, Jeff R. Gehlhausen, Alexandra Tabachnikova, Kerrie Greene, Laura Tabacof, Valter Silva Monteiro, Julio Silva, Kathy Kamath, Minlu Zhang, Abhilash Dhal, Isabel M. Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki
Abstract
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2,3,4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
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Serotonin reduction in post-acute sequelae of viral infectionArticle in Cell Andrea C. Wong, Ashwarya S. Devason, Iboro C. Umana,Sara Cherry,Christoph A. Thaiss,Maayan Levy Published:October 16, 2023DOI:https://doi.org/10.1016/j.cell.2023.09.013
HighlightsLong COVID is associated with reduced circulating serotonin levels
Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
Peripheral serotonin deficiency impairs cognition via reduced vagal signaling
SummaryPost-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
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Long COVID Linked With Viral Persistence, Serotonin DeclineEmily Harris
JAMA. Published online November 1, 2023. doi:10.1001/jama.2023.21170
A study linking viral infection with reduced levels of serotonin, a neurotransmitter involved in learning, memory, and mood, has proposed a new potential mechanism underlying post–COVID-19 condition. Also known as long COVID, the condition involves symptoms such as fatigue, memory loss, and cognitive impairment.
Using results from human participants, mice, and organoid cultures, the researchers found that long COVID was tied with a decline in serotonin. A viral reservoir in the gut appeared to trigger inflammation that decreased intestinal absorption of tryptophan, serotonin’s precursor molecule.
Serotonin activity supports vagus nerve function, among other roles. In the study, serotonin loss was associated with lower nerve activity. Dysfunction in the vagus nerve was linked with characteristic long COVID symptoms such as memory loss and hippocampal dysfunction.
“Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving,” Sara Cherry, PhD, an author of the study published in Cell, said in a statement. “Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials.”
Published Online: November 1, 2023. doi:10.1001/jama.2023.21170
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Brain Behav Immun Health . 2023 Apr 27:30:100627. doi: 10.1016/j.bbih.2023.100627. 2023 Jul.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde 1, Alyssa C Indart 1, Peter H R Green 1 2, Robert H Yolken 3, Dane B Cook 4, Sanjay K Shukla 5, Suzanne D Vernon 6, Armin Alaedini 1 7 2 8
PMID: 37396339 PMCID: PMC10308215 DOI: 10.1016/j.bbih.2023.100627
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.
© 2023 Published by Elsevier Inc.
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Medscape Medical News
Nirmatrelvir-Ritonavir Ineffective at Reducing Most Post-COVID Condition Becky Ellis October 30, 2023
TOPLINE:
Nirmatrelvir-ritonavir doesn't reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
METHODOLOGYA retrospective study of 9593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post-COVID-19 conditions (PCCs).Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
The incidence of PCCs was analyzed 31 to 180 days after treatment.
TAKEAWAY:The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
No statistically significant reduction of other conditions was found.
Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.
IN PRACTICE:"Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions," the authors write.
SOURCE:The study was funded by the US Department of Veterans Affairs and was published online in Annals of Internal Medicine on October 30. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.
LIMITATIONS:A large number of outcomes were observed, so it's possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.
Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the International Classification of Diseases, 10th Revision, which was used for diagnosis codes.
Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
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Postacute sequelae of COVID-19 at 2 yearsBenjamin Bowe, Yan Xie & Ziyad Al-Aly
Nature Medicine volume 29, pages2347–2357 (2023)
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6–89.6) and 642.8 (95% CI: 596.9–689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9–31.0%) and 21.3% (18.2–24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.
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Characterising the evolving SARS-CoV-2 seroprevalence in urban and rural Malawi between February 2021 and April 2022: a population-based cohort studyLouis Banda, Antonia Ho,Stephen Kasenda ,Annie Chauma Mwale, AbenaS Amoah,Amelia Crampin * Published:October 27, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.020
HighlightsThis was a longitudinal SARS-CoV-2 serosurvey in an urban & rural cohort in Malawi
Post-Omicron SARS-CoV-2 seroprevalence was very high (rural: 89%; urban: 94%)
Most SARS-CoV-2 infections were subclinical; few required healthcare attendants
Seroconversion risk varied by location & age across the successive infection waves
Hybrid immunity was associated with higher seroprevalence and antibody titresAbstractObjectivesTo investigate the changing SARS-CoV-2 seroprevalence and associated health and sociodemographic factors in Malawi between February 2021 and April 2022.
