This month’s Research Digest highlights the breadth of ME/CFS research, spanning biological mechanisms, clinical assessment, diagnostic inequities, and care for people with severe illness. The featured studies examine potential biomarkers of illness severity, the impact of autonomic dysfunction, disparities in diagnosis, and outcomes from specialised care. Together, these findings reinforce ME/CFS as a complex, multi-system condition and point to opportunities for improved diagnosis and more appropriate care.
Contributing Digesters: Solène, Anna and Lauren.
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- Introduction to Edition 124
- SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
- Autonomic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: Findings from the multi-site clinical assessment of ME/CFS (MCAM) study in the USA
- Unequal access to diagnosis of myalgic encephalomyelitis in England
- Specialised care for severely affected ME/CFS patients
BIOMARKER
SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Authors: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I…, Moreau A (Université de Montréal, Canada)
Publication: Journal of Translational Medicine (July, 2025)
Link: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06829-0
Easy Read Overview: This study looked at a protein called SMPDL3B, which helps control the immune system and fat metabolism, to see if it plays a role in ME/CFS. Researchers measured SMPDL3B in blood samples from two large groups of people with ME/CFS and compared the results with healthy controls. They found that people with ME/CFS had higher levels of SMPDL3B, and those with the highest levels also had more severe symptoms. The authors say SMPDL3B might be useful as a marker of how severe the illness is, but more research is needed.
Sphingomyelin phosphodiesterase acid-like 3B (SMP-DL3B) is an essential immune-regulatory protein and is also involved in fat metabolism. The authors investigated its role in ME/CFS pathophysiology and its potential as a biomarker of disease severity.
The study included two independent cohorts. The Canadian cohort included 249 people with ME/CFS (Canadian Consensus Criteria) of which 208 were women, and 63 healthy controls (33 women) who were frequency-matched by age and sex. For replication, the authors used a Norwegian cohort of 141 people with ME/CFS (119 women), also diagnosed according to the Canadian Consensus Criteria. All participants from both cohorts were recruited before the COVID-19 pandemic, and blood samples were taken to analyse for SMPDL3B.
ME/CFS symptoms and severity were assessed with the 36-Item Short-Form Health Survey, Multidimensional Fatigue Inventory, and DePaul Symptom Questionnaire in the Canadian cohort. In the Norwegian cohort, a physician categorised disease severity from mild to severe ME/CFS (participants with very severe ME/CFS were excluded).
SMPDL3B levels in plasma were significantly higher in the Canadian ME/CFS cohort compared with controls. To evaluate the potential of SMPDL3B as a biomarker for disease severity, the authors used 30 ng/mL as a threshold to separate the Canadian ME/CFS cohort into low and high plasma SMPDL3B. Participants with SMPDL3B plasma levels above 30 ng/mL presented significantly greater symptoms and disease severity than those below 30 ng/mL. This finding was replicated in the Norwegian cohort.
The authors also found sex differences in the ME/CFS cohort: women had greater cognitive impairments, sleep problems, and post-exertional malaise, while men presented lower severity scores, but higher reduced motivation. The authors found that oestradiol modulated SMPDL3B levels in vitro, suggesting that oestradiol may contribute to the observed differences between men and women.
These findings suggest that SMPDL3B may be a biomarker of disease severity and a target for therapeutic interventions. However, further studies are needed to fully understand and validate its potential.
BIOLOGY
Autonomic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Findings from the multi-site clinical assessment of ME/CFS (MCAM) study in the USA
Author: Issa A, Lin J-M S, Chen Y, Attell J, Brimmer D, Bertolli J, Unger ER (Centers for Disease Control & Prevention, USA)
Publication: Journal of Clinical Medicine (September, 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12428951/pdf/jcm-14-06269.pdf
Easy Read Overview: The study looked at how problems with the autonomic nervous system affect people with ME/CFS. It found that almost all people with ME/CFS had at least one autonomic symptom, and these symptoms were much more common than in healthy people. People with ME/CFS who had symptoms like orthostatic intolerance or stomach and eye-related issues were more likely to have more severe illness. The authors suggest that treating these autonomic problems may help reduce symptoms and improve daily functioning.
Autonomic dysfunction symptoms (dysautonomia) are common for many people with ME/CFS. This study investigated the impact of autonomic symptoms on ME/CFS severity.
Data that had been collected as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study were analysed for this study. The study included 442 participants (301 with ME/CFS, 141 healthy controls (HCs)) aged 18-70 years, across seven ME/CFS clinics. Clinicians at each site determined participant eligibility.
Dysautonomia was assessed using three tools: medical history, the self-reported validated Composite Autonomic Symptom Scale 31 (COMPASS-31, covering six autonomic dysfunction domains), and the NASA Lean Test (assessing orthostatic intolerance).
Illness severity was assessed using various tools, including the Centers for Disease Control and Prevention Symptom Inventory (CDC-SI), Patient-Reported Outcomes Measurement Information System (PROMIS) measures, Orthostatic Grading Scale (OGS), and the 36-item Short-Form Health Survey (SF-36v2).
Almost all participants with ME/CFS reported at least one autonomic symptom (ME/CFS 97%, HCs 38%). Compared to HCs, participants with ME/CFS had a statistically significantly higher autonomic symptom burden, functional impairment and illness severity, evident across all three dysautonomia assessment tools.
The findings suggest that for people with ME/CFS, autonomic dysregulation may contribute to the level of severity in fatigue, sleep disturbances, cognitive function, pain, post-exertional malaise (PEM), and functional impairment. Participants with symptoms in the OI, gastrointestinal, and/or pupillomotor domains had significantly higher illness severity, compared to those without these symptoms.
