In this month’s 117th edition of the Research Digest, we explore advancements in the understanding and diagnosis of post-viral conditions, including long COVID and ME/CFS. Highlights include a new algorithm to improve long COVID diagnosis across diverse populations, a comparison of cognitive challenges in ME/CFS and multiple sclerosis, and promising insights from tryptophan metabolism research. We also share two powerful personal stories that bring attention to the everyday realities of living with, and caring for someone with, severe ME/CFS.
Contributing Digesters: Shan, Sarah and Simone.
We hope you enjoy the Easy Read Overview and audio summary we’ve included under each article’s title – it’s now even easier to stay informed of the latest ME/CFS and long COVID research!
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Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19
Authors: Azhir A, Hügel J, Tian J, Cheng J, Basset IV, Bell DS, … Estiri H (Massachusetts General Hospital, USA)
Name and Date of Publication: Med. 14 March 2025
Link: https://doi.org/10.1016/j.medj.2024.10.009
Easy Read Overview: Scientists studied health records to create a better tool for finding and predicting long COVID (PASC) symptoms, which current methods often miss or get wrong. Their new algorithm works more accurately across different ages, genders, and ethnic groups, even spotting rare symptoms like hearing loss and diabetic issues. It can help doctors diagnose long COVID more fairly and correctly, and the tool is free for use in any healthcare system.
Current diagnostic codes for post-acute sequelae of SARS-CoV-2 (PASC) are often inaccurate, biased across demographics, and underestimate their true prevalence. Similarly, the criteria to predict those most at risk of developing post-acute sequelae of SARS-CoV-2 (PASC) are inadequate. The authors conducted a retrospective longitudinal case-control study to develop a more accurate precision phenotyping algorithm. This tool aims to not only improve diagnosis but also predict the onset, affected systems, and duration of PASC across different demographic groups.
The study analysed the electronic health records (EHR) of three groups: 85,364 confirmed COVID-19 patients (at least one year post-infection), 170,497 post-pandemic individuals without COVID-19, and 39,817 pre-pandemic controls. A Sequential Pattern Mining algorithm, based on WHO’s PASC definition and Clinical Classifications Software, was used to sift through this data. The outputs were independently reviewed and refined.
Compared to the International Classification of Diseases U09.9 diagnosis code, the new algorithm achieved 79.9% diagnostic precision—an improvement of 2.7%—and more accurately estimated community prevalence. It effectively excluded false positives (due to pre-existing conditions) and identified false negatives (conditions misdiagnosed, but linked to prior COVID-19). The breadth of data allowed the algorithm to detect rarer sequelae beyond common symptoms like fatigue or sleep issues, including vision and hearing loss, diabetic complications, and sexual dysfunction.
The algorithm also provided a more balanced demographic analysis, which allowed for better analysis of which sequelae are more common based on age, gender, and ethnicity. For example, those under 45 were more likely to develop gynaecological, dermatological, or psychiatric sequelae; women had higher odds of PASC in certain organs; Asian and Hispanic patients had lower PASC risk; while Black patients faced higher risk regardless of age or health status.
The authors emphasise that their algorithm aligns with the National Academies of Sciences, Engineering, and Medicine’s (NASEM) newly proposed broad definition of PASC as an infection-associated chronic condition (IACC). They have made their tools and data publicly available for integration into any healthcare system.
Figure: Selection Criteria for cases and controls. Cases are infected at least once by SARS-CoV-2, whereas the pre-pandemic controls had a viral infection in 2018.
Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis /Chronic Fatigue Syndrome and Multiple Sclerosis
Authors: Sebaiti MA, Oubaya N, Gounden Y, Samson C, Lechapt E, Wahab A … & Authier F-J (Paris-East Creteil University, France)
Name and Date of Publication: Diagnostics. 17 February, 2025
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC11854609/pdf/diagnostics-15-00487.pdf
Easy Read Overview: This study compared thinking and memory problems in people with ME/CFS and multiple sclerosis (MS). It found that both groups had trouble with memory and attention, but people with ME/CFS had more difficulty remembering new information. The results suggest that special brain training could help people with ME/CFS improve their thinking skills.
ME/CFS involves a range of disabling symptoms, with cognitive impairments being one of the most commonly reported. The aim of this study was to identify a specific cognitive profile unique to ME/CFS. Multiple sclerosis (MS) was used as a comparison group due to the overlapping symptoms of pain, cognitive impairment and fatigue.
A retrospective analysis of patient data from the Henri Mondor Hospital in France was undertaken. Data from 40 participants with ME/CFS (Fukuda criteria), and 40 participants with MS (relapsing-remitting) were included in this study. All participants had completed a screening of cognitive function and neuropsychological tests. Neuropsychological tests assessed short and long-term memory, visual and auditory processing, processing speed, executive function, working memory, and planning ability. All participants completed the tests in the same order.
The authors found that both ME/CFS and MS participant groups showed deficits in episodic memory retrieval, visual selective attention, and reading speed. ME/CFS participants were also found to have a lower performance in consolidation processes than MS participants. In both groups, performance on the cognitive tests was not related to levels of fatigue, pain and depression.
