Are Circulating FGF21 and NT-proBNP promising novel biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, disabling, and complex multisystem illness of unknown etiology. The protein FGF21 regulates glucose homeostasis and lipid metabolism, and the protein NT-proBNP is strongly associated with an elevated cardiovascular risk; however, little is known about their role in ME/CFS patients. To address this gap, we explored the association between FGF21 and NT-proBNP and oxidative stress and inflammatory markers in ME/CFS.

Twenty-one ME/CFS patients and 20 matched healthy controls were included in the study. Participants filled out validated self-reported questionnaires on their current health status covering demographic and clinical characteristics. Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxides levels (p = 0.009 and p = 0.021, respectively) in ME/CFS. These ME/CFS patients also had significantly increased levels of inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α, and C-reactive protein (p < 0.05 for all) but not for IL-8 (p = 0.833) in ME/CFS, indicating low-grade systemic inflammation status. Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls.

Significantly positive correlations were found between NT-proBNP levels and IL-1β and IL-6 (p = 0.04 and p = 0.01) in ME/CFS patients but not between FGF21 and these cytokines. In contrast, no significant correlations were found for either FGF21 or NT-proBNP in controls. These findings lead to the hypothesis that elevated FGF21 and NT-proBNP levels and the association between NT-proBNP and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS.

Source: Domingo JC, Cordobilla B, Ferrer R, Giralt M, Alegre-Martin J, Castro-Marrero J. Are Circulating FGF21 and NT-proBNP promising novel biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Antioxid Redox Signal. 2020 Dec 22. doi: 10.1089/ars.2020.8230. Epub ahead of print. PMID: 33353469. https://pubmed.ncbi.nlm.nih.gov/33353469/

Food Implications in Central Sensitization Syndromes

Abstract:

Fibromyalgia (FM), chronic fatigue syndrome (CFS) and multiple chemical sensitivity (MCS) are some of the central sensitization syndromes (CSSs). The complexity of their diagnosis, the high interindividual heterogeneity and the existence of multi-syndromic patients requires a multifaceted treatment. The scientific literature is contradictory regarding the role of food in CSS, and evidence on the role of nutrition in MCS is particularly scarce. This review consists in gathering information about the current status of dietary recommendations (i.e., special dietary interventions, the role of additives, presence of micronutrient deficiencies, nutritional supplements and elimination of other nutrients and substances) and discussing the scientific evidence in depth to shed light on appropriate nutritional treatment managements for CSS patients. Current indications show that dietary modifications may vastly improve the patients’ quality of life at a low cost. We suggest personalized treatment, taking into consideration the severity of the disease symptoms, quality of life, coexistence with other diseases, pharmacological treatment, changing clinical characteristics, nutritional status, energy requirements and food tolerances, among others, as the best ways to tailor specific dietary interventions. These approaches will partially overcome the lack of scientific and clinical research on MSC. Patients should also be advised on the serious consequences of following dietary guidelines without a dietitian’s and clinician’s supervision.

Source: Aguilar-Aguilar E, Marcos-Pasero H, Ikonomopoulou MP, Loria-Kohen V. Food Implications in Central Sensitization Syndromes. J Clin Med. 2020 Dec 19;9(12):E4106. doi: 10.3390/jcm9124106. PMID: 33352747. https://pubmed.ncbi.nlm.nih.gov/33352747/

Advances in Clinical Research on Traditional Chinese Medicine Treatment of Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is one of the most common chronic diseases in modern society and affects patients’ quality of life to a certain extent. To date, the etiology and pathogenesis of CFS are still not completely clear. Various therapies have been developed, but there is still a lack of specific drugs or treatments. As a kind of adjuvant therapy, traditional Chinese medicine (TCM) has aroused widespread concern about the improvement of CFS. Although a large number of clinical randomized controlled trials have confirmed the therapeutic effect of TCM on CFS, the exact efficacy is still controversial. This article summarizes the clinical research methods and efficacy of TCM in the treatment of CFS over the past five years from the perspectives of syndrome differentiation, external treatment, and combination therapy.

Source: Zhang X, Wang M, Zhou S. Advances in Clinical Research on Traditional Chinese Medicine Treatment of Chronic Fatigue Syndrome. Evid Based Complement Alternat Med. 2020 Dec 2;2020:4715679. doi: 10.1155/2020/4715679. PMID: 33343675; PMCID: PMC7725552. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725552/ (Full text)

Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves severe fatigue, unrefreshing sleep, and cognitive impairment, leading to functional difficulties; prior studies have not evaluated risk factors with behavioral and immune data collected prior to developing ME/CFS.. Up to 5% of university students develop infectious mononucleosis (IM) annually, and 9-12% meet criteria for ME/CFS six months later. We sought to determine predictors of ME/CFS.

