Tag: symptoms

The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Purpose: Leptin is a member of the cytokine family; its receptor (LEPR-b) is the longest form receptor expressed in cells of the immune system; wherein LEPR-b deficiency causes a decrease in CD4+ cells. LEPR-b is located in hypothalamic and brain stem nuclei, and it primarily regulates energy status. As well, leptin indirectly regulates widespread pain and exercise tolerance by decreasing circulating cortisol.

Hyperinsulinemia increases leptin production in adipocytes on a diurnal rhythm; however, the precise relationship between insulin, leptin and pro-inflammatory markers remains uncertain. In clinical settings, high-sensitivity C-reactive protein (hsCRP) has been widely used, as an inflammatory predictor for leptin-related cardiometabolic outcomes and chronic inflammatory symptoms.

Leptin-related metabolic and inflammation dysregulations have been clinically reported in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but not fully elucidated. We examined the association of plasma insulin, leptin, and hsCRP levels with ME/CFS self-reported symptom severity.

Methods: Prospective analyses were conducted on ME/CFS patients who met Fukuda/CDC criteria at Birmingham hospital, Alabama, U.S.A. The independent variables were hyperinsulinemia (>174 μIU/mL), hyperleptinemia/hypoleptinemia (>18.3/<3.3 ng/mL), residual inflammation risk (hsCRP ≥2 and ≠26.2 mg/L) and within-individual-variability (WIV) for each biomarker.

WIV was defined for each individual as standard deviation/sample residuals adjusting for time and calculated from once-daily random plasma samples over 10–12 weeks.

The primary outcomes were:

(1) ME/CFS symptom score trends [generalized pain, persistent fatigue, sleep disturbance, impairment of concentration and memory (brain fog), and post-exertional malaise (PEM)] calculated from the MFI-20 questionnaire with anchors from 0 to 100 and recorded once daily over a matching 12–14 weeks, and

(2) dichotomized symptom severity, with severe symptoms defined as scores > 60/100. After adjusting for age and time, we reported: (1) standard errors (SEM) and p-values for symptom trends using multivariable mixed-effect linear regression models, and (2) odds ratios for severe symptoms using multivariable alternating logistic regression models.

Results: We included 29 ME/CFS patients. All were females and >18 years old. Hyperinsulinemia, hyperleptinemia/hypoleptinemia, and residual inflammation risk were 7%, 80%/7%, and 74%, respectively.

The medians of insulin-WIV, leptin-WIV and hsCRP-WIV were [(0.24; IQR 0.15–0.38), (0.25; IQR 0.15–0.40), (0.33; IQR 0.18–0.51)] respectively. On average, hyperleptinemic patients had the highest leptin-WIV and 50% of them had residual inflammation risk.

Severe (fatigue, pain, brain fog, sleep disturbance, and PEM) were reported in 50%, 29%, 41%, 30%, and 57% of patients, respectively. In the adjusted analysis, worse fatigue scores (7.49; SEM, 2.23; p = 0.002) were associated with higher insulin-WIV.

Hyperleptinemia (OR 1.54; 95% CI 1.13–2.09) compared to hypoleptinemia, and residual inflammation risk (OR 1.65; 95% CI 1.21–2.25) were associated with higher odds of severe fatigue. Worse pain scores (7.17; SEM, 2.30; p = 0.005) were associated with higher leptin-WIV, and (8.45; SEM, 2.25; p = 0.0009) higher hsCRP-WIV, and residual inflammation risk (OR 1.75; 95% CI 1.34–2.29) was associated with higher odds of severe pain.

Severe brain fog scores (9.20; SEM, 2.44; p = 0.0008) were associated with higher insulin-WIV, higher leptin-WIV (4.73; SEM, 2.12; p = 0.03). Residual inflammation risk (OR 1.40; 95% CI 1.16–1.77) was associated with higher odds of severe brain fog.

Hyperleptinemia (OR 0.60; 95% CI 0.43–1.19) was associated with lower odds of severe PEM compared to hypoleptinemia, and better sleep quality was associated (6.07; SEM, 1.70; p = 0.001) with higher insulin-WIV, and (3.37; SEM, 1.47; p = 0.03) higher leptin-WIV.

Conclusions: In patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.

