Stevens – American ME and CFS Society

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

Abstract:

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, $\dot{V}$ e, $\dot{V}$ O₂, $\dot{V}$ CO₂, $\dot{V}$ _T, HR, O₂pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for $\dot{V}$ e/ $\dot{V}$ CO₂, PetCO_2, O₂pulse, work, $\dot{V}$ 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.

Source: Keller, B., Receno, C.N., Franconi, C.J. et al. 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. J Transl Med 22, 627 (2024). https://doi.org/10.1186/s12967-024-05410-5 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05410-5#Abs1 (Full text)

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

Abstract:

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.

Source: Davenport TE, Stevens SR, Stevens J, Snell CR, Van Ness JM. Development and measurement properties of the PEM/PESE activity questionnaire (PAQ). Work. 2023 Mar 13. doi: 10.3233/WOR-220553. Epub ahead of print. PMID: 36938768. https://content.iospress.com/articles/work/wor220553 (Full text)

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

Abstract:

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.

Source: Davenport, Todd E; Chu, Lily; Stevens, Staci R; Stevens, Jared; Snell, Christopher R; Van Ness, J. Mark. Two symptoms can accurately identify post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome. Work. 1 Jan. 2023 : 1 – 15. https://content.iospress.com/articles/work/wor220554 (Full text)

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

Abstract:

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.

Source: Moore GE, Keller BA, Stevens J, Mao X, Stevens SR, Chia JK, Levine SM, Franconi CJ, Hanson MR. Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Medicina. 2023; 59(3):571. https://doi.org/10.3390/medicina59030571 (Full text)

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

Summary:

ME/CFS is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we used single-cell RNA-seq (scRNA-seq) to examine immune cells in cohorts of patients and controls. Post-exertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. Thus, to detect changes coincident with PEM, we also performed scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients displayed dysregulation of classical monocytes suggestive of inappropriate differentiation and migration to tissue. We were able to identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlated with metrics of disease severity. Comparing the transcriptome at baseline and post-exercise challenge, we discovered patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation following exercise.

Highlights ME/CFS is a debilitating disease with unknown causes. Here, we provide, for the first time, an extensive single cell resolution dataset detailing the gene expression programs of circulating immune cells of ME/CFS cases at baseline and after symptom provocation. We were able to detect robust dysregulation in certain immune cells from patients, with dysregulation of classical monocytes manifesting the strongest signal. Indeed, the fraction of aberrant monocytes in ME/CFS patients correlated with the degree of disease severity. Surprisingly, platelet transcriptomes were also altered in ME/CFS, and they were the only component of the immune system that showed large-scale changes following symptom provocation.

Source: Faraz Ahmed, Luyen Tien Vu, Hongya Zhu, David Shing Huk Iu, Elizabeth A. Fogarty, Yeonui Kwak, Weizhong Chen, Carl J. Franconi, Paul R. Munn, Susan M. Levine, Jared Stevens, Xiangling Mao, Dikoma C. Shungu, Geoffrey E. Moore, Betsy A. Keller, Maureen R. Hanson, Jennifer K. Grenier, Andrew Grimson. Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation. bioRxiv 2022.10.13.512091; doi: https://doi.org/10.1101/2022.10.13.512091 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00602-X (Full text)

Diminished Cardiopulmonary Capacity During Post-Exertional Malaise

Abstract:

Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO₂ max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms.

Purpose: To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS.

Methods: Peak oxygen consumption (VO₂ peak), percentage of predicted peak heart rate (HR%), and VO₂ at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours.

Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO₂ peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO₂ peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%.

Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.

Source: J. Mark Vanness, Christopher R. Snell & Staci R. Stevens (2007) Diminished Cardiopulmonary Capacity During Post-Exertional Malaise, Journal of Chronic Fatigue Syndrome, 14:2, 77-85, DOI: 10.1300/J092v14n02_07

Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions – A Case Series

Abstract:

Purpose: Measurements obtained during maximal cardiopulmonary exercise testing (CPET) demonstrate high test–retest reliability, which indicates low error variance. However, measurements obtained from people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may depart from typically observed high reproducibility, which could represent functionally relevant biological variability that is characteristic of the underlying pathophysiology. The purpose of this case series was to document individual experiences with test–retest variability in CPET measurements in individuals with ME/CFS compared with other fatiguing health conditions.

Methods: In this case series, 6 women matched for age and body mass index underwent 2 maximal CPETs spaced 24 hours apart. Clients comprised 1 sedentary individual without fatigue, 1 active individual without fatigue, 1 individual with multiple sclerosis (MS), 1 individual diagnosed with HIV, 1 individual with ME/CFS and low maximal volume of oxygen consumed (VO₂max), and 1 high-functioning individual with ME/CFS and high VO₂max. Percent change in CPET measurements between tests was calculated for each client.

Results: Nondisabled clients and clients with MS and HIV reproduced or improved in their volume of oxygen consumed (VO₂), workload (WL), heart rate (HR), and minute ventilation (VE) at ventilatory anaerobic threshold (VAT) and at peak exercise (except peak WL and VE for the individual with HIV). Neither individual with ME/CFS reproduced VO₂, WL, HR, or VE at VAT within literature estimates.