Methods: We enrolled college students at the start of the school year (Time 1), identified those who developed IM (Time 2) and followed them for 6 months (Time 3), identifying three groups: those who developed ME/CFS, those who developed severe ME/CFS (meeting >1 set of criteria) and those who were asymptomatic. We conducted 8 behavioral and psychological surveys and analyzed cytokines at three time points.

Results: 238 of the 4501 students (5.3%) developed IM; 6 months later, 55 of the 238 (23%) met criteria for ME/CFS and 157 (66%) were asymptomatic. 67 of the 157 asymptomatic students served as controls. Students with severe-ME/CFS were compared to students who were asymptomatic at three time points. The former group was not different from the latter group at Time 1 (prior to developing IM) in stress, coping, anxiety or depression, but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13. At Time 2 (when they developed IM), the two ME/CFS groups tended to have more autonomic complaints and behavioral symptoms while the severe- ME/CFS group had higher levels of IL-12 and lower levels of IL-13 than the recovered group.

Conclusion: At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered.

Source: Leonard A Jason, PhD, Joseph Cotler, PhD, Mohammed F Islam, PhD, Madison Sunnquist, PhD, Ben Z Katz, MD, Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, Clinical Infectious Diseases, , ciaa1886, https://doi.org/10.1093/cid/ciaa1886

Impact of Long-Term Cryopreservation on Blood Immune Cell Markers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for Biomarker Discovery

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmune disorder characterized by numerous symptoms of unknown etiology. The ME/CFS immune markers reported so far have failed to generate a clinical consensus, perhaps partly due to the limitations of biospecimen biobanking. To address this issue, we performed a comparative analysis of the impact of long-term biobanking on previously identified immune markers and also explored additional potential immune markers linked to infection in ME/CFS.

A correlation analysis of marker cryostability across immune cell subsets based on flow cytometry immunophenotyping of fresh blood and frozen PBMC samples collected from individuals with ME/CFS (n = 18) and matched healthy controls (n = 18) was performed. The functionality of biobanked samples was assessed on the basis of cytokine production assay after stimulation of frozen PBMCs. T cell markers defining Treg subsets and the expression of surface glycoprotein CD56 in T cells and the frequency of the effector CD8 T cells, together with CD57 expression in NK cells, appeared unaltered by biobanking. By contrast, NK cell markers CD25 and CD69 were notably increased, and NKp46 expression markedly reduced, by long-term cryopreservation and thawing. Further exploration of Treg and NK cell subsets failed to identify significant differences between ME/CFS patients and healthy controls in terms of biobanked PBMCs.

Our findings show that some of the previously identified immune markers in T and NK cell subsets become unstable after cell biobanking, thus limiting their use in further immunophenotyping studies for ME/CFS. These data are potentially relevant for future multisite intervention studies and cooperative projects for biomarker discovery using ME/CFS biobanked samples. Further studies are needed to develop novel tools for the assessment of biomarker stability in cryopreserved immune cells from people with ME/CFS.

Source: Gómez-Mora E, Carrillo J, Urrea V, Rigau J, Alegre J, Cabrera C, Oltra E, Castro-Marrero J, Blanco J. Impact of Long-Term Cryopreservation on Blood Immune Cell Markers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Implications for Biomarker Discovery. Front Immunol. 2020 Nov 17;11:582330. doi: 10.3389/fimmu.2020.582330. PMID: 33329554; PMCID: PMC7732598. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732598/  (Full text)

Chronic fatigue syndrome: source of controversy

Abstract:

Chronic fatigue syndrome (CFS) remains a controversial medical disorder. A combination of poorly executed studies using variable case definitions and diagnostic criteria have led to controversial results. These controversies cloud our vision on CFS, and lead to scepticism and frustration among patients, doctors and researchers. For future perspective, interdisciplinary studies of high quality with large well-defined patient groups and adequate controls are needed.

Source: Raijmakers RPH, van der Meer JWM. Het chronische-vermoeidheidsyndroom: bron van ophef [Chronic fatigue syndrome: source of controversy]. Ned Tijdschr Geneeskd. 2020 Dec 10;164:D5611. Dutch. PMID: 33332043. [Article in Dutch] https://pubmed.ncbi.nlm.nih.gov/33332043/

The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis

Abstract:

Background: The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET.

Methods: We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO2peak, Workloadpeak) and at ventilatory threshold (VO2@VT, Workload@VT).

Results: The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: -10.8 at Test 1 vs. -33.0 at Test 2, p < 0.05), which may reflect present the functional impairment associated with PEM.

Conclusions: Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.

