Tag: long Covid

Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK

Abstract:

Objectives: This study aims to provide an in-depth analysis of the symptoms, coexisting conditions and service utilisation among people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. The major research questions include the clustering of symptoms, the relationship between key factors and diagnosis time, and the perceived impact of National Institute for Health and Care Excellence (NICE) guidelines on patient care.

Design: Cross-sectional survey using secondary data analysis.

Setting: Community-based primary care level across the UK, incorporating online survey participation.

Participants: A total of 10 458 individuals responded to the survey, of which 8804 confirmed that they or a close friend/family member had ME/CFS or long COVID. The majority of respondents were female (83.4%), with participants from diverse regions of the UK.

Primary and secondary outcome measures: Primary outcomes included prevalence and clustering of symptoms, time to diagnosis, and participant satisfaction with National Health Service (NHS) care, while secondary outcomes focused on symptom management strategies and the perceived effect of NICE guidelines.

Results: Fatigue (88.2%), postexertional malaise (78.2%), cognitive dysfunction (88.4%), pain (87.6%) and sleep disturbances (88.2%) were the most commonly reported symptoms among participants with ME/CFS, with similar patterns observed in long COVID. Time to diagnosis for ME/CFS ranged widely, with 22.1% diagnosed within 1-2 years of symptom onset and 12.9% taking more than 10 years. Despite updated NICE guidelines, only 10.1% of participants reported a positive impact on care, and satisfaction with NHS services remained low (6.9% for ME/CFS and 14.4% for long COVID).

Conclusions: ME/CFS and long COVID share overlapping but distinct symptom clusters, indicating common challenges in management. The findings highlight significant delays in diagnosis and low satisfaction with specialist services, suggesting a need for improved self-management resources and better-coordinated care across the NHS.

Source: Mansoubi M, Richards T, Ainsworth-Wells M, Fleming R, Leveridge P, Shepherd C, Dawes H. Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK. BMJ Open. 2025 Apr 2;15(4):e094658. doi: 10.1136/bmjopen-2024-094658. PMID: 40180399. https://bmjopen.bmj.com/content/15/4/e094658 (Full text)

Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC)

Summary:

  • Immune dysregulation is a key aspect of post-acute sequelae of coronavirus disease 2019 (PASC), also known as long COVID, with sustained activation of immune cells, T cell exhaustion, skewed B cell profiles, and disrupted immune communication thereby resulting in autoimmune-related complications.
  • The gut is emerging as a critical link between microbiota, metabolism and overall dysfunction, potentially sharing similarities with other chronic fatigue conditions and PASC.
  • Immunothrombosis and neurological signalling dysfunction emphasise the complex interplay between the immune system, blood clotting, and the central nervous system in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
  • Clear research gaps in the design of PASC studies, especially in the context of longitudinal research, stand out as significant areas of concern.

Source: Adhikari, A., Maddumage, J., Eriksson, E.M., Annesley, S.J., Lawson, V.A., Bryant, V.L. and Gras, S. (2024), Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC). Med J Aust, 221: S40-S48. https://doi.org/10.5694/mja2.52456 https://onlinelibrary.wiley.com/doi/full/10.5694/mja2.52456 (Full text)

The metabolic and physiologic impairments underlying long COVID associated exercise intolerance

Abstract:

Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO2), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS-CoV-2 infection has implications on EO2 and exercise capacity (VO2) nor has there been assessment of anerobic ATP generation in long COVID patients. iCPET was performed on 47 long COVID patients (i.e., full cohort; n = 8 with severe SARS-CoV-2 infection). ‘

In a subset of patients (i.e., metabolomic cohort; n = 26) metabolomics on venous and arterial blood samples during iCPET was performed. In the full cohort, long COVID patients exhibited reduced peak EO2 with reduced peak VO2 (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO2 [88% predicted (IQR 81% – 108%) vs. 70% predicted (IQR 64% – 89%); p = 0.02] and EO2 [0.59(IQR 0.53-0.62) vs. 0.53(IQR 0.50-0.48); p = 0.01) were lower in severe versus mild infection.

