Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

Background: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients. Methods and Findings: In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on selfreported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. Conclusion: The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS

Minimum Competency Recommendations for Programs That Provide Rehabilitation Services for Persons With Disorders of Consciousness: A Position Statement of the American Congress of Rehabilitation Medicine and the National Institute on Disability, Independent Living and Rehabilitation Research Traumatic Brain Injury Model Systems

Persons who have disorders of consciousness (DoC) require care from multidisciplinary teams with specialized training and expertise in management of the complex needs of this clinical population. The recent promulgation of practice guidelines for patients with prolonged DoC by the American Academy of Neurology, American Congress of Rehabilitation Medicine (ACRM), and National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) represents a major advance in the development of care standards in this area of brain injury rehabilitation. Implementation of these practice guidelines requires explication of the minimum competencies of clinical programs providing services to persons who have DoC. The Brain Injury Interdisciplinary Special Interest Group of the ACRM, in collaboration with the Disorders of Consciousness Special Interest Group of the NIDILRR-Traumatic Brain Injury Model Systems convened a multidisciplinary panel of experts to address this need through the present position statement. Content area-specific workgroups reviewed relevant peer-reviewed literature and drafted recommendations which were then evaluated by the expert panel using a modified Delphi voting process. The process yielded 21 recommendations on the structure and process of essential services required for effective DoC-focused rehabilitation, organized into 4 categories: diagnostic and prognostic assessment (4 recommendations), treatment (11 recommendations), transitioning care/long-term care needs (5 recommendations), and management of ethical issues (1 recommendation). With few exceptions, these recommendations focus on infrastructure requirements and operating procedures for the provision of DoC-focused neurorehabilitation services across subacute and postacute settings

SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients

Obesity is a known risk factor for severe respiratory tract infections. In this prospective study, we assessed the impact of being obese or overweight on longitudinal SARS-CoV-2 humoral and cellular responses up to 18 months after infection. 274 patients provided blood samples at regular time intervals up to 18 months including obese (BMI ≥30, n=32), overweight (BMI 25-29.9, n=103) and normal body weight (BMI 18.5-24.9, n=134) SARS-CoV-2 patients. We determined SARS-CoV-2 spike-specific IgG, IgA, IgM levels by ELISA and neutralising antibody titres by neutralisation assay. RBD- and spike-specific memory B cells were investigated by ELISpot, spike- and non-spike-specific IFN-γ, IL-2 and IFN-γ/IL-2 secreting T cells by FluoroSpot and T cell receptor (TCR) sequencing was performed. Higher BMI correlated with increased COVID-19 severity. Humoral and cellular responses were stronger in overweight and obese patients than normal weight patients and associated with higher spike-specific IgG binding titres relative to neutralising antibody titres. Linear regression models demonstrated that BMI, age and COVID-19 severity correlated independently with higher SARS-CoV-2 immune responses. We found an increased proportion of unique SARS-CoV-2 specific T cell clonotypes after infection in overweight and obese patients. COVID-19 vaccination boosted humoral and cellular responses irrespective of BMI, although stronger immune boosting was observed in normal weight patients. Overall, our results highlight more severe disease and an over-reactivity of the immune system in overweight and obese patients after SARS-CoV-2 infection, underscoring the importance of recognizing overweight/obese individuals as a risk group for prioritisation for COVID-19 vaccination

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs). Materials and methods: In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire–Short Form (DSQ-SF). Results: The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%–79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months. Conclusion: Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.publishedVersio

Lymphocyte subsets during follow-up in the KTS-1-2008 and KTS-2-2010 trials.

