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BACKGROUND: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). OBJECTIVE: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS. METHODS: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence. RESULTS: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM. CONCLUSION: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Post-exertional malaise (PEM) is a defining characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the pa...

BACKGROUND Clinical observations have indicated that hours of upright activity (HUA) reported by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients correlated with orthostatic symptoms and impaired physical function. This study examined the relationship between HUA and orthostatic intolerance (OI). METHODS Twenty-five female ME/CFS subjects and 25 age and race matched female healthy controls (HCs) were enrolled. Subjects reported HUA (defined as hours per day spent with feet on the floor) and completed questionnaires to assess the impact of OI on daily activities and symptoms. ME/CFS patients were categorized into those with

BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.MethodsUsing regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.ResultsIn ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).ConclusionOur findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.One Sentence SummaryPlasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with ‘long COVID’. However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease. Here, we performed deep multi-‘omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients – those with short-term disease (10y, n=79). Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways. Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-‘omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.ResultsUsing shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.ConclusionsOur findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

BackgroundGenomics-driven discoveries of microbial species have provided extraordinary insights into the biodiversity of human microbiota. In addition, a significant portion of genetic variation between microbiota exists at the subspecies, or strain, level. High-resolution genomics to investigate species- and strain-level diversity and mechanistic studies, however, rely on the availability of individual microbes from a complex microbial consortia. High-throughput approaches are needed to acquire and identify the significant species- and strain-level diversity present in the oral, skin, and gut microbiome. Here, we describe and validate a streamlined workflow for cultivating dominant bacterial species and strains from the skin, oral, and gut microbiota, informed by metagenomic sequencing, mass spectrometry, and strain profiling.ResultsOf total genera discovered by either metagenomic sequencing or culturomics, our cultivation pipeline recovered between 18.1–44.4% of total genera identified. These represented a high proportion of the community composition reconstructed with metagenomic sequencing, ranging from 66.2–95.8% of the relative abundance of the overall community. Fourier-Transform Infrared spectroscopy (FT-IR) was effective in differentiating genetically distinct strains compared with whole-genome sequencing, but was less effective as a proxy for genetic distance.ConclusionsUse of a streamlined set of conditions selected for cultivation of skin, oral, and gut microbiota facilitates recovery of dominant microbes and their strain variants from a relatively large sample set. FT-IR spectroscopy allows rapid differentiation of strain variants, but these differences are limited in recapitulating genetic distance. Our data highlights the strength of our cultivation and characterization pipeline, which is in throughput, comparisons with high-resolution genomic data, and rapid identification of strain variation.

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness of unknown origin that may have familial risks. Low natural killer (NK) lymphocyte activity was proposed as a risk for familial CFS in 1998. Since then, there have been many studies of NK lymphocytes in CFS in general populations but few in familial CFS. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK lymphocytes helps control viral infections. ADCC is affected by variant CD16A receptors for antibody that are genetically encoded by FCGR3A. METHODS: This report characterizes ADCC effector NK cell numbers, ADCC activities, and FCGR3A variants of five families each with 2–5 CFS patients, their family members without CFS and unrelated controls. The patients met the Fukuda diagnostic criteria. We determined: CD16Apositive blood NK cell counts; EC50s for NK cell recognition of antibody; ADCC lytic capacity; FCGR3A alleles encoding CD16A variants, ROC tests for biomarkers, and synergistic risks. RESULTS: CFS patients and their family members had fewer CD16Apositive NK cells, required more antibody, and had ADCC that was lower than the unrelated controls. CFS family members were predominantly genetically CD16A F/F s for the variant with low affinity for antibodies. ROC tests indicated unsuitability of ADCC as a biomarker for CFS because of the low ADCC of family members without CFS. Familial synergistic risk vs. controls was evident for the combination of CD16Apositive NK cell counts with ADCC capacity. CONCLUSIONS: low ADCC may be a risk factor for familial CFS. Furthermore, characterization of familial CFS represents an opportunity to identify pathogenic mechanisms of CFS.

