Tag: long Covid

Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID

Abstract:

Study objectives: Sleep electroencephalographic (EEG) microstructures are related to brain functions, providing a window into the unrefreshing, non-restorative sleep and daytime fatigue symptoms in long COVID (LC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We aim to characterize sleep EEG microstructural differences in individuals with LC and age-sex-matched healthy controls (HC), and also ME/CFS, using overnight in-lab facility-measured polysomnography (PSG).

Methods: 28 LC and 28 HC participants came from a single-center research study. 19 ME/CFS participants came from a single clinical center. Sleep EEG was processed to extract spectral band powers, spindles, slow oscillations (SO, 0.5-1 Hz), spindle-SO coupling, brain age index (BAI), alpha-delta patterns, and infraslow oscillation relative band power (ISO, 0.005-0.03 Hz).

Results: Compared to HC, LC had higher SO power during wake before sleep and REM sleep. In N2 and N3, LC showed a faster within-spindle frequency drop (chirp) and shorter SO peak duration in the frontal region. LC showed widespread, early spindle-SO coupling phase at SO trough for both fast and slow spindles, with early fast spindle-SO coupling associated with worse sleep quality. ME/CFS shared some differences with LC but had higher SO-uncoupled slow spindle densities in frontal and central regions, more alpha-delta patterns in the first half of the night, and widespread elevated ISO power in the slow sigma band (11-13 Hz).

Conclusions: These findings suggest that LC and ME/CFS are associated with plausibly pathological sleep EEG microstructure changes, illuminating the pathobiology of post-infectious processes on brain activity.

CLINICAL TRIAL INFORMATION

Trial 1: Sleep and Inflammatory Resolution Pathway, https://clinicaltrials.gov/study/NCT03377543, NCT03377543.

Trial 2: Pain in Long COVID-19: the Role of Sleep, https://clinicaltrials.gov/study/NCT05606211, NCT05606211.

Source: Sun H, Dang R, Li P, Xiao W, Scott-Sutherland J, Sassower KC, Westover MB, Felsenstein D, Thomas RJ, Haack M, Mullington JM. Facility-Measured Sleep Electroencephalographic Microstructures in Long COVID. Sleep. 2026 Apr 22:zsag090. doi: 10.1093/sleep/zsag090. Epub ahead of print. PMID: 42017829. https://pubmed.ncbi.nlm.nih.gov/42017829/

Comparing ME/CFS following mononucleosis with Long COVID

Abstract:

Objectives: Long COVID following SARS-CoV-2 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) following infectious mononucleosis (IM) are examples of post-infectious chronic illnesses. Behavioral and pathophysiological underpinnings of both ME/CFS following IM and Long COVID are not well understood.

Methods: We studied ME/CFS development following IM in a diverse group of college students who were enrolled before the onset of IM. We categorized those meeting either moderate or severe ME/CFS criteria. We subsequently recruited a matched sample of those infected with SARS-CoV-2, some of whom recovered and others of whom developed Long COVID. We compared and contrasted ME/CFS and Long COVID following IM and SARS-CoV-2 infection in terms of somatic symptoms, coping strategies, depression and anxiety symptoms, and functional status.

Results: In general, the Long COVID group’s symptom burden was less than that of the Severe ME/CFS group but more than that of the Moderate ME/CFS group.

Discussion: These findings may allow investigators a better understanding of these post-viral illness pathophysiologies.

Source: Jason LA, Furst J, Katz BZ. Comparing ME/CFS following mononucleosis with Long COVID. Chronic Illn. 2026 Apr 15:17423953251347108. doi: 10.1177/17423953251347108. Epub ahead of print. PMID: 41984971. https://pubmed.ncbi.nlm.nih.gov/41984971/

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia).

Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS).

Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations.

Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms.

Source: Barr J, Marsden L, Dassanayake T, Almutairi N, McKeever V, Gaber T, Tarrant R, Godfrey B, Witton S, Sivan M. Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID. J Clin Med. 2026 Mar 25;15(7):2510. doi: 10.3390/jcm15072510. PMID: 41976810. https://www.mdpi.com/2077-0383/15/7/2510 (Full text)

Making Invisible Illnesses Visible: Recognizing and Responding to Infection Associated Chronic Conditions

Abstract:

The emergence of post-COVID conditions (PCC) has renewed attention to infection-associated chronic conditions and illnesses (IACCI), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Lyme disease-associated chronic symptoms. Millions of Americans are affected by these debilitating, misunderstood conditions, which share symptom profiles and pathophysiologic abnormalities. IACCI have received insufficient clinical attention and research investment.

