Tag: long Covid

Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of lif

Abstract:

Purpose: The aim of this study was to investigate the impact of post-exertional malaise (PEM) frequency and PEM severity on health-related quality of life (HRQoL) among individuals with Long COVID.

Methods: We conducted a cross-sectional online survey including adults in Germany with self-reported Long COVID and PEM. Fatigue severity was assessed with the Fatigue Assessment Scale (FAS), and HRQoL was measured using the EQ-5D-3L (descriptive index and visual analogue scale [EQ-VAS]). Associations between PEM frequency, fatigue, and HRQoL were examined using correlations and non-parametric group comparisons. Multiple linear regression models were fitted to predict HRQoL while controlling for age, sex, employment status, and subjective social status.

Results: Higher PEM frequency was associated with significantly lower EQ-5D index scores (ρ = – 0.32, p<.001). PEM severity was also strongly correlated with reduced HRQoL (EQ-5D index: ρ = – 0.43, p<.001). In multivariable regression models, greater fatigue and higher PEM frequency independently predicted poorer HRQoL, even after adjustment for sociodemographic factors.

Conclusion: Both PEM frequency and PEM severity substantially impair HRQoL in individuals with Long COVID. These findings underscore the clinical relevance of PEM as a key symptom and highlight the need for targeted management strategies to mitigate its impact on daily life.

Clinical trial number: German Clinical Trials Register DRKS00026007; registration date: 9 September 2021.

Source: Thölking T, Müller F, Riester T, Lampe V, Theil LM, Hummers E, Sarpari K, Dopfer-Jablonka A, Happle C, Steffens S, Meier-Maiwald M, Mikuteit M, Schröder D. Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of life. Health Qual Life Outcomes. 2026 May 11;24(1):64. doi: 10.1186/s12955-026-02523-x. PMID: 42116095; PMCID: PMC13162394. https://pmc.ncbi.nlm.nih.gov/articles/PMC13162394/ (Full text)

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from post-exertional malaise. The accompanying physical inactivity may contribute to a lower aerobic capacity and may explain skeletal muscle adaptations in these patients. Here, we compare whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in long COVID and ME/CFS patients, and healthy age- and sex-matched controls.

Bed rest alters respiratory and cardiovascular responses to maximal exercise, which are dissimilar in patients. Bed rest causes muscle atrophy without altering fiber type. Both patient groups have more glycolytic fibers, and ME/CFS patients display type I-specific atrophy. Only after bed rest is oxidative phosphorylation capacity associated with maximal oxygen uptake.

As skeletal muscle characteristics differ between patients and healthy individuals after bed rest, physical inactivity cannot solely explain the lower exercise capacity and skeletal muscle adaptations in long COVID and ME/CFS patients.

Source: Charlton BT, Slaghekke A, Appelman B, Eggelbusch M, Huijts JY, Noort W, Hendrickse PW, Bloemers FW, Posthuma JJ, van Amstel P, Goulding RP, Degens H, Jaspers RT, van Vugt M, Wüst RCI. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. Nat Commun. 2026 Jul 28;17(1):9125. doi: 10.1038/s41467-026-75725-y. PMID: 42649155. https://www.nature.com/articles/s41467-026-75725-y (Full text)

Medical invalidation is associated with structural barriers in postacute immune mediated syndromes based on patient perspectives in Germany

Abstract:

Post-acute immune-mediated syndromes (PAIMS), including Long COVID/Post-COVID (LC/PC), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and post-acute COVID-19 vaccination syndrome (PACVS), are characterized by persistent, multisystemic symptoms and significant healthcare challenges. A key issue is medical invalidation, defined as the dismissal or delegitimization of patients’ reports of symptoms. This cross-sectional online study, conducted in Germany between October and December 2025 (N = 577), examined healthcare experiences, access barriers, and perceived invalidation.

Although healthcare utilization was high, 87% of participants reported difficulties accessing appropriate treatment. Major barriers included lack of available therapies (60%) or not being taken seriously (26%). Perceived invalidation by medical personnel was moderate across all groups (LC: M = 2.80; ME/CFS: M = 2.99; PACVS: M = 3.03) and did not differ significantly (Welch-F(2, 190.50) = 2.87, p = 0.059) between groups. Invalidation occurred not only within healthcare settings but was particularly pronounced in interactions with authorities and workplaces. Social media and online communities served as important sources of information and support, especially among individuals with ME/CFS.

