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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.

Background Myalgic 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. Methods Using 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. Results In 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). Conclusion Our 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 Summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

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...

BackgroundSome patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.MethodsWe evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.ParticipantsPeople with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.ResultsThe NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).ConclusionsA test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

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.

Light AR, Bateman L, Jo D, Hughen RW, VanHaitsma TA, White AT, Light KC (University of Utah, Salt Lake City, UT, USA). Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med 2012; 271: 64–81. Objectives. To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise. Design. Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments. Results. No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor’s transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls. Conclusions. At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

ADCC (antibody-dependent cell-mediated cytotoxicity) requires the cytotoxic subset of NK cells that can also recognize antibody. In vivo function may depend on the number of these ADCC NK cells. We report on ADCC activity and the number of IgG FcR-positive NK cells/ul blood as risk factors for chronic fatigue syndrome (CFS). ADCC capacity was measured as CX1:1 (PMID 29113954), the % Daudi B tumor cells killed at a 1:1 ratio of CD16A FcR-pos CD56pos NK effector cells to Daudi targets with obinutuzumab anti-CD20. CFS patients met the 1994 Fukuda diagnostic guidelines. We examined 5 families with 2 or more patients per family, comparing patients with their non-CFS family members and with unrelated healthy controls. ADCC activity and effector cell counts were similar between CFS patients and their family members. Surprisingly, the CX1:1 of both the CFS patients and their non-CFS family members was low, 77% of the controls (P=0.03). The ADCC effector cell counts/ul blood were also lower for both (two-tailed P=0.09, insignificant). The potential for synergistic interaction of low CX1:1 and low effector cell counts was 24-fold greater for CFS family members than for unrelated healthy controls (P

Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective.This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced.Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function.The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.

To assess the burden of fibromyalgia (FM) in patients with FM taking antidepressant medication for comorbid depression.Symptom burden, impact on work and activity, and healthcare resource utilisation (HCRU) was examined at randomisation in patients enrolled in a clinical trial. Symptom burden was estimated based on self-reported health status measures. The Work Productivity and Activity Impairment: Specific Health Problem scale adapted to FM and a separate HCRU questionnaire were completed. The relationship between FM severity and burden was evaluated.The total population analysed comprised 193 patients; 71 (36.8%) had moderate FM and 119 (61.7%) severe FM. Patients had moderate pain, severe impairment in functioning due to FM, sleep disruption, mild anxiety, and mild depression. In the 7 days preceding randomisation, an average of 58.0% overall work impairment was reported, with 15.2% of working hours missed and 54.0% productivity while at work. In the 3 months preceding randomisation, on average, 5.0 visits per patient were made to healthcare professionals. Physical treatments were used by 34.7% and supplements by 31.6% of patients. Prescription and non-prescription medications, as well as professional services providing help with activities of daily living (ADL) that are impacted by FM, were used by75% of patients. In addition, 50.4 hours of unpaid help was provided for ADL assistance. Total out-of-pocket expenditures were US$307.1, €410.4, or C$211.3, depending on location. FM burden worsened with increasing FM severity.This study demonstrates the significant burden of FM in patients with comorbid depression treated with an antidepressant.

Background There are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM. Methods Patients, ages 13–17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. Results The milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM. Conclusions The open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment. Trial registration NCT01328002; NCT01331109 Electronic supplementary material The online version of this article (doi:10.1186/s12969-015-0025-9) contains supplementary material, which is available to authorized users.

Cytokine alterations are more strongly correlated with illness duration than with measures of illness severity., Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness. Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246). Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disease of unknown pathogenesis consisting of a variety of flu-like symptoms including severe fatigue. Initial analysis of the use of rintatolimod (Poly I: Poly C 12U), a selective TLR3 agonist, in a Phase III, double-blind, randomized, placebo-controlled trial of CFS/ME demonstrated statistical significance (p 9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes). For this subset of patients (n=126), 33% (n=20), and 12% (n=8) of rintatolimod vs. placebo patients, respectively, improved ET duration by ≥ 25% (p=0.004) while 23% (n=14) compared to 4.5% (n=3) of rintatolimod vs. placebo patients, respectively improved ET duration by ≥ 50% (p=0.003). This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses. A frequency distribution analysis of ≥ 25% improvement, 9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015). A continuous responder analysis using 5% increments from ≥ 25% to ≥ 50% provided a robust clinical enhancement in ET effect in the rintatolimod cohorts as compared to placebo. The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization. Rintatolimod was generally well-tolerated in this CFS/ME population. Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.

