ME/CFS and Long Covid Research: 16 – 20 November 2023

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

RESEARCH INDEX

The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

VIEW THE ME/CFS AND LONG COVID RESEARCH INDEX

Audio commentary by Dr Katrina Pears

There have been seven new ME/CFS studies and twenty-nine new Long Covid studies this week.

We have highlighted one of the ME/CFS studies in more detail below:

Paper one (1) is of a slightly different nature than the studies we usually see, and is the first study of its kind to analyse the top 100 most cited research articles in the field of ME/CFS.

The researchers used the tool Web of Science to establish the top 100 list of most cited ME/CFS research between 2000 and 2023. The most frequently cited paper is “Myalgic encephalomyelitis: International Consensus Criteria” by Carruthers et al., 2001, which has 662 citations.

Other findings included:

3356 articles on ME/CFS were published between 2000 and 2023.
Articles were cited in 67 reputable journals.
Research studies have been produced by 250 institutions across 26 countries, with the US having the highest number of publications, followed by the UK and Belgium.
The journal with the highest publication volume and total citations was the Lancet followed by: Archives of Internal Medicine, Brain Behaviour and Immunity, Journal of Translational Medicine, and Paediatrics.
The majority of research was published between 2006 and 2016, with a high number of research achievements being generated. (Although this ranking didn’t include research between 2022 and 2023, due to the time taken for articles to be cited.)
The first 20 most cited papers account for approximately 41% of the total citations.

Although this study does not expand our knowledge of the field, it does provide an interesting read as well as highlighting key areas. This also allowed the researchers to suggest future recommendations for research, which include the search for biological markers, with a particular focus on immunology; the advancement of diagnostic techniques; the screening of risk genes associated with CFS; and the conduct of epidemiological investigations.

From studying the list of most cited research it is reassuring to see that the majority of this is biomedical research. Although, the second most cited paper is that by White et al., 2011, “Comparison of adaptive pacing therapy, cognitive behavior therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial”. This might be due to the number of people viewing the article to critique it, understand the flaws and reanalyse the data. Therefore, the top 100 list displayed does not necessarily represent the value of the research to the field.

The authors clearly have a wide knowledge breadth of ME/CFS, with an understanding of the barriers involved. Therefore, it is unusual that the term chronic fatigue syndrome/CFS is used only throughout the text (and not myalgic encephalomyelitis/ ME). Although this term was not excluded completely, it is listed in the key terms used to search the database, alongside alternative names, such as postviral fatigue syndrome, and systemic exertion intolerance disease. The authors even analyse the top 15-occuring keywords in the 100 papers listed, with ME ranking at 12, with only 6 occurrences, compared to CFS ranking at 1 with 31 occurrences.

One small point about data presentation in this study, it is a shame that the table presenting the top 100 papers does not include the rank (i.e. 1-100) so you have no idea when looking through the list where a certain paper falls.

ME/CFS Research References

1. Frontiers in chronic fatigue syndrome research: An analysis of the top 100 most influential articles in the field

Wang, Xingxin; Li, Xuhao; Dong, Tiantian; Yu, Wenyan; Jia, Zhixia; Chen, Jun.

Medicine 102(46):p e35754, November 17, 2023.

Abstract

Chronic fatigue syndrome (CFS) is a complex constellation of symptoms that significantly reduces the quality of life among affected individuals and increases public health expenditures.

We conducted a search on the Web of Science Core Collection database and selected the top 100 cited articles in the field of CFS. Several literature analysis tools, including CiteSpace 6.1.R6, VOSviewer 1.6.19, and Scimago Graphica 1.0.30, were utilized to integrate the most influential research papers and academic journals in order to obtain a comprehensive understanding of the CFS field.

The top 100 highly-cited publications were published in 67 reputable journals, with contributions from 250 institutions across 26 countries/regions involved in CFS research. This demonstrates the extensive attention and coverage of CFS research by high-quality academic journals and institutions, highlighting the interdisciplinary and multidisciplinary nature of CFS studies. The journal with the highest publication volume and total citations was Lancet.

The top 5 co-occurring keywords were chronic fatigue syndrome, cognitive behavior therapy, epidemiology, definition, and disorders, indicating the ongoing attention researchers have devoted to the diagnostic criteria and clinical studies of CFS.

Cluster analysis results suggested that primary care, infectious retrovirus, gene expression, and metabolomics may become the focal points and trends in future CFS research.

The prospective research directions in this field include the search for biological markers, with a particular focus on immunology; the advancement of diagnostic techniques; the screening of risk genes associated with CFS; and the conduct of epidemiological investigations.

2. Predictors of treatment response trajectories in chronic fatigue syndrome

Van Oudenhove, Lukas, Soetkin Debysera, Elfi Vergaelend, Stephan Claesd, Maaike Van Den Houte.