Conclusions: Measurements during CPET for individual patients may relate to potential condition-specific deficits in cardiac, pulmonary, and metabolic functioning.

Source: Larson, Benjamin PT, DPT¹; Davenport, Todd E. PT, DPT, MPH, OCS^2,3; Stevens, Staci R. MA³; Stevens, Jared BS³; Van Ness, J. Mark PhD^3,4; Snell, Christopher R. PhD³. Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions: A Case Series. Cardiopulmonary Physical Therapy Journal: October 2019 – Volume 30 – Issue 4 – p 145-152 doi: 10.1097/CPT.0000000000000100 https://journals.lww.com/cptj/Abstract/2019/10000/Reproducibility_of_Measurements_Obtained_D%20uring.4.aspx

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation

The physiology underlying postexertional symptom exacerbation (PESE) is abnormal in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and likely long COVID. Activity pacing approaches appear warranted to accommodate the unusual physiological deficits of PESE.

The Rationale for Heart Rate Monitoring

Similar to people living with ME/CFS,⁷ people living with long COVID have reported finding activity pacing to be helpful. This idea is reflected in current safe rehabilitation guidelines for this condition.⁸ PESE is challenging to self-manage because of the variability in onset, duration, and nature from person to person.^2,6 Social stigma associated with PESE may lead people to overexert to meet the demands of their daily tasks. This stigma may be exacerbated by people telling patients that “it’s all in their head” or they “just need to exercise.” Variability and stigma, in turn, make it difficult to identify important activity triggers in the early stages of learning to manage PESE.

PESE is characterized by aerobic system dysfunction. Pacing based on heart rate can help the patient avoid the dysfunctional aerobic system by keeping their activity intensity at a level anaerobic metabolism will dominate. Heart rate monitoring (HRM) provides an element of predictive potential for the patient to understand when their activities exceed physiological limits and eventually may result in PESE. In this post, we will discuss activity pacing to manage PESE that is based on HRM.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation. Published online on February 23, 2022. https://doi.org/10.2519/jospt.blog.20220223 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation

In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE.

Graded Exercise May Be Harmful to People With PESE

It is not surprising that patients with PESE frequently report worsening symptoms and function with exercise prescribed based on time and activity quotas,¹ based on the physiological evidence. The United Kingdom’s Pacing, graded Activity, and Cognitive behaviour therapy, a randomized Evaluation (UK PACE) compared the clinical outcomes of specialist medical care, adaptive pacing, and graded exercise therapy (GET) in 641 people with idiopathic, disabling fatigue.⁹ In this study, GET was a quota-based progressive exercise program, where subjects incrementally increased exercise regardless of symptoms. PESE was not a specific recruitment criterion for this trial.^8,9 The trial did not adhere to the published protocol, without appropriate justification. The raw data was independently reanalyzed according to the original protocol,¹⁰ Upon reanalysis, most symptomatic and functional outcome findings from the UK PACE trial did not reach thresholds for clinical relevance. Many ME/CFS experts contend the results of GET are marginal, probably not clinically relevant or beneficial.¹⁰

Despite the important concerns of the UK PACE trial, the trial continues to exert outsized influence on clinical guidelines.³ Some countries’ systems developed formal treatment pathways based on flawed results. Treatment pathways involving GET may have exposed an untold number of patients with ME/CFS worldwide to a GET program that, at best, is marginally effective, and at worst, may be harmful. Recent clinical guidelines for people with PESE, such as long COVID, no longer involve GET.^6,7 These omissions reflect the ongoing re-evaluation of how clinical care should proceed for people with PESE, including people with long COVID. Implicit to this re-evaluation is a further reflection on the generally accepted idea that “movement is medicine” in a way that universally benefits clinical populations.

Read the full article HERE.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation. JOSPT blog, Published online on February 16, 2022. https://doi.org/10.2519/jospt.blog.20220216 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation

In a previous post on the JOSPT Blog, we outlined the connection between postacute sequalae to novel coronavirus (long COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through their common clinical presentation: postexertional symptom exacerbation (PESE). PESE suggests the presence of abnormal physiological responses to exercise/activity. These physiological responses may be measured using cardiopulmonary exercise testing (CPET), which allows for careful characterization of cardiac, pulmonary, and metabolic functioning during exercise. We will review the characteristic findings on CPET in people with PESE.

The Physiology of PESE

One well-established protocol involves consecutive-day CPETs.⁸ In deconditioned people and people with a whole host of health conditions, CPET measurements demonstrate low error variance. Yet, CPET measurements are known to vary between tests in people with PESE.² The observed variation in people with PESE reflects the biological variance associated with PESE.² Clues about biological variance can provide important information about the underlying pathoetiology, severity, and functional limitations present.^2,8 CPET data from peak exertion and ventilatory anaerobic threshold (VAT) provide important snapshots of physiological functioning. Data from peak exertion tells us about the physiology of a person’s “top-end” performance, and data from VAT elucidates the physiology of more “everyday” levels of exertion.

Read the rest of this article HERE.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 2: Physiological Characteristics During Acute Exercise Are Abnormal in People With Postexertional Symptom Exacerbation. JOSPT blog, Published online on February 9, 2022. https://doi.org/10.2519/jospt.blog.20220209 (Full text)