Tag: long Covid

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)

Dysregulated NK-cell gene expression defines the enduring symptoms of long COVID-19

Abstract:

Introduction: Long-term COVID-19 syndrome (LTCS) or “long COVID” is a debilitating post-viral condition affecting approximately 2%–8% of individuals after SARS-CoV-2 infection. It manifests typically ≥3 months post-infection with symptoms persisting for at least 2 months, including fatigue, pulmonary dysfunction, and cognitive impairment, in the absence of alternative diagnoses. The biological mechanisms underlying LTCS remain poorly defined, yet emerging evidence implicates immune dysregulation.

Methods: We profiled plasma antibodies and cytokines from healthy controls (HC, N = 66), convalescents (CONV, N = 24), and LTCS patients (N = 94), followed by multiparametric 14-color flow cytometry of PBMCs from HC (N = 9), CONV (N = 6), and LTCS (N = 23) participants. To gain mechanistic insight, we performed single-cell transcriptomic profiling (scRNA-seq) on PBMCs from HC (N = 8), CONV (N = 6), and LTCS (N = 32) individuals.

Results: LTCS patients exhibited elevated anti-SARS-CoV-2 IgG (spike S1/RBD/N) titers compared with HC, but displayed significantly reduced systemic cytokine levels, including IFN-γ, TNF-α, IL-6, and IL-10. Flow cytometry revealed marked depletion of CD56+CD16+ NK cells and CD56+CD3+ NKT cells, accompanied by altered T-cell activation states. scRNA-seq confirmed NK type I cell loss and uncovered broad transcriptional reprogramming with upregulation of PDCD4, CHD1, CXCR4, and SLC7A5 and downregulation of TGFBR3, RIPOR2, and MBNL1. Gene set enrichment analyses indicated activation of circadian and translational programs and suppression of olfactory receptor, neurotransmitter receptor, and GABA-gated ion-channel pathways. Functional assays validated reduced NK-cell inflammatory capacity in LTCS participants.

Discussion: LTCS is characterized by systemic cytokine attenuation and a quantitative and functional NK-cell deficit coupled to neurosensory pathway suppression. These findings identify NK cells as key sentinels of LTCS pathophysiology and highlight an NK-centric neuroimmune axis as a promising target for biomarker discovery and therapeutic intervention.

Source: Ray U, Schulze Selting A, Perera RP, Yang Z, Lysenkov V, Göpel S, Bitzer M, Salker MS, Ossowski S, Riess O, Casadei N and Singh Y (2026) Dysregulated NK-cell gene expression defines the enduring symptoms of long COVID-19. Front. Immunol. 17:1720551. doi: 10.3389/fimmu.2026.1720551 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1720551/full?media_id=3855960893360206425_63872469980&media_author_id=63872469980&ranking_info_token=GCBhMjBlODkzODk5NGI0NWIwYjM3MmUwYjkyNDUyYmY5YyWmsvQCJoKX3psNGBMzODU1OTYwODkzMzYwMjA2NDI1KANndG4A&utm_source=ig_text_feed_timeline (Full text)

Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients

Abstract:

Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with unresolved pathophysiology and limited diagnostic options. Extracellular vesicles (EVs) carry disease-specific protein and miRNA signatures and may enable improved disease profiling. We aimed to identify novel protein and miRNA markers as potential biomarkers in plasma EVs from female ME/CFS patients, including post-COVID-19 ME/CFS and post-infectious ME/CFS of other origins, compared with healthy controls.

EVs were isolated from plasma by size-exclusion chromatography and characterized for number, size, morphology, and surface marker expression. Flow cytometry showed that small EVs strongly expressed tetraspanins, with only minor differences between ME/CFS patients and healthy donors. Proteomic profiling of EVs from ME/CFS patients identified altered cargo proteins, including hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit compared with healthy controls (n ≤ 10/cohort). Small RNA sequencing followed by qPCR revealed significant downregulation of hsa-let-7b-5p in EVs from post-COVID-19 ME/CFS patients (n = 12) versus healthy controls (n = 15). Reduced hsa-let-7b-5p expression correlated with impaired physical functioning and increased fatigue, pain, and immune activation.