PsyArXiv, 13 Nov. 2023. [Preprint]

Abstract

Background: The response to cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS) varies greatly between patients, but predictors of treatment success are largely unknown. We aimed to identify patient subgroups based on treatment response trajectory, identify pre-treatment predictors of subgroup membership, and disentangle the direction of predictor – outcome relationships over time.

Methods: 297 CFS patients were enrolled in a standardized CBT program. Self-reported levels of fatigue, depressive, anxiety, and somatic symptoms, perceived stress, and positive affect were collected pre-treatment, after sessions 3 and 10, and post-treatment. Latent Class Growth Analysis (LCGA) was used to identify subgroups based on fatigue trajectories during treatment with predictors of subgroup allocation. Cross-lagged structural equation models were used to disentangle predictor-outcome relationships.

Results: LCGA identified four treatment response trajectory subgroups, which can be labelled as “no improvement” (Class 4, 23%), “weak improvement” (Class 3, 45%), “moderate improvement” (Class 1, 23%), and “strong improvement” (Class 4, 9%). Higher pre-treatment levels of depressive, anxiety, and somatic symptoms, perceived stress, and lower levels of positive affect predicted membership of the “no improvement” subgroup. Reductions in anxiety preceded reductions in fatigue, while the depressive symptoms – fatigue relationship was bidirectional.

Conclusions: A standardized CBT program for CFS is moderately effective at the group level, with important individual differences in treatment response. Higher pre-treatment levels of anxious, depressive, and somatic symptoms and perceived stress are predictors of lack of response, suggesting these may need to be treated separately prior to enrolling patients in the standardized CBT treatment program.

3. Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome

Azcue N, Del Pino R, Acera M, Fernández-Valle T, Ayo-Mentxakatorre N, Pérez-Concha T, Murueta-Goyena A, Lafuente JV, Prada A, López de Munain A, Ruiz Irastorza G, Martín-Iglesias D, Ribacoba L, Gabilondo I, Gómez-Esteban JC, Tijero-Merino B.

J Transl Med. 2023 Nov 15;21(1):814.

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms.

Methods: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 healthy controls (HC). The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively. Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and HC, as well as, analyze the relationship of these symptoms with cognition and fatigue.

Results: Statistically significant differences were found between groups in heart rate using the Kruskal-Wallis test (H), with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC. Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance.

Conclusions: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN.

4. Clinical outcomes, medical costs, and medication usage patterns of different somatic symptom disorders and functional somatic syndromes: a population-based study in Taiwan

Wu, C., Chen, T., Liao, S., Huang, W., & Huang, W.

Psychological Medicine, 1-9.

Abstract

Background: Somatic symptom disorders (SSD) and functional somatic syndromes (FSS) are often regarded as similar diagnostic constructs; however, whether they exhibit similar clinical outcomes, medical costs, and medication usage patterns has not been examined in nationwide data. Therefore, this study focused on analyzing SSD and four types of FSS (fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, functional dyspepsia).

Methods: This population-based matched cohort study utilized Taiwan's National Health Insurance (NHI) claims database to investigate the impact of SSD/FSS. The study included 2 615 477 newly diagnosed patients with SSD/FSS and matched comparisons from the NHI beneficiary registry. Healthcare utilization, mortality, medical expenditure, and medication usage were assessed as outcome measures. Statistical analysis involved Cox regression models for hazard ratios, generalized linear models for comparing differences, and adjustment for covariates.

Results: All SSD/FSS showed significantly higher adjusted hazard ratios for psychiatric hospitalization and all-cause hospitalization compared to the control group. All SSD/FSS exhibited significantly higher adjusted hazard ratios for suicide, and SSD was particularly high. All-cause mortality was significantly higher in all SSD/FSS. Medical costs were significantly higher for all SSD/FSS compared to controls. The usage duration of all psychiatric medications and analgesics was significantly higher in SSD/FSS compared to the control group.

Conclusion: All SSD/FSS shared similar clinical outcomes and medical costs. The high hazard ratio for suicide in SSD deserves clinical attention.

5. Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review

Izabelle de Mello Gindri, Gustavo Ferrari, Luiz Paulo S. Pinto, Juliana Bicca, Isis Kelly dos Santos, Darlan Dallacosta, and Carlos Rodrigo de Mello Roesler.

Am J Physiol Endocrinol Metab. 2023 Nov 16. [Epub ahead of print]

Abstract

Purpose: NAD+ is an essential pyridine nucleotide cofactor that is present in cells and in several important biological processes, including oxidative phosphorylation and production of adenosine triphosphate, DNA repair, calcium-dependent secondary messenger and gene expression. The purpose of this systematic review is to examine whether the coenzyme formulae NAD+ and NADH are safe and effective when acting as a supplement to humans.

