Tag: Stevens

We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID

Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID. Journal of Orthopedic & Sports Physical Therapy. Published online on March 10, 2021
https://doi.org/10.2519/jospt.blog.20210310

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

Abstract:

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.

Source: Davenport, Todd E., Ward, Michael K., Stevens, Staci R., Stevens, Jared, Snell, Christopher R., VanNess, J. Mark. Cardiopulmonary responses to exercise in an individual with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during long-term treatment with intravenous saline: A case study. Work, vol. Pre-press, no. Pre-press, pp. 1-7, 2020 https://content.iospress.com/articles/work/wor203214

Post-exertional Symptoms Distinguish Myalgic encephalomyelitis/chronic Fatigue Syndrome Subjects From Healthy Controls

Abstract:

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.

Source: Mateo LJ, Chu L, Stevens S, et al. Post-exertional symptoms distinguish myalgic encephalomyelitis/chronic fatigue syndrome subjects from healthy controls [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203168. doi:10.3233/WOR-203168 https://pubmed.ncbi.nlm.nih.gov/32568143/

Properties of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Myalgic encephalomyelitis/chronic Fatigue Syndrome

Abstract:

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 (formula 2,1; 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.

Source: Davenport TE, Stevens SR, Stevens MAJ, Snell CR, Van Ness JM. Properties of measurements obtained during cardiopulmonary exercise testing in individuals with myalgic encephalomyelitis/chronic fatigue syndrome [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203170. doi:10.3233/WOR-203170

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

Abstract:

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.

Source: Bouquet J, Li T, Gardy JL, Kang X, Stevens S, Stevens J, VanNess M, Snell C, Potts J, Miller RR, Morshed M, McCabe M, Parker S, Uyaguari M, Tang P, Steiner T, Chan WS, De Souza AM, Mattman A, Patrick DM, Chiu CY. Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing. PLoS One. 2019 Mar 21;14(3):e0212193. doi: 10.1371/journal.pone.0212193. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212193 (Full article)
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Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Abstract:

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.

Source: Todd E. Davenport, Mary Lehnen, Staci R. Stevens, J. Mark VanNess, Jared Stevens and Christopher R. Snell. Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front. Pediatr., 22 March 2019 | https://doi.org/10.3389/fped.2019.00082 https://www.frontiersin.org/articles/10.3389/fped.2019.00082/full (Full article)

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

Abstract:

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.

Source: Staci Stevens, Chris Snell, Jared Stevens, Betsy Keller and J. Mark VanNess.  Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Pediatr., 04 September 2018 | https://doi.org/10.3389/fped.2018.00242 https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full  (Full article)

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

Abstract:

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.

 

Source: Snell CR, Stevens SR, Davenport TE, Van Ness JM.Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Phys Ther. 2013 Nov;93(11):1484-92. doi: 10.2522/ptj.20110368. Epub 2013 Jun 27. https://academic.oup.com/ptj/article/93/11/1484/2735315/Discriminative-Validity-of-Metabolic-and-Workload?searchresult=1 (Full article)

 

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

Abstract:

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.

 

Source: Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, Lapp CW, Peterson DL; Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell WM.Collaborators (12). A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334. Epub 2012 Mar 14.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/ (Full article)

 

Reliability and validity of Short Form 36 Version 2 to measure health perceptions in a sub-group of individuals with fatigue

Abstract:

PURPOSE: To determine the validity and reliability of Short Form 36 Version 2 (SF36v2) in sub-groups of individuals with fatigue.

METHOD: Thirty subjects participated in this study, including n = 16 subjects who met case definition criteria for chronic fatigue syndrome (CFS) and n = 14 non-disabled sedentary matched control subjects. SF36v2 and Multidimensional Fatigue Inventory (MFI-20) were administered before two maximal cardiopulmonary exercise tests (CPETs) administered 24 h apart and an open-ended recovery questionnaire was administered 7 days after CPET challenge. The main outcome measures were self-reported time to recover to pre-challenge functional and symptom status, frequency of post-exertional symptoms and SF36v2 sub-scale scores.

RESULTS: Individuals with CFS demonstrated significantly lower SF36v2 and MFI-20 sub-scale scores prior to CPET. Between-group differences remained significant post-CPET, however, there were no significant group by test interaction effects. Subjects with CFS reported significantly more total symptoms (p < 0.001), as well as reports of fatigue (p < 0.001), neuroendocrine (p < 0.001), immune (p < 0.01), pain (p < 0.01) and sleep disturbance (p < 0.01) symptoms than control subjects as a result of CPET. Many symptom counts demonstrated significant relationships with SF36v2 sub-scale scores (p < 0.05). SF36v2 and MFI-20 sub-scale scores demonstrated significant correlations (p < 0.05). Various SF36v2 sub-scale scores demonstrated significant predictive validity to identify subjects who recovered from CPET challenge within 1 day and 7 days (p < 0.05). Potential floor effects were observed for both questionnaires for individuals with CFS.

CONCLUSION: Various sub-scales of SF36v2 demonstrated adequate reliability and validity for clinical and research applications. Adequacy of sensitivity to change of SF36v2 as a result of a fatiguing stressor should be the subject of additional study.

 

Source: Davenport TE, Stevens SR, Baroni K, Van Ness JM, Snell CR. Reliability and validity of Short Form 36 Version 2 to measure health perceptions in a sub-group of individuals with fatigue. Disabil Rehabil. 2011;33(25-26):2596-604. doi: 10.3109/09638288.2011.582925. Epub 2011 Jun 20. https://www.ncbi.nlm.nih.gov/pubmed/21682669