The authors conclude that this study highlights the similarities and differences in cognitive profiles of ME/CFS and MS patients. The impairment in consolidation processes shown by ME/CFS participants helps define a specific cognitive phenotype for ME/CFS, especially as this was not correlated with pain, fatigue or depression. The authors suggest that future research, especially with functional imaging, may identify the neurobiological mechanism causing this. The authors also propose that this research can be used to assist the management of ME/CFS, by considering implementing cognitive training with a focus on verbal learning strategies and working memory exercises.
Untargeted metabolomics and quantitative analysis of tryptophan metabolites in myalgic encephalomyelitis patients and healthy volunteers: A comparative study using high-resolution mass spectrometry
Authors: Abujrais S, Vallianatou T, and Bergquist J (Uppsala University, Sweden)
Name and Date of Publication: ACS Chemical Neuroscience. September 20, 2024
Link: https://doi.org/10.1021/acschemneuro.4c00444
Easy Read Overview: Researchers studied people with ME/CFS and found changes in how their bodies process tryptophan, a substance important for energy, mood, and the immune system. They found that different patients had different changes, but some common chemical differences were seen in all ME/CFS patients. These results may help doctors find better ways to diagnose and treat ME/CFS in the future.
The tryptophan metabolic pathway has received attention in ME/CFS research due to its involvement in immune function, neurotransmission and energy production. These authors used untargeted metabolomics – scanning a biological sample for a wide range of chemical compounds, without choosing them in advance – as well as targeted analysis of tryptophan and its metabolites, to gain a better understanding of the altered metabolic pathways underlying ME/CFS.
Plasma samples were obtained from 19 patients from Stora Sköndal in Stockholm (ME-SK), and 19 patients from Gottfries Clinic (ME-GC), as well as 24 healthy controls (HC). The 38 ME/CFS patients met three diagnosis criteria – Canadian Consensus Criteria, International Consensus Criteria, and Institute of Medicine (IOM) criteria. A pooled plasma sample was created for quality control (QC). Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was used for both targeted and untargeted analysis.
Analysis found significant differences between the two ME/CFS cohorts, suggesting the metabolic impact of ME/CFS can vary widely, however, 30 common significantly altered metabolites were identified. The untargeted analysis found dysregulation of quinolinic acid and indoleacetic acid (tryptophan metabolic products), L-adrenaline and S-adenosyl-L-homocysteine (SAH), and the vitamin B3, the arginine-proline and the aspartate-asparagine pathways.
The targeted analysis of tryptophan metabolites and related compounds also identified differences between ME-SK and ME-GC, as well as between ME/CFS and HC. The analysis found significantly altered levels of hypoxanthine, a biomarker for hypoxia, indicative of reduced oxygen extraction in ME/CFS; nicotinamide and riboflavin, which are important in energy production; and phenylalanine, involved in neurotransmission. Significant alteration were also observed in metabolites within the serotonin pathway, which is involved in mood and sleep regulation, and in the kynurenine pathway, which is associated with neurotransmission, inflammation and immune response (with alteration of 3-hydroxyanthranilic acid (3HAA) posing significant health implications). Differences in some metabolites between sex and/or age indicated potential age-related changes, as well as biological differences between male and female ME/CFS presentation.
This study identified several potential biomarkers, as well as potential targets for the treatment of ME/CFS. The authors recommend that further studies, particularly into the kynurenine pathway, use similar sample sizes and analytic methods to avoid discrepancies and to examine the effect of medications, as well as the menstrual cycle, on the metabolites.
ME/Chronic fatigue syndrome: The mysterious illness trapping people in their bodies
Authors: Madden-Smith Z
Name and Date of Publication: Re: News. May 12, 2025
Link: https://youtu.be/DsOAq6cs564?si=1Z0kkbLvX9FjAO40
This New Zealand video news story explores the impact of severe ME/CFS on those who live with the condition as well as their carers. It highlights the difficulty getting access to sufficient care in New Zealand and one mother’s solution in setting up a shared care system.
“Someone who is so physically unwell is being treated so poorly, as if they can just snap out of it. I don’t think I can think of another condition that would be treated this way. It just blows my mind,” said researcher Dr Anna Brooks.
“I just don’t think we’ve got to grips with this situation. Why is this not an emergency?” says ME/CFS educator Rose Silvester.
The video runs for 16 minutes and includes some music that may be difficult for some to tolerate.
My wife has largely been bedbound for decades. Then our child joined her in isolation
Authors: McCluskey P
Name and Date of Publication: SBS News. 20 May 2025
Link: https://www.sbs.com.au/news/insight/article/toll-of-being-bedbound-with-me-cfs-chronic-fatigue-syndrome/dew0m9ikt
Peter McCluskey is carer for his wife and daughter, who both live with ME/CFS. In this article, he writes about his experience.
“The hardest part of being an ME/CFS carer is witnessing relentless suffering.
The quality of life for those with severe ME/CFS is often compared to that of late-stage cancer. But with this syndrome, the suffering is unending.
I effectively have a front row seat to a misery show that just goes on and on.
Equally challenging is communicating with some health professionals, who dismiss or downplay the illness, leaving carers and patients feeling invalidated and hopeless.
This deepens the isolation of managing this illness alone, amplifying the emotional toll on carers who must constantly advocate against disbelief while supporting their loved ones.”