Compared to traditional autonomic dysautonomia screening tools (i.e., tilt table tests, cardiovascular autonomic reflex tests, or heart rate variability assessments), the COMPASS-31 and Lean Test are more accessible and affordable, enabling quicker diagnosis and treatment.
The authors suggest that treating dysautonomia symptoms in people with ME/CFS may reduce illness severity and improve functional capacity, and highlight this as an important area for future research. They also call for further research to assess innovations in autonomic testing technologies and protocols.
CLINICAL CARE
Unequal access to diagnosis of myalgic encephalomyelitis in England
Authors: Samms GL, Ponting CP (The University of Edinburgh, UK)
Publication: BMC Public Health (April, 2025)
Link: https://link.springer.com/article/10.1186/s12889-025-22603-9
Easy Read Overview: The study looked at how common ME/CFS is in England and which groups are less likely to be diagnosed. It found that ME/CFS diagnoses were lower in older adults, people from non-white ethnic groups, and people living in more disadvantaged areas. The researchers also estimated that about 0.60% of people in the UK may have been diagnosed with ME/CFS at some point in their lives. They suggest that better training for health workers and more research into diagnostic tests could help people get diagnosed sooner.
Evidence about prevalence and barriers to diagnosis of ME/CFS helps to inform policy decisions. For individuals, accurate, timely diagnosis informs symptom management and treatment. However, prevalence estimates vary greatly, and people with ME/CFS report diagnostic delays. This study seeks to determine prevalence and investigate factors influencing the diagnosis of ME/CFS in England.
National Health Service (NHS) Hospital Episode Statistics (HES) data (1/4/1989-7/10/2023) were analysed to stratify individuals in England diagnosed with ME/CFS (using ICD-10 code G93.3 Postviral fatigue syndrome), by age, gender, ethnicity, level of deprivation (a measure of social and economic disadvantage), General Practice, and NHS England Integrated Care Board (ICB) (42 areas).
Prevalence of the study population diagnosed with ME/CFS was 0.16%. Of these, 0.25% were female and 0.065% male (ratio 3.88:1). Prevalence varied by age, peaking at about 50 years for females and over a decade later for males.
Prevalence varied by ethnicity, with white prevalence 4.9-fold higher than other-than-white prevalence (0.24% and 0.049%, respectively). This pattern was also seen when analysed by gender, deprivation, and ICBs, and was more pronounced compared to other common diseases.
ME/CFS prevalence varied 1.5-fold by level of deprivation and was lowest for those living in the three most deprived areas.
The study found diagnosis of ME/CFS was disproportionately low for older females (>60yrs) and males (>80yrs), other-than-white ethnic groups, and people living in and GP practices located in areas of greater deprivation. Improved estimates of prevalence enable more accurate assessment of the burden imposed by ME/CFS to underpin policy decisions.
To estimate the prevalence within the UK of people diagnosed with ME/CFS, the authors used the findings from the English population data. Based on several assumptions (including minimal barriers to diagnosis), the authors estimate the 2023 UK lifetime prevalence of ME/CFS to be approximately 0.60% overall, 0.92% for females and 0.25% for males.
The authors suggested that deficits in ME/CFS diagnosis across groups could be addressed by prioritising improved practitioner training and research into diagnostic tests.
CLINICAL CARE
Specialised care for severely affected ME/CFS patients
Authors: Saugstad OD, Sollie MG, Torp HA, Storla DG (Røysumtunet, Norway)
Publication: Fatigue: Biomedicine, Health & Behavior (October, 2025)
Link: https://doi.org/10.1080/21641846.2025.2565101
Easy Read Overview: This study looked at a special care unit in Norway that supports people with severe ME/CFS in a quiet, low-stimulation environment. Researchers reviewed the medical records of 24 adults who stayed there for at least three months. About half of the patients showed meaningful improvement in their illness by the end of their stay. The authors note that people with severe ME/CFS often struggle to get proper care, and this kind of tailored, low-stimulation support may help improve their quality of life.
This study describes outcomes from a specialised Norwegian residential unit that began admitting people with severe or very severe ME/CFS in June 2021. The unit provides a low-stimulation environment and individually tailored care for individuals who often face major barriers in conventional healthcare. This study aimed to examine changes in illness severity in patients who attended the unit during its first three years of operation.
The authors conducted a retrospective review of medical records from adults diagnosed with ME/CFS (Canadian Consensus Criteria) and classified as severe or very severe based on NICE guidelines who had stayed at the unit for at least three months. The study included twenty-four patients aged 18–68. Most were women (83%), and nearly three-quarters were very severely affected upon admission. Care focused on sensory-adapted environments, assistance with daily activities, nutritional support, pacing strategies and (when clinically appropriate) adjunctive treatments including thiamine, vitamin B12, NADH, coenzyme Q10, low-dose naltrexone, or low-dose aripiprazole.
At the end of their stay, half of the patients experienced meaningful improvement: seven (29%) improved by at least one severity level, and five (21%) improved within their existing severity category. Younger age and shorter illness duration were associated with better outcomes: those who improved had a mean illness duration of 2.3 years, compared with 6.7 years in those without measurable improvement.
The authors note that patients with severe and very severe ME/CFS often have limited access to appropriate services, and specialised care environments may help stabilise symptoms and enhance quality of life. They conclude that structured, low-stimulation, individually tailored care shows promise for this patient group, and that further research is needed to clarify which components of care contribute most to improvement.