We outline elements of a patient-centered approach to care, emphasizing validation of patients’ experiences, multidisciplinary management, and symptom-focused treatment. Opportunities to strengthen clinical practice include a new CMS code for chronic condition management, extended visits, and creation of welcoming care environments. Advances in PCC and ME/CFS research provide a foundation for exploring shared mechanisms and developing targeted therapies. Improved surveillance, harmonized research, and inclusive trial designs are needed to define disease burden and accelerate therapeutic progress. Coordinated action by clinicians, researchers, and policymakers can help address longstanding gaps and improve outcomes for all individuals with IACCI

Source: Iskander JK, Haridopolos S. Making Invisible Illnesses Visible: Recognizing and Responding to Infection Associated Chronic Conditions. Clin Infect Dis. 2026 Apr 9:ciag240. doi: 10.1093/cid/ciag240. Epub ahead of print. PMID: 41967005. https://pubmed.ncbi.nlm.nih.gov/41967005/

The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID: An Adaptive Randomized Trial

Abstract:

Background: Postacute sequelae of SARS-CoV-2, or long COVID, presents a major therapeutic challenge, with fatigue being a prevalent and debilitating symptom.

Objective: To assess the efficacy of fluvoxamine and metformin for long COVID fatigue.

Design: Randomized, placebo-controlled, adaptive trial. (ClinicalTrials.gov: NCT06128967).

Setting: Outpatient sites in Brazil.

Participants: 399 adults with fatigue persisting 90 or more days after confirmed SARS-CoV-2 infection.

Intervention: Participants were randomly assigned to fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or matching placebo for 60 days.

Measurements: The primary outcome was change in Fatigue Severity Scale (FSS) score.

Results: Fluvoxamine showed a significant reduction in fatigue compared with placebo at day 60 (mean difference, -0.43 [95% credible interval {CrI}, -0.80 to -0.07]), with a sustained effect at day 90 (mean difference, -0.58 [CrI, -0.98 to -0.16]). Fluvoxamine also improved quality-of-life scores with high posterior probability. Metformin showed no significant benefit. Adverse events were less frequent with fluvoxamine (20.0%) than with metformin (28.8%) or placebo (29.7%). Grade 3 and higher adverse events were rare across all groups.

Limitations: The 90-day follow-up period limits conclusions about the durability of treatment effects, and the exclusive focus on fatigue as the primary outcome does not address other prevalent long COVID symptoms, leaving fluvoxamine’s broader therapeutic utility uncertain.

Conclusion: Fluvoxamine, but not metformin, may be an effective treatment for reducing fatigue and improving quality of life in patients with long COVID.

Primary funding source: The Latona Foundation.

Source: Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Ferreira TS, Reis LLF, Figueiredo Guimaraes Almeida AP, Menezes Amaral M, Savassi LCM, de Souza Campos VH, Campos Simplicio MI, Barra Ribeiro L, de Souza Medeiros T, Campos Siqueira T, Vieira TS, Drumond Rausse N, Garofolo TC, Fagundes Silva EC, Harari O, D’Urso G, Forrest JI, Park J, Nachega JB, Lindsell C, Glenn JS, Thorlund K, Dybul M, Mills EJ; REVIVE Investigators. The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial. Ann Intern Med. 2026 Mar 31. doi: 10.7326/ANNALS-25-03959. Epub ahead of print. PMID: 41911553. https://www.acpjournals.org/doi/10.7326/ANNALS-25-03959 (Full text)

The Role of ME/CFS Phenotype in Outpatient Post-COVID Rehabilitation

Abstract:

Post-COVID-19 syndrome (PCS) shares core clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), particularly persistent fatigue and post-exertional malaise (PEM). However, the prevalence of ME/CFS among PCS rehabilitation outpatients remains unclear.

Medical records of 216 PCS rehabilitation outpatients (57% female; age 47.7±12.5; January 2021 to April 2022) were retrospectively reviewed. During rehabilitation and at a six-month telephone follow-up, ME/CFS was diagnosed using the Canadian Consensus Criteria (CCC). Demographics, body mass index (BMI), FAS, and 6MWT were compared between phenotype and non-phenotype groups using logistic regression, repeated measures ANOVA, and chi-square tests (α=0.05). Of 216 patients, 15 (93% female; age 40.6±10.7; BMI 25.7±5.6) met ME/CFS criteria, yielding a prevalence of 6.9%.