Larger clinical trials are needed to further examine the prediction and causality of these biomarkers in the development of ME/CFS diagnosis. The efficacy and safety of anti-inflammatory therapies may be evaluated in sub-clusters of ME/CFS with metabolic responses and inflammation dysregulations to improve patient-reported symptoms.

Source: Rahaf Al Assil and Jarred W Younger. “The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” in Karandrea S, Agarwal N, Organizing Committee of Cardiometabolic Health Congress. Report from the Scientific Poster Session at the 16th Annual Cardiometabolic Health Congress in National Harbor, USA, 14–17 October 2021. Proceedings. 2022; 80(1):6. https://doi.org/10.3390/proceedings2022080006 (Full text)

Comparing Operationalized Approaches for Substantial Reduction of Functioning in Chronic Fatigue Syndrome and Myalgic Encephalomyelitis

Abstract:

A core criterion for Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) is a substantial reduction in functioning from pre-illness levels. Despite its ubiquity in diagnostic criteria, there is considerable debate regarding how to measure this domain. The current study assesses five distinct methods for measuring substantial reductions. The analysis used an international, aggregated dataset of patients (N = 2,368) and controls (N=359) to compare the effectiveness of each method.

Four methods involved sophisticated analytic approaches using the Medical Outcomes Survey Short Form-36; the fifth method included a single self-report item on the DePaul Symptom Questionnaire (DSQ). Our main finding was that all methods produced comparable results, though the DSQ item was the most valid in differentiating patients from controls. Having a simple, reliable method to capture a substantial reduction in functioning has considerable advantages for patients and health care workers.

Source: Wiedbusch E, Jason LA. Comparing Operationalized Approaches for Substantial Reduction of Functioning in Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. Arch Community Med. 2022;4(1):59-63. doi: 10.36959/547/653. Epub 2022 Apr 21. PMID: 35673386; PMCID: PMC9168545. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168545/ (Full text)

A Comprehensive Update of the Current Understanding of Chronic Fatigue Syndrome

Abstract:

This is a comprehensive literature review of chronic fatigue syndrome (CFS). We provide a description of the background, etiology, pathogenesis, diagnosis, and management regarding CFS. CFS is a multifaceted illness that has many symptoms and a wide array of clinical presentations.

As of recent, CFS has been merged with myalgic encephalomyelitis (ME). Much of the difficulty in its management has stemmed from a lack of a concrete understanding of its etiology and pathogenesis. There is a potential association between dysfunction of the autoimmune, neuroendocrine, or autonomic nervous systems and the development of CFS. Possible triggering events, such as infections followed by an immune dysregulation resulting have also been proposed. In fact, ME/CFS was first described following Epstein Barr virus (EBV) infections, but it was later determined that it was not always preceded by EBV infection.

Patient diagnosed with CFS have shown a noticeably earlier activation of anaerobic metabolism as a source of energy, which is suggestive of impaired oxygen consumption. The differential diagnoses range from tick-borne illnesses to psychiatric disorders to thyroid gland dysfunction. Given the many overlapping symptoms of CFS with other illnesses makes diagnosing it far from an easy task.

The Centers for Disease Control and Prevention (CDC) considers it a diagnosing of exclusion, stating that self-reported fatigue for at minimum of six months and four of the following symptoms are necessary for a proper diagnosis: memory problems, sore throat, post-exertion malaise, tender cervical or axillary lymph nodes, myalgia, multi-joint pain, headaches, and troubled sleep. In turn, management of CFS is just as difficult.

Treatment ranges from conservative, such as cognitive behavioral therapy (CBT) and antidepressants, to minimally invasive management. Minimally invasive management involving ranscutaneous electrical acupoint stimulation of target points has demonstrated significant improvement in fatigue and associated symptoms in a 2017 randomized controlled study. The understanding of CFS is evolving before us as we continue to learn more about it. As further reliable studies are conducted, providing a better grasp of what the syndrome encompasses, we will be able to improve our diagnosis and management of it.

