A Systematic Review of Biological Mechanisms of Fatigue in Chronic Illness.
Matura Lea Ann,Malone Susan,Jaime-Lara Rosario,Riegel Barbara
Biological research for nursing
Fatigue, a commonly reported symptom, is defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases the ability to function and carry out daily activities. To date, cancer researchers have been in the forefront in investigating the possible biological mechanisms of fatigue, identifying inflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and activation of the autonomic nervous system. The purpose of this systematic review is to describe fatigue and what is known about the biological mechanisms described in cancer in five chronic, noninfectious illnesses: heart failure, multiple sclerosis, chronic kidney disease, rheumatoid arthritis, and chronic obstructive pulmonary disease. We searched PubMed and EMBASE using fatigue as a major Medical subject headings (MeSH) heading with each individual disease added as a search term followed by each biological mechanism. We included only primary research articles published in English between 1996 and 2016 describing studies conducted in adult humans. We identified 26 relevant articles. While there is some evidence that the biological mechanisms causing fatigue in cancer are also associated with fatigue in other chronic illnesses, more research is needed to explore inflammation, the HPA axis, and the autonomic nervous system, and other mechanisms in relation to fatigue in a variety of chronic illnesses.
Identifying and validating blood mRNA biomarkers for acute and chronic insufficient sleep in humans: a machine learning approach.
Laing Emma E,Möller-Levet Carla S,Dijk Derk-Jan,Archer Simon N
Acute and chronic insufficient sleep are associated with adverse health outcomes and risk of accidents. There is therefore a need for biomarkers to monitor sleep debt status. None are currently available. We applied elastic net and ridge regression to transcriptome samples collected in 36 healthy young adults during acute total sleep deprivation and following 1 week of either chronic insufficient (<6 hr) or sufficient sleep (~8.6 hr) to identify panels of mRNA biomarkers of sleep debt status. The size of identified panels ranged from 9 to 74 biomarkers. Panel performance, assessed by leave-one-subject-out cross-validation and independent validation, varied between sleep debt conditions. Using between-subject assessments based on one blood sample, the accuracy of classifying "acute sleep loss" was 92%, but only 57% for classifying "chronic sleep insufficiency." A reasonable accuracy for classifying "chronic sleep insufficiency" could only be achieved by a within-subject comparison of blood samples. Biomarkers for sleep debt status showed little overlap with previously identified biomarkers for circadian phase. Biomarkers for acute and chronic sleep loss also showed little overlap but were associated with common functions related to the cellular stress response, such as heat shock protein activity, the unfolded protein response, protein ubiquitination and endoplasmic reticulum-associated protein degradation, and apoptosis. This characteristic response of whole blood to sleep loss can further aid our understanding of how sleep insufficiencies negatively affect health. Further development of these novel biomarkers for research and clinical practice requires validation in other protocols and age groups.
Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.
Russell Alice,Hepgul Nilay,Nikkheslat Naghmeh,Borsini Alessandra,Zajkowska Zuzanna,Moll Natalie,Forton Daniel,Agarwal Kosh,Chalder Trudie,Mondelli Valeria,Hotopf Matthew,Cleare Anthony,Murphy Gabrielle,Foster Graham,Wong Terry,Schütze Gregor A,Schwarz Markus J,Harrison Neil,Zunszain Patricia A,Pariante Carmine M
The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.
Fatigue scores correlate with other self-assessment data, but not with clinical and biomarker parameters, in CIS and RRMS.
