Tag: long Covid

How I treat my patients with Myalgic Encephalomyelitis, Chronic Fatigue Syndrome (ME/CVS), fibromyalgia or “long COVID”

Abstract:

Common to Myalgic encephalomyelitis, chronic fatigue syndrome and so-called long Covid is the panoply of complaints, with Post Exertional Malaise (PEM) as the most typical symptom. Added to that are permanent feeling of fatigue, decreased capacity to concentrate, so-called brain fog, non restorative sleep, diffuse pain, and – in case of long Covid – respiratory distress.

Several recent studies have confirmed my original hypothesis that poor metabolism and energy production by the mitochondria are responsible for the majority of these phenomena. I have suggested that inhibition of Pyruvate dehydrogenase (Pdh) activity is the major reason for this. Pdh inhibition is probably caused by the excess of the phosphatase: Pyruvate Dehydrogenase Kinase (PDK). The latter results from “Systemic Immune Disorder” (what I called “SID”) and inflammation.

Based on this hypothesis I have applied oral and infusion treatment modalities which were successful in approximately 80% of 130 consecutive patients. The pivotal substances are sodium dichloroacetate, that reduces PDK, Meldonium, that facilitates intracellular glucose metabolism, and low dose Nalexone, that optimises the function of microglia.

Source: Comhaire F. How I treat my patients with Myalgic Encephalomyelitis, Chronic Fatigue Syndrome (ME/CVS),
Fibromyalgia or “long COVID”. J Clin Images Med Case Rep. 2025; 6(3): 3508. https://jcimcr.org/pdfs/JCIMCR-v6-3508.pdf (Full text)

Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID

Abstract:

Objectives Patients with Long COVID experience disabling fatigue, autonomic dysfunction, reduced exercise capacity, and post-exertional malaise (PEM). Heart rate variability (HRV) can evaluate autonomic function and monitor overexertion, potentially helping to mitigate PEM. This study aimed to use continuous multi-day HRV recordings to monitor overexertion and study autonomic function in Long COVID.

Method Heart rate and HRV were continuously measured in 127 patients with long COVID (43±11 years, 32% male) and 21 healthy controls (42±13 years, 48% male), and daily life activities tracked in a logbook. Participants underwent a (sub)maximal cardiopulmonary exercise test to determine heart rate at the first ventilatory threshold (VT1) to study HRV responses to exercise at different intensities.

Results HRV was lower in patients with long COVID compared to healthy controls during various daily activities and sleep (p<0.027). HRV remained lower for 24 hours after exercise below, at or above VT1 in patients, but not in healthy controls (p=0.010). Nighttime HRV decreased with intense exercise and longer durations in patients with long COVID (p=0.018), indicative of exercise-induced diurnal disturbances of the autonomic nervous system in long COVID.

Conclusion Heart rate variability, assessed by wearables, confirms autonomic dysfunction in patients with long COVID. The delayed recovery of the sympathovagal balance after exercise close and above to VT1 suggests that VT1 can be practically interpreted as a PEM threshold.

Application These results confirm the applicability of wearables to assess autonomic function and manage overexertion in long COVID patients.

What is already known on this topic Patients with long COVID often experience fatigue, autonomic dysfunction, and post-exertional malaise (PEM). HRV can be used as a non-invasive tool to measure autonomic function and recovery. Anecdotal evidence suggests lower HRV in patients with long COVID, but measurements are usually very short.

What this study adds This study demonstrates that continuous HRV monitoring through wearables can effectively identify overexertion and autonomic dysfunction during daily activities in patients with long COVID. Patients with long COVID have a lower heart rate variability during sleep and HRV remained significantly lower for a longer period after moderate-to-heavy exercise, that is generally associated with the induction of post-exertional malaise.