Compared with non-ME/CFS phenotype, ME/CFS phenotype patients were significantly younger (p=0.01) and predominantly female (p=0.003). Baseline FAS was significantly higher (35.8±6.4 vs. 27.8±8.6, p=0.001) and did not improve (Δ +1.3±4.5 vs. Δ -5.1±6.2, p<0.001). Baseline 6MWT was significantly lower (479±132 m vs. 540±96.1 m, p=0.02) and both groups improved over time, but between-group change was not significant (p=0.49).

Approximately 7% of PCS in outpatient rehabilitation exhibit ME/CFS, characterized by severe, persistent fatigue, female predominance, and attenuated functional gains. While the FAS is a practical screening tool, confirmation via CCC remains essential. Future studies should validate these findings and explore tailored rehabilitation strategies for patients with ME/CFS.

Source: Kaiserseder M, Prüfer F, Untersmayer-Elsenhuber E, Zwick RH. Welche Rolle spielt der ME/CFS-Phänotyp in einer ambulanten Post-COVID-Rehabilitation? [The Role of ME/CFS Phenotype in Outpatient Post-COVID Rehabilitation]. Pneumologie. 2026 Mar 30. German. doi: 10.1055/a-2823-6976. Epub ahead of print. PMID: 41911688. https://pubmed.ncbi.nlm.nih.gov/41911688/ (Full text available in German)

Long COVID disability burden in US adults

Abstract:

Background: Five years since the scientific and patient communities first identified the syndrome now known as Long COVID, affected individuals lack treatments, and the US lacks population-based data on its disability burden and correlation with National Institutes of Health (NIH) funding. Moreover, akin to other debilitating conditions it often co-occurs with, e.g., Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, Long COVID disproportionately impacts females whose concerns are often marginalized.

Methods: We quantify Long COVID years lived with disability (YLDs= prevalence x disability weight) in US adults and its actual/YLD-commensurate average annual NIH FY2022-2024 funding versus 68 comparator conditions, by sex predominance. We derive Long COVID prevalence from Census Bureau surveys (9/2022-8/2023) and apply disability weights from the Global Burden of Disease Study.

Results: Long COVID YLDs approximate those of Alzheimer’s and Asthma. Long COVID received 14% of its disability commensurate funding: $106 million vs. $739.8 million. ME/CFS is the most under-funded condition, receiving <1% of its YLD proportionate funding. Among conditions analyzed, 24 are female-predominant (we estimate Long COVID funding two ways), 12 male-predominant, and 33 show no sex predominance. Among the 12 below-median funded/above-median YLD conditions, 7/12 are female-predominant, none are male-predominant. Median funding/per YLD is 5.2 times higher for male- vs. female-predominant conditions (7.0 vs 1.3 million per YLD, p = 0.007). Overall, YLDs explain 6.5% of funding variance in a linear regression model using YLD as the sole predictor (Adjusted R-squared: 0.065).

Conclusions: With chronic conditions like Long COVID rising, disability burden merits greater consideration in funding decisions, as does biological sex.

Source: Bonuck K, Gao Q, Congdon S, Kim RS. Long COVID disability burden in US adults. Commun Med (Lond). 2026 Mar 31;6(1):177. doi: 10.1038/s43856-026-01516-7. PMID: 41917225. https://www.nature.com/articles/s43856-026-01516-7 (Full text)

Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystemic disorder mostly triggered by viral infections, with core symptoms including post-exertional malaise (PEM), fatigue, pain, and cognitive dysfunction. Its prevalence has increased significantly in the context of the coronavirus disease 2019 (COVID-19) pandemic. Despite its severity and impact on patients’ quality of life, ME/CFS remains poorly understood.

On May 12 and 13, 2025, the 3rd International Conference hosted by the Charité Fatigue Center brought together nearly 200 researchers from various disciplines on-site, and around 3,700 participants online to discuss recent advances in ME/CFS research, diagnostics, clinical care, and therapeutic trials. The program featured 33 lectures by international experts on key topics such as post-COVID syndrome (PCS), care structures, and pathophysiological mechanisms including cardiovascular dysregulation, immune dysregulation, autoimmune mechanisms, and metabolic dysfunction.

In addition, results from clinical trials addressing disease mechanisms, including those specifically targeting autoantibodies, were presented. While public awareness and funding opportunities have increased in the wake of the pandemic and the emergence of PCS, ME/CFS remains severely underresearched. Sustained and adequately funded research efforts are urgently required to advance understanding, identify diagnostic markers, and develop targeted therapeutic interventions.