Overall, the findings reveal substantial structural barriers in the care of PAIMS and highlight the need for improved clinical education, better care coordination, and stronger institutional recognition of these conditions.

Source: Saad J, Hensen J, Bergelt C, Lerch SP. Medical invalidation is associated with structural barriers in postacute immune mediated syndromes based on patient perspectives in Germany. Sci Rep. 2026 Aug 25;16(1):26687. doi: 10.1038/s41598-026-67883-2. PMID: 42642464; PMCID: PMC13507045. https://pmc.ncbi.nlm.nih.gov/articles/PMC13507045/ (Full text)

Virus reactivation in acute and long COVID-19

Abstract:

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein-Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2-7.

Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID.

Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID.

This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.

Source: Maguire C, Chen J, Rouphael N, Morse BA, Hoch A, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R; IMPACC Network; Corry D, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Messer WB, Davis MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brakenridge SC, Ehrlich LIR, Montgomery RR, Shaw A, Hough CL, Hafler D, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze S, Krammer F, Bosinger SE, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, Melamed E. Virus reactivation in acute and long COVID-19. Nature. 2026 Aug;656(8128):700-711. doi: 10.1038/s41586-026-10740-z. Epub 2026 Aug 5. PMID: 42557313; PMCID: PMC13489964. https://pmc.ncbi.nlm.nih.gov/articles/PMC13489964/ (Full text)

Exploring the influence of long COVID upon self-identity: a systematic literature review

Abstract:

Background: Long COVID (LC) is understood to be a multisystemic illness involving symptoms of an enduring nature. As underlying pathophysiological mechanisms of LC become better understood, attention has turned towards the psychological aspects of LC lived experience. Comparable conditions, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), are known to significantly impact self-identity. However, no prior review has explored this topic in the LC population. This review sought to offer an original and exploratory narrative of LC patients’ experiences connected to self-identity.

Methods: A systematic literature review using a Narrative Synthesis approach. Twenty-one qualitative studies (including 613 participants), published between January 2021-March 2025, exploring the influence of LC upon perceptions of self-identity were reviewed. Narrative Synthesis (NS) and PRISMA guidelines were followed.

Results: Four main themes emerged: “Grief and Loss of the Familiar Self”, “Reflections of Self, Mirrored by Others”, “Threats to Identity”, and “Repairing Fractured Identity”.

Conclusions: For many, LC ruptures self-narratives that contribute to a stable and continuous sense of self across time. This can bring forth a strong grieving response to perceived losses and the unfamiliarity of self. Despite this, narratives of post-traumatic growth (PTG) were realised. Current guidance lacks direction for psychological interventions targeting LC-related distress. Acknowledgement of identity-based challenges must also be reflected in future guidance, with clear recommendations for clinical practice. Qualitative longitudinal exploration of LC’s influence upon self-identity should be prioritised. Similarly, the acceptability and feasibility of interventions targeting identity-transformation work require further investigation.

Trial registration: PROSPERO ID: CRD420251008410.

Source: Holmes-McCoid HJ, Lecky FE. Exploring the influence of long COVID upon self-identity: a systematic literature review. Arch Public Health. 2026 Aug 11;84(1):189. doi: 10.1186/s13690-026-02017-8. PMID: 42638142. https://link.springer.com/article/10.1186/s13690-026-02017-8 (Full text)

Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study

Abstract:

Background: Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health.

Methods: The “All Eyes on PCS” is a prospective observational study assessing the microcirculation using retinal vessel analysis (RVA). Both dynamic and static parameters (DVA and SVA) were compared across never SARS-CoV-2 infected individuals (NI, n = 96), SARS-CoV-2 recovered individuals (n = 102), and PCS patients (n = 102), including a subgroup fulfilling ME/CFS criteria (n = 62). Analyses were complemented by propensity score-based weighting and multivariable adjustment. Associations with symptom severity and circulating biomarkers of endothelial dysfunction and inflammation were examined.

