Tag: dysautonomia

‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention

Abstract:

Background: An understanding of the nature of long Covid (LC) is evolving, with recent evidence highlighting the role of increased sympathetic activation and decreased parasympathetic response. Building upon this emerging science, the ‘Transforming Long COVID’ (TLC) programme was developed to support participants in their recovery by (i) introducing education on the neuroscience underpinning persistent symptoms (with a particular focus on the autonomic nervous system) and (ii) the development of self-management strategies to support recovery. The aim of this study was to examine the feasibility of the TLC programme with a cohort of people significantly affected by LC.

Methods: Seventeen participants took part in the 8-week TLC programme which comprised of seven content sessions and one discussion (Q&A) session. Participants completed survey scales (investigating anxiety, pain-related interference, pain catastrophising, sleep disturbance and fatigue) at baseline, immediately post-programme (at 8 weeks), and retention (at 13 weeks). Participants also took part in focus group interviews to investigate their experiences of the programme.

Results: Fourteen participants (82%) attended at least six of the seven TLC content sessions. Decreases in mean values over time were observed across all measures, indicating a positive (non-significant) change. Participants reported an increase in understanding of LC, new hope for recovery, belief that they now had a realistic pathway for recovery, validation of their experiences and symptoms, meaningful improvements in function, and enhanced ability to respond to and attenuate physical symptoms. No adverse events were reported. Participants highlighted a number of programme strengths, along with some potential areas for improvement.

Conclusion: The TLC programme was shown to be feasible based on engagement, adherence, acceptable completion of surveys, and no adverse events. Study findings point to the potential for this programme to be refined, trialled and evaluated with a larger sample.

Patient or public contribution: Four people (living with LC, ME/CFS, chronic migraine and chronic Lyme, fibromyalgia, and centralised pain syndrome), who have experience of applying a recovery approach aligned with the TLC programme, acted in a PPI (Public and Patient Involvement in research) capacity on this study. In addition, the lead author has personal experience with the illness, and developing the recovery approach, which helped inform programme structure and development [1]. These individuals provided advice and guidance on the potential structure for the group programme, course duration, tool selection, and language and wording of the programme and materials. Further detail is provided in the Supplementary Materials.

Source: Belton S, Goss H, Whyte E, McCaffrey N, Gibney S, Sheridan K. ‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention. Health Expect. 2026 Jun;29(3):e70681. doi: 10.1111/hex.70681. PMID: 42076812. https://onlinelibrary.wiley.com/doi/10.1111/hex.70681 (Full text)

Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disease characterized by heterogeneous symptom patterns. Previous work suggested that specific symptoms tend to co‑occur, pointing toward underlying biological mechanisms. This study aimed to empirically validate literature‑based, hypothesis‑driven symptom clusters and assess whether they reflect distinct neuroimmune and autonomic pathophysiological pathways.

Methods: Symptom data from 748 adults with ME/CFS (≥20 years) participating in the APAV‑ME/CFS study were analyzed. Symptoms were assigned to predefined mechanistic groups informed by current pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), evaluated the coherence, distinctiveness, and hierarchical structure of each cluster. Robustness was tested using a stratified, randomized training dataset.

Results: A coherent Brain factor (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) showed excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal symptoms demonstrated stronger internal consistency than Immune symptoms, and model comparisons supported a two‑factor Gut–Immune structure. Across all analyses, symptom groups emerged as internally consistent and statistically distinct. A higher‑order SEM including a common latent factor yielded excellent fit for the Autonomic symptom complex.

Conclusions: The findings support ME/CFS as a complex neuroimmune–autonomic multisystem disorder and suggest that symptom clusters align with functional biological systems. Mechanism-aligned symptom subgrouping may enable pathophysiology-guided diagnostics, patient stratification, and targeted therapeutic development. The proposed interpretations of underlying mechanisms derive from the integration of existing literature and were not directly measured in this study. The identified clusters therefore indicate mechanistic alignment rather than direct mechanistic validation.

Source: Habermann-Horstmeier L, Horstmeier LM. Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model. J Transl Med. 2026 Apr 28;24(1):606. doi: 10.1186/s12967-026-08159-1. PMID: 42050709; PMCID: PMC13126800. https://pmc.ncbi.nlm.nih.gov/articles/PMC13126800/ (Full text)

Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID (LC) are complex multisystem conditions with significant functional disability. Many patients experience symptoms of orthostatic intolerance, which can be captured in some cases as Orthostatic Hypotension (OH) or Postural orthostatic Tachycardia Syndrome (PoTS) on objective testing. Conservative treatments are recommended for first-line symptom management, but there is a lack of efficacy evidence. This study aims to assess the feasibility of an 8-week clinically supervised, personalised Dysautonomia Management Protocol (DMP) in a cohort of ME/CFS and LC patients with subjective and objective evidence of orthostatic intolerance (dysautonomia).