These findings indicate that EV cargo differences, particularly hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit, as well as hsa-let-7b-5p, represent promising candidates for ME/CFS diagnosis and patient stratification.

Source: Seifert M, Schäfers J, Douglas FF, Schwarzburg C, Boristowski D, Birke A, Klein O, Sotzny F, Rubarth K, Windzio L, Beez CM, Peters CK, Wittke K, Scheibenbogen C, Greco A. Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients. Int J Mol Sci. 2026 Feb 28;27(5):2314. doi: 10.3390/ijms27052314. PMID: 41828537. https://www.mdpi.com/1422-0067/27/5/2314 (Full text)

Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients

Abstract:

Chronic persistence of systemic symptoms after recovery from active CoVID-19 has become a significant disease burden, named post-CoVID syndrome. Among many pathophysiological hypotheses we focus on impaired hemostasis as well as reactivation of latent Epstein-Barr virus.

We now introduce a novel diagnostic morphological approach for visualizing microaggregates circulating in peripheral venous blood, which are large enough to impede capillary blood flow. In addition, secretion of interferon gamma by mononuclear leukocytes in response to peptides of Epstein-Barr virus is increased in these patients.

As a promising therapeutic approach, we provide retrospective data on the effect of anti-thrombotic and virostatic drugs, respectively. In a large number of patients, clinical improvement was observed after platelet inhibition, particularly when EBV was also treated with antiviral therapy.

Source: Wick N, Hermann M, Lisch C, Gerth R, Wick G, Untersmayr E, Marth T, Bachler M, Fries D. Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients. Sci Rep. 2026 Mar 8. doi: 10.1038/s41598-026-42952-8. Epub ahead of print. PMID: 41796205. https://www.nature.com/articles/s41598-026-42952-8 (Full text available as PDF file)

A multiomics recovery factor predicts long COVID in the IMPACC study

Abstract:

BACKGROUND: Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.

METHODS: We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.

RESULTS: Participants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.

CONCLUSION: The multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04378777.

FUNDING:

National Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).

Source: Gabernet G, Maciuch J, Gygi JP, Moore JF, Hoch A, Syphurs C, Chu T, Doni Jayavelu N, Corry DB, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Rouphael N, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Hough CL, Messer WB, Davis MM, Nadeau KC, Pulendran B, Kraft M, Bime C, Reed EF, Schaenman J, Erle DJ, Calfee CS, Atkinson MA, Brakenridge SC, Melamed E, Shaw AC, Hafler DA, Augustine AD, Becker PM, Ozonoff A, Bosinger SE, Eckalbar W, Maecker HT, Kim-Schulze S, Steen H, Krammer F, Westendorf K; IMPACC Network; Peters B, Fourati S, Altman MC, Levy O, Smolen KK, Montgomery RR, Diray-Arce J, Kleinstein SH, Guan L, Ehrlich LI. A multiomics recovery factor predicts long COVID in the IMPACC study. J Clin Invest. 2025 Sep 9;135(21):e193698. doi: 10.1172/JCI193698. PMID: 40924481; PMCID: PMC12582403. https://pmc.ncbi.nlm.nih.gov/articles/PMC12582403/ (Full text)

Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection

Abstract:

Plasma proteomic profiling of 92 individuals with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), assessed a mean of 34 months after acute infection, revealed a distinct inflammatory signature. Using proximity extension assay technology, 358 proteins were quantified, identifying 26 differentially expressed proteins (DEPs) in PASC: 23 upregulated and 3 downregulated.

The most upregulated proteins were Oncostatin M (OSM) and IL-1 receptor antagonist (IL1RN). Additional increases were observed in IL-6, IL-12B, IL-2, CCL22, CSF3, CSF1, and HLA-DRA, as well as proteins involved in tissue remodeling and angiogenesis such as ANGPTL2 and TGFA. Random forest analysis confirmed IL1RN, OSM, ANGPTL2, HLA-DRA, and CLEC4A as strong discriminators between patients and controls.