Results: PCS patients showed reduced venular flicker-induced dilation compared with recovered individuals (3.7% ± 2.2 vs. 4.8% ± 3.0, p = 0.006) and narrower retinal arterioles (CRAE) compared with both recovered (178.3 ± 15.5 μm vs. 186.1 ± 15.7 μm, p = 0.001) and NI individuals (184.4 ± 14.3 μm, p = 0.009). Arteriolar-to-venular ratio (AVR) was lower in PCS compared with NI (0.83 ± 0.06 vs. 0.87 ± 0.06, p < 0.001) and recovered participants (0.86 ± 0.07, p = 0.034). Findings remained largely consistent after age and sex balancing and adjustment for CV risk factors, although the association for AVR was attenuated. PCS patients fulfilling ME/CFS criteria showed the most pronounced retinal microvascular alterations, and a combined model discriminated ME/CFS patients with good accuracy (AUC = 0.79). Higher symptom burden was associated with lower AVR (r = – 0.21, p = 0.037), particularly for neurocognitive symptoms. IL-6, ICAM-1, and VCAM-1 were elevated in PCS and ME/CFS, and lower AVR was associated with inflammatory and iron-related markers (all adjusted p < 0.01).

Conclusions: PCS is associated with persistent endothelial dysfunction, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. These findings support the potential use of RVA as a non-invasive tool for assessing and monitoring endothelial health in post-viral syndromes, with implications for cardiovascular risk stratification.

Trial registration: The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552).

Source: Wallraven T, Günthner R, Lethen I, Ribeiro A, Lech M, Oertel FC, Reeß LG, Haller B, Streese L, Hanssen H, Basta-Wunderle M, Schmaderer C. Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study. BMC Med. 2026 Aug 19;24(1):456. doi: 10.1186/s12916-026-05144-9. PMID: 42625188. https://link.springer.com/article/10.1186/s12916-026-05144-9 (Full text)

Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging

Abstract:

Background: Post-COVID-19 Syndrome (PCS) encompasses a range of persistent symptoms, including cognitive and autonomic disturbances, potentially linked to microvascular or neuroinflammatory mechanisms. Retinal imaging provides a non-invasive window into the central nervous system and vascular integrity. This study aimed to assess retinal structural and microvascular alterations in PCS patients and explore their relationship with symptom severity.

Methods: In this monocentric, cross-sectional, exploratory study, we performed Optical Coherence Tomography (OCT) and OCT Angiography (OCTA) in patients with PCS and a group of COVID-19 recovered individuals. Multiple circulating biomarkers reflecting endothelial dysfunction and chronic inflammation were measured. Associations with validated symptom scores (PCS Score, C19-YRS, PHQ-9, GAD-7) were evaluated.

Results: After adjusting for age and gender, no significant differences were observed in OCTA-derived vessel density (VD) or foveolar avascular zone (FAZ) between PCS patients and COVID-19-recovered controls. However, PCS patients exhibited significant thinning of the peripapillary retinal nerve fibre layer (pRNFL), ganglion cell inner plexiform layer (GCIP), and total macular volume (TMV). Lower values of these structural parameters were consistently observed in patients with higher symptom severity. Vascular parameters (VD and FAZ) were not related to clinical scores. Higher MCP-1 levels, a chemokine associated with chronic inflammation, were linked to lower inner nuclear layer and GCIP thickness.

Conclusion: Structural retinal alterations in PCS were associated with symptom burden and may reflect underlying neuroinflammatory or neurodegenerative processes. OCT parameters could serve as potential non-invasive biomarkers, warranting further investigation in longitudinal, multicenter studies.

Source: Wunderle M, Wicklein R, Ribeiro A, Carbajo-Lozoya J, Wöhnl A, Negele J, Kesseler V, Wild A, Niedermayer S, Lethen I, Lech M, Menten MJ, Kreitner L, Schmaderer C, Wallraven T. Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging. Brain Behav Immun Health. 2026 Jul 25;56:101315. doi: 10.1016/j.bbih.2026.101315. PMID: 42571220; PMCID: PMC13451791. https://pmc.ncbi.nlm.nih.gov/articles/PMC13451791/ (Full text)

Recovery trajectories and predictors of symptom resolution in post-COVID-19 condition: a population-based cohort study

Abstract:

Background: SARS-CoV-2 infection can lead to persistent symptoms, known as Post-COVID-19 Condition (PCC). Previous studies on PCC prognosis mainly looked at severe cases in rehabilitation settings and without knowledge about pre-infection symptom levels. Uncertainty remains about recovery trajectory in the general population, its predictors, and whether recovery differs by symptom.