“Recovering” from COVID-19 does not guarantee a return to a person's usual state of health. For one thing, some people with multi-system injury—particularly to the brain, heart and kidneys—may develop permanent dysfunction of those organs. In addition, a more subtle form of chronic illness may develop. For some people with COVID-19, even those who are only mildly affected at first, the ensuing weeks and months of “recovery” bring a surprise and a betrayal: they do not return to full health. Although nucleic acid tests no longer detect the virus, people still suffer from ongoing symptoms. They call themselves “long haulers,” and the condition is being called “long COVID.”

Background Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT. Methods A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS patients who had been sick for less than 4 years ( 10 ME/CFS). The 10-minute NLT involves measurement of blood pressure and heart rate while resting supine and every minute for 10 min while standing with shoulder-blades on the wall for a relaxed stance. Spontaneously reported symptoms are recorded during the test. ANOVA and regression analysis were used to test for differences and relationships in hemodynamics, symptoms and upright activity between groups. Results At least 5 min of the 10-minute NLT were required to detect hemodynamic changes. The 10 ME/CFS and HCs. The 10 ME/CFS and HCs. The circulatory decompensation observed in the Conclusions Circulatory decompensation characterized by increased heart rate and abnormally narrow pulse pressure was identified in a subgroup of ME/CFS patients who have been sick for 10 ME/CFS group had less pronounced hemodynamic changes during the NLT possibly from adaptation and compensation that occurs over time. The 10-minute NLT is a simple and clinically useful point-of-care method that can be used for early diagnosis of ME/CFS and help guide OI treatment.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3-11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774-0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806-0.846) and ME/CFS without sr-IBS (AUC = 0.754-0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.

Background The search for a biomarker specific for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been long, arduous and, to date, unsuccessful. Researchers need to consider their expenditures on each new candidate biomarker. In a previous study of antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer lymphocytes, we found lower ADCC for ME/CFS patients vs. unrelated donors but ruled against low ADCC as a biomarker because of similar ADCC for patients vs. their family members without ME/CFS. Objective We applied inclusion of family members without ME/CFS, from families with multiple CFS patients, as a second non-ME/CFS control group in order to re-examine inflammation in ME/CFS. Method Total and CD16A-positive 'non-classical' anti-inflammatory monocytes were monitored. Results Non-classical monocytes were elevated for patients vs. unrelated healthy donors but these differences were insignificant between patients vs. unaffected family members. Conclusions Inclusion of family members ruled against biomarker considerations for the monocytes characterized. These pilot findings for the non-classical monocytes are novel in the field of ME/CFS. We recommend that occupational therapists advocate and explain to family members without ME/CFS the need for the family members' participation as a second set of controls in pilot studies to rapidly eliminate false biomarkers, optimize patient participation, and save researchers' labor.

ADCC (antibody-dependent cell-mediated cytotoxicity) is dependent on the varying capacity of NK cells to kill, the affinities ofFCGR3A-encoded CD16A receptors for antibody, and the presence of antigen-specific antibodies.In vivoADCC depends on the number of CD16A receptor-positive NK cells in blood. We hypothesized that low ADCC cell function or low effector cell numbers could be biomarkers or risk factors for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We measured NK cell ADCC lytic capacity and antibody recognition, CD16Apositive NK cells/µl blood, andFCGR3Ahomozygosity for the F allele that encodes low affinity CD16A antibody receptors. ME/CFS patients met the Fukuda 1994 diagnostic criteria. In this pilot report, we examined 5 families, each with 2 to 5 ME/CFS patients, and compared 11 patients, 22 family members without ME/CFS, and 16 unrelated healthy controls. ADCC was measured as CX1:1 cytotoxic capacity (the percentage of51Cr-Daudi tumors with obinutuzumab anti-CD20 antibody that were killed at a 1:1 ratio of CD16Apos NKs to Daudis) and CX-slope. Individual CX1:1 capacities varied from 16.2% to 81.8% and were comparable between patients and unaffected family members, while the ADCC of both family groups was lower than the unrelated healthy controls. The lack of difference between patients and their unaffected family members indicates that low ADCC is unsuitable as a diagnostic biomarker for ME/CFS. Familial CD16Apos NK blood cell counts were lower than unrelated healthy controls. The potential for synergistic effects of combined low CX1:1 and low effector cell counts occurring in the same individual was 24-fold greater for CFS family members than for unrelated controls.FCGR3Aof the families was predominantly F/F homozygous, correlating with the observed low EC50 for NK recognition of target cell-bound antibody. In summary, low ADCC is unsuitable as a biomarker, but could be a familial risk factor, for ME/CFS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1.