Source: Lim EJ, Kang EB, Jang ES, Son CG. The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis. J Clin Med. 2020 Dec 14;9(12):E4040. doi: 10.3390/jcm9124040. PMID: 33327624. https://pubmed.ncbi.nlm.nih.gov/33327624/

Could Cognitive Behavioural Therapy Be an Effective Treatment for Long COVID and Post COVID-19 Fatigue Syndrome? Lessons from the Qure Study for Q-Fever Fatigue Syndrome

Abstract:

An increasing number of young and previously fit and healthy people who did not require hospitalisation continue to have symptoms months after mild cases of COVID-19. Rehabilitation clinics are already offering cognitive behavioural therapy (CBT) as an effective treatment for long COVID and post-COVID-19 fatigue syndrome based on the claims that it is effective for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-the most common post-infectious syndrome-as no study into the efficacy of CBT for post-COVID-19 fatigue syndrome has been published. Re-analyses of these studies, however, showed that CBT did not lead to objective improvements in heterogeneous groups of ME/CFS patients, nor did it restore the ability to work.

The group of patients with long COVID and post-COVID-19 fatigue syndrome, on the other hand, is homogeneous. We therefore analysed the Dutch Qure study, as it studied the efficacy of CBT in a homogeneous group of patients who developed Q-fever fatigue syndrome-which affects up to 30% of patients-after the largest reported outbreak of Q-fever, to see if CBT might potentially be an effective treatment for long-haulers after COVID-19 infection.

Our reanalysis found that the Qure study suffered from many serious methodological problems, which included relying on one subjective primary outcome in a study without a control group for the non-blinded CBT treatment group, using a post hoc definition of improvement, waiting 2 years before publishing their objective actometer results and ignoring the null effect of said results. Moreover, only 10% of participants achieved a clinically meaningful subjective improvement in fatigue as a result of CBT according to the study’s own figures.

Consequently, CBT has no subjective clinically meaningful effect in nine out of every ten patients that are treated with it. Additionally, the subjective improvement in fatigue was not matched by an improvement in disability, even though the disability was fatigue related according to the researchers. On top of this, CBT did not lead to an objective improvement in physical performance. Therefore, it cannot be said that CBT is an effective treatment for Q-fever fatigue syndrome either. It seems therefore unlikely that CBT will reduce disability or lead to objective improvement in long COVID or in post-COVID-19 fatigue syndrome.

Source: Vink M, Vink-Niese A. Could Cognitive Behavioural Therapy Be an Effective Treatment for Long COVID and Post COVID-19 Fatigue Syndrome? Lessons from the Qure Study for Q-Fever Fatigue Syndrome. Healthcare (Basel). 2020 Dec 11;8(4):E552. doi: 10.3390/healthcare8040552. PMID: 33322316. https://www.mdpi.com/2227-9032/8/4/552 (Full text)

Measuring improvement and deterioration in myalgic encephalomyelitis/chronic fatigue syndrome: the pitfalls of the Chalder Fatigue Questionnaire

Adamson et al. considered a 2-point decrease in Chalder Fatigue Questionnaire score to indicate improvement in fatigue and a 2-point increase in Chalder Fatigue Questionnaire score to indicate deterioration in fatigue.1 While intuitively appealing, data exist that suggest a more complex relationship between changes in Chalder Fatigue Questionnaire scores and clinical change.

Collin and Crawley studied treatment outcomes at 11 specialist myalgic encephalomyelitis/chronic fatigue syndrome clinics in England.2 The authors tabulated mean change in Chalder Fatigue Questionnaire score at one year against Clinical Global Impression scores (see additional file 1, table S3). A 2-point decrease in Chalder Fatigue Questionnaire score was reported patients who deemed their health as follows: ‘no change’, ‘a little worse’, ‘much worse’ and ‘very much worse’. The mean changes in Chalder Fatigue Questionnaire score in those categories were similar, with overlapping 95% confidence intervals within the range [4.77, 2.29]. This suggests that a 2-point decrease in Chalder Fatigue Questionnaire score indicates deterioration or no change in the health of a person with myalgic encephalomyelitis/chronic fatigue syndrome, not improvement.

Read the rest of this letter here: https://sci-hub.se/10.1177/0141076820977843

Source: Kirke KD. Measuring improvement and deterioration in myalgic encephalomyelitis/chronic fatigue syndrome: the pitfalls of the Chalder Fatigue Questionnaire. J R Soc Med. 2020 Dec 15:141076820977843. doi: 10.1177/0141076820977843. Epub ahead of print. PMID: 33319615.

Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched

Abstract:

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies.

Methods: We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study’s factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice’s description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups.

Results: We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case-control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants.

Conclusion: The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.

Source: Muller AE, Tveito K, Bakken IJ, Flottorp SA, Mjaaland S, Larun L. Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched. J Transl Med. 2020 Dec 14;18(1):484. doi: 10.1186/s12967-020-02665-6. PMID: 33317576. https://pubmed.ncbi.nlm.nih.gov/33317576/