In the metabolomic cohort, 12 metabolites were significantly consumed, and 41 metabolites were significantly released (p-values < 0.05). Quantitative metabolomics demonstrated significant increases in inosine and succinate arteriovenous gradients during exercise. Peak VO2 was significantly correlated with peak venous succinate (r = 0.68; p = 0.0008) and peak venous lactate (r = 0.49; p = 0.0004). Peak EO2 and consequently peak VO2 impact long COVID patients in a severity dependent manner.

Exercise intolerance associated with long COVID is defined by impaired aerobic and anaerobic energy production. Peak venous succinate may serve as a potential biomarker in long COVID.

Source: Leitner BP, Joseph P, Quast AF, Ramirez MA, Heerdt PM, Villalobos JG, Singh I. The metabolic and physiologic impairments underlying long COVID associated exercise intolerance. Pulm Circ. 2024 Nov 13;14(4):e70009. doi: 10.1002/pul2.70009. PMID: 39544193; PMCID: PMC11560803. https://pmc.ncbi.nlm.nih.gov/articles/PMC11560803/ (Full text)

Prevalence of EBV, HHV6, HCMV, HAdV, SARS-CoV-2, and Autoantibodies to Type I Interferon in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome, also termed long COVID. In this study, potential mechanisms behind this exhaustion were investigated.

First, the viral load of Epstein-Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity.

We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression and severe ME/CFS, respectively. HCMV and SARS-CoV-2 were found only in immunosuppressed controls. Notably, anti-IFN-I autoAbs in ME/CFS and controls did not differ, except in a severe ME/CFS case showing an increased level.

We conclude that ME/CFS patients, compared to controls, have a significantly higher load of EBV. IFN-I autoAbs cannot explain IFN-I dysfunction, with the possible exception of severe cases, also reported in severe SARS-CoV-2. We forward that additional mechanisms, such as the viral evasion of IFN-I effect via the degradation of IFN-receptors, may be present in ME/CFS, which demands further studies.

Source: Hannestad U, Allard A, Nilsson K, Rosén A. Prevalence of EBV, HHV6, HCMV, HAdV, SARS-CoV-2, and Autoantibodies to Type I Interferon in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Viruses. 2025 Mar 14;17(3):422. doi: 10.3390/v17030422. PMID: 40143349; PMCID: PMC11946815. https://pmc.ncbi.nlm.nih.gov/articles/PMC11946815/ (Full text)

Health outcomes one year after Omicron infection among 12,789 adults: a community-based cross-sectional study

Summary:

Background: Characterizing the paradigm and impact of long COVID is crucial for addressing this worldwide health challenge. This study aimed to investigate the prevalence of long COVID one year after primary Omicron infection and characterize differences in long-term health consequence between participants with persistent long COVID and those who fully recovered.

Methods: This a community-based cross-sectional study conducted from December 2023 to March 2024 at the China-Japan Friendship Hospital and 16 administrative districts in Beijing. 12,789 participants infected with Omicron between December 2022 and January 2023 were recruited through stratified multistage random sampling and included in the final analysis. Of them, 376 participants with persistent long COVID and 229 without long COVID were matched for further physical examinations. The primary outcome was the prevalence of long COVID one year after infection. Secondary outcomes included muscle strength, exercise capacity, health-related quality of life (HRQoL), mental health, work status, laboratory tests, and examinations.