Methods
Four three-monthly serosurveys were conducted within a longitudinal population-based cohort in rural Karonga District and urban Lilongwe, testing for SARS-CoV-2 S1 IgG antibodies using an enzyme-linked immunosorbent assay. Population seroprevalence was estimated in all and unvaccinated participants. Bayesian mixed effects logistic models estimated the odds of seropositivity in the first survey, and of seroconversion between surveys, adjusting for age, sex, occupation, location, and assay sensitivity/specificity.
Results
Of 2005 participants (Karonga,n=1005;Lilongwe,n=1000), 55.8% were female and median age was 22.7 years. Between Surveys 1-4, population-weighted SARS-CoV-2 seroprevalence increased from 26.3% to 89.2% and 46.4% to 93.9% in Karonga and Lilongwe, respectively. At Survey 4, seroprevalence did not differ by COVID-19 vaccination status in adults, except for those aged 30+ in Karonga (unvaccinated:87.4%,95% credible interval 79.3-93.0%; 2 doses:98.1%,94.8-99.5%). Location and age were associated with seroconversion risk. Individuals with hybrid immunity had higher SARS-CoV-2 seropositivity and antibody titres, than those infected.
Conclusions
High SARS-CoV-2 seroprevalence combined with low morbidity and mortality indicate that universal vaccination is unnecessary at this stage of the pandemic, supporting change in national policy to target at-risk groups.
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Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants
Jane Agergaard, Jesper Damsgaard Gunst, Berit Schiøttz-Christensen, Lars Østergaard, Christian Wejse Published:October 29, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.022
Highlights
Trajectory of long COVID in SARS-CoV-2 wild-type, Alpha, Delta, and Omicron
Similar patterns of symptoms and severity of long COVID across all four variants
No clinically significant decline in median severity up to 1.5 years after infection
More than 50% of long COVID patients failed to improve using any outcome measure
Patients infected with Omicron may experience severe non-improving long COVID
Abstract
Objectives
Knowledge is limited on how changing SARS-CoV-2 variants may translate into different characteristics and affect prognosis of patients with long COVID, especially following Omicron variants. We compared long-term prognosis of patients in a Danish Post COVID Clinic infected with wild-type strain, Alpha, Delta, or Omicron variants as well as the pre-Omicron compared to the Omicron period.
Methods
At enrollment a Post COVID symptom Questionnaire (PCQ), and standard health scores, were registered, and repeated four times until 1.5 years after infection. PCQ was the primary outcome to assess severity of long COVID, and delta PCQ to assess failure to improve.
Results
A total of 806 patients were enrolled. Patients infected with Omicron and Delta variants presented with more severe long COVID (median PCQ 43 in Delta vs 38 in wild-type, P=0.003) and health scores (EQ5D-index was 0.70 in Omicron vs 0.76 in wild-type, P=0.009 and 0.78 pre-Omicron, P=0.006). At 1.5 year after infection patients had no clinically meaningful decline in severity of long COVID, and 57% (245/429) of patients failed to improve 1.5 years after infection, with no differences between variants.
Conclusions
More than half of patients referred to a Post COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants of SARS-CoV-2.
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Medscape Medical News
Inside a Long COVID Clinic's Fight to Meet Crushing Patient NeedsSolarina Ho November 17, 2023
Janna Friedly was thrilled, hopeful — and relieved — by the email that had landed in her inbox: After years of fighting an uphill battle to treat patients with long COVID, her Seattle clinic, one of the first and longest-running facilities in the US, was finally getting a much-needed financial boost from the US Department of Health and Human Services.
The multimillion-dollar grant, which came through in September, was going to help Friedly and her colleagues at the University of Washington's Post-COVID Rehabilitation and Recovery Care at Harborview Medical Center meet some of the crushing demands of long COVID care.
"This entire year has been really filled with patients that have been trying to get access to the clinic for a year. And they're still struggling," said Friedly, MD, MPH, chair of the Department of Rehabilitation Medicine at the University of Washington School of Medicine and executive director at Harborview.
