Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations.

BACKGROUND: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking. METHODS: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case-control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed. RESULTS: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V ˙ e, V ˙ O2, V ˙ CO2, V ˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V ˙ e/ V ˙ CO2, PetCO2, O2pulse, work, V ˙ O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1. CONCLUSIONS: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Background and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET). Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1-64 days, while the range in CTL was 1-10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET. Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.

Development and measurement properties of the PEM/PESE activity questionnaire (PAQ).

BACKGROUND: Existing instruments often are inappropriate to measure the effects of post-exertional malaise (PEM) and post-exertional symptom exacerbation (PESE) on activities of daily living (ADLs). A validated questionnaire to measure self-reported ability with ADLs would advance research and clinical practice in conditions like myalgic encephalomyelitis and Long Covid. OBJECTIVE: Determine the measurement properties of the PEM/PESE Activity Questionnaire (PAQ). METHODS: The PAQ is adapted from the Patient Specific Functional Scale. Respondents rated three self-selected ADLs on two 0-100 scales, including current performance compared to (1) a 'good day' and (2) before illness. Respondents provided a Burden of Functioning rating on a 0-100 scale, anchored at 0 being the activity took "No time, effort, and resources at all" and 10 being "All of my time, effort, and resources." Respondents took the PAQ twice, completing a demographic questionnaire after the first PAQ and before the second PAQ. Descriptive statistics and intraclass correlation coefficients were calculated for each scale to assess test-retest reliability. Minimum detectable change outside the 95% confidence interval (MDC95) was calculated. Ceiling and floor effects were determined when the MDC95 for average and function scores crossed 0 and 100, respectively. RESULTS: n = 981 responses were recorded, including n = 675 complete surveys. Test-retest reliability was generally fair to excellent, depending on function and scale. MDC95 values generally indicated scale responsiveness. Ceiling and floor effects were noted infrequently for specific functions. CONCLUSION: The PAQ is valid, reliable, and sensitive. Additional research may explore measurement properties involving functions that were infrequently selected in this sample.

Two symptoms can accurately identify post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Post-exertional malaise (PEM) is the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yet its diverse manifestations make it difficult to recognize. Brief instruments for detecting PEM are critical for clinical and scientific progress. OBJECTIVE: To develop a clinical prediction rule for PEM. METHOD: 49 ME/CFS and 10 healthy, sedentary subjects recruited from the community completed two maximal cardiopulmonary exercise tests (CPETs) separated by 24 hours. At five different times, subjects reported symptoms which were then classified into 19 categories. The frequency of symptom reports between groups at each time point was compared using Fisher's exact test. Receiver operating characteristics (ROC) analysis with area under the curve calculation was used to determine the number of different types of symptom reports that were sufficient to differentiate between ME/CFS and sedentary groups. The optimal number of symptoms was determined where sensitivity and specificity of the types of symptom reports were balanced. RESULTS: At all timepoints, a maximum of two symptoms was optimal to determine differences between groups. Only one symptom was necessary to optimally differentiate between groups at one week following the second CPET. Fatigue, cognitive dysfunction, lack of positive feelings/mood and decrease in function were consistent predictors of ME/CFS group membership across timepoints. CONCLUSION: Inquiring about post-exertional cognitive dysfunction, decline in function, and lack of positive feelings/mood may help identify PEM quickly and accurately. These findings should be validated with a larger sample of patients.

Psychomotor function and response inhibition in chronic fatigue syndrome.

Most research points to cognitive slowing in chronic fatigue syndrome (CFS), although there have been negative reports. The present study is one of few that examines fine motor processing and the inhibition of automatic responses in a well-characterised CFS population. A total of 35 female CFS patients without current major depression and 25 female controls performed two computerised figure-copying tasks. The cognitive and fine motor processing of visual-spatial information was measured by recording reaction time (RT) and movement time (MT), respectively. The inhibition of automatic responses was assessed by introducing 'conflicting patterns' (i.e., patterns that were difficult to draw from the preferred left to right). A multivariate general linear model was adopted for the statistical analysis of the movement recordings. As a result, CFS was significantly associated with longer RT and MT in the pooled and in the task-specific analyses. However, there was no interaction between disease status and conflicting character of the patterns. In conclusion, these performance data on the figure-copying tasks provide confirmatory evidence for psychomotor slowing in CFS, but not for a disturbed inhibition of automatic responses. Computerised figure-copying tasks may be promising tools for use in neurobiological research and clinical trials in CFS.