Håkansson Irene,Johansson Lovisa,Dahle Charlotte,Vrethem Magnus,Ernerudh Jan
Multiple sclerosis and related disorders
BACKGROUND:Fatigue is common in multiple sclerosis and is associated with reduced quality of life. This study aimed to assess the correlation between fatigue scores and data from other self-assessment questionnaires, neuropsychological tests and neuroimaging, as well as data on neuroimmunological markers in cerebrospinal fluid (CSF) and serum/plasma, in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). METHODS:Modified fatigue impact scale (MFIS) scores were determined in 38 patients with newly diagnosed CIS or RRMS at baseline and after one year in a prospective longitudinal cohort study. Non-parametric correlation analyses were used to assess associations between MFIS scores and other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36)), as well as with neuropsychological test performances (e.g. Auditory Consonant Trigram Test (ACTT)), clinical parameters (e.g. disease duration and expanded disability status scale (EDSS)), magnetic resonance imaging (MRI) data (number of T2 lesions in brain MRI and total brain volume) and several neurodegenerative/neuroinflammatory markers in CSF and serum/plasma (IL-1β, IL-6, CXCL1, CXCL10, CXCL13, CCL-22 in plasma; neurofilament light chain (NFL) in serum; IL-6, CXCL1, CXCL10, CXCL13, CCL22, NFL and chitinase-3-like-1 (CHI3L1) in CSF. CSF and serum/plasma from 21 age- and sex-matched healthy controls were available for comparison. RESULTS:At both baseline and one-year follow-up, fatigue scores correlated significantly with HAD, MSIS-29 and SF-36 scores and ACTT performance (Spearman´s rho 0.45-0.78, all p ≤ 0.01) but not with the other neuropsychological test results, disease duration, EDSS ratings, number of T2 lesions, total brain volume or neurodegenerative/neuroinflammatory markers, including neurofilament light chain levels in CSF and serum. In group comparisons, MFIS scores were similar in patients fulfilling no evidence of disease activity-3 (NEDA-3) (n = 18) and patients not fulfilling NEDA-3 (n = 20) during one year of follow-up (p > 0.01). CONCLUSIONS:In this cohort of patients with newly diagnosed CIS and RRMS, fatigue scores were associated with mood, disease impact on daily life and quality of life as well as with alterations of attentive functions. Study results indicate that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters like EDSS, T2 lesions and NFL levels.
Discovery and identification of fatigue-related biomarkers in human saliva.
Xu Y-L,Gong Y-N,Xiao D,Zhao C-X,Gao X-H,Peng X-H,Xi A-P,He L-H,Lu L-P,Ding M,Li Y,Jianjun H,Su X-H,Liu F-L,Wang J-Z,Liu Z-J,Zhang J-Z
European review for medical and pharmacological sciences
OBJECTIVE:To identify stable and specific biomarkers/biomarker combinations for fatigue assessment and establish a discriminant model. PATIENTS AND METHODS:Saliva was collected and electroencephalogram analysis was performed for 47 emergency physicians while awake and after continuoutas duty for 18-24 h. Physicians were divided into the fatigue and non-fatigue groups. Protein spectra of completely quantified saliva specimens were identified before and after long working hours using mass spectrometry. Data were analyzed through Proteome Discoverer software combined with SEQUEST to search protein databases. Proteins were characterized by collision-induced dissociation spectra. A global internal standard (GIS) was added to each group of samples and labeled by tandem mass tags m/z 131.1. All data were compared with GIS, and data between groups were further compared. Qualitative and quantitative data on proteins were exported for fatigue-related proteomic analysis, and a fatigue assessment model was established. RESULTS:We identified 767 salivary proteins in the fatigue group. The correct rates of the discriminant function of the non-fatigue and fatigue groups were 97.1% and 91.7%, respectively (the total correct rate was 95.7%). CONCLUSIONS:We identified 30 fatigue-related protein markers from saliva. We also established a fatigue assessment model for emergency physicians using salivary biomarkers.
Prevalence and factors associated with fatigue in female patients with systemic lupus erythematosus.
Carrión-Barberà Irene,Salman-Monte Tarek Carlos,Castell Sonia,Castro Francisco,Ojeda Fabiola,Carbonell Jordi
OBJECTIVE:To determine the prevalence of fatigue in our cohort as well as the factors to which it is associated, its relationship with demographic variables, vitamin D levels, treatment, systemic lupus erythematosus (SLE) symptoms and disease activity. METHODS:A cross-sectional study was carried out including 102 consecutive female patients with SLE (American College of Rheumatology 1997 criteria) who attended the Parc de Salut Mar between January 2012 and May 2014. Variables collected were: sociodemographic data, vitamin D supplementation, fatigue VAS, pharmacological treatment, main serological markers of SLE, and plasma levels of 25(OH)-vitD. The association between fatigue and the different variables was evaluated by the Spearman's Rho correlation coefficient for the continuous variables, the Mann-Whitney U test for the categorical and the Kruskal-Wallis test for the seasons of the year. RESULTS:The fatigue variable was evaluated through a fatigue VAS with a mean score of 52.84 (range 0-100), a median of 59 and a standard deviation of 29.86. A statistically significant relationship was found between fatigue and age, MHAQ, SLICC, summer and photosensitivity. As for the relationship between fatigue and vitamin D insufficiency (defined as 25-(OH)-vitD≤30 levels), the sample was divided into patients receiving vitamin D supplements (n=60) and patients without supplements (n=40), finding a significant relationship in that last group. CONCLUSIONS:A statistically significant association was found between the presence of fatigue and age, MHAQ, SLICC, photosensitivity, fibromyalgia and summer, and with vitamin D insufficiency in the group of patients without supplements (n=40).
Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [C]PBR28 PET study.
Tamm Sandra,Cervenka Simon,Forsberg Anton,Estelius Johanna,Grunewald Johan,Gyllfors Pär,Karshikoff Bianka,Kosek Eva,Lampa Jon,Lensmar Catarina,Strand Victoria,Åkerstedt Torbjörn,Halldin Christer,Ingvar Martin,Olgart Höglund Caroline,Lekander Mats
Brain, behavior, and immunity
Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.
Co-variation of fatigue and psychobiological stress in couples' everyday life.
Doerr Johanna M,Nater Urs M,Ehlert Ulrike,Ditzen Beate
OBJECTIVE:There is limited knowledge about how fatigue develops and worsens and what influences fluctuations in daily fatigue. Stress was found to influence fatigue, and being in a relationship seems to either increase or decrease stress depending on the couple interaction. In this study, co-variation of fatigue, self-reported stress, and biological stress markers in couples' everyday lives was investigated. Specifically, we examined a) whether momentary couple interactions moderated dyadic outcomes and b) whether and how stress and relationship measures influenced individual momentary fatigue. METHODS:Forty heterosexual couples (age: 28 ± 5 years) reported subjective fatigue and stress levels 4 times a day for 5 consecutive days (1600 measures). Furthermore, participants reported whether they had interacted with their partner since the last data entry and, if so, they rated the valence of this interaction. Salivary cortisol (a measure of HPA axis activity) and alpha amylase (a measure of ANS activity) were analyzed as biological stress markers from saliva samples obtained at the same time points. Moment-to-moment data were analyzed using dyadic multilevel models to account for the nested design. RESULTS:Stress (women and men: p ≤ 0.001) and fatigue (women: p = .003, men: p = .020) showed patterns of co-variation within couples, especially if partners had interacted with each other since the previous data entry. Cortisol was also found to co-vary between partners (women: unstandardized coefficient (UC) = 0.12, p ≤ .001, men: UC = 0.18, p ≤ .001), whereas the regulation of alpha-amylase levels depending on the partner's levels was only present in women (UC = 0.11, p = .002). Valence of couple interaction was negatively associated with fatigue (women: UC = -0.13, p ≤ .001, men: UC = -0.06, p = .011). There was no momentary association of fatigue with an individual's own or the partner's subjective or biological stress markers. CONCLUSIONS:Fatigue and stress levels during the day seem to co-vary within couples. These associations were particularly strong when the partners had interacted with each other since the last measurement. These data underline the importance of social factors in fatigue and stress in everyday life.
Investigating daily fatigue scores during two-week offshore day shifts.
Riethmeister Vanessa,Bültmann Ute,Gordijn Marijke,Brouwer Sandra,de Boer Michiel
OBJECTIVES:This study examined daily scores of fatigue and circadian rhythm markers over two-week offshore day shift periods. METHODS:A prospective cohort study among N = 60 offshore day-shift workers working two-week offshore shifts was conducted. Offshore day shifts lasted from 07:00 - 19:00 h. Fatigue was measured objectively with pre- and post-shift scores of the 3-minute psychomotor vigilance tasks (PVT-B) parameters (reaction times, number of lapses, errors and false starts) and subjectively with pre- and post-shift Karolinska Sleepiness Scale (KSS) ratings. Evening saliva samples were collected on offshore days 2,7 and 13 to measure circadian rhythm markers such as dim-light melatonin onset times and cortisol. Generalized and linear mixed model analyses were used to examine daily fatigue scores over time. RESULTS:Complete data from N = 42 offshore day shift workers was analyzed. Daily parameters of objective fatigue, PVT-B scores (reaction times, average number of lapses, errors and false starts), remained stable over the course of the two-week offshore day shifts. Daily subjective post-shift fatigue scores significantly increased over the course of the two-week offshore shifts. Each day offshore was associated with an increased post-shift subjective fatigue score of 0.06 points (95%CI: .03 - .09 p < .001). No significant statistical differences in subjective pre-shift fatigue scores were found. Neither a circadian rhythm phase shift of melatonin nor an effect on the pattern and levels of evening cortisol was found. CONCLUSION:Daily parameters of objective fatigue scores remained stable over the course of the two-week offshore day shifts. Daily subjective post-shift fatigue scores significantly increased over the course of the two-week offshore shifts. No significant changes in circadian rhythm markers were found. Increased post-shift fatigue scores, especially during the last days of an offshore shift, should be considered and managed in (offshore) fatigue risk management programs and fatigue risk prediction models.