The tremendous demand and backlog had prompted the clinic in January 2023 to severely limit referrals to King County and the university. It was a hard decision that meant the rest of Washington, Wyoming, Alaska, Montana and Idaho — the five-state "WWAMI" region the clinic served — lost access to critical post-COVID healthcare.
At Harborview, there is now hope. The grant money will allow Friedly and her colleagues to make meaningful headway on their ambitious goals. But they are also realistic about the formidable task ahead.
Their circumstances are hardly unique. Clinics across the country are facing daunting challenges — amid dire patient needs, insufficient funding from state and federal health agencies has led to significant hurdles in patient care, especially for vulnerable and underserved communities, according to interviews and surveys with more than a dozen long COVID clinics, doctors, advocates, and patients. At the same time, a lack of training and education on long COVID within the broader medical community is hurting patients.
The grant announcement of a million dollars a year for up to 5 years per clinic — awarded to nine established multidisciplinary centers across the US through the Agency for Healthcare Research and Quality (AHRQ) of HHS — provides considerable relief.
But how far can $5 million stretch, given that long COVID is so complex, the needs of patients are so great, and the resources clinics have to manage them are so limited?
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SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study View ORCID ProfileEmily Hadley, View ORCID ProfileYun Jae Yoo, View ORCID ProfileSaaya Patel, View ORCID ProfileAndrea Zhou, View ORCID ProfileBryan Laraway, View ORCID ProfileRachel Wong, View ORCID ProfileAlexander Preiss, View ORCID ProfileRob Chew, Hannah Davis, View ORCID ProfileChristopher G Chute, View ORCID ProfileEmily R Pfaff, View ORCID ProfileJohanna Loomba, View ORCID ProfileMelissa Haendel, View ORCID ProfileElaine Hill, View ORCID ProfileRichard Moffitt, the N3C and RECOVER consortia the N3C and RECOVER consortia
doi: https://doi.org/10.1101/2023.01.03.22284042
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. 00001401819.
AbstractAlthough the COVID-19 pandemic has persisted for over 2 years, reinfections with SARS-CoV-2 are not well understood. We use the electronic health record (EHR)-based study cohort from the National COVID Cohort Collaborative (N3C) as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative to characterize reinfection, understand development of Long COVID after reinfection, and compare severity of reinfection with initial infection. We validate previous findings of reinfection incidence (5.9%), the occurrence of most reinfections during the Omicron epoch, and evidence of multiple reinfections. We present novel findings that Long COVID diagnoses occur closer to the index date for infection or reinfection in the Omicron BA epoch. We report lower albumin levels leading up to reinfection and a statistically significant association of severity between first infection and reinfection (chi-squared value: 9446.2, p-value: 0) with a medium effect size (Cramer’s V: 0.18, DoF = 4).
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Complement dysregulation is a predictive and therapeutically amenable feature of long COVID
Kirsten Baillie, Helen E Davies, Samuel B K Keat, Kristin Ladell, Kelly L Miners, Samantha A Jones, Ermioni Mellou, View ORCID ProfileErik J M Toonen, View ORCID ProfileDavid A Price, B Paul Morgan, Wioleta M Zelek
doi: https://doi.org/10.1101/2023.10.26.23297597
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice. 003040347
ABSTRACTBackground Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.
Methods We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.
Findings Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.
Conclusions These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.
Funding This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.
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Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2
- Phillip Joseph, MD, Inderjit Singh, MD,Rudolf Oliveira, MD, PhD,
- Kristine Madsen, MS,Aaron B. Waxman, MD, PhD,David M. Systrom, MD
Topic ImportancePostacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.
Review FindingsEarly studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.
SummaryThis review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.
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Front. Neurosci., 26 June 2023 Sec. Autonomic Neuroscience
Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1203514
Fatigue: Physiology and Pathology
Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes
Heather Day1 Brayden Yellman2 Sarah Hammer2 Candace Rond2 Jennifer Bell2 Saeed Abbaszadeh2 Greg Stoddard1 Derya Unutmaz3 Lucinda Bateman2 Suzanne D. Vernon2*
- 1School of Medicine, The University of Utah, Salt Lake City, UT, United States
- 2Bateman Horne Center, Salt Lake City, UT, United States
- 3Jackson Laboratory for Genomic Medicine, School of Medicine, University of Connecticut, Farmington, CT, United States
Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.
Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.
Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.
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CONCISE REVIEW FOR CLINICIANS| VOLUME 98, ISSUE 10, P1544-1551, OCTOBER 2023
Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Stephanie L. Grach, MD, MS Jaime Seltzer, MS Tony Y. Chon, MD Ravindra Ganesh, MD, MBBS https://doi.org/10.1016/j.mayocp.2023.07.032
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic neurologic disease often preceded by infection. There has been increased interest in ME/CFS recently because of its significant overlap with the post-COVID syndrome (long COVID or post-acute sequelae of COVID), with several studies estimating that half of patients with post-COVID syndrome fulfill ME/CFS criteria. Our concise review describes a generalist approach to ME/CFS, including diagnosis, evaluation, and management strategies.
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Post-acute sequelae of SARS-CoV-2 (PASC) in nursing home residents: A retrospective cohort studySophie E. Clark MD, Liza Bautista MD, Karen Neeb MSN, CNP, Ana Montoya MD, MPH, Kristen E. Gibson MPH, Julia Mantey MPH, MUP, Mohammed Kabeto MS
First published: 10 November 2023 https://doi.org/10.1111/jgs.18678
Presentation: poster presentation at American Geriatric Society, Long Beach CA, May 2023.
AbstractBackgroundPost-acute sequelae of SARS-CoV-2 (PASC) describes a syndrome of physical and cognitive decline that persists after acute symptoms of infection resolve. Few studies have explored PASC among nursing home (NH) residents.
MethodsA retrospective cohort study was conducted at two NHs in Michigan. COVID-positive patients were identified from March 21, 2020 to October 26, 2021. The comparison group were patients who lived at the same NH but who were never infected during the study period. Minimum Data Set was used to examine trajectories of functional dependence (Activity of Daily Living [ADL] composite score) and cognitive function (Brief Interview for Mental Status [BIMS]). Linear mixed-effects models were constructed to estimate short-term change in function and cognition immediately following diagnosis and over time for an additional 12 months, compared to pre-COVID and non-COVID trajectories and adjusting for sex, age, and dementia status.
ResultsWe identified 171 residents (90 COVID-19 positive, 81 non-COVID) with 719 observations for our analyses. Cohort characteristics included: 108 (63%) ≥ 80 yrs.; 121 (71%) female; 160 (94%) non-Hispanic white; median of 3 comorbidities (IQR 2–4), with no significant differences in characteristics between groups. COVID-19 infection affected the trajectory of ADL recovery for the first 9 months following infection, characterized by an immediate post-infection decrease in functional status post-infection (−0.60 points, p = 0.002) followed by improvement toward the expected functional trajectory sans infection (0.04 points per month following infection, p = 0.271).ConclusionsNH residents experienced a significant functional decline that persisted for 9 months following acute infection. Further research is needed to determine whether increased rehabilitation services after COVID-19 may help mitigate this decline.
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Naltrexone 6 mg once daily versus placebo in woNaltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial: a randomised, double-blind, placebo-controlled trialKarin Due Bruun, MD ,Prof Robin Christensen, PhD,Prof Henrik Bjarke Vaegter, PhD,Morten Rune Blichfeldt-Eckhardt, PhD Lars Bye-Møllert al.
https://doi.org/10.1016/S2665-9913(23)00278-3
SummaryBackgroundLow-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia.
MethodsWe did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18–64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30).
FindingsWe screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was –1·3 points (95% CI –1·7 to –0·8) in the low-dose naltrexone group and –0·9 (–1·4 to –0·5) in the placebo group, corresponding to a between-group difference of –0·34 (–0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred.
InterpretationThis study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021–2022
NCHS Data Brief No. 488, December 2023
Anjel Vahratian, Ph.D., M.P.H., Jin-Mann S. Lin, Ph.D., Jeanne Bertolli, Ph.D., M.P.H., and Elizabeth R. Unger, Ph.D., M.D.
Key findings
Data from the National Health Interview Survey
- In 2021–2022, 1.3% of adults had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
- The percentage of adults who had ME/CFS increased with age through ages 60–69 and then declined among those age 70 and older.