Antibody-dependent cell-mediated cytotoxicity (ADCC) supports anti-viral protection and monoclonal antibody anti-tumor therapies. We used two assays to compare ADCC of healthy donors: CX@1:1 (the percentage cells killed at a 1:1 ratio of CD16Apositive NK cells to ‘target’ cells that were pre-labeled with saturating antibody); and EC50 (the effective concentration of antibody that supports 50% of maximal ADCC). CX@1:1 measures lytic capacity while the EC50 measures cellular recognition; there was no correlation between the 2 assays though we observed 4.5-fold differences among donors in each assay. We correlated ADCC with 5 cytometric parameters (the median fluorescent intensities [MFIs] of the CD16A IgG Fc-receptor; the %NK cells positive & MFIs of the adhesion molecule CD2; the MFIs of perforin; and the %CD16Apositive of CD56positive NK cells) and with CD16A V&F genotypes that affect FcR affinity. For CX@1:1, the best donor killed 73% of targets while the worst killed 16% and perforin levels correlated weakly (P=0.11). Unexpectedly and inexplicably, the %CD16Apositive cells among NK cells correlated (P

Lucinda Bateman,1 Robert H Palmer,2 Joel M Trugman,2 Yuhua Lin2 1Fatigue Consultation Clinic, Salt Lake City, UT, 2Forest Research Institute, Jersey City, NJ, USA Background: The purpose of this study was to evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia patients experiencing inadequate clinical response to duloxetine after receiving treatment for 6 weeks or longer. Methods: This exploratory study included 107 patients with fibromyalgia who had been treated with duloxetine 60 mg/day for at least 4 weeks prior to enrollment. Following a 2-week open-label period on duloxetine, patients who had visual analog scale pain scores ≥ 40 and were dissatisfied with current treatment were randomized 4:1 to milnacipran 100 mg/day (n = 86) or placebo (n = 21) for 10 weeks of double-blind treatment. The small placebo group was included solely to blind the study and minimize expectation bias among patients and investigators, and there was no preplanned statistical comparison between treatment groups. The primary efficacy parameter was the percentage of patients rating themselves as “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC) at the final visit. Other efficacy parameters included changes in one-week recall visual analog scale pain, Fibromyalgia Impact Questionnaire Revised (FIQR), and Multiple Ability Self-Report Questionnaire (MASQ). Results: Of patients switched to milnacipran, 32.9% were classified as PGIC responders, and they also demonstrated improvement in visual analog scale pain, FIQR total, and MASQ total scores (mean changes from baseline were −12.3, −7.77, and −2.39, respectively). Nausea and dizziness were the most common treatment-emergent adverse events in patients switched to milnacipran, reported in 21% and 15%, respectively, of patients in this group. Conclusion: Results from this exploratory study suggest that switching from duloxetine to milnacipran may be beneficial in some patients with fibromyalgia who have an inadequate response to duloxetine. Further research investigating the efficacy and safety of switching fibromyalgia therapies is warranted. Keywords: fibromyalgia, milnacipran, duloxetine, switch

Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p0.005 and r=-0.34, p0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection., IMPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen dediscovery that may be helpful to others working in this field.

Chronic fatigue syndrome (CFS) is a multisystem disorder characterized by prolonged and severe fatigue that is not relieved by rest. Attempts to treat CFS have been largely ineffective primarily because the etiology of the disorder is unknown. Recently, CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations. We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blind manner using molecular, serological, and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS patients. We did not find XMRV or related MLVs either as viral sequences or infectious viruses, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies. Our findings do not support an association between CFS and MLV-related viruses, including XMRV, and the off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.