Techniques of data mining and machine learning were applied to a large database of medical and facility claims from commercially insured patients to determine the prevalence, gender demographics, and costs for individuals with provider-assigned diagnosis codes for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). The frequency of diagnosis was 519–1,038/100,000 with the relative risk of females being diagnosed with ME or CFS compared to males 1.238 and 1.178, respectively. While the percentage of women diagnosed with ME/CFS is higher than the percentage of men, ME/CFS is not a “women's disease.” Thirty-five to forty percent of diagnosed patients are men. Extrapolating from this frequency of diagnosis and based on the estimated 2017 population of the United States, a rough estimate for the number of patients who may be diagnosed with ME or CFS in the U.S. is 1.7 million to 3.38 million. Patients diagnosed with CFS appear to represent a more heterogeneous group than those diagnosed with ME. A machine learning model based on characteristics of individuals diagnosed with ME was developed and applied, resulting in a predicted prevalence of 857/100,000 (p > 0.01), or roughly 2.8 million in the U.S. Average annual costs for individuals with a diagnosis of ME or CFS were compared with those for lupus (all categories) and multiple sclerosis (MS), and found to be 50% higher for ME and CFS than for lupus or MS, and three to four times higher than for the general insured population. A separate aspect of the study attempted to determine if a diagnosis of ME or CFS could be predicted based on symptom codes in the insurance claims records. Due to the absence of specific codes for some core symptoms, we were unable to validate that the information in insurance claims records is sufficient to identify diagnosed patients or suggest that a diagnosis of ME or CFS should be considered based solely on looking for presence of those symptoms. These results show that a prevalence rate of 857/100,000 for ME/CFS is not unreasonable; therefore, it is not a rare disease, but in fact a relatively common one.

Background: Postural orthostatic tachycardia syndrome (POTS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been associated with a variety of viral triggers, but to the best of our knowledge, cases following West Nile virus (WNV) infection are not yet reported in the literature. Here we present a case meeting the criteria for POTS, ME/CFS, and fibromyalgia following a likely WNV infection.Purpose: To present a case suggesting WNV as another possible trigger of POTS and ME/CFS, and to highlight the importance of POTS evaluation and treatment.Methods: The patient presented to a chronic fatigue clinic in 2012. Multiple behavioral and pharmaceutical interventions were integrated, particularly targeting POTS symptoms.Results: As the patient’s POTS symptoms significantly diminished, widespread pain was eliminated, and fitness and function improved. The patient still manages ME/CFS symptoms, although post-exertional malaise is less severe.Conclusions: This case report demonstrates t...

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p<0.04). Pregabalin responders (n=12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p<0.03) and no longer differed from controls (p>0.26). Cardiovascular responses of nonresponders (n=7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p<0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients.

The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic illness that is often disabling. This paper introduces the Chronic Fatigue Initiative, which conducted a large multi-center study to more fully characterize ME/CFS and ultimately to describe and understand the underlying mechanisms and pathogenesis of this illness. Methods: A total of 203 patients with ME/CFS (cases) and 202 matched healthy controls (HCs) were enrolled from 5 geographically different expert clinical sites to create a well-characterized population linked to a national biorepository. ME/CFS subjects were compared to a one-to-one matched HC population for analyses of symptoms and illness severity. Cases were further evaluated for frequency and severity of symptoms and symptom clusters, and the effects of illness duration and acute vs. gradual onset. Results: This study collected more than 4000 pieces of data from each subject in the study. Marked impairment was demonstrated for cases vs. controls. S...