- White non-Hispanic (1.5%) adults were more likely to have ME/CFS compared with Asian non-Hispanic (0.7%) and Hispanic (0.8%) adults.
- Adults with a family income less than 100% of the federal poverty level (2.0%) were more likely to have ME/CFS, followed by those at 100–199% (1.7%), and those at or above 200% (1.1%).
- The percentage of adults who had ME/CFS increased with increasing rurality of their place of residence.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after activity, and other symptoms (1). It affects all age, sex, and racial and ethnic groups and costs the U.S. economy about $18–$51 billion annually (2–5). This report describes the percentage of adults who had ME/CFS at the time of interview by selected demographic and geographic characteristics based on data from the 2021–2022 National Health Interview Survey (NHIS).
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December 28, 2023 Post–COVID-19 Condition in Children 6 and 12 Months After Infection
Frederick Dun-Dery, PhD, MPhil1; Jianling Xie, MD, MPH2; Kathleen Winston, MSc3; et alBrett Burstein, MDCM, PhD, MPH4,5; Jocelyn Gravel, MD, MSc6; Jason Emsley, MSc, MD, PhD7; Vikram Sabhaney, MD8; Roger Zemek, MD9,10; Simon Berthelot, MD, MSc11; Darcy Beer, MD12; April Kam, MD, MScPH13; Gabrielle Freire, MDCM, MHSc14; Ahmed Mater, MD15; Robert Porter, MD, MSc16; Naveen Poonai, MD, MSc17,18,19; Anne Moffatt, MD20; Andrew Dixon, MD21; Marina I. Salvadori, MD22,23; Stephen B. Freedman, MDCM, MSc24; for the Pediatric Emergency Research Canada (PERC) COVID Study Group
JAMA Netw Open. 2023;6(12):e2349613. doi:10.1001/jamanetworkopen.2023.49613
Key Points
Question What proportion of children meet the post–COVID-19 condition (PCC) symptom definition at 6 and 12 months following SARS-CoV-2 testing in pediatric emergency departments?
Findings In this cohort study, at 6 and 12 months, a statistically greater number of children with SARS-CoV-2 positive tests compared with those with negative tests met the PCC symptom and quality of life change definition. However, the absolute risk differences were very small (0.42% and 0.51% at 6 and 12 months, respectively).
Meaning Although there is an increased prevalence of symptoms consistent with the PCC definition that reduce quality of life among SARS-CoV-2 infected children, very few infected children develop PCC.
Abstract
Importance There is a need to understand the long-term outcomes among children infected with SARS-CoV-2.
Objective To quantify the prevalence of post–COVID-19 condition (PCC) among children tested for SARS-CoV-2 infection in pediatric emergency departments (EDs).
Design, Setting, and Participants Multicenter, prospective cohort study at 14 Canadian tertiary pediatric EDs that are members of the Pediatric Emergency Research Canada network with 90-day, 6-month, and 12-month follow-up. Participants were children younger than 18 years who were tested for SARS-CoV-2 infection between August 2020 and February 2022. Data were analyzed from May to November 2023.
Exposure The presence of SARS-CoV-2 infection at or within 14 days of the index ED visit.
Main Outcomes and Measures Presence of symptoms and QoL reductions that meet the PCC definition. This includes any symptom with onset within 3 months of infection that is ongoing at the time of follow-up and affects everyday functioning. The outcome was quantified at 6 and 12 months following the index ED visit.
Results Among the 5147 children at 6 months (1152 with SARS-CoV-2 positive tests and 3995 with negative tests) and 5563 children at 12 months (1192 with SARS-CoV-2 positive tests and 4371 with negative tests) who had sufficient data regarding the primary outcome to enable PCC classification, the median (IQR) age
was 2.0 (0.9-5.0) years, and 2956 of 5563 (53.1%) were male. At 6-month follow-up, symptoms and QoL changes consistent with the PCC definition were present in 6 of 1152 children with positive SARS-CoV-2 tests (0.52%) and 4 of 3995 children with negative SARS-CoV-2 tests (0.10%; absolute risk difference, 0.42%; 95% CI, 0.02% to 0.94%). The PCC definition was met at 12 months by 8 of 1192 children with positive SARS-CoV-2 tests (0.67%) and 7 of 4371 children with negative SARS-CoV-2 tests (0.16%; absolute risk difference, 0.51%; 95% CI, 0.06 to 1.08%). At 12 months, the median (IQR) PedsQL Generic Core Scale scores were 98.4 (90.0-100) among children with positive SARS-CoV-2 tests and 98.8 (91.7-100) among children with negative SARS-CoV-2 tests (difference, −0.3; 95% CI, −1.5 to 0.8; P = .56). Among the 8 children with SARS-CoV-2 positive tests and PCC at 12-month follow-up, children reported respiratory (7 of 8 patients [88%]), systemic (3 of 8 patients [38%]), and neurologic (1 of 8 patients [13%]) symptoms.