Source: Noor N, Urits I, Degueure A, Rando L, Kata V, Cornett EM, Kaye AD, Imani F, Narimani-Zamanabadi M, Varrassi G, Viswanath O. A Comprehensive Update of the Current Understanding of Chronic Fatigue Syndrome. Anesth Pain Med. 2021 Jun 26;11(3):e113629. doi: 10.5812/aapm.113629. PMID: 34540633; PMCID: PMC8438707. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438707/  (Full text)

Long COVID Patient Symptoms and its Evaluation and Management

Abstract:

While the acute case burdens and deaths from the COVID-19 pandemic (in Nepal approaching 700,000 and 10,000 respectively) have been costly, the characteristics and potentially huge dimensions of the chronic disease sequelae of this infectious disease are only slowly becoming apparent. We reviewed Pub Med, major medical meeting and medical journal, and investigative journalist materials seeking to frame and describe COVID-19 chronic disease.

The consequences of COVID-19 infections follow major organ damage, and induction of immunological and hormonal systems dysfunction. The first injuries are consequent to direct viral effects on tissues, and vasculitis, endothelialitis, thrombosis and inflammatory events. Pulmonary, cardiac, brain, and kidney tissues incur function-limiting damage, with dyspnea, arrythmias, decreased exercise capacity, cognitive dysfunction, and decreased glomerular filtration rates.

The second process is characterized by immune dysregulation and autoimmunity, and dysfunction of hormonal regulation systems, with high, fluctuating levels of physical and mental fatigue, multiple-site pain and ache, and non-restorative sleep, in 10-30% of cases.

This communication proposes evaluation and management of chronic COVID-19 patients with efficient assessment of commonest symptoms, targeted physical examination and organ function testing, and interventions based on specific organ functional status, and experience with similar chronic immune syndromes, such as myalgic encephalomyelitis.

Source: Sundar Shrestha D, Love R. Long COVID Patient Symptoms and its Evaluation and Management. JNMA J Nepal Med Assoc. 2021 Aug 12;59(240):823-831. doi: 10.31729/jnma.6355. PMID: 34508486. https://pubmed.ncbi.nlm.nih.gov/34508486/

COVID-19 symptoms over time: comparing long-haulers to ME/CFS

Abstract:

Introduction: Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.

Methods: 278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.

Results: Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.

Conclusions: These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.

Source: Leonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson & Brianna Mabie (2021) COVID-19 symptoms over time: comparing long-haulers to ME/CFS, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1922140 https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1922140

Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design

Abstract:

Objective: To explore the relationship between symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM). The hypothesis predicated that there would be no significant differences between the group’s symptom experience.

Design: A quasiexperimental design. Structural equation modelling (SEM) and invariance testing.

Participants: Males (M) and females (F) >16 with a confirmed diagnosis of CFS/ME or FM by a general practitioner or specialist. CFS/ME (n=101, F: n=86, M: n=15, mean (M) age M=45.5 years). FM (n=107, F: n=95, M: n=12, M=47.2 years).

Outcome measures: Diagnostic criteria: the American Centers for Disease Control and Prevention (CDC) for CFS/ME and the American College of Rheumatology (ACR) criteria for FM. Additional symptom questionnaires measuring: pain, sleep quality, fatigue, quality of life, anxiety and depression, locus of control and self-esteem.

Results: Invariance was confirmed with the exception of the American CDC Symptom Inventory, Fibromyalgia Impact Questionnaire and Hospital Anxiety and Depression Scale (p<0.05) based on five questions. Consequently, it was erroneous to conclude differences. Therefore, the Syndrome Model was created. SEM could not have tested the ACR previously, as it comprised a single data point. Thus, it was combined with these three questionnaires, increasing the data points, to create this new measurable model. Results confirmed no significant differences between groups (p=0.07 (p<0.05)).

Conclusion: Participants responded in a similar manner to the questionnaire, confirming the same symptom experience. It is important to consider this in context with differing criteria and management guidelines, as this may influence diagnosis and the trajectory of patient’s management. With the biomedical cause currently unclear, it is the symptom experience and the impact on quality of life that is important. These findings are meaningful for patients, clinicians and policy development and support the requirement for future research.

Source: Mckay PG, Walker H, Martin CR, Fleming M. Exploratory study into the relationship between the symptoms of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and fibromyalgia (FM) using a quasiexperimental design. BMJ Open. 2021 Feb 1;11(2):e041947. doi: 10.1136/bmjopen-2020-041947. PMID: 33526500. https://bmjopen.bmj.com/content/11/2/e041947.long (Full text)

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules

Abstract:

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.