Background: Epidemiologic data that inform our understanding of the type, frequency, and burden of co-morbidities with chronic fatigue syndrome is limited. Purpose: To elucidate co-morbid and consequent conditions, using data from a clinical epidemiology study of long-term CFS patients. Methods: Some 960 adults with CFS were identified at four sites specializing in the diagnosis and treatment of CFS. Patients reported their demographics, CFS course, other medical diagnoses, and current functioning. We determined associations between: co-morbidities and a patient's current health relative to their health when diagnosed with CFS; CFS symptom severity at onset and subsequent diagnosis with a co-morbid condition; and presence of a co-morbidity and functional ability. We also modeled the change in CFS symptom severity over time as it relates to the presence of a co-morbidity. Results: Of the sample, 84% was diagnosed with one or more co-morbid conditions after CFS onset. Fibromyalgia, depression, anxiety, and ...

Natural killer (NK) lymphocyte ADCC supports anti-viral protection and monoclonal antibody (mAb) anti-tumor therapies. To predict in vivo ADCC therapeutic responses of different individuals, measurement of both ADCC cellular lytic capacity and their NK cellular receptor recognition of antibodies on 'target' cells are needed, using clinically available amounts of blood. Twenty ml of blood provides sufficient peripheral blood mononuclear cells (PBMCs) for the new assay for lytic capacity described here and for an antibody EC50 assay for Fc-receptor recognition. For the lytic capacity assay, we employed flow cytometry to quantify the CD16A IgG Fc-receptor positive NK effector cells from PBMCs to avoid loss of NKs during isolation. Targets were 51Cr-labeled Daudi B cells pretreated with excess obinutuzumab type 2 anti-CD20 mAb and washed; remaining free mAb was insufficient to convert B cells in the PBMCs into 'targets'. We calculated: the percentage Daudis killed at a 1:1 ratio of CD16A-positive NK cells to Daudis (CX1:1); lytic slopes; and ADCC50 lytic units. Among 27 donors, we detected wide ranges in CX1:1 (16-73% targets killed) and in lytic slopes. Slope variations prevented application of lytic units. We recommend CX1:1 to compare individuals' ADCC capacity. CX1:1 was similar for purified NK cells vs. PBMCs and independent of CD16A V & F genotypes and antibody EC50s. With high mAb bound onto targets and the high affinity of obinutuzumab Fc for CD16A, CX1:1 measurements discern ADCC lytic capacity rather than antibody recognition. This assay allows ADCC to be quantified without NK cell isolation and avoids distortion associated with lytic units.

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. Results Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. Conclusions Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0261-y) contains supplementary material, which is available to authorized users.

Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM. This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75–450 mg/day) for the treatment of adolescents (12–17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0–10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact. A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), −0.66 (−1.51, 0.18), P = 0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P

Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Murovska M, Pall ML, Stevens S (Independent, Vancouver, BC, Canada; Independent, Calgary, AB, Canada; Department of Physiology and Medicine, Vrije University of Brussels, Himmunitas Foundation, Brussels, Belgium; Department of Medicine,University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center, Miami, FL, USA; Department of Medicine, University of Alberta, Edmonton, AB, Canada; Honorary Consultant for NHS at Peterborough/Cambridge, Lowestoft, Suffolk, UK; Gold Coast Public Health Unit, Southport, Queensland; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Faculty of Health Sciences, McMaster University and St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada; Independent, Durham, UK; Howick Health and Medical Centre, Howick, New Zealand; Fatigue Consultation Clinic, Salt Lake Regional Medical Center; Internal Medicine, Family Practice, University of Utah, Salt Lake City, UT, USA; ME/CFS Center, Oslo University Hospital HF, Norway; Department of Paediatrics, State University of New York, Buffalo, NY; Independent, Pavia, Italy; Harbor-UCLA Medical Center, University of California, Los Angeles, CA; EV Med Research, Lomita, CA, USA; University of Limerick, Limerick, Ireland; Pain Clinic, Konyang University Hospital, Daejeon, Korea; Donvale Specialist Medical Centre, Donvale, Victoria, Australia; Departments or Anesthesiology, Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Department of Medicina Nuclear, Clinica Las Condes, Santiago, Chile; Whittemore Peterson Institute, University of Nevada, Reno, NV, USA; Miwa Naika Clinic, Toyama, Japan; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR; Department of Sports Sciences, University of the Pacific, Stockton, CA USA). Myalgic encephalomyelitis: International Consensus Criteria (Review). J Intern Med 2011; 270: 327–338. The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.