Methods: We analysed data from Lifelines, a prospective population-based observational cohort. Adults completed 31 COVID-19 questionnaires between March 2020 and October 2022 providing longitudinal symptom data to assess PCC status, and recovery. PCC was defined as at least one moderately severe symptom, among 12 identified as PCC-specific, that worsened 90-150 days after infection. Cox-proportional hazard models estimated recovery, defined as symptom decline to an individual’s pre-infection baseline, adjusted for symptoms present at PCC diagnosis, age, sex, BMI, smoking, hospitalization, vaccination, and comorbidities.

Findings: We analysed time series of 809 cases (mean age 55.0; [SD 11.0]; 590 [73%] female; mean follow up 368 days; [SD 200]). Symptom decline to pre-infection baseline or below was observed in 558 participants; the Kaplan-Meier 24-month symptom decline estimate was 92%. Greater symptom burden was associated with a lower likelihood of recovery (HR per additional symptom 0.69, 95% CI 0.63-0.76), whereas younger age had a higher likelihood of recovery compared with middle adulthood (HR 1.52, 95% CI 1.06-2.18). Median time to symptom decline was 226 days (IQR 182-372), with most improvement within the first 235 days before slowing and plateauing.

Interpretation: Most individuals with PCC recover, but older adults and those with multiple symptoms are at higher risk of prolonged illness, underscoring the need for ongoing support.

Source: Brunet JL, van Ockenburg SL, Leyli-Abadi M, Lunter G, Rosmalen JGM. Recovery trajectories and predictors of symptom resolution in post-COVID-19 condition: a population-based cohort study. Lancet Reg Health Eur. 2026 Aug 8;69:101802. doi: 10.1016/j.lanepe.2026.101802. PMID: 42604070; PMCID: PMC13476563. https://pmc.ncbi.nlm.nih.gov/articles/PMC13476563/ (Full text)

Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID

Abstract:

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC.
In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups.
Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories.
This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance.
These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts.

Source: Moezzi A, Elremaly W, Leveau C, Franco A, Nepotchatykh O, Armstrong CW, Moreau A. Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID. International Journal of Molecular Sciences. 2026; 27(15):7000. https://doi.org/10.3390/ijms27157000 https://www.mdpi.com/1422-0067/27/15/7000 (Full text)

Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms

Abstract:

Background: U.S. Veterans experience a high burden of COVID-19; characterizing immune responses associated with COVID-19 outcomes could help improve treatment. Changes in peripheral blood cytokines over time may predict both acute outcomes and long COVID symptoms.

Methods: Cytokine concentrations were quantified from peripheral blood collected 0-7 days (early) and 14-42 days (post-acute) after enrollment from SARS-CoV-2 positive participants in the EPIC3 study, a prospective, longitudinal cohort following U.S. Veterans. Responses were correlated with Veterans Affairs Severity Index for COVID-19 criteria and chronic symptoms with the modified Medical Research Council Dyspnea scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive function, and PROMIS Fatigue scores 3 months after enrollment (60-135 days). Trends in cytokine concentration with COVID-19 severity were assessed. Odds of COVID-19 severity and long-term symptoms were estimated with logistic regression adjusted for sex, age, and morbidity. Longitudinal changes in cytokine concentration were examined for participants sampled during both time periods, by severity and long-term symptom group.

Results: Early HGF, IL-18, IL-1RA, IP-10, and VEGF-A and post-acute MIP-1α and VEGF-A concentrations trended positively with increasing COVID-19 severity (q-values < 0.05, Jonckheere-Terpstra trend test). Increases in EGF, MIP-1β, and RANTES concentration and decreases in MIP-1α concentration over time were associated with mild rather than moderate or severe disease. Increases in MIP-1β and RANTES concentration and decreases in Eotaxin concentration over time were associated with the absence of long-term symptoms.

Conclusions: Worse COVID-19 severity by 30 days was associated with higher early and post-acute period cytokine concentrations. Participants with long-term symptoms did not see resolution of cytokine responses over time.

Source: Mendall C, Li X, Pakanati V, Liu C, Wang T, Morelli D, Korpak A, Baraff A, Isaacs SN, Chang KM, Le E, Holodniy M, Sugimoto JD, Smith NL, Lee JS, Ross JM, Shah JA. Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms. Front Immunol. 2026 Jul 15;17:1870109. doi: 10.3389/fimmu.2026.1870109. PMID: 42528778; PMCID: PMC13415590. https://pmc.ncbi.nlm.nih.gov/articles/PMC13415590/ (Full text)