Methods: ME/CFS and LC patients with objective dysautonomia on the 10 min active Lean Test (LT) were recruited to an 8-week DMP, with interventions introduced cumulatively every two weeks. Interventions included increasing daily fluid intake to 3 litres and salt intake to 10 g, pacing to avoid crashes and calf activation. Baseline and weekly data collection included the LT, Composite Autonomic Symptom Score questionnaire (COMPASS-31) and Yorkshire Rehabilitation Scale (YRS).

Results: Sixteen participants completed the 8-week program, five discontinued during the program, and one was withdrawn following a severe crash. The COMPASS-31 improved by 7.7 points from week 1 to week 8 (p = 0.045), with a medium Cohen’s d effect size of 0.55. For the same period, there was a non-significant (p = 0.16) improvement in the YRS symptom severity score by 2 points. Comparing the final two weeks of the program with the first two weeks, mean heart rate during the LT decreased by 4.8 beats per minute (p = 0.032), with a medium Cohen’s d effect size of 0.44. Adherence to the interventions was highly variable, with none of the patients able to fully employ all four recommendations.

Conclusions: The results suggest that targeted conservative interventions could influence autonomic function and symptom reduction. However, the magnitude of change was limited, and statistical significance might not necessarily relate to a clinically significant improvement in symptoms.

Source: Barr J, Marsden L, Dassanayake T, Almutairi N, McKeever V, Gaber T, Tarrant R, Godfrey B, Witton S, Sivan M. Testing a Personalised Dysautonomia Management Protocol in Patients with Orthostatic Intolerance and a Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Long COVID. J Clin Med. 2026 Mar 25;15(7):2510. doi: 10.3390/jcm15072510. PMID: 41976810. https://www.mdpi.com/2077-0383/15/7/2510 (Full text)

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders

Abstract:

Postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are heterogeneous disorders with overlapping complex, multi-factorial and multi-systemic pathophysiology. POTS and ME/CFS are the most common phenotypes of Long COVID that can lead to significant disability and functional impairment.

The exact pathophysiologic mechanisms of these disorders alone or in combination are still being investigated, but important mechanistic factors have been identified, such as autonomic dysfunction, immune dysregulation, autoimmunity, mitochondrial dysfunction, cerebral hypoperfusion, and neuroinflammation.

To this end, we believe that these conditions should be viewed as neuroimmune disorders and should be included in the field of neuroimmunology, with its educational curriculum, training, and clinical care pathways. Including these disorders as part of neuroimmunology subspecialty is the key to advancing the science and clinical care of this underserved patient population with these complex and disabling conditions.

Source: Blitshteyn S, Doherty TA, Steinman L. Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders. Immunotargets Ther. 2026 Feb 2;15:581262. doi: 10.2147/ITT.S581262. PMID: 41859298; PMCID: PMC12998959. https://pmc.ncbi.nlm.nih.gov/articles/PMC12998959/ (Full text)

Autonomic Dysfunction in Patients with Acute Infection with Coxiella burnetii

Abstract:

Background: Coxiella burnetii is a common zoonotic pathogen that can lead not only to acute or chronic Q fever but also to post-infectious syndromes, where autonomic nervous system (ANS) dysfunction has been suggested as a contributing mechanism. This study aimed to assess autonomic function in patients presenting with polymorphic symptoms, dysautonomia, or ME/CFS who had serological evidence of acute infection with Coxiella burnetii.

Methods: A total of 156 participants were evaluated, including 100 seropositive patients and 56 matched controls. All subjects underwent standardized cardiovascular reflex tests (CART), beat-to-beat analysis of heart rate and blood pressure with baroreflex indices, 24 h Holter ECG with HRV assessment, and, in the Coxiella group, head-up tilt testing (HUTT).

Results: A significantly higher prevalence of autonomic dysfunction was observed in the Coxiella group, predominantly affecting parasympathetic regulation, with abnormal CART scores, reduced LF power and baroreflex effectiveness, and a high rate of positive HUTT findings characterized by extreme blood pressure variability. Although long-term HRV measures did not differ significantly between groups, short-term indices consistently indicated ANS impairment.

Conclusions: These findings suggest that Coxiella burnetii infection may trigger persistent autonomic dysfunction, potentially contributing to the development of ME/CFS and syncope in affected individuals. Further longitudinal studies are needed to clarify pathophysiological mechanisms and clinical implications.