Findings: Among 12,789 participants (media [IQR] age, 48.4 [37.3 to 61.4] years; 7817 females [61.1%]), 995 of them (7.8%) experienced long COVID within one year, with 651 (5.1%) having persistent symptoms. Fatigue (598/995 [60.1%]) and post-exertional malaise (367/995 [36.9%]) were the most common symptoms. Brain fog had the lowest resolution proportion as 4.2% within one year. The odds of long COVID increased with reinfections (odds ratios for one reinfection 2.592 [95% CI: 2.188 to 3.061]; two or more: 6.171 [3.227 to 11.557]; all p < 0.001). Participants with persistent long COVID had markedly lower muscle strength (upper-limb: 26.9 ± 12.4 vs. 29.1 ± 14.5 Kg; lower-limb: 40.0 [27.0 to 62.0] vs. 43.0 [28.0 to 59.0] s), worse exercise capacity and poorer HRQoL, and meaningful difference in laboratory tests results compared to those without long COVID. They also exhibited significantly higher proportions of abnormal lung function (FEV1 %pred<80%: 13.0% vs. 2.0%; DLco %pred<80%: 32.7% vs. 19.9%) and lung imaging abnormalities (23.5% vs. 13.6%).

Interpretation: The considerable health burden of long COVID and the progression of neurological symptoms following Omicron infection warrant close monitoring. Utilizing professional questionnaires and developing reliable diagnostic tools are necessary for improving diagnosis and treatment of long COVID.

Funding: This work was supported by Beijing Research Center for Respiratory Infectious Diseases (BJRID2024-012), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-CoV19-005/CIFMS 2021-I2M-1-048), the National Natural Science Foundation of China (82241056/82200114/82200009), the New Cornerstone Science Foundation.

Source: Zhang, Hui et al.Health outcomes one year after Omicron infection among 12,789 adults: a community-based cross-sectional study. The Lancet Regional Health – Western Pacific, Volume 0, Issue 0, 101507  https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(25)00044-6/fulltext (Full text)

Gulf War Illness: A Historical Review and Considerations of a Post-Viral Syndrome

Abstract:

Gulf War Illness (GWI) is a condition that affects 30-40% of nearly 700,000 Veterans who were deployed to Operations Desert Shield/Storm/Sabre (ODS/S/S) between August 1990 and June 1991 and is characterized by a constellation of symptoms, including fatigue, mood/cognition, chronic pain, gastrointestinal (most frequently referred to as “irritable bowel syndrome”), respiratory, and skin issues.

We review the development of various case definitions for GWI, as well as exposure theories. Despite heavy investment in research, both the pathophysiology and underlying cause of GWI remain areas of active inquiry. Similarities have previously been noted in symptomatology between GWI and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and more recently, long COVID (LC), a late effect of infection with the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2).

These conditions are discussed with respect to the similarities of their symptomatology and pathophysiology. Long COVID is a post-viral syndrome, and ME/CFS is widely considered to be likely post-infectious as well. This comparison leads to the proposal of the hypothesis that GWI may also be post-viral. Given the similarity of GWI and LC, it is possible that Veterans with GWI had an antecedent infection with a virus related to SARS-CoV-2, potentially the Middle East Respiratory Syndrome Coronavirus (MERS) or an ancestor of this virus. The MERS antibodies have been found in dromedary camels in Saudi Arabia since 1983 to the present, including the time of ODS/S/S. There is abundant evidence to support further investigation into this topic.

Source: Bast E, Jester DJ, Palacio A, Krengel M, Reinhard M, Ashford JW. Gulf War Illness: A Historical Review and Considerations of a Post-Viral Syndrome. Mil Med. 2025 Mar 21:usaf092. doi: 10.1093/milmed/usaf092. Epub ahead of print. PMID: 40117126. https://pubmed.ncbi.nlm.nih.gov/40117126/

Efficacy of vitamin D replacement therapy on 28 cases of myalgic encephalomyelitis/chronic fatigue syndrome after COVID-19 vaccination

Abstract:

Background: Prolonged symptoms have been reported following both COVID-19 infection and vaccination, with some cases leading to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Of 80 patients presenting to our hospital with postvaccination syndrome, 28 met the diagnostic criteria for ME/CFS. We conducted a retrospective study on these 28 patients.

Methods: We measured serum 25-hydroxyvitamin D levels in 28 patients who developed ME/CFS after COVID-19 vaccination between August 2022 and February 2024. Vitamin D replacement therapy included dietary counseling, sun exposure recommendations, and oral vitamin D supplementation. We evaluated changes in blood vitamin D levels and symptom improvement.