Source: Fehrer A, Windzio L, Schoening S, Steiner S, Aschenbrenner AC, Babel N, Behrends U, Bellmann-Strobl J, Cammà G, Cash A, Doehner W, den Dunnen J, Fluge Ø, Franke C, Hoffmann K, Kedor C, Kim L, Löhden W, Mella O, Mihatsch LL, Peluso MJ, Puta C, Putrino D, Ramoji A, Sato W, Sawitzki B, Schlieper G, Schoenfeld Y, Seifert M, Sigurdsson F, Slaghekke A, Sommerfelt K, Sotzny F, Stein E, Steinacker JM, Stingl M, Systrom DM, Tronstad KJ, Wirth K, Wörmann B, Wüst RCI, Yamamura T, Scheibenbogen C. Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center. Autoimmun Rev. 2026 Mar 25:104043. doi: 10.1016/j.autrev.2026.104043. Epub ahead of print. PMID: 41895458. https://www.sciencedirect.com/science/article/pii/S1568997226000571 (Full text)

Putting the PASC score to the test: Clinical vs. statistical accuracy in long COVID diagnosis

Abstract:

Objective: To validate the RECOVER Post-Acute Sequelae of SARS-CoV-2 infection (PASC) score in a cohort of patients who develop long COVID (LC) or fully recover while iteratively improving the tool’s sensitivity and specificity.

Methods: A cross-sectional study in 130 LC patients followed at LC clinics in Baltimore, MD, USA, who met the National Academies of Sciences, Engineering, and Medicine (NASEM) 2024 LC definition, and 60 SARS-CoV-2 exposed but fully recovered individuals. LC participants were required to have at least one neuropsychiatric symptom. Participants completed comprehensive surveys and questionnaires assessing symptoms based on published methods to determine PASC score. Using the NASEM 2024 LC definition as the “true” condition, we compared evaluation metrics for the RECOVER PASC score cutoff (PASC > 12) and the presence of individual/multiple symptoms. Evaluation metrics (e.g., sensitivity, specificity, F1) were calculated based on these classifications for the overall PASC score and symptom combinations.

Results: The LC cohort (n = 130) had a mean age of 47.2 years and was predominantly female (72%), White (79%), and well-educated (77% > 16 years). Controls (n = 60) were similar demographically. LC diagnosis and PASC scores were significantly associated (χ2 = 102.99, P < 0.001). The PASC score showed excellent specificity (100%) and positive predictive value (PPV; 100%) albeit limited sensitivity (80%), missing 20% of participants with LC. We found that loss of smell/taste, post-exertional malaise, or lack of sexual desire or capacity demonstrated 94% sensitivity, 92% specificity, and 96% PPV, 87% NPV, and an F1 score of 0.949.

Conclusion: Validation of the RECOVER PASC supports its utility and highlights the need for ongoing refinement of the LC definition. We call for national efforts to develop readily implementable clinical tools for LC diagnosis.

Source: Azola A, Dastgheyb RM, Easter R, Parker H, Della Penna C, Santiuste I, Schultz H, Ehrenspeck A, Veenhuis R, Rubin LH. Putting the PASC Score to the Test: Clinical vs. Statistical Accuracy in Long COVID Diagnosis. J Gen Intern Med. 2025 Nov 17. doi: 10.1007/s11606-025-10042-6. Epub ahead of print. PMID: 41249654. https://link.springer.com/article/10.1007/s11606-025-10042-6 (Full text)

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders

Abstract:

Postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are heterogeneous disorders with overlapping complex, multi-factorial and multi-systemic pathophysiology. POTS and ME/CFS are the most common phenotypes of Long COVID that can lead to significant disability and functional impairment.

The exact pathophysiologic mechanisms of these disorders alone or in combination are still being investigated, but important mechanistic factors have been identified, such as autonomic dysfunction, immune dysregulation, autoimmunity, mitochondrial dysfunction, cerebral hypoperfusion, and neuroinflammation.

To this end, we believe that these conditions should be viewed as neuroimmune disorders and should be included in the field of neuroimmunology, with its educational curriculum, training, and clinical care pathways. Including these disorders as part of neuroimmunology subspecialty is the key to advancing the science and clinical care of this underserved patient population with these complex and disabling conditions.

Source: Blitshteyn S, Doherty TA, Steinman L. Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders. Immunotargets Ther. 2026 Feb 2;15:581262. doi: 10.2147/ITT.S581262. PMID: 41859298; PMCID: PMC12998959. https://pmc.ncbi.nlm.nih.gov/articles/PMC12998959/ (Full text)