Conclusions and Relevance In this cohort study of children tested for SARS-CoV-2 infection in Canadian pediatric EDs, although children infected with SARS-CoV-2 reported increased chronic symptoms, few of these children developed PCC, and overall QoL did not differ from children with negative SARS-CoV-2 tests.
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Long COVID: New Info on Who Is Most Likely to Get ItSolarina Ho December 27, 2023 Medscape Medical news.
The COVID-10 pandemic may no longer be a global public health emergency, but millions continue to struggle with the aftermath: Long COVID. New research and clinical anecdotes suggest that certain individuals are more likely to be afflicted by the condition, nearly 4 years after the virus emerged.
People with a history of allergies, anxiety or depression, arthritis, and autoimmune diseases and women are among those who appear more vulnerable to developing long COVID, said doctors who specialize in treating the condition.
Many patients with long COVID struggle with debilitating fatigue, brain fog, and cognitive impairment. The condition is also characterized by a catalog of other symptoms that may be difficult to recognize as long COVID, experts said. That's especially true when patients may not mention seemingly unrelated information, such as underlying health conditions that might make them more vulnerable. This makes screening for certain conditions and investigating every symptom especially important.
The severity of a patient's initial infection is not the only determining factor for developing long COVID, experts said.
"Don't judge the person based on how sick they were initially," said Mark Bayley, MD, medical director of the Toronto Rehabilitation Institute at University Health Network and a professor with the Temerty Faculty of Medicine at the University of Toronto. "You have to evaluate every symptom as best you can to make sure you're not missing anything else."
Someone who only had a bad cough or felt really unwell for just a few days and recovered but started feeling rotten again later — "that's the person that we are seeing for long COVID," said Bayley.
While patients who become severely sick and require hospitalization have a higher risk of developing long COVID, this group size is small compared with the much larger number of people infected overall. As a result, despite the lower risk, those who only become mild to moderately sick make up the vast majority of patients in long COVID clinics.
A small Northwestern Medicine study found that 41% of patients with long COVID never tested positive for COVID-19 but were found to have antibodies that indicated exposure to the virus.
Doctors treating patients with long COVID should consider several risk factors, specialists said. They include:
- A history of asthma, eczema, or allergies
- Signs of autonomic nervous system dysfunction
- Preexisting immune system issues
- Chronic infections
- Diabetes
- Being slightly overweight
- A preexisting history of anxiety or depression
- Joint hypermobility (being "double-jointed" with pain and other symptoms)
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Long COVID in Nursing Home Residents Manifests as Functional DeclineEmily Harris
JAMA. 2024;331(1):15. doi:10.1001/jama.2023.24682
People living in nursing homes tended to need more help with activities of daily living, such as bathing and dressing, for months following infection with SARS-CoV-2 compared with their peers who were not infected, a retrospective cohort study found. Nursing home residents also experienced modest declines in cognition after COVID-19 infection.
The findings were based on data from 171 residents, most of whom were aged 80 years or older. About 94% of participants were White individuals. In addition, all participants had multiple comorbidities, with more than half living with dementia.
The nursing home residents who had COVID-19 experienced improvements in both their functional status and cognition within 1 year after their illness. Moreover, most residents were unvaccinated at the time of their diagnoses, which occurred between March 2020 and October 2021. The results might therefore reflect the highest rates of long COVID early in the pandemic before widespread vaccination, the researchers wrote in the Journal of the American Geriatrics Society.
Published Online: December 13, 2023. doi:10.1001/jama.2023.24682
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