How this study might affect research, practice, or policy This study supports the use of wearables for assessing autonomic function and overexertion in daily life, helping patients with long COVID in pacing daily activities to mitigate symptoms of post-exertional malaise. HRV tracking after exercise shows that VT1 is a potential threshold for PEM. Sports physicians and physiotherapists can incorporate HRV biofeedback measures into pacing advice to patients. Additional research is needed to further investigate the effect of such an intervention.

Source: Twan Ruijgt, Anouk Slaghekke, Anneke Ellens, Kasper W. Janssen, Rob C.I. Wüst.. Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID. medRxiv 2025.03.18.25320115; doi: https://doi.org/10.1101/2025.03.18.25320115 https://www.medrxiv.org/content/10.1101/2025.03.18.25320115v1.full-text (Full text)

Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome”

Abstract:

Post-COVID Syndrome (PCS), also known as Long COVID, is characterized by persistent and often debilitating neurological sequelae, including fatigue, cognitive dysfunction, motor deficits, and autonomic dysregulation (Dani et al., 2021). This study investigates structural and functional alterations in the brainstem and cerebellar peduncles of individuals with PCS using diffusion tensor imaging (DTI) and volumetric analysis. Forty-four PCS patients (15 bedridden) and 14 healthy controls underwent neuroimaging. Volumetric analysis focused on 22 brainstem regions, including the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), periaqueductal gray (PAG), and midbrain reticular formation (mRt).

Significant volume reductions were observed in the SCP (p < .001, Hedges’ g = 3.31) and MCP (p < .001, Hedges’ g = 1.77), alongside decreased fractional anisotropy (FA) in the MCP, indicative of impaired white matter integrity. FA_Avg fractional anisotropy average tested by FreeSurfer Tracula, is an index of white matter integrity, reflecting axonal fiber density, axonal diameter and myelination. These neuroimaging findings correlated with clinical manifestations of motor incoordination, proprioceptive deficits, and autonomic instability. Furthermore, volume loss in the dorsal raphe (DR) and midbrain reticular formation suggests disruption of pain modulation and sleep-wake cycles, consistent with patient-reported symptoms.

Post-mortem studies provide supporting evidence for brainstem involvement in COVID-19. Radtke et al. (2024) reported activation of intracellular signaling pathways and release of immune mediators in brainstem regions of deceased COVID-19 patients, suggesting an attempt to inhibit viral spread. While viral genetic material was detectable, infected neurons were not observed. Matschke et al. (2020) found that microglial activation and cytotoxic T lymphocyte infiltration were predominantly localized to the brainstem and cerebellum, with limited involvement of the frontal lobe. This aligns with clinical observations implicating the brainstem in PCS pathophysiology. Cell-specific expression analysis of genes contributing to viral entry (ACE2, TMPRSS2, TPCN2, TMPRSS4, NRP1, CTSL) in the cerebral cortex showed their presence in neurons, glial cells, and endothelial cells, indicating the potential for SARS-CoV-2 infection of these cell types. Associations with autoimmune diseases with specific autoantibodies, including beta-2 and M-2 against G-protein coupled alpha-1, beta-1, beta-2 adrenoceptors against angiotensin II type 1 receptor or M1,2,3-mAChR, among others, voltage-gated calcium channels (VGCC) are known (Blitshteyn et al. 2015 and Wallukat and Schminke et al. 2014).

These findings support the “Broken Bridge Syndrome” hypothesis, positing that structural disconnections between the brainstem and cerebellum contribute to PCS symptomatology. Furthermore, we propose that chronic activation of the Extended Autonomic System (EAS), encompassing the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, may perpetuate these symptoms (Goldstein, 2020). Perturbations in this system may relate to the elevation of toxic autoantibodies AABs (Beta-2 and M-2), specific epitopes of the COVID virus’s SPIKE protein and Cytokine storm of IL-1, IL-6, and IL-8 in their increased numbers (1,000->10,000)

Further research is warranted to elucidate the underlying neuroinflammatory mechanisms, EAS dysregulation, and potential therapeutic interventions for PCS