Inflammation and fatigue in early, untreated Parkinson's Disease.
Herlofson K,Heijnen C J,Lange J,Alves G,Tysnes O-B,Friedman J H,Fagundes C P
Acta neurologica Scandinavica
OBJECTIVES:Parkinson's disease (PD)-related fatigue is a significant clinical problem, and the pathological processes that cause fatigue remain unknown. The aim of the present study was to explore the possible association of peripheral inflammation markers and fatigue in PD. MATERIALS & METHODS:We included 47 drug naïve, newly diagnosed PD patients with low (≤3.0) or high (>5.5) fatigue levels as evaluated by the Fatigue Severity Scale (FSS). Strict diagnostic criteria were applied for inclusion. Patients with possible confounding causes for fatigue were excluded. Serum concentrations of a panel of inflammatory markers (IL-8, TNF-α, MCP1, MIP-1β, IL-6, IL-6R, p-selectin, E-selectin-1, ICAM, VCAM-1, CCL5, IL1-Ra, and TNFR1) were measured using ELISA technology in PD patients with and without fatigue to assess the potential relationships of fatigue in newly diagnosed, treatment-naïve patients. RESULTS:Fatigued PD patients had significantly higher levels of the IL-1 receptor antagonist (IL1-Ra) (1790 pg/mL (SD1007) vs 1262 pg/mL (SD379)) and of the adhesion molecule VCAM 1 (1071 ng/mL (SD276) vs 895 ng/mL (SD229)) than non-fatigued patients. A binary logistic regression model, including high or low FSS score as the dependent variable and UPDRS motor score, MADRS, MMSE, ESS, and IL1-Ra/VCAM-1 as independent variables, showed a significant effect both for IL1-Ra and VCAM-1. CONCLUSIONS:Higher serum levels of the inflammatory molecules IL1-Ra and VCAM-1 were associated with higher fatigue levels in patients with newly diagnosed, drug-naïve PD. These findings highlight an altered immune response as a potential contributor to PD-related fatigue, from the earliest clinical stages of the disease.
Changes in urinary amino acids excretion in relationship with muscle activity markers over a professional cycling stage race: in search of fatigue markers.
Corsetti Roberto,Barassi Alessandra,Perego Silvia,Sansoni Veronica,Rossi Alessandra,Damele Clara Anna Linda,Melzi D'Eril Gianlodovico,Banfi Giuseppe,Lombardi Giovanni
The aim of this study was to identify the relationship between metabolic effort, muscular damage/activity indices, and urinary amino acids profile over the course of a strenuous prolonged endurance activity, as a cycling stage race is, in order to identify possible fatigue markers. Nine professional cyclists belonging to a single team, competing in the Giro d'Italia cycling stage race, were anthropometrically characterized and sampled for blood and urine the day before the race started, and on days 12 and 23 of the race. Diet was kept the same over the race, and power output and energy expenditure were recorded. Sera were assayed for muscle markers (lactate dehydrogenase, aspartate aminotransferase, and creatine kinase activities, and blood urea nitrogen), and creatinine, all corrected for plasma volume changes. Urines were profiled for amino acid concentrations, normalized on creatinine excretion. Renal function, in terms of glomerular filtration rate, was monitored by MDRD equation corrected on body surface area. Creatine kinase activity and blood urea were increased during the race as did serum creatinine while kidney function remained stable. Among the amino acids, taurine, glycine, cysteine, leucine, carnosine, 1-methyl histidine, and 3-methyl histidine showed a net decreased, while homocysteine was increased. Taurine and the dipeptide carnosine (β-alanyl-L-histidine) were significantly correlated with the muscle activity markers and the indices of effort. In conclusion, the metabolic profile is modified strikingly due to the effort. Urinary taurine and carnosine seem useful tools to evaluate the muscle damage and possibly the fatigue status on a long-term basis.
Monitoring training load and fatigue in soccer players with physiological markers.