Cardiopulmonary responses to exercise in an individual with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during long-term treatment with intravenous saline: A case study.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) causes significant impairment in daily activities, including the ability to pursue daily activities. Chronotropic intolerance is becoming better characterized in ME/CFS and may be the target of supportive treatment. OBJECTIVE: To document the effect of repeated intravenous (IV) saline administration on cardiovascular functioning and symptoms in a 38-year old female with ME/CFS. METHODS: The patient received 1 L of 0.9% IV saline through a central line for a total of 675 days. Single CPETs were completed periodically to assess the effect of treatment on cardiopulmonary function at peak exertion and ventilatory anaerobic threshold (VAT). An open-ended symptom questionnaire was used to assess subjective responses to CPET and self-reported recovery time. RESULTS: Improvements were noted in volume of oxygen consumed (VO2), heart rate (HR), and systolic blood pressure (SBP) at peak and VAT. Self-reported recovery time from CPET reduced from 5 days to 1-2 days by the end of treatment. The patient reported improved quality of life related, improved capacity for activities of daily living, and reduced symptoms. CONCLUSIONS: IV saline may promote beneficial effects for cardiopulmonary function and symptoms in people with ME/CFS, which should be the focus of formal study.

Post-exertional symptoms distinguish Myalgic Encephalomyelitis/Chronic Fatigue Syndrome subjects from healthy controls.

BACKGROUND: Post-exertional malaise (PEM) is an exacerbation of symptoms that leads to a reduction in functionality. Recognition of PEM is important for the diagnosis and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). OBJECTIVE: Symptoms following cardiopulmonary exercise testing were compared between ME/CFS patients and healthy controls. METHODS: Open-ended questionnaires were provided to subjects following two maximal exercise tests, 24 hours apart. Subjects evaluated how they felt at five time points. Responses were classified into 19 symptom categories. RESULTS: ME/CFS subjects (n = 49) reported an average of 14±7 symptoms compared to 4±3 by controls (n = 10). During the seven days afterwards, ME/CFS subjects reported 4±3 symptoms. None were reported by controls. Fatigue, cognitive dysfunction, and sleep problems were reported with the greatest frequency. ME/CFS patients reported more symptom categories at higher frequencies than controls. The largest differences were observed in cognitive dysfunction, decrease in function, and positive feelings. CONCLUSIONS: A standardized exertional stimulus produced prolonged, diverse symptoms in ME/CFS subjects. This provides clues to the underlying pathophysiology of ME/CFS, leading to improved diagnosis and treatment.

Properties of measurements obtained during cardiopulmonary exercise testing in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Diminished cardiopulmonary exercise test (CPET) performance indicates the physiological basis for reduced capacity for activities of daily living and work. Thus, it may be a biomarker for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). OBJECTIVE: To determine statistical properties of cardiac, pulmonary, and metabolic measurements obtained during CPET in people with ME/CFS. METHODS: Fifty-one females with ME/CFS and 10 sedentary females with similar age and body mass received cardiac, pulmonary, and metabolic measurements during 2 CPETs separated by 24 hours. Two-way analysis of variance and effect size calculations (Cohen's d) were used to assess the magnitude and statistical significance of differences in measurements between groups. Reliability of CPET measurements was estimated using intraclass correlation coefficients (ICC2,1). Responsiveness of CPET measurements was assessed using minimum detectable change outside the 95% confidence interval (MDC95) and coefficients of variation (CoV). RESULTS: CPET measurements demonstrated moderate to high reliability for individuals with ME/CFS. Comparing subjects with ME/CFS and control subjects yielded moderate to large effect sizes on all CPET measurements. MDC95 for all individuals with ME/CFS generally exceeded control subjects and CoVs for CPET measurements were comparable between groups. CONCLUSIONS: CPET measurements demonstrate adequate responsiveness and reproducibility for research and clinical applications.

The effect of arm abduction angle and contraction intensity on perceived exertion.