Source: Ziaja Peter Christof, Young Yvette Susanne, Stark Sadre-Chirazi Michael, Lindner Thomas, Zurék Grzegorz, Sedlacik Jan. Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome” medRxiv 2025.04.08.25325108; doi: https://doi.org/10.1101/2025.04.08.25325108 https://www.medrxiv.org/content/10.1101/2025.04.08.25325108v1.full-text (Full text)

‘A gift and a curse’: the benefits and limitations of self-tracking Long COVID

Abstract:

People living with Long COVID are dealing with significant challenges related to limited understanding of this novel condition, social stigma, and lack of support from medical professionals and others in their lives. This article discusses findings from a qualitative study about how people with Long COVID have spontaneously engaged in self-tracking for the purposes of understanding and managing their illness. It draws on 30 semi-structured interviews with study participants in the USA, UK, Australia, Germany, Denmark and Canada.

The study’s findings reveal that the personal health data generated by people with Long COVID through practices of self-tracking create new forms of knowledge about a novel post-viral condition and to some extent challenge the power differentials and fraught sociopolitical climate of the pandemic. The benefits provided by self-tracking data reflect the often psychologised and understudied position of post-viral conditions such as Long COVID.

All participants described self-tracking as a valuable tool to gain insight into symptoms and evaluate interventions. It provided them with a sense of empowerment, control, encouragement, and very importantly, validation. However, for some participants, self-tracking their Long COVID symptoms was also sometimes experienced as overwhelming, anxiety-inducing, and frustrating. The study findings are interpreted with references to the broader contexts of novel chronic illness, medical power, lay expertise, COVID politics and digitised information and care work.

Source: Jayadeva, S., & Lupton, D. (2025). ‘A gift and a curse’: the benefits and limitations of self-tracking Long COVID. Information, Communication & Society, 1–17. https://doi.org/10.1080/1369118X.2025.2483834 https://www.tandfonline.com/doi/full/10.1080/1369118X.2025.2483834 (Full text)

Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection.

Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease.

We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.

Source: Humer B, Dik WA, Versnel MA. Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review. Front Immunol. 2025 Mar 25;16:1483764. doi: 10.3389/fimmu.2025.1483764. PMID: 40201181; PMCID: PMC11975576. https://pmc.ncbi.nlm.nih.gov/articles/PMC11975576/ (Full text)

Wearable Devices Enable Long COVID Patients to Decrease Symptom Severity: A Case Series From Pilot User Testing

Abstract:

Purpose: Long COVID is a debilitating condition that is estimated to affect over 65M individuals across the world after a Coronavirus Disease 2019 (COVID-19) infection and has no broadly effective treatments. People with Long COVID have reported that pacing helps manage their symptoms, but it is difficult to implement. Based on experiences in the Long COVID community, we hypothesized that wearable devices can help individuals pace and reduce their Long COVID symptom severity.

Methods: To inform the design of a larger study, we performed user testing by distributing Garmin® devices, the study surveys and pacing educational materials to 11 individuals with Long COVID, and conducting interviews to learn about their experience.

Results: Eight of the 9 (89%) individuals reported that the information provided was helpful for their symptom management, and 2 testers did not complete the final survey. Four (44%) users had not used a wearable device before and none had trouble setting up their device. Due to the limited sample size and lack of control group, generalizability is unknown.

Conclusions: The most user testers reported that the study materials were helpful for their symptom management. These results are a promising indication of the potential for wearable devices and educational materials to help individuals with Long COVID, and potentially other chronic conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), decrease symptom severity.

Source: Goosen A, Foster-Bonds R, Vogel JM. Wearable Devices Enable Long COVID Patients to Decrease Symptom Severity: A Case Series From Pilot User Testing. Cardiopulm Phys Ther J. 2024 Dec 3;36(2):99-104. doi: 10.1097/CPT.0000000000000268. PMID: 40190996; PMCID: PMC11970588. https://pmc.ncbi.nlm.nih.gov/articles/PMC11970588/ (Full text)

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)