METHODS: Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.

FINDINGS: The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.

IMPLICATIONS: The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies. (Clin Ther. 2019;41:XXX-XXX) © 2019 Elsevier Inc.

Copyright © 2019. Published by Elsevier Inc.

Source: Jeffrey MG, Nathanson L, Aenlle K, Barnes ZM, Baig M, Broderick G, Klimas NG, Fletcher MA, Craddock TJA. Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules. Clin Ther. 2019 Mar 6. pii: S0149-2918(19)30047-5. doi: 10.1016/j.clinthera.2019.01.011. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30851951

Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis

Abstract:

BACKGROUND: Considerable controversy has transpired regarding the core features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Current case definitions differ in the number and types of symptoms required. This ambiguity impedes the search for biological markers and effective treatments.

PURPOSE: This study sought to empirically operationalize symptom criteria and identify which symptoms best characterize the illness.

METHODS: Patients (n=236) and controls (n=86) completed the DePaul Symptom Questionnaire, rating the frequency and severity of 54 symptoms. Responses were compared to determine the threshold of frequency/severity ratings that best distinguished patients from controls. A Classification and Regression Tree (CART) algorithm was used to identify the combination of symptoms that most accurately classified patients and controls.

RESULTS: A third of controls met the symptom criteria of a common CFS case definition when just symptom presence was required; however, when frequency/severity requirements were raised, only 5% met criteria. Employing these higher frequency/severity requirements, the CART algorithm identified three symptoms that accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.

CONCLUSIONS: Minimum frequency/severity thresholds should be specified in symptom criteria to reduce the likelihood of misclassification. Future research should continue to seek empirical support of the core symptoms of ME and CFS to further progress the search for biological markers and treatments.

 

Source: Jason LA, Sunnquist M, Brown A, Evans M, Vernon SD, Furst J, Simonis V. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue. 2014 Jan 1;2(1):40-56. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912876/ (Full article)

 

Symptom occurrence in persons with chronic fatigue syndrome

Abstract:

This investigation compared differences in the occurrence of symptoms in participants with CFS, melancholic depression, and no fatigue (controls). The following Fukuda et al. [Ann. Intern. Med. 121 (1994) 953] criteria symptoms differentiated the CFS group from controls, but did not differentiate the melancholic depression group from controls: headaches, lymph node pain, sore throat, joint pain, and muscle pain. In addition, participants with CFS uniquely differed from controls in the occurrence of muscle weakness at multiple sites as well as in the occurrence of various cardiopulmonary, neurological, and other symptoms not currently included in the current case definition. Implications of these findings are discussed.

 

Source: Jason LA, Torres-Harding SR, Carrico AW, Taylor RR. Symptom occurrence in persons with chronic fatigue syndrome. Biol Psychol. 2002 Feb;59(1):15-27. http://www.ncbi.nlm.nih.gov/pubmed/11790441

 

Co-existence of chronic fatigue syndrome with fibromyalgia syndrome in the general population. A controlled study

Abstract:

OBJECTIVE: To determine the proportion of adults with fibromyalgia syndrome (FMS) in the general population who also meet the 1988 Centre for Disease Control (CDC) criteria for chronic fatigue syndrome (CFS).

METHODS: Seventy-four FMS cases were compared with 32 non-FMS controls with widespread pain and 23 with localized pain, all recruited in a general population survey.

RESULTS: Among females, 58.0% of fibromyalgia cases met the full criteria for CFS, compared to 26.1% and 12.5% of controls with widespread and localized pain, respectively (p=0.0006). Male percentages were 80.0, 22.2, and zero, respectively (p=0.003). Compared to those with FMS alone, those meeting the case definitions for both FMS and CFS reported a worse course, worse overall health, more dissatisfaction with health, more non-CFS symptoms, and greater disease impact. The number of total symptoms and non-CFS symptoms were the best predictors of co-morbid CFS.

CONCLUSIONS: There is significant clinical overlap between CFS and FMS.

 

Source: White KP, Speechley M, Harth M, Ostbye T. Co-existence of chronic fatigue syndrome with fibromyalgia syndrome in the general population. A controlled study. Scand J Rheumatol. 2000;29(1):44-51. http://www.ncbi.nlm.nih.gov/pubmed/10722257