Source: Milovanović B, Marković N, Ristanović E, Atanasievska Kujović S, Đorđevski N, Petrovic M, Milošević M, Bulatovic S, Bojić M. Autonomic Dysfunction in Patients with Acute Infection with Coxiella burnetii. Pathogens. 2025 Dec 19;15(1):3. doi: 10.3390/pathogens15010003. PMID: 41598987. https://www.mdpi.com/2076-0817/15/1/3 (Full text)

Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are relatively common and disabling multisystem disorders that share overlapping features, including post-infectious onset and similar clinical manifestations such as brain fog, fatigue, muscle pain, and dysautonomia with orthostatic intolerance. These similarities suggest that Long COVID and ME/CFS may share common pathophysiological mechanisms, though the underlying mechanisms remain poorly understood, partly due to the difficulty in quantifying many of the symptoms.

Materials and methods: This retrospective study evaluated Long COVID and pre-COVID ME/CFS patients who completed autonomic testing between 2018 and 2023 at the Brigham and Women’s Faulkner Hospital Autonomic Laboratory. The evaluations included autonomic tests (Valsalva maneuver, deep breathing, tilt-table test, and sudomotor function) with capnography and transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in the middle cerebral artery, neuropathic assessment through skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (ICPET), and laboratory analyses covering metabolic, inflammatory, autoimmune, and hormonal profiles.

Results: A total of 143 Long COVID and 170 ME/CFS patients were analyzed and compared to 73 healthy controls and 290 patients with hypermobile Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS exhibited more severe peripheral neurodegeneration compared to the other groups. Laboratory tests did not distinguish between the conditions.

Conclusion: Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.

Source: Novak P, Systrom DM, Witte A, Marciano SP, Felsenstein D, Milunsky JM, Milunsky A, Krier J, Fishman MC. Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. PLoS One. 2026 Jan 23;21(1):e0341278. doi: 10.1371/journal.pone.0341278. PMID: 41576003. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0341278 (Full text)

Long COVID: a long road ahead

Abstract:

The SARS-CoV-2 pandemic caused an estimated 400 million people worldwide to experience Long COVID and post-COVID complications leading to significant chronic illness and disability with its devastating physical, societal and economic consequences. Since post-acute infectious syndromes have not been given adequate consideration prior to the pandemic, many millions of people with Long COVID worldwide have been left disabled as currently available therapies are largely symptomatic and only partially effective.

A case of a previously healthy woman with Long COVID and post-COVID autonomic dysfunction and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is presented here from the perspective of a physician-patient relationship and a broader context of medical care and public health. Immunologic and autonomic mechanistic factors and therapies as these relate to Long COVID are highlighted.

Complexities and issues pertaining to patient care, public health and education of neurologists and other specialists regarding Long COVID, dysautonomia and ME/CFS diagnosis and treatment are discussed, in conjunction with the need to develop and diversify effective therapies for people living with these highly disabling conditions.

Source: Blitshteyn S. Long COVID: a long road ahead. Oxf Open Immunol. 2025 Dec 13;6(1):iqaf010. doi: 10.1093/oxfimm/iqaf010. PMID: 41426345; PMCID: PMC12718103. https://pmc.ncbi.nlm.nih.gov/articles/PMC12718103/ Full text)

Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing

Abstract:

Background: Persistent symptoms (eg, heart palpitations, lightheadedness, fatigue) despite resolution of acute COVID-19 infection is termed “long COVID syndrome” or simply “long COVID.” Long COVID is believed to be associated with autonomic dysfunction, but the nature and severity of any autonomic disturbances are not well understood.

Objective: This study sought to compare autonomic function measures in patients with long COVID, control subjects, and individuals with pure autonomic failure.

Methods: Patients referred for autonomic testing were classified into 3 groups: long COVID (acute COVID-19 infection ≥12 weeks before testing), control subjects (COVID-19 negative, normal autonomic tests), and pure autonomic failure (COVID-19 negative, abnormal autonomic testing). Heart rate and blood pressure were recorded during active standing, Valsalva maneuver, respiratory sinus arrhythmia, and tilt-table testing.

Results: Compared with control subjects, patients with long COVID exhibited both a greater heart rate increase and blood pressure drop with active standing and tilt-table testing (all P < 0.05). They also had lower Valsalva ratios and respiratory sinus arrhythmia values than did control subjects (both P < 0.05). Compared with pure autonomic failure patients, patients with long COVID had a greater heart rate increase but a lower drop in blood pressure with active standing and tilt-table testing and lesser respiratory sinus arrhythmia values and Valsalva ratios (all P < 0.001). After age and sex adjustment, autonomic dysfunction measures in patients with long COVID were comparable with those in the pure autonomic failure group. Further, autonomic testing abnormalities were observed in patients referred up to 40 months after infection.

