Tag: long covid symptoms

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)

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)

Prevalence of Post-COVID Symptoms Across Variants of Concern and Follow-up Periods: A Systematic Review and Meta-Analysis

Abstract:

Objectives: The interaction between SARS-CoV-2 variants of concern (VoC) and post-COVID symptom duration remains unexplored. This is the first study to evaluate post-COVID prevalence stratified by VoC and follow-up periods.

Methods: Six databases were searched (12/2019-12/2024) for studies of adults with laboratory-confirmed SARS-CoV-2 and symptoms lasting ≥3 months. Data were stratified by VoC (Alpha through Omicron) and follow-up (<6 vs. ≥6 months) to estimate pooled prevalence using random-effects models.

Results: Pooled prevalence across 35 studies (n=159,000) was 28.5% (95% CI: 21.6-36.0), higher in pre-Omicron (35.5%) than Omicron (22.8%) eras (p=0.04). Symptoms persisted beyond six months in 29.9% of cases. Fatigue was the most prevalent symptom across all VoCs and follow-ups followed by brain fog, dyspnea, and sleep impairment. Pre-Omicron variants were linked to dyspnea and anosmia, while Omicron was associated with brain fog and paresthesia. Most symptoms showed no significant reduction beyond six months. Sleep problems were higher in early pre-Omicron cohorts but improved over time; conversely, palpitations and ocular manifestations increased in later pre-Omicron follow-ups.

Conclusions: Post-COVID condition remains a burden despite vaccination. Distinct symptomatology patterns across VoC and timelines highlight the need for tailored management strategies to mitigate long-term global impacts.

Source: Lugtu EJ, Iv DYP, Cabunoc MH, Bautista JL, Pleta FM, Ng JA, Shahid F, Carandang THDC, Lippi G, Henry BM, Fernández-de-Las-Peñas C, Notarte KI. Prevalence of Post-COVID Symptoms Across Variants of Concern and Follow-up Periods: A Systematic Review and Meta-Analysis. Int J Infect Dis. 2026 Mar 10:108522. doi: 10.1016/j.ijid.2026.108522. Epub ahead of print. PMID: 41819160. https://www.ijidonline.com/article/S1201-9712(26)00157-8/fulltext (Full text)

Symptom Patterns, Recovery, and Impact of Long COVID: Findings From a Longitudinal Survey

Abstract:

Background: Long COVID is a predominantly multisystem, often disabling, condition that develops following SARS-CoV-2 infection. We aimed to characterize the pattern, triggers, and impact of Long COVID symptoms.
Methods: Data from a 1-year follow-up of an online survey originally conducted in November 2020 were used. Surveys were coproduced with people living with Long COVID. Participants were adults with Long COVID following confirmed or probable SARS-CoV-2 infection who were not hospitalized in the first 2 weeks of illness. The baseline survey recruited from social media and online support groups using convenience nonprobability sampling.
Results: Of the 2210 first survey participants invited, 1153 (52%) responded to the follow-up survey. The mean age was 47.7 years (standard deviation 10.6) with 84% females, 83% UK-based, 78% university-qualified, and 90% reporting good to excellent health before SARS-CoV-2 infection. Median duration of illness was 19.8 months (interquartile range, 19.3–20.1) at follow-up. Only 5% of participants reported full recovery, and 45% reported a constant pattern of illness (as opposed to fluctuating or relapsing) compared to 17% at baseline. An equal proportion reported being unable to work at baseline (20.4%) and follow-up (20.6%). However, a higher proportion reported being made redundant or taking early retirement at follow-up (8.9%) than at baseline (2.2%).
Conclusions: This study highlights the prolonged nature of Long COVID as well as the impact on work. This has the potential to widen health inequalities and increase hardship in individuals whose life circumstances and job types may not allow them to make necessary adaptations.

Source: Nida Ziauddeen, Marija Pantelic, Margaret E O’Hara, Claire Hastie, Nisreen A Alwan, Symptom Patterns, Recovery, and Impact of Long COVID: Findings From a Longitudinal Survey, Open Forum Infectious Diseases, Volume 13, Issue 2, February 2026, ofag040, https://doi.org/10.1093/ofid/ofag040 https://academic.oup.com/ofid/article/13/2/ofag040/8495807?login=false (Full text)

Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome

Abstract:

The objective of this study was to quantify the variability of cortical blood flow during cognitive load as an indicator of disease-related changes in cerebral capillary blood flow intermittency in patients with post-COVID-19 syndrome. The regulation of cerebral blood flow in the dorsolateral prefrontal cortex under cognitive load was examined using high-resolution functional near-infrared spectroscopy in 36 subjects including 12 patients with post-COVID-19 syndrome and two control groups [12 coronary artery disease patients matched for age and 12 young healthy individuals (CTRL)].

To induce cognitive load, a Flanker task and an N-back task were employed. The structure of temporal variability of local blood flow regulation was assessed using sample entropy at 17 channels spanning both brain hemispheres. The spatial variability of the regional blood flow pattern was evaluated using the coefficient of variation (CV) from sample entropies across all channels.

