Tag: long covid symptoms

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)

Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases

Abstract:

Background: Post-exertional malaise (PEM), which is the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is also reported in a proportion of patients with post-COVID-19 syndrome (PCS). Our objective was to identify determinants that may be linked to the emergence of PEM in PCS patients.

Methods: Patients fulfilling the World Health Organization definition for PCS who attended the post-COVID unit of the Internal Medicine Department of Angers University Hospital, France, between June 2020 and December 2023 were included retrospectively. Their medical records were reviewed to extract information on COVID-19 infection history, characteristics of post-exertional malaise (PEM), fatigue severity, and relevant epidemiological variables.

Results: The study included 220 patients, grouped according to whether post-exertional malaise was present (PCS/PEM+) or absent (PCS/PEM-). PEM was observed in 26.4% of patients and was significantly linked to earlier COVID onset in 2020/2021 (OR 5.68 (95% CI: 1.66-19.45), p = 0.006), as well as higher fatigue levels (OR 2.07 (95% CI: 1.22-3.50), p = 0.007).

Conclusions: Patients who contracted COVID-19 during the pre-Omicron period reported PEM more frequently than those infected in later waves. This observation could reflect differences in viral characteristics following the emergence of the Omicron variant; however, alternative explanations-such as increasing vaccination coverage, accumulating post-infectious immunity, or other unmeasured factors-cannot be ruled out. Based on the observed link between PEM and symptom severity, PCS patients should be systematically assessed for the presence of PEM.

Source: Ghali A, Lavigne C, Ghali M, Lacombe V. Post-Exertional Malaise in Post-COVID-19 Syndrome: A Shift in the Frequency Across Pandemic Phases. J Clin Med. 2026 Apr 13;15(8):2948. doi: 10.3390/jcm15082948. PMID: 42074751. https://www.mdpi.com/2077-0383/15/8/2948 (Full text)

A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a neuroimmune disease characterized by debilitating post-exertional malaise (PEM), brain-fog/cognitive problems, and dysregulation of the autonomic nervous system. Currently, there are no objective biomarkers for ME/CFS despite decades of research.

Here, we compile evidence from literature that supports taste dysfunction, particularly alterations of taste perception mediated by Type II taste receptor cells, may be a critical underrecognized feature of ME/CFS. The impetus is drawn from the emerging evidence of clinicopathological similarities between long-COVID and ME/CFS. We discuss in parallel the mechanisms of cellular metabolism, inflammation, vascular dysfunction, and autonomic dysregulation in ME/CFS and long-COVID pathophysiology.

We postulate that mechanistically, dysregulation of ATP signaling through P2X2/P2X3 purinergic receptors underlies both gustatory impairment and core ME/CFS symptoms. Adopting information from the NIH-RECOVER shared resources, we present evidence that suggests chemosensory dysfunction as a potential indicator of progression/severity of PEM. We discuss standardized taste testing as a non-invasive screening tool complementary to molecular biomarkers for ME/CFS.

Notwithstanding, we acknowledge the limitations, confounding and contributing factors such as medications and deficiencies that may exacerbate or independently cause taste-related symptoms in ME/CFS.

In conclusion, we present a compelling case for the multi-factorial role of taste dysfunction in ME/CFS and suggest specific research priorities for investigating the relationship between chemosensory function and post-viral chronic illness.

Source: Srinivasan M, Joseph PV. A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID. Front Med (Lausanne). 2026 Apr 8;13:1808646. doi: 10.3389/fmed.2026.1808646. PMID: 42040552; PMCID: PMC13107777. https://pmc.ncbi.nlm.nih.gov/articles/PMC13107777/ (Full text)

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)