Conclusions: When adjusted for age and sex, patients with long COVID may demonstrate persistent autonomic dysfunction that is similar to patients with pure autonomic failure.

Source: Keller C, Mascarenhas L, Reyes JL, Duval S, Benditt DG. Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing. J Am Coll Cardiol. 2025 Nov 21:S0735-1097(25)09919-X. doi: 10.1016/j.jacc.2025.09.1608. Epub ahead of print. PMID: 41369621. https://pubmed.ncbi.nlm.nih.gov/41369621/

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome

Abstract:

Background: Hypermobility Spectrum Disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are multisystemic connective tissue disorders involving joint hypermobility and numerous other manifestations. Autonomic dysfunction, chronic pain, and chronic fatigue are known comorbidities of HSD and h-EDS that can affect patient quality of life (QoL), but there are limited data on the severity of autonomic symptoms, prevalence of comorbid conditions and QoL in patients with HSD/h-EDS.

Methods: We utilized the Composite Autonomic Symptom Scale (COMPASS-31) to assess autonomic symptom severity, Short-Form 36 (SF-36) to assess QoL, and the Beck Depression Inventory Second Edition (BDI-II) in a cohort of women with physician-diagnosed HSD or h-EDS, who completed these questionnaires anonymously.

Results: 84 women (mean age of 37.1 ± 8.4 years) completed the study. 58.3 % reported having physician-diagnosed postural orthostatic tachycardia syndrome (POTS), 32.1 % had mast cell activation syndrome (MCAS), 54.8 % had migraine, 26.2 % had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 98.8 % reported experiencing chronic pain. Importantly, 25 % of patients reported having all three diagnoses: HSD/h-EDS, POTS and MCAS. Mean COMPASS-31 score was 54.45 (range 18.79-80.93), indicating severe autonomic dysfunction, which was significantly higher than in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis as shown in prior studies. Mean SF-36 score was 32.38 (SD = 22.91) indicating poor QoL, which was worse than in patients with POTS, multiple sclerosis, rheumatoid arthritis, and lupus as determined by prior studies.

Conclusions: This study demonstrates that women with HSD/h-EDS experience severe autonomic dysfunction, chronic pain, chronic comorbid conditions and reduced QoL. More than half of participants in this cohort had POTS and migraine, with one in four having a clinical triad of HSD/h-EDS, POTS and MCAS.

Source: Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome. Auton Neurosci. 2025 Oct 14;262:103356. doi: 10.1016/j.autneu.2025.103356. Epub ahead of print. PMID: 41118678. https://pubmed.ncbi.nlm.nih.gov/41118678/

Understanding concussion in myalgic encephalomyelitis/chronic fatigue syndrome: Findings from the 2023 National Health Interview study

Abstract:

Background: Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms (dysautonomia, dizziness, balance impairments) may theoretically contribute to an association with concussion, the nature of this association has not been determined. This study explored the association between ME/CFS and concussion, as well as risk factors for concussion, history of recent falls, and feelings of being dizzy or off balance.

Method: 2023 National Health Interview Survey data were utilized. United States adults (unweighted N = 29,373) responded to items regarding sociodemographic factors, ME/CFS status, and history of concussion, falls, and feeling off balance or dizzy. Logistic regression analyses assessed the association between ME/CFS and concussion, falls, and feeling dizziness or balance problems within the past year, adjusting for sociodemographic factors.

Results: Individuals with ME/CFS had 4.89 times greater odds of reporting concussion in the past year compared to individuals without ME/CFS. Individuals with ME/CFS also had 2.86 times greater odds of having fallen within the past year and 5.88 times greater odds of reporting feeling dizzy or off balance in the past year.

Conclusions: ME/CFS status may be associated with concussion status. Healthcare practitioners should improve concussion screening and referrals for reducing concussion risk among individuals with ME/CFS.

Source: Sirotiak Z, Adamowicz JL, Thomas EBK. Understanding concussion in myalgic encephalomyelitis/chronic fatigue syndrome: Findings from the 2023 National Health Interview study. Brain Inj. 2025 Oct 16:1-8. doi: 10.1080/02699052.2025.2575479. Epub ahead of print. PMID: 41103060. https://pubmed.ncbi.nlm.nih.gov/41103060/