Results revealed a notable discrepancy in that patients with post-COVID-19 syndrome exhibited reduced temporal variability (lower sample entropy) but elevated spatial variability (higher CV) in comparison to coronary artery disease patients during cognitive load (P = 0.02). In the N-back task, the spatial variability increased from healthy individuals to coronary artery disease patients to patients with post-COVID-19 syndrome and was associated with longer reaction time and with lower accuracy.

The results confirmed that dynamic cerebral blood flow is altered in patients with post-COVID-19 syndrome, which may be related to fatigue during cognitive tasks. Sample entropy and CV values represent different aspects of blood flow regulation fluctuation. Their simultaneous analysis enabled a meaningful distinction between groups suggesting disease-related changes in brain haemodynamic. The presented method is therefore suitable for describing current states of cortical blood flow regulation and for documenting intervention results in patients with post-COVID-19 syndrome or patients with similar symptoms (e.g. myalgic encephalomyelitis/chronic fatigue syndrome).

Source: Kutz DF, Garbsch R, Mooren FC, Schmitz B, Voelcker-Rehage C. Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome. Brain Commun. 2026 Feb 10;8(1):fcag036. doi: 10.1093/braincomms/fcag036. PMID: 41728261; PMCID: PMC12917544. https://pmc.ncbi.nlm.nih.gov/articles/PMC12917544/ (Full text)

Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing

Abstract:

Introduction: Chronic pain is a significant and debilitating symptom observed in individuals with post-COVID condition (PCC), yet the underlying mechanisms remain poorly understood. This study aimed to investigate whether changes in psychophysical indicators of myofascial pain perception and modulation are present in individuals with PCC compared to symptom-free healthy controls (HC), and whether these changes correlate with the severity of clinical symptoms.

Methods: The study involved 84 individuals with PCC and 50 HC, assessing pain detection and tolerance thresholds (PDT and PTT), spatial and temporal summation of pain (SSP and TSP), and conditioned pain modulation (CPM) using phasic cuff pressure on the legs.

Results: Results indicated that individuals with PCC exhibited lower PDT and PPT (PDT: d = -0.557, p = 0.0022; PTT: d = -0.575, p = 0.0016), increased TSP (d = 0.424, p = 0.02) and decreased SSPPTT (d = -0.532, p = 0.0038) compared to HC CPM effects (CPMPDT: p = 0.058; CPMPTT: p = 0.43) did not differ significantly between groups but post hoc analysis revealed a significantly higher proportion of inhibitory responders among HC. Subgroup analyses highlighted that these effects were particularly pronounced in participants that reported chronic pain among their PCC symptoms, as well as those with more severe PCC symptomatology.

Conclusion: The findings suggest that individuals with PCC demonstrate altered myofascial pain perception, indicative of central sensitization. These results underscore the need for further research into targeted therapeutic strategies for managing chronic pain in PCC.

Significance statement: Individuals with post-COVID condition (PCC) often experience persistent pain. Using quantitative sensory testing of deep tissue pain, we found that individuals with PCC had lower pain detection and tolerance thresholds, stronger spatial and temporal summation, and a higher proportion of facilitatory conditioned pain modulation compared to healthy controls. This pattern is consistent with nociplastic pain, suggesting altered central pain processing in PCC. Understanding these mechanisms is essential for developing targeted treatments of chronic pain in this growing patient population.

Source: Lange H, Reichert J, Vock S, Hermes M, Beiner E, Eich W, Friederich HC, Treede RD, Tesarz J. Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing. Eur J Pain. 2026 Feb;30(2):e70203. doi: 10.1002/ejp.70203. PMID: 41699921. https://pubmed.ncbi.nlm.nih.gov/41699921/

The fatigue spectrum in a community-based long haul COVID cohort

Abstract:

Introduction: In a Long Haul COVID referral clinic we describe the primary presentations of fatigue according to the CDC 2015 criteria for myalgic encephalitis/chronic fatigue syndrome (ME/CFS).

Methods: Between September 2021 and April 2022, 277 patients (61% women, 54 yrs: range 18-90 yrs) presented an average of 10 months after an acute COVID-19 infection (22% hospitalized). The clinical data were analyzed to conpare those with or without a primary or co-primary complaint of fatigue, subdivided as meeting ME/CFS criteria or not.

Results: 209 (73.5%) people (64% women) presented with fatigue. The Fatigue Severity Score was 5.33 (out 7) in those with 5.31 (SD1.54) vs. without 4.43 (SD1.65) a primary fatigue complaint (p > 0.001). Anxiety (58% vs. 38%, p < 0.02) and any psychiatric diagnosis (66% vs. 44%%, p < 0.01), but not depression itself, were overrepresented in those with Fatigue and ME/CFS. Those with prior managed sleep conditions did not increase risk for fatigue presentation. Of those with fatigue and an elevated FSS, 45/209 (21.9%) met criteria for ME/CFS. In those not meeting these criteria, associated ME/CFS symptoms were less consistent. Physical functioning by ECOG (1.88 (0.78) and 26% >2) did correlate with fatigue status. Depression was present (PHQ9 12.34 (5.95) with 63% >10) to a moderate or higher degree and was different with fatigue complaints. Brain fog (51.9%) was similar among the three categories, and correlated with FSS > 4, ECOG, and depression.