Results: At initial visit, 27 of 28 patients diagnosed with ME/CFS had insufficient or deficient serum 25-hydroxyvitamin D levels (16 ± 4 ng/mL, mean ± SD). Following vitamin D replacement therapy, we observed an increase in blood vitamin D levels (28 ± 5 ng/mL) associated with a decrease in ME/CFS diagnostic symptoms (from 10.3 ± 2.1 to 3.3 ± 2.0). Notably, 23 of 28 patients (82%) no longer met ME/CFS diagnostic criteria after the therapy. Among the symptoms, sleep problems showed the most improvement (71%), followed by autonomic symptoms (68%).

Conclusions: For patients developing ME/CFS after COVID-19 vaccination with insufficient or deficient vitamin D levels, appropriate vitamin D replacement therapy under medical guidance may lead to symptomatic relief. We are preparing a randomized controlled trial to evaluate the efficacy of vitamin D replacement therapy in individuals with ME/CFS who have developed vitamin D deficiency following COVID-19 infection or vaccination.

Source: Kodama S, Konishi N, Hirai Y, Fujisawa A, Nakata M, Teramukai S, Fukushima M. Efficacy of vitamin D replacement therapy on 28 cases of myalgic encephalomyelitis/chronic fatigue syndrome after COVID-19 vaccination. Nutrition. 2025 Feb 18;134:112718. doi: 10.1016/j.nut.2025.112718. Epub ahead of print. PMID: 40090177. https://www.sciencedirect.com/science/article/pii/S089990072500036X (Full text)

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS

Abstract:

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined.

In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. ‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Source: Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med. 2025 Mar 10;23(1):297. doi: 10.1186/s12967-025-06220-z. PMID: 40059164. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06220-z (Full text)

Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures

Abstract:

Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS.

In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-α and IL-6. We found that exposure to TNF-α produced both a concentration-independent and concentration-dependent response in neural activity.

Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL – 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-α (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-α (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1β, IL-4, and CXCL-10) that were observed at higher TNF-α concentrations.

Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL-10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-α, while at high concentrations of TNF-α the addition of IL-6 had little to no effect. Conversely, the changes to electrophysiological features induced by IL-6 were lost when the cultures were co-stimulated with TNF-α regardless of the concentration, suggesting that TNF-α may play a more pronounced role in altering neural function.

These results indicate that increased concentrations of key inflammatory cytokines associated with long-COVID can directly impact neural function and may be a component of the cognitive impairment associated with long-COVID and other post-viral infection disorders.

Source: Goshi N, Lam D, Bogguri C, George VK, Sebastian A, Cadena J, Leon NF, Hum NR, Weilhammer DR, Fischer NO, Enright HA. Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures. Front Cell Neurosci. 2025 Feb 12;19:1512591. doi: 10.3389/fncel.2025.1512591. PMID: 40012566; PMCID: PMC11860967. https://pmc.ncbi.nlm.nih.gov/articles/PMC11860967/ (Full text)

Novel Oronasal Drainage for Long COVID: Proposed Mechanisms-Case Report

Abstract:

Long COVID, potentially emerging post COVID-19 infection, involves extreme health challenges. Based on current literature in the field, we propose a novel approach to Long COVID treatment based on epipharyngeal abrasive therapy targeting ostia of the oral and nasal mucosa, having been identified for the first time. The presented case report documents the application of innovative oronasal drainage (OND), a novel treatment integrating physiological, biochemical, and fluid mechanical components simultaneously.

OND led to remarkable improvements and even remissions of various symptoms, along with enhanced hand blood circulation. While the case suggests potential efficacy in Long COVID therapy, acknowledging inherent limitations is essential and its impact needs further validation through clinical trials.

Source: Lorenz C, Frankenberger R. Novel Oronasal Drainage for Long COVID: Proposed Mechanisms-Case Report. Viruses. 2025 Jan 31;17(2):210. doi: 10.3390/v17020210. PMID: 40006965. https://www.mdpi.com/1999-4915/17/2/210 (Full text)