Gene set enrichment analysis demonstrated activation of multiple immune pathways, including Inflammatory Response, TNF-α/NF-κB signaling, IL-6/JAK/STAT3, IL-2/STAT5, and Allograft Rejection, indicating persistent activation of innate and adaptive immunity. STRING network analysis highlighted a tightly connected cytokine-driven inflammatory module. Plasma spike protein levels did not differ between patients and controls, suggesting that PASC-related inflammation may persist independently of ongoing viral replication.

Overall, the findings indicate a consistent low-grade inflammatory state in PASC without evidence for distinct biological subtypes.

Source: Fineschi S, Klar J, Schuster J, Bergquist J and Dahl N (2026) Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection. Front. Immunol. 17:1775044. doi: 10.3389/fimmu.2026.1775044  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1775044/full (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)

ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators

Abstract:

To identify ICD-10-GM codes recorded in the year preceding a Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) diagnosis, we conducted a 1:5 matched case–control study using statutory health insurance data of 6–27-year-olds with ME/CFS (ICD-10-GM: G93.3, 2020–2022). Cases (n = 6,077) were matched 1:5 to controls by birth year, sex, and postal code. ICD-10-GM codes from the preceding year were analyzed using multivariable conditional logistic regression, reporting odds ratios (OR) and 95% confidence intervals. Most cases were female and aged 18–27 years.

Forty-four ICD-10-GM code classes were associated with increased and four with decreased odds, spanning 13 diagnostic chapters. Most associations were in chapters F (mental/behavioral disorders), R (respiratory diseases), and M (musculoskeletal disorders). Frequent conditions included fatigue, depression, pain disorders, and somatoform disorders (≥ 10% in cases; ORs 1.11–2.19. Rare diagnoses (≤ 1% prevalence), such as fibromyalgia (OR 2.08, 95% CI: 1.20–3.59) and mild cognitive impairment (2.93, 1.21–7.10), were strongly associated. Four COVID-19 or vaccination-related code classes were identified, with post-COVID-19 condition showing the highest OR (3.84, 2.97–4.98). Several ICD-10-GM codes, including COVID-19 related codes, were associated with later ME/CFS diagnoses.

Prospective studies should clarify timing relative to ME/CFS onset, and distinguish between pre-existing conditions, comorbidities, early manifestations, or misdiagnoses.

Source:Wirth M, Haastert B, Linnenkamp U, Andrich S, Icks A, Pricoco R, Behrends U, De Bock F. ICD-10 Diagnoses prior to ME/CFS diagnosis in children and young people suggest potential early diagnostic indicators. Sci Rep. 2026 Feb 26. doi: 10.1038/s41598-026-40848-1. Epub ahead of print. PMID: 41741569. https://www.nature.com/articles/s41598-026-40848-1 (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)

Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial

Abstract:

Background: In the context of long COVID, persistent fatigue is among the most prevalent symptoms that can develop after SARS-CoV-2 infection. Mitochondrial myopathy and endothelial dysfunction, which are triggers of inflammation, have emerged as prominent causes of long COVID-induced fatigue. Interestingly, the intake of flavanols, particularly (−)-epicatechin (EC), has been associated with the positive modulation of endothelial and mitochondrial structure and function.
Methods: In this work, we conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether an EC-enriched supplement (ECES) improves plasma markers of inflammation, endothelial structure, and fatigue-related endpoints in patients with long COVID-19.
Results: The study included 46 subjects (mean age 52 years) who were instructed to consume two capsules/day for 90 days of either ECES (n = 23) or placebo (n = 23). Endpoints assessed included mean changes in plasma inflammatory markers (IL-1β, IL-6, and TNF-α) and endothelial dysfunction markers (syndecan-1), handgrip strength, fatigue scale, and quality of life (QoL). The results showed significant improvements in the ECES group for inflammatory markers, syndecan-1, and fatigue compared with the placebo group.
Conclusions: The results yield intriguing positive findings for EC and open a new avenue for treating long COVID.
Source: Munguía L, Silva S, Villarreal F, Nájera N, Ceballos G. Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial. Journal of Clinical Medicine. 2026; 15(4):1468. https://doi.org/10.3390/jcm15041468 https://www.mdpi.com/2077-0383/15/4/1468 (Full text)