The objective of the present investigation was to examine the effects of voluntary contraction intensity and arm elevation angle on ratings of perceived exertion in healthy young adults. Twelve healthy young adults participated in six separate experimental sessions, during which maximal and sub-maximal arm abduction contractions were performed at one of the following randomly assigned arm angles: 15 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , and 90 degrees arm angles (degrees). The sub-maximal arm abduction contractions (10 s) were performed to target intensities ranging from 10 to 90% of the maximal voluntary contraction (MVC), in randomly ordered 10% increments. Perceived exertion was sampled with a modified Borg category-ratio scale immediately, following each sub-maximal contraction. Voluntary arm abduction torque was significantly (p < 0.05) lower at 45 degrees , 60 degrees , 75 degrees and 90 degrees , as compared to 15 degrees . The ratings of perceived exertion increased significantly (p < 0.05) across the range of contraction intensities, with no significant differences between arm angles. The perceived exertion response, as a function of contraction intensity, was best described as linear across the 30 degrees -90 degrees , while a power function described the response at 15 degrees . The major findings demonstrated that arm position plays a minimal role in mediating the growth in the perceived exertion response, as a function of contraction intensity.

Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Post-exertional malaise (PEM) is the hallmark clinical feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM involves a constellation of substantially disabling signs and symptoms that occur in response to physical, mental, emotional, and spiritual over-exertion. Because PEM occurs in response to over-exertion, physiological measurements obtained during standardized exertional paradigms hold promise to contribute greatly to our understanding of the cardiovascular, pulmonary, and metabolic states underlying PEM. In turn, information from standardized exertional paradigms can inform patho-etiologic studies and analeptic management strategies in people with ME/CFS. Several studies have been published that describe physiologic responses to exercise in people with ME/CFS, using maximal cardiopulmonary testing (CPET) as a standardized physiologic stressor. In both non-disabled people and people with a wide range of health conditions, the relationship between exercise heart rate (HR) and exercise workload during maximal CPET are repeatable and demonstrate a positive linear relationship. However, smaller or reduced increases in heart rate during CPET are consistently observed in ME/CFS. This blunted rise in heart rate is called chronotropic intolerance (CI). CI reflects an inability to appropriately increase cardiac output because of smaller than expected increases in heart rate. The purposes of this review are to (1) define CI and discuss its applications to clinical populations; (2) summarize existing data regarding heart rate responses to exercise obtained during maximal CPET in people with ME/CFS that have been published in the peer-reviewed literature through systematic review and meta-analysis; and (3) discuss how trends related to CI in ME/CFS observed in the literature should influence future patho-etiological research designs and clinical practice.

Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing.

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a syndrome of unknown etiology characterized by profound fatigue exacerbated by physical activity, also known as post-exertional malaise (PEM). Previously, we did not detect evidence of immune dysregulation or virus reactivation outside of PEM periods. Here we sought to determine whether cardiopulmonary exercise stress testing of ME/CFS patients could trigger such changes. ME/CFS patients (n = 14) and matched sedentary controls (n = 11) were subjected to cardiopulmonary exercise on 2 consecutive days and followed up to 7 days post-exercise, and longitudinal whole blood samples analyzed by RNA-seq. Although ME/CFS patients showed significant worsening of symptoms following exercise versus controls, with 8 of 14 ME/CFS patients showing reduced oxygen consumption ([Formula: see text]) on day 2, transcriptome analysis yielded only 6 differentially expressed gene (DEG) candidates when comparing ME/CFS patients to controls across all time points. None of the DEGs were related to immune signaling, and no DEGs were found in ME/CFS patients before and after exercise. Virome composition (P = 0.746 by chi-square test) and number of viral reads (P = 0.098 by paired t-test) were not significantly associated with PEM. These observations do not support transcriptionally-mediated immune cell dysregulation or viral reactivation in ME/CFS patients during symptomatic PEM episodes.

Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Background: Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Maximal CPET is used to evaluate the coordinated metabolic, muscular, respiratory and cardiac contributions to energy production in patients with ME/CFS. In this patient population, CPET also elicits a robust post-exertional symptom flare (termed, post-exertional malaise); a cardinal symptom of the disease. CPET measures are highly reliable and reproducible in both healthy and diseased populations. However, evidence to date indicates that ME/CFS patients are uniquely unable to reproduce CPET measures during a second test, despite giving maximal effort during both tests, due to the effects of PEM on energy production. Methodology: To document and assess functional impairment due to the effects of post-exertional malaise in ME/CFS, a 2-day CPET procedure (2-day CPET) has been used to first measure baseline functional capacity (CPET1) and provoke post-exertional malaise, then assess changes in CPET variables 24 h later with a second CPET to assess the effects of post-exertional malaise on functional capacity. The second CPET measures changes in energy production and physiological function, objectively documenting the effects of post-exertional malaise. Use of CPET as a standardized stressor to induce post-exertional malaise and quantify impairment associated with post-exertional malaise has been employed to examine ME/CFS pathology in several studies. This article discusses the results of those studies, as well as the standardized techniques and procedures for use of the 2-day CPET in ME/CFS patients, and potentially other fatiguing illnesses. Conclusions: Basic concepts of CPET are summarized, and special considerations for performing CPET on ME/CFS patients are detailed to ensure a valid outcome. The 2-day CPET methodology is outlined, and the utility of the procedure is discussed for assessment of functional capacity and exertion intolerance in ME/CFS.

Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS).

Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects. Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.

Subclassifying chronic fatigue syndrome through exercise testing.

PURPOSE: The purpose of this study was to examine physiological responses of persons with chronic fatigue syndrome (CFS) to a graded exercise test. METHODS: Cardiopulmonary exercise tests were performed on 189 patients diagnosed with CFS. Based on values for peak oxygen consumption, patients were assigned to one of four impairment categories (none, mild, moderate, and severe), using American Medical Association (AMA) guidelines. A one-way MANOVA was used to determine differences between impairment categories for the dependent variables of age, body mass index, percentage of predicted [OV0312]O(2), resting and peak heart rates, resting and peak systolic blood pressure, respiratory quotient (RQ), and rating of perceived exertion. RESULTS: Significant differences were found between each impairment level for percentage of predicted [OV0312]O(2) and peak heart rate. Peak systolic blood pressure values for the "moderate," and "severe" groups differed significantly from each other and both other groups. The more impaired groups had lower values. The no impairment group had a significantly higher peak RQ than each of the other impairment levels (all P < 0.001). Peak [OV0312]O(2) values were less than predicted for all groups. Compared with the males, the women achieved actual values for peak [OV0312]O(2) that were closer to their predicted values. CONCLUSION: Despite a common diagnosis, the functional capacity of CFS patients varies greatly. Stratifying patients by function allows for a more meaningful interpretation of the responses to exercise and may enable differential diagnosis between subsets of CFS patients.

Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome.

The elevated RNase L enzyme activity observed in some Chronic Fatigue Syndrome (CFS) patients may be linked to the low exercise tolerance and functional impairment that typify this disease. The purpose of this investigation was to determine if specific indicators of physical performance can predict abnormal RNase L activity in CFS patients. Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. This measure was employed as the dependent variable in a discriminant function analysis, with peak V02, exercise duration and Karnofsky Performance Scores (KPS) serving as the independent variables. All three variables entered the single significant function (p < 0.001). The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. The results suggest that both exercise testing and the RNase L biomarker have potential to aid in the diagnosis of CFS.

Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome.

BACKGROUND: Reduced functional capacity and postexertion fatigue after physical activity are hallmark symptoms of chronic fatigue syndrome (CFS) and may even qualify for biomarker status. That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing in people with CFS. Test reproducibility in people who are healthy is well documented. Test reproducibility may not be achievable in people with CFS because of delayed symptoms. OBJECTIVE: The objective of this study was to determine the discriminative validity of objective measurements obtained during cardiopulmonary exercise testing to distinguish participants with CFS from participants who did not have a disability but were sedentary. DESIGN: A prospective cohort study was conducted. METHODS: Gas exchange data, workloads, and related physiological parameters were compared in 51 participants with CFS and 10 control participants, all women, for 2 maximal exercise tests separated by 24 hours. RESULTS: Multivariate analysis showed no significant differences between control participants and participants with CFS for test 1. However, for test 2, participants with CFS achieved significantly lower values for oxygen consumption and workload at peak exercise and at the ventilatory or anaerobic threshold. Follow-up classification analysis differentiated between groups with an overall accuracy of 95.1%. LIMITATIONS: Only individuals with CFS who were able to undergo exercise testing were included in this study. Individuals who were unable to meet the criteria for maximal effort during both tests, were unable to complete the 2-day protocol, or displayed overt cardiovascular abnormalities were excluded from the analysis. CONCLUSIONS: The lack of any significant differences between groups for the first exercise test would appear to support a deconditioning hypothesis for CFS symptoms. However, the results from the second test indicated the presence of CFS-related postexertion fatigue. It might be concluded that a single exercise test is insufficient to reliably demonstrate functional impairment in people with CFS. A second test might be necessary to document the atypical recovery response and protracted fatigue possibly unique to CFS, which can severely limit productivity in the home and workplace.

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME. METHODS AND FINDINGS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated. CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800.