For over a decade, investigators have examined whether patients with chronic fatigue syndrome (CFS) show altered serum cytokine profiles. Early studies (Gupta, Aggarwal, See, & Starr, 1997; Moss, Mercandetti, & Vojdani, 1999) suggested that CFS patients showed evidence of an enhanced pro-inflammatory state, reflected in higher levels of TNF-α and lower levels of IL-10 together with higher IL-6, which is often interpreted as having mixed pro- and anti-inflammatory effects. Other studies (Borish et al., 1998; Zhang et al., 1999) found elevated levels of both proinflammatory cytokines (including TNF-α, IL-2, and IFNγ) and anti-inflammatory cytokines (IL-10) but only in some of the CFS patients, specifically, those with active allergies, psychiatric symptoms, or with GulfWar syndrome. More recent studies have generally not supported the link between CFS and a greater proinflammatory cytokine profile. Instead, numerous studies have observed that their CFS samples showed IL-6 and pro-inflammatory cytokines that were lower or not different or even showed higher anti-inflammatory cytokines compared to controls (Amel, Kashipaz, Swinden, Todd, & Powell, 2003; Gaab et al., 2005; Patarca-Montero, Antoni, Fletcher & Klimas, 2001; Skowera et al., 2004; terWolbeek et al., 2007; Visser et al., 2001). Prospective studies of several infectious disorders known to lead to CFS in a small subgroup of those who are infected have also yielded mixed observations in regard to whether pro-inflammatory cytokines like IL-1β, TNF-α, IL-2, and IFNγ or IL-6 remain elevated in those patients who do develop CFS in the postinfectious state (Kerr & Tyrrell, 2003; Vollmer-Conna et al., 2007). Nevertheless, antiviral treatments and similar interventions have proven successful in some CFS patients (Kerr, Cunniffe, Kelleher, Bernstein, & Bruce, 2003; Lerner, Beqaj, Deeter, & Fitzgerald, 2007). Several studies have used exercise as a stimulus when they compared cytokine profiles in CFS patients and healthy individuals. Post-exercise exacerbation of the central symptoms of CFS lasting 24–48 h or longer (including worsening of physical fatigue, problems with memory and concentration, and both muscle and joint pain) is so common that it is part of the Centers for Disease Control (CDC) diagnostic profile for CFS (Fukuda et al., 1994). CFS patients often remark that if they try to follow an exercise regimen, after each bout of exercise there is a significant cost for the next several days in terms of greater symptoms and less ability to function (symptom flare [SF]). Exercise physiologists have documented that several cytokines are increased from 4 to 24 h after sustained or strenuous exercise even in very fit individuals, and these include both pro-inflammatory IL-1β and anti-inflammatory IL-10, as well as IL-6 and IL-8 (Nielsen & Pedersen, 2007; Patarca-Montero et al., 2001; Peake et al., 2005, 2008; Pedersen & Fischer, 2007). LaManca and colleagues (1999) used a maximal exercise task that did cause a worsening of fatigue and other symptoms in their CFS patients but produced no differences in cytokine responses between CFS and control groups. Although a maximal exercise task may help demonstrate physiological and performance limits in this disorder, this type of challenge is too extreme to generalize to real-life experiences; a mild to moderate exercise task is thus a more appropriate choice to mimic what CFS patients do naturally that can lead to such a SF. Gupta, Aggarwal, and Starr (1999) reported that when CFS patients were tested twice, once when feeling a typical level of fatigue for their condition and once during a natural SF, they showed significantly greater IL-6 levels during the SF. They also attempted to experimentally induce SF through exercise, but only examined cytokine responses immediately after exercise, before the SF was manifested, when CFS patients and controls did not differ. In contrast, Cannon et al. (1999) employed a mild leg exercise task (15 min of stair-step exercise) but examined post-exercise responses for 24 h after exercise, which did induce increases in both IL-6 and IL-1β. They found that although CFS and control groups did not differ in terms of IL-1β, CFS patients did have modestly higher lipopolysccharide-stimulated IL-6 levels if post-exercise levels were combined with pre-exercise levels (Cannon et al., 1999). However, this study was not definitive because their exercise task was so mild or involved such a restricted set of muscles that it failed to induce an increase in fatigue or other symptoms, nor did they examine a full profile of proinflammatory and anti-inflammatory cytokines. Because pro-inflammatory and anti-inflammatory cytokines are mutually inhibitory, changes in one type can secondarily lead to changes in the other, indicating the need to study both types (for reviews, see Elenkov & Chrousos, 2002; Elenkov, Wilder, Chrousos, & Vizi, 2000). The present study used a moderate exercise task to examine worsening of the central symptoms of fatigue and pain in CFS patients for 48 h after the exercise task while also monitoring pre- and post-exercise cytokine responses for this full period. Our protocol improves upon earlier research in the following ways: (a)We attempted to control for variables that might have caused SF at baseline by asking both CFS and control subjects to refrain from all exercise for 48 h prior to the study and by not testing patients who recently were diagnosed or needed additional medical intervention. (b) We employed a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients. (c) Physical fatigue, mental fatigue, and overall pain symptoms were obtained concurrently with blood samples for cytokines at five times: pre-exercise and at 0.5, 8, 24, and 48 h post-exercise. (d) Whereas prior studies in CFS typically assessed only one or two cytokines, our cytokine profile included six pro-inflammatory cytokines/ligands, four anti-inflammatory/regulatory cytokines, and two exercise-responsive cytokines that have mixed effects. We included one new pro-inflammatory marker, CD40 ligand (CD40L), that has not been previously examined in this population. Genetic alterations that reduce levels of CD40L have been shown to enhance vulnerability to opportunistic infections (Danielian, Oleastro, Rivas, Cantisano, & Zelazko, 2007), a pattern typical of a subgroup of CFS patients.