Methods: This systematic review of randomized clinical trials performed a search in six electronic databases. Two reviewers assessed and extracted the studies independently. The risk of bias in studies was performed using the version 2 of the Cochrane risk of bias tool for randomized trials.

Results: This review includes 10 studies, with a total of 489 participants. The studies included different clinical conditions, such as chronic fatigue syndrome (CFS); older adults; Parkison disease; overweight, postmenopausal prediabetes and Alzheimer disease. Based on studies, the supplementation with NADH and precursors was well tolerated and observed clinical results such as, a decrease in anxiety conditions and maximum heart rate was observed after a stress test, increased muscle insulin sensitivity, insulin signaling. Quality of life, fatigue intensity and sleep quality among others were evaluated on patients with CFS.

All studies showed some side effects, thus, the most common associated with NAD's use are muscle pain, nervous disorders, fatigue, sleep disturbance, headaches. All adverse events cataloged by the studies did not present a serious risk to the health of the participants.

Conclusion: Overall, these findings support that the oral administration of NADH can be associated to an increase in general quality of life and improvement on health parameters (e.g., a decrease in anxiety, maximum heart rate). NADH supplementation is safe and has a low incidence of side effects. Future investigations are needed to evidence the clinical benefits regarding specific diseases and doses administered.

Ryabkova, V.A.; Rubinskiy, A.V.; Marchenko, V.N.; Trofimov, V.I.; Churilov, L.P.

Preprints 2023, 2023111228.

Abstract

Background: There is a considerable overlap between clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia).

This study aimed to objectively assess autonomic function in patients with PCC and in patients with ME/CFS whose disease was not related to COVID-19.

Methods: Synchronous recordings of an electrocardiogram, continuous dynamics of blood pressure in the digital artery using the Penaz method and ultrasound pneumotachography with the spirography function were obtained with spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting PCC definition and 32 healthy controls.

Heart rate variability (HRV), systolic and diastolic blood pressure variability (RV), respiration variability were assessed at rest and in tests with fixed respiratory rates. At rest, indicators of baroreflex regulation were additionally determined (baroreflex effectiveness index and baroreflex sensitivity).

Results: The total power, power of very low frequency, low-frequency and high-frequency of RR interval variability at rest as well as baroreflex effectiveness index in up-ramps of arterial blood pressure and baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to HC.

Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing HRV parameters return to normal in PCC, but not in ME/CFS.

Correlation analysis revealed a close relationship of HRV, RV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in ME/CFS and PCC.

Conclusion: A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependant dysautonomia was identified in ME/CFS and PCC. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationship between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

7. A Quick and Practical Approach to Secure a Chronic Fatigue Syndrome Diagnosis: The Novel Functional Limitation Index

Corbalán JA, Feltes G, Silva D, Gómez-Utrero E, Núñez-Gil IJ.

Journal of Clinical Medicine. 2023; 12(22):7157.

Abstract

Chronic Fatigue Syndrome (CFS) is a serious, clinical, long-term condition with an unclear etiology and a difficult diagnosis. Our aim is to propose an objective physiological parameter (Functional Limitation Index, FLI) that describes the degree of functional impairment to support clinical suspicion.

Materials and Methods: We consecutively included all CFS patients who consulted in the Exercise Physiology Department at our hospital, a dedicated referral unit for CFS, from 2009 to 2022. For comparison purposes, we included two control groups. Thus, three cohorts were included: the CFS group (patients with a previous definitive diagnosis), healthy voluntaries and a sportspeople/trained cohort (amateur athletes). All patients underwent a body composition test, spirometry, basal ECG in supine and standing positions and double peak effort ergospirometry with criteria of maximality.

Results: The CFS+ group comprised 183 patients (85% female, mean age 46.2 years) and the CFS− included 161 cases (25.5% female, mean age 41.2 years); there were 93 patients in the healthy and 68 in the trained cohort.

The CFS+ presented a lower functional class and scored worse in all of the performance parameters. The FLI was significantly higher in CFS+ (2.7 vs. 1.2; p < 0.001). The FLI displayed a good discrimination power (AUC = 0.94, p < 0.001), with a higher AUC than all of the other spirometric variables recorded. The best dichotomic overall FLI cutoff would be 1.66 with good specificity and sensitivity (S = 0.874, E = 0.864, Youden Index = 0.738).

Conclusions: The Functional Limitation Index (FLI) could provide an easy and accurate diagnosis of this condition in both genders in a one-day assessment.

Long-COVID Research References

Dr Katrina Pears,
Research Correspondent.
The ME Association.

RESEARCH INDEX

Audio commentary by Dr Katrina Pears

ME/CFS Research References

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