Conclusions: The fatigue phenotype in those presenting with it as a primary complaint comprises 21% meeting ME/CFS criteria and 79% which do not. In all the Long Haul COVID presentations. brain fog had separate, distinguishing features. Post-COVID fatigue is a spectrum which will confound clinical trials.

Source: Carter IV, May A, Hsieh IC, Torer J, Rosenberg D, Strohl KP. The fatigue spectrum in a community-based long haul COVID cohort. Sleep Breath. 2026 Jan 31;30(1):27. doi: 10.1007/s11325-025-03512-y. PMID: 41620575. https://link.springer.com/article/10.1007/s11325-025-03512-y (Full text)

Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy

Abstract:

Background: Post-COVID condition (PCCo) affects 5-10% of individuals following SARS-CoV-2 infection, with cognitive disturbances being a major feature. Central hypotheses regarding its pathophysiology include disturbed cell energy metabolism and oxidative stress pointing to mitochondrial dysfunction. However, brain energy metabolism remains unexplored.

Methods: We investigated cerebral high-energy phosphate metabolism in 27 PCCo patients and 23 fully recovered controls using whole-brain 31P-MRSI at 3T. ATP/PCr ratios were quantified throughout the brain and analyzed with voxel-based and regional statistics including correlations with neuropsychological performance (Montreal Cognitive Assessment and Trail Making Test Part B). Statistical analysis employed voxel-wise comparisons with age as covariate, followed by region-of-interest analysis of cingulate cortex subdivisions.

Results: PCCo patients showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across anterior (ACC), mid- (MCC), and posterior (PCC) cingulate cortices. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in PCCo patients meeting ME/CFS criteria.

Conclusions: Our study provides first in vivo evidence of impaired brain energy metabolism in PCCo, with anterior cingulate dysfunction directly linked to cognitive impairment. The observed pH-ATP/PCr relationship suggests broader disruption of cellular bioenergetic regulation. These findings support mitochondrial dysfunction as a key pathophysiological mechanism and may inform targeted therapeutic strategies.

Source: Weber-Fahr W, Dommke S, Sack M, Alzein N, Becker R, Demirakca T, Ende G, Schilling C. Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy. Biol Psychiatry. 2026 Jan 10:S0006-3223(26)00021-1. doi: 10.1016/j.biopsych.2026.01.004. Epub ahead of print. PMID: 41525818.  https://www.biologicalpsychiatryjournal.com/article/S0006-3223(26)00021-1/fulltext (Full text)

Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers

Abstract:

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, and postacute COVID-19 vaccination syndrome (PACVS) present overlapping but distinct clinical challenges. We hypothesize that PASC and PACVS share clinical features but differ in symptom patterns and biomarker profiles. This study aims to identify differences in presentation and distinguish immunologic biomarkers relevant to general clinical practice.

Methods: This cross-sectional study analyzed 181 patients from a PASC clinic at Columbia University Irving Medical Center. Patients were divided into PASC with myalgic encephalomyelitis/chronic fatigue syndrome (MECFS), PASC without MECFS (LC), and PACVS groups. Prevalence and severity of self-reported symptoms, as well as immunologic abnormalities, were compared across groups.

Results: Fatigue was the most common symptom (Total: 88.95%; MECFS: 100.00%; PACVS: 92.86%; LC: 78.05%). The MECFS group generally reported more symptoms across all organ systems. The PACVS group reported higher rates of atypical chief complaints such as peripheral neuropathy (17.9%), tinnitus (7.1%), and rash (10.7%) compared to the other groups (P = <.01). Functional impairment was comparable between the MECFS and PACVS groups and less severe in the LC group. All groups had high rates of autoantibody positivity and cytokine elevation. The PACVS group showed significantly higher rates of anticardiolipin IgM (PACVS 42.9%, LC 11.6%; P = .02) and anti-U1-RNP (PACVS 21.4%, LC 2.3%; P = .04) positivity compared to the LC group.

Conclusions: PASC and PACVS share symptom overlap but exhibit distinct biomarker patterns, particularly elevated autoantibody levels in PACVS. These findings suggest autoimmune involvement, warranting further investigation for targeted therapies.

Source: Purpura L, Heisler T, Palmer S, Shah J, Graham A, Seo GY, Sturiza A, Javier X, Pinto G, Rosa A, Bosco J, Reis K, Sobieszczyk ME, Yin MT. Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers. Clin Infect Dis. 2026 Jan 9:ciaf624. doi: 10.1093/cid/ciaf624. Epub ahead of print. PMID: 41510565. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf624/8417802 (Full text)