Djaoui Léo,Haddad Monoem,Chamari Karim,Dellal Alexandre
Physiology & behavior
The quantification and monitoring of training load (TL) has been the topic of many scientific works in the last fifteen years. TL monitoring helps coaches to individually prescribe, follow-up, analyse, adjust and programme training sessions. In particular, the aim of the present review was to provide a critical literature report regarding different physiological markers of TL monitoring, particularly in soccer, as the load is specific to individual sports. Therefore, the interests and limitations of heart rate (HR), HR variability (HRV) and biochemical variables (blood, urinary and hormonal variations) were analysed, with a special focus on daily measures (before, during and after training) and monitoring throughout a whole season. It appears that the most relevant markers were the resting HR before training, HR reserve during training, HRV during rest days, blood lactate, and blood and salivary immunological status in follow-ups throughout the season. Urinary markers indicative of the players' hydration status also deserve attention. However, these objective markers should be considered with a subjective marker of TL such as the rating of perceived exertion to give a more precise quantification of TL and its perception. Future research could be directed towards urinary marker analysis and the analysis of specific markers of TL, which could be related to injury occurrence and to performance during competition.
Influence of Personalized Exercise Recommendations During Rehabilitation on the Sustainability of Objectively Measured Physical Activity Levels, Fatigue, and Fatigue-Related Biomarkers in Patients With Breast Cancer.
Zimmer Philipp,Baumann Freerk T,Oberste Max,Schmitt Joachim,Joisten Niklas,Hartig Philipp,Schenk Alexander,Kuhn Rafaela,Bloch Wilhelm,Reuss-Borst Monika
Integrative cancer therapies
PURPOSE:Only one-third of patients with breast cancer reach the recommended activity level of 15 to 25 MET h/wk. The aim of this study was to determine the influence of personalized exercise recommendations during rehabilitation on patients' physical activity level, fatigue, and self-perceived cognitive function as well as on side effect-associated biomarkers. METHODS:Total metabolic rate, physical activity level, mean MET and steps, fatigue, self-perceived cognitive functioning , and biomarkers (C-reactive protein [CRP], interleukin 6, macrophage migration inhibiting factor [MIF], tumor necrosis factor [TNF]-α, brain-derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF1]) were assessed in 60 patients with breast cancer in the aftercare phase before ( t) and 8 months after ( t) the intervention. The rehabilitation program consisted of an initial 3-week period and a 1-week stay after 4 months. RESULTS:Paired t-test indicated a statistically significant increase in all activity outcomes from t to t. Patients' mean activity level significantly increased from 14.89 to 17.88 MET h/wk. Fatigue and self-perceived cognitive functioning significantly improved from t to t. CRP levels significantly decreased, and BDNF as well as IGF1 levels significantly increased over time. Correlation analysis revealed statistically significant negative associations between fatigue, physical activity, and markers of inflammation (TNF-α and MIF). Furthermore, significant positive correlations between subjective cognitive functioning and all dimensions of fatigue were observed. CONCLUSIONS:The results support the importance of personalized exercise recommendations to increase physical activity levels in patients with breast cancer. Furthermore, the results highlighti an association between physical activity, fatigue, and inflammation.
Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.
Kristiansen Miriam Skjerven,Stabursvik Julie,O'Leary Elise Catriona,Pedersen Maria,Asprusten Tarjei Tørre,Leegaard Truls,Osnes Liv Toril,Tjade Trygve,Skovlund Eva,Godang Kristin,Wyller Vegard Bruun Bratholm
Brain, behavior, and immunity
INTRODUCTION:Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls. MATERIALS AND METHODS:A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS:The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p = 0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 × 10 cells/L, p = 0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p = 0.01) and plasma epinephrine (363 vs 237 nmol/L, p = 0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p = 0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p = 0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B = 4.5 × 10, p < 0.001), urine norepinephrine (B = 9.6 × 10, p = 0.044) and high-frequency power of heart rate variability (B = -3.7 × 10, p = 0.024). CONCLUSIONS:In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.
Effects of an Exercise Intervention on Cancer-Related Fatigue and Its Relationship to Markers of Oxidative Stress.