Objective: To evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia (FM) patients with inadequate response to duloxetine. Background Milnacipran and duloxetine are approved for the management of FM. As individual patient responses to analgesic medications differ, switching therapies to achieve greater benefit or avoid certain side effects is common. Design/Methods: Patients receiving duloxetine 60 mg/day for ≥4 weeks at screening were eligible. After 2 weeks of open-label duloxetine 60 mg/day, patients with VAS pain scores ≥40 (range, 0-100 mm) and dissatisfied with duloxetine were randomized 4:1 to milnacipran 100 mg/day (n=86) or placebo (n=21) for 10 weeks. The primary efficacy parameter was responder status based on Patient Global Impression of Change (PGIC), with responders defined as patients rating themselves “much improved” or “very much improved”. The secondary efficacy parameter was change from baseline in 1-week recall VAS pain score. Statistical analyses were descriptive and used LOCF to impute missing data. Results: In patients switched from duloxetine to milnacipran, 32.9% were PGIC responders and the mean decrease from baseline in VAS pain was 12.3 mm at the Week 10 visit (23.8% of placebo-treated patients were PGIC responders and the mean decrease in VAS pain was 1.3 mm). In a post hoc analysis, 34.2%, 29.1%, and 25.3% of patients switched to milnacipran had ≥30%, ≥40%, and ≥50% improvement in VAS pain scores, respectively. The most common (TEAEs) in patients switched to milnacipran were nausea (21%) and dizziness (15%); nausea and dizziness occurred in 29% and 5% of patients switched to placebo, respectively. Conclusions: These results suggest that FM patients with an inadequate response to duloxetine treatment may benefit from a switch to milnacipran for management of their symptoms. Additionally, a direct switch from duloxetine to milnacipran was safe and well tolerated in this study. Supported by: Forest Laboratories, Inc. Disclosure: Dr. Bateman has received personal compensation for activities with Forest Laboratories consultations and The Speakers Bureau as a consultant and/or speaker. Dr. Spera has received personal compensation for activities with Forest Research Institute as an employee. Dr. Palmer has received personal compensation for activities with Forest Laboratories, Inc. as an employee. Dr. Trugman has received personal compensation for activities with Forest Laboratories as an employee. Dr. Thacker has received personal compensation for activities with Forest Laboratories, Inc. as and employee. Dr. Lin has received personal compensation for activities with Forest Research Institute as an employee.