<p>Panels A-D: Lymphocyte subsets among patients included in the randomized KTS-1-2008 study, in the rituximab group (red) and the placebo group (black), determined by flowcytometry and shown as million cells per liter at baseline (0 months), and at 1, 2, 3, 4, 6, 8, 10, and 12 months follow-up (n = 30). Panel A: CD3+ T-cells, panel B: CD4+ T helper cells, panel C: CD8+ cytotoxic T-cells, panel D: CD56+/16+ NK-cells. For 29 patients, data on lymphocyte populations were missing for 16 out of 261 (6.1%) time points. For General linear model (GLM) for repeated measures these were replaced by interpolation between preceding and succeeding values. The missing values were not replaced in the plots. Panels E-J: T-cell activation markers among patients included in the KTS-1-2008 trial, at baseline and through 12-months follow-up, and shown as percentage of the CD4+ T helper cell population, as determined by flowcytometry. Panel E: Regulatory T-cells, panel F: CD69+ cells, panel G: CD154+ cells, panel H: CD278+ (ICOS) cells, panel I: HLA-DR+ cells. Panel J shows the percentage of HLA-DR+ cells among the CD8+ cytotoxic T-cells. For 29 patients, data on T-regulatory cells and T-cell activation parameters were missing for 30 out of 261 (11.5%) time points. For GLM, missing values were replaced by interpolation between the preceding and succeeding analyses (not replaced in the plots). Panels K-O: Lymphocyte subsets among patients in the KTS-2-2010 study receiving rituximab maintenance therapy, determined by flowcytometry and shown as million cells per liter at baseline (0 months), and 3, 6, 12, 15, 20, and 24-months follow-up. Responders to B-cell depletion therapy are shown in red and non-responders in blue. Panel K: Ratio of CD4+/CD8+ T-cells, panel L: CD3+T- cells, panel M: CD4+ T helper cells, panel N: CD8+ cytotoxic T-cells, panel O: CD56/16+ NK-cells. In three patients, data on lymphocyte subpopulations for at least three time points were missing, these three were omitted leaving 23 patients for GLM analyses to assess the interaction between time and response group. In these 23 patients, 15/161 (9.3%) data were missing; these were replaced by interpolation between preceding and succeeding values (not replaced in the plots). Analyses for interaction between time and intervention group, i.e. assessing for difference in course of the variables over time, between the rituximab and placebo groups (panels A-J), or between responders and nonresponders to rituximab maintenance treatment (panels K-O), were performed using GLM for repeated measures. Error bars denote 95% confidence intervals (CI) for the mean values. The dotted lines indicate lower and upper normal reference values as established at Haukeland University Hospital.</p

Training Course in Focused Assessment with Sonography for HIV/TB in HIV Prevalent Medical Centers in Malawi

Purpose: This article describes the process of training medical providers of different backgrounds about the “focused assessment with sonography for HIV-associated TB” (FASH) exam to expand the availability of ultrasound for TB diagnosis in resource poor settings in the central region of Malawi. Methods and Materials: A survey was completed by the 19 eligible participants before and after a 4-day training course regarding the utility of the FASH exam. A six-question quiz was used to assess knowledge of the use of ultrasound in the FASH exam before and after the course. Results: Participants’ knowledge of the FASH technique significantly improved after the four-day course with a 32% increase in total quiz questions answered correctly (p<0.001). Ninety-five percent (n= 18) of participants answered that they would “likely” incorporate FASH in their clinical practice. Furthermore, 100% (n=19) of participants agreed that the FASH exam would improve their ability to diagnose TB and 95% (n=18) agreed that FASH would improve patient care in their clinic. Conclusions: After completing a 4-day training course, medical providers were more knowledgeable about the FASH exam and its findings, and felt more comfortable using ultrasound for the diagnosis of TB. Participants were also unanimous in opinion that the FASH ultrasound exam would improve their ability to diagnose TB

Serum BAFF levels during follow-up in the KTS-1-2008 and KTS-2-2010 trials.

<p>Panel A: Serum BAFF levels at baseline and at 3, 6, and 8-months follow-up in the placebo arm of the KTS-1-2008 trial, relative to baseline levels (n = 13). Panel B: Serum BAFF levels at baseline, and at 3, 6, and 8-months follow-up in the rituximab arm of the randomized KTS-1-2008 trial, relative to baseline levels (n = 14). Panel C: Serum BAFF levels at baseline and at 3, 6, and 10-months follow-up in the open-label KTS-2-2010 rituximab maintenance trial, relative to baseline levels (n = 22). Panel D: Serum APRIL levels at baseline, and at 3 and 8-months follow-up in the placebo arm of the KTS-1-2008 trial, relative to baseline levels (n = 12). Panel E: Serum APRIL levels at baseline, and at 3 and 8-months follow-up in the rituximab arm of the KTS-1-2008 trial, relative to baseline levels (n = 13). P-values from Repeated measures One-way ANOVA with Dunnett’s test for adjusted p-values for individual comparisons of the different time points to baseline. Error bars denote mean and 95% CI.</p

Serum BAFF levels at baseline.

<p>Panel A: Baseline serum BAFF levels (pg/mL) in 70 ME/CFS patients and in 56 healthy controls. Serum samples before treatment in the KTS-1-2008 and KTS-2-2010 trials (n = 38), and in addition 32 samples from ME/CFS patients fulfilling Canadian diagnostic criteria, were included. Panel B: Baseline APRIL serum concentrations (ng/mL), in ME/CFS patients included in KTS-1-2008 study (n = 28) and in healthy controls (n = 22). P-values from unpaired t-test (equal variances not assumed). Error bars denote mean and 95% confidence intervals (CI).</p