Repka Chris P,Hayward Reid
Integrative cancer therapies
BACKGROUND:Although the underlying mechanisms of cancer-related fatigue (CRF) are not fully characterized, treatment-associated oxidative stress may play a role. The purpose of this study was to determine the effect of an exercise intervention on the relationship between CRF and oxidative stress. METHODS:Upon cessation of radiation or chemotherapy, 8 cancer patients participated in a 10-week exercise intervention (EX), while 7 continued standard care (CON). Blood draws and fatigue questionnaires were administered to cancer patients before and after the intervention as well as to 7 age-matched individuals with no cancer history. Changes in plasma 8-hydroxy-deoxyguanosine (8-OHdG), protein carbonyls, antioxidant capacity, and fatigue were compared between groups. Correlations between CRF and oxidative stress were evaluated. RESULTS:Mean total fatigue scores decreased significantly (5.0 ± 2.2 to 2.6 ± 1.5, P < .05) in EX, but not in CON. Antioxidant capacity significantly increased (+41%; P < .05) and protein carbonyls significantly decreased (-36%; P < .05) in EX, but not in CON. Increases in antioxidant capacity were significantly correlated with reductions in affective ( r = -.49), sensory ( r = -.47), and cognitive fatigue ( r = -.58). Changes in total ( r = .46) and affective ( r = .47) fatigue exhibited significant correlations with changes in 8-OHdG over time, while behavioral ( r = .46) and sensory ( r = .47) fatigue changes were significantly correlated with protein carbonyls. CONCLUSIONS:Oxidative stress may be implicated in CRF, while improved antioxidant capacity following an exercise intervention may play a role in mitigating CRF in cancer survivors.
Objective physical and mental markers of self-reported fatigue in women undergoing (neo)adjuvant chemotherapy for early-stage breast cancer.
Mortimer Joanne E,Waliany Sarah,Dieli-Conwright Christina M,Patel Sunita K,Hurria Arti,Chao Joseph,Tiep Brian,Behrendt Carolyn E
BACKGROUND:Objective, treatment-independent markers of cancer-related fatigue are needed to advance clinical trials. In the current study, the authors evaluated physical, neurocognitive, and serologic markers for correlation with self-reported fatigue before and after (neo)adjuvant chemotherapy for patients with early-stage breast cancer. METHODS:Women with AJCC TNM Stage I-III breast cancer consented to assessment before and after the completion of 4 cycles of dose-dense doxorubicin and cyclophosphamide. Assessment included self-reported fatigue (using the Brief Fatigue Inventory), depression (using the Center for Epidemiologic Studies-Depression Scale [CES-D]), Pittsburgh Sleep Quality Index, and 28 objective measures (grip strength in dominant and nondominant hands, 6-minute walk, daily total energy expenditure, 14 neurocognitive tests, and 10 serologic markers). Generalized linear regression models of fatigue were constructed (1 model per marker), and adjusted for depression, timing before/after chemotherapy, menopausal status, obesity, and educational level. P values were adjusted to control the False Discovery Rate. RESULTS:Of 28 subjects, 3 withdrew without completing baseline assessments. Prechemotherapy and postchemotherapy data were available for the evaluation of physical measures (25 subjects aged 50.6 ± 9.5 years), neurocognitive tests (22 subjects), and serologic markers (10 subjects). On covariate-adjusted analysis, interleukin (IL)-12 was found to be associated with fatigue at both assessments (P<.01). Serum eotaxin (P < .01), IL-1RA (P < .01), monocyte chemoattractant protein 1 (MCP-1) (P<.01), and performance on 2 neurocognitive (Trail Making) tests (P<.01 and P = .02, respectively) were found to be inversely associated with fatigue before chemotherapy but not afterward, whereas daily energy expenditure, serum MCP-1, and serum macrophage inflammatory protein 1a (MIP-1a) were found to be associated with fatigue after receipt of chemotherapy but not before (P<.01 for each). The association between energy expenditure and fatigue was detectable only if an actively athletic subject with outlier values of energy expenditure was excluded. CONCLUSIONS:Serum IL-12 merits confirmatory testing as an objective, treatment-independent measure of fatigue in patients with early-stage breast cancer. Cancer 2017;123:1810-1816. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain.
Freidin Maxim B,Wells Helena R R,Potter Tilly,Livshits Gregory,Menni Cristina,Williams Frances M K
Biochimica et biophysica acta. Molecular basis of disease
BACKGROUND:Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue. MATERIAL AND METHODS:Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue. RESULTS:While no association between fatigue and metabolites was identified in twins without CWP (n=711), in participants with CWP (n=395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (β=-0.452±0.116; p=1.2×10). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p=1.5×10 and p=3.1×10, respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC=75%; 95% CI 69-80%). CONCLUSION:The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP.