Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome

PurposePrevious Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data.MethodsPatients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m²) infusions: 2 infusions 2 weeks apart (induction), followed by maintenance treatment at 3, 6, 10, and 15 months. The measured rituximab concentrations and ADAs in serum samples included 23 of 28 patients from the trial.FindingsThere were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = −0.47; P = 0.03). None of the patients had ADAs at any time point.ImplicationsClinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.     

Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms. Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts to treat ME/CFS have been directed mainly toward symptom management. These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and -executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define. Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies in which a more focused precision-medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.     

Brainstem perfusion is impaired in chronic fatigue syndrome

We looked for brain perfusion abnormalities in patients withmyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).An initial pilot study revealed widespread reduction of regionalbrain perfusion in 24 ME/CFS patients, compared with 24 normalvolunteers. Hypoperfusion ofthe brainstem (0.72±0.05vs. 0.80±0.04, p<0.0001) was marked and constant.We then tested whether perfusion to the brainstem in ME/CFSpatients differs from thatin normals, patients with major depression,and others with epilepsy. Data from a total of 146 subjectswere included in the present study: 40 normal volunteers, 67patients with ME/CFS(24 in the pilot study, 16 with no psychiatricdisorders, 13 with ME/CFS and depression, 14 with ME/CFS andother psychiatric disorders), 10 epileptics, 20 young depressedpatientsand 9 elderly depressed individuals. Brain perfusionratios were calculated using ⁹⁹Tc^m-hexamethylpropylene amineoxime (⁹⁹Tc^m- HMPAO) and single-photon emission tomography (SPET)with a dedicated three-detector gamma camera computer/system(GE Neurocam). Brainstem hypoperfusion was confirmed in allME/CFS patients. Furthermore, the 16 ME/CFS patients with nopsychiatric disorders and the initial 24 patients inthe pilotstudy showed significantly lower brainstem perfusion (0.71$0.03)than did depressed patients (0.77$0.03; ANOVA, p<0.0001).Patients with ME/CFS have a generalized reduction of brain perfusion,with a particular pattern of hypoperfusion of the brainstem.     

Practice Nurses' views of their role in the management of Chronic Fatigue Syndrome/Myalagic Encephalitis: a qualitative study

Background  

NICE guidelines suggest that patients with Chronic Fatigue Syndrome/Myalgic Encephalitis (CFS/ME) should be managed in Primary Care. Practice Nurses are increasingly being involved in the management of long-term conditions, so are likely to also have a growing role in managing CFS/ME. However their attitudes to, and experiences of patients with CFS/ME and its management must be explored to understand what barriers may exist in developing their role for this group of patients. The aim of this study was to explore Practice Nurses' understanding and beliefs about CFS/ME and its management.     

Gender-specific reference values for high-sensitivity cardiac troponin T and I in well-phenotyped healthy individuals and validity of high-sensitivity assay designation

ObjectiveTo determine gender-specific reference limits of high-sensitivity (hs) cardiac troponins (cTn) and validity of hs assay designation for both genders.MethodsAfter screening with a questionnaire, 827 presumably healthy individuals were further selected based on clinical criteria (n = 740), clinical criteria plus cardiac imaging including stress magnetic resonance imaging or stress echocardiography (n = 726), and extended cardio-pulmonary parameters (n = 626). Blood samples were measured with hs-cTnT (Roche Diagnostics) on a cobas e602 analyzer as well as hs-cTnI (Abbott Diagnostics) on an ARCHITECT_i2000_SR. The impact of health definition, statistical methods, instrument selection and limit of detection (LoD) on overall and gender-specific 99th percentiles was assessed.ResultsMedian age was 56 years (50.9% female) for the total study cohort. 99th percentiles for females and males ranged between 13.1 and 13.3 ng/L and 16.8–19.9 ng/L for hs-cTnT as well as 10.3–12.5 ng/L and 27.4–29.7 ng/L for hs-cTnI depending on health definition. Utilization of stricter health definition criteria reduced the difference of the gender-specific 99th percentiles between males and females for hs-cTnT to 3.7 ng/L (males 16.8 ng/L, females 13.1 ng/L), whereas the difference rather increased for hs-cTnI to 19.4 ng/L (males 29.7 ng/L, females 10.3 ng/L). Values > LoD could be measured in the majority of males and females using hs-TnT (81.4–83.3% and 96.5–96.9%, respectively). In contrast, values > LoD could not be observed in the majority of females using hs-cTnI (38.4–41.1%).ConclusionsIn a well-phenotyped healthy cohort, reference values for hs-cTnT were slightly higher, whereas hs-cTnI cut-offs were considerably lower than previously observed. Gender differences were more pronounced in hs-cTnI than in hs-cTnT and were further reduced for hs-cTnT by application of stricter health definition criteria. Contrary to hs-cTnI, hs-cTnT fulfilled criteria for hs designation for both genders.     

Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome

PurposeA role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CSF.MethodsSera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.FindingsOverall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.ImplicationsThe results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.     

Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome

Purpose

The complex and varied presentation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has made it difficult to diagnose, study, and treat. Its symptoms and likely etiology involve multiple components of endocrine and immune regulation, including the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, and their interactive oversight of immune function. We propose that the persistence of ME/CFS may involve changes in the regulatory interactions across these physiological axes. We also propose that the robustness of this new pathogenic equilibrium may at least in part explain the limited success of conventional single-target therapies.

Symptoms of chronic fatigue syndrome/myalgic encephalopathy are not determined by activity pacing when measured by the chronic pain coping inventory

Objectives

Chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) is a chronic illness which can cause significant fatigue, pain and disability. Activity pacing is frequently advocated as a beneficial coping strategy, however, it is unclear whether pacing is significantly associated with symptoms in people with CFS/ME. The first aim of this study was therefore to explore the cross-sectional associations between pacing and levels of pain, disability and fatigue. The second aim was to explore whether changes in activity pacing following participation in a symptom management programme were related to changes in clinical outcomes.

Chronic fatigue syndrome or myalgic encephalomyelitis

Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a debilitating illness that affects many systems of the body, particularly the nervous and immune systems. The condition affects all age, racial, ethnic and socioeconomic groups. This article focuses on the knowledge, understanding and skills necessary to recognise, assess, manage and support patients with CFS/ME. The principles of management and rehabilitation can be applied by nurses and other healthcare professionals irrespective of the clinical setting and context.     

Frailty is not independently associated with intensive care unit length of stay: An observational study

BackgroundFrailty is independently associated with morbidity and mortality in critically ill patients. However, the association between preadmission frailty and the degree of treatment received in the intensive care unit (ICU) remains unclear.ObjectiveTo describe patient length of stay in an ICU and the treatments provided according to the extent of patient frailty.MethodsSingle-centre retrospective cohort study of adult patients admitted to a tertiary ICU between January 2018 and December 2019. Frailty was assessed using the Clinical Frailty Scale (CFS). The primary outcome was ICU length of stay stratified by CFS score (1–8). Secondary outcomes were the proportion of patients with each CFS score treated with vasoactive agents, invasive ventilation, noninvasive ventilation, renal replacement therapy, and tracheostomy. Poisson regression and competing risks regression was used to analyse associations between ICU length of stay and potential confounders.ResultsThe study cohort comprised 2743 patients, with CFS scores known for 2272 (83%). Length of stay in the ICU increased with each increment in the CFS up to a score of 5, beyond which it decreased with higher frailty scores. After adjusting for age, illness severity, admission type, and treatment limitation, CFS scores were not independently associated with length of stay in the ICU (P = 0.31). The proportion of patients receiving specific ICU treatments peaked at different CFS scores, being highest for vasoactive agents at CFS 5 (47%), invasive ventilation CFS 3 (51%), noninvasive ventilation CFS 6 (11%), renal replacement therapy CFS 6 (8.2%), and tracheostomy CFS 5 (2.2%). Increasing frailty was associated with increased mortality and discharge to a destination other than home.ConclusionsThe extent of frailty is not independently associated with length of stay in the ICU. The proportion of patients receiving specific ICU treatments peaked at different CFS scores.     

Sex differences in trunk,pelvis, hip and knee kinematics and eccentric hip torque in adolescents

BackgroundAdolescents have a high incidence of knee joint dysfunctions, with up to 28% of adolescents reporting knee pain. Although adolescent females have a greater incidence of knee injuries in comparison to males, few studies conducted biomechanical evaluations in this population aiming to identify sex differences. If trunk and/or lower limb biomechanical impairments are identified in female adolescents, the implementation of early interventions for injury prevention will be better justified. The purpose of this study was to compare the trunk, pelvis, hip and knee kinematics during a single-leg squat task, as well as the isokinetic eccentric hip torque, between male and female healthy adolescents.MethodsForty-four healthy adolescents were divided into two groups, group of males (n = 22) and group of females (n = 22). Kinematics during single-leg squat were assessed using a electromagnetic tracking system. For the evaluation of eccentric hip torque in the three planes an isokinetic dynamometer was used. Group differences were assessed using a one-way multivariate analysis of variance.FindingsResults showed that adolescent females presented greater hip adduction, hip external rotation and knee abduction, as well as smaller trunk flexion during single-leg squat in comparison to males. Additionally, adolescent females showed smaller isokinetic eccentric hip torque normalized by body mass in all planes in comparison to males.InterpretationThese sex differences in terms of trunk/lower limb kinematics and eccentric hip torque generation might play an important role in the greater incidence of overuse knee injuries observed in adolescent females.     

The Energy Envelope Theory and myalgic encephalomyelitis/chronic fatigue syndrome.

Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have little stamina and endurance, and pose a challenge for nursing professionals. The Energy Envelope Theory, which posits that maintaining expended energy levels consistent with available energy levels may reduce the frequency and severity of symptoms, is particularly useful when working with clients with ME/CFS. Anecdotal support from the client community for this theory supports its use as a management tool for ME/CFS, but little formal research has been done in this area. In this study, a daily energy quotient was established by dividing the expended energy level by the perceived energy level and multiplying by 100. It was predicted that those participants who expended energy beyond their level of perceived energy would have more severe fatigue and symptoms and lower levels of physical and mental functioning. Findings are congruent with the Energy Envelope Theory as they indicated that the daily energy quotient was related to several indices of functioning including depression, anxiety, fatigue, pain, quality of life, and disability. The overall results provide support for a strategy health care professionals can use when working with clients with ME/CFS.     

AIDS and CFS/ME: a tale of two syndromes

Both HIV/AIDS and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) presented major challenges for medicine, science and society. This article explores what could have impeded investigation of--and specifically pharmaceutical engagement with--CFS/ME, in contrast to the impressive achievements seen in HIV/AIDS. It explores the obstruction of mind-body dualism in a historical context, and examines some of the possible obstacles to pharmaceutical enquiry. Nothing of real substance is identified that would justify the lack of investment and interest in solutions for patients with CFS/ME.     

Evaluating cancer related fatigue during treatment according to children's,adolescents' and parents' perspectives in a sample of Greek young patients

IntroductionCancer related fatigue in children and adolescents has received limited clinical attention. The aim of the study is to assess the change in fatigue scores during cancer treatment according to children's, adolescents' and parents' perspectives and to describe the possible causes of fatigue from children's, adolescents' and parents' view.Patients and methodsThe sample consisted of 40 children aged 7–12 years old, 29 adolescents aged 13–15 years old with cancer and one of their parents. Three measurements were performed for the evaluation of cancer related fatigue. Three versions of the instrument for the assessment of fatigue in pediatric patients with cancer were used: «The Child Fatigue Scale» (CFS), «The Adolescent Fatigue Scale» (AFS) and «The Parent Fatigue Scale» (PFS). The survey was performed from March 2003 till October 2006.ResultsChildren (F = 6.85, p = 0.00), adolescents (F = 4.15, p = 0.03) and parents (F = 3.98, p = 0.02) reported a statistically significant increase in fatigue scores during their treatment. The hospital environment was assessed as the most contributing factor of fatigue by the three groups.ConclusionsCancer treatment was found significantly to increase children's fatigue levels. Medical procedures and the hospital environment seemed to be major causative factors of the fatigue experienced by young patients with cancer during their treatment.     

Measuring the physical activity level and pattern in daily life in persons with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review

Background: A lower activity level and imbalanced activity pattern are frequently observed in persons with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) due to debilitating fatigue and post-exertional malaise (PEM). To provide an optimal treatment strategy, insight into a patient’s current physical activity level and pattern is necessary and identification of reliable and valid measures or scales measuring physical activity level and pattern in this population is warranted.

Objective: To identify measures or scales used to evaluate activity level and/or pattern in patients with CFS/ME and review their psychometric properties.

Methods: A systematic literature search was performed in the electronic databases PubMed and Web of Science until 12 October 2016. First, articles including relevant measures were identified. Secondly, psychometric properties of relevant measurement instruments were extracted and rated based on the COSMIN checklist.

Results: The review was performed and reported according to PRISMA statement. A total of 51 articles and 15 unique measurement instruments were found, but only three instruments have been evaluated in patients with CFS: the Chronic Fatigue Syndrome-Activity Questionnaire (CFS-AQ), Activity Pattern Interview (API) and International Physical Activity Questionnaire-Short Form (IPAQ-SF), all self-report instruments measuring physical activity level.

Conclusions: The IPAQ-SF, CFS-AQ and API are all equally capable of evaluating the physical activity level, but none of these are optimal to use. Although often used as gold standard to capture physical activity patterns, activity monitors have not yet been evaluated in these patients. More research is needed to evaluate the psychometric properties of existing instruments, including activity monitors.     

Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective

Purpose: To inform an operationalised definition of recovery from myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) for research and practice. Without a consensus on defining and measuring recovery, there will continue to be controversy amongst researchers, clinicians, and patients when interpreting treatment outcomes.

Method: This study explores physicians’ views on recovery from ME and CFS. We conducted semi-structured interviews with 10 physician participants who are experts in the ME and CFS field. Our deductive thematic analysis, using a realist perspective, provided a framework for differentiating recovery and significant improvement.

Results: Physicians conceptualised recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age), whereas they viewed significant improvement as a substantial reduction in symptoms with considerable functional gains, where patients may operate in daily life but still must cope or be treated.

Conclusions: Our findings provide recommendations and approaches for measuring: daily functioning, symptomatology, quality of life, and physical functioning.

• Implications for rehabilitation

• Physicians viewed recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age).

• Recovery from myalgic encephalomyelitis and chronic fatigue syndrome should be viewed as multidimensional, considering patients’ daily life, psychosocial functioning, and overall physical functioning.

• These findings can improve practitioner-client interactions, as they provide recommendations for measuring recovery in research and practice.

     

Gender-related reference intervals of urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine determined by liquid chromatography-tandem mass spectrometry in Serbian population

ObjectivesAlthough there are many nucleobase modifications, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is one of the dominant form of oxidative modifications of DNA. Urinary 8-oxodG is potentially the best non-invasive biomarker of oxidative stress. Defining reference interval for urinary 8-oxodG is a prerequisite for its clinical use as biomarker.Design and methodsReference population included 229 healthy Serbian adults (130 males and 99 females). The spot urinary 8-oxodG was determined using high performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Urinary creatinine was measured by the kinetic Jaffé method.ResultsAnalytical performances of the HPLC-MS/MS: CVs within and between-run variations were 5.6% and 2.6%; LOD and LOQ were 1.65 nmol/L and 3.30 nmol/L; mean recovery and relative accuracy were 96% and 97%. Creatinine level was higher in males than in females, but no gender difference in 8-oxodG level was observed. Upon the adjustment of 8-oxodG to creatinine (8-oxodG/creatinine), higher values were obtained in females (1.38 ± 0.65 nmol/mmol) than in males (1.05 ± 0.48 nmol/mmol). Distribution of 8-oxodG/creatinine in spot urine sample was log-normal and gender-related reference intervals (estimated as the 2.5th–97.5th percentiles) were 0.45–2.22 nmol/mmol for males, and 0.54–3.11 nmol/mmol for females. Body mass index (BMI) affects excretion of the 8-oxodG in males, independently of urinary creatinine, while in females it does not. Therefore, BMI might contribute to the gender-related differences of 8-oxodG/creatinine in spot urine samples.ConclusionsThis is the first established gender-related reference intervals of spot urinary 8-oxodG/creatinine. Our results contribute to the full validation of 8-oxodG as biomarker of oxidative stress.     

A Feasibility Study to Develop and Test a Cognitive Behavioral Stress Management Mobile Health Application for HIV-Related Fatigue

ContextExacerbated by life stressors, fatigue is the most common symptom for people living with HIV.ObjectiveTo adapt, develop, and assess the feasibility of a Cognitive Behavioral Stress Management Mobile Health (CBSM mHealth) application (app) for HIV-related fatigue.MethodsThis study had two phases: app development with key informants (N = 5) and a randomized controlled trial (N = 30). Patients randomized to the intervention group completed 10 weekly CBSM modules; those in the control group received a generic healthy lifestyle app. Measures included HIV-related fatigue, depression, anxiety, stressful life events, CD4 count, HIV viral load, credibility and acceptability of the intervention, and barriers to treatment participation.ResultsWe were able to recruit participants for this study, and they were able to complete the required measures. They found the intervention to be credible and acceptable and reported few barriers to treatment participation. The direction of change in the primary outcome, a decrease in fatigue, is in the expected direction and provides evidence of the promise of the intervention, which still needs to be tested in an adequately powered trial. For completers (randomized to the intervention group and completed at least 80% of the modules), there were significant changes (95% CI; lower scores indicate improvement) in fatigue intensity (from 64.2 to 59.7) and overall fatigue-related functioning (from 6.6 to 4.2).ConclusionWe have proof of concept as to the feasibility, acceptability, and initial signals of efficacy for an mHealth intervention to help people with HIV-related fatigue better cope with stress and reduce their fatigue.