What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults

Abstract:

The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations. It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test.

The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes. It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount. The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for ME/CFS and emphasises that cognitive behavioural therapy (CBT) should only be offered as a supportive intervention.

Because of the rigorous methodology required by NICE Committee review and the inclusion of the testimony of people with lived experience as committee members, this guideline will influence the future diagnosis and management of ME/CFS in the UK and beyond.

Source:  Kingdon, C.C.; Lowe, A.; Shepherd, C.; Nacul, L. What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults . Preprints 2022, 2022110016 (doi: 10.20944/preprints202211.0016.v1).  https://www.preprints.org/manuscript/202211.0016/v1 (Full text available as PDF file)

Bias in Exercise Trials for ME/CFS: the Importance of Objective Outcomes and Long-term Follow-up

Sharpe and colleagues recommend that patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) be offered cognitive behavior therapy (CBT) and graded exercise therapy (GET)1, advice that contrasts with recent NICE guidance on ME/CFS.2 The authors argue that “there are many randomized trials indicating the safety and efficacy of these treatments.”1

All of these trials, however, were nonblinded and relied on subjective symptom questionnaires as their main outcomes, a combination that creates a high risk of response bias. Treatment manuals used in these trials included explicit encouragements to raise patients’ expectations of GET and CBT. One patient booklet, for example, informed patients: “You will experience a snowballing effect as increasing fitness leads to increasing confidence in your ability. You will have conquered CFS by your own effort and you will be back in control of your body again.”3 These encouragements were not provided to participants in the control group and might have influenced how patients rated their health. In contrast to what Sharpe and colleagues claim, measuring the expectations of patients before the trial begins, does not address how therapists might have influenced symptom reporting during the trial.

There are further arguments that suggest these trials might have measured response bias rather than improvements in health. There were, for example, no clinically significant differences on objective outcome measures that are less prone to response bias such as employment figures, activity levels, or fitness tests.3 In addition, at long-term follow-up, the control group seemed to perform just as well as participants who received GET or CBT. This could not be explained by additional treatment received after the trial ended.4 These findings are difficult to interpret if patients did indeed rehabilitate successfully following GET or CBT. It is unfortunate that the authors, who were primary researchers in many of these trials, do not address these concerns.

Lastly, Sharpe and colleagues argue that “harm reported from patient community surveys reflects poorly implemented therapy.”1 Patient surveys, however, indicate that ME/CFS patients report harm of GET even if prescribed by a specialist or physiotherapist.5 The authors have previously been challenged for misrepresenting the findings of these surveys.5 Post-exertional malaise or a marked worsening of symptoms when patients exceed their energy limit, is a characteristic feature of ME/CFS.2 There are therefore reasonable safety concerns about treatments such as GET and CBT that try to push patients to exceed their limits.

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Source: Tack, M. Bias in Exercise Trials for ME/CFS: the Importance of Objective Outcomes and Long-term Follow-up. J GEN INTERN MED 37, 3193 (2022). https://doi.org/10.1007/s11606-022-07704-0  (Full text)

Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?

Abstract:

Purpose: The pathophysiology of chronic fatigue associated with post-COVID syndrome is not well recognized. It is assumed that this condition is partly due to vascular dysfunction developed during an acute phase of infection. There is great demand for a diagnostic tool that is able to clinically assess post-COVID syndrome and monitor the rehabilitation process.

Patients and methods: The Flow Mediated Skin Fluorescence (FMSF) technique appears uniquely suitable for the analysis of basal microcirculatory oscillations and reactive hyperemia induced by transient ischemia. The FMSF was used to measure vascular circulation in 45 patients with post-COVID syndrome. The results were compared with those for a group of 26 amateur runners before and after high-intensity exercise as well as for a control group of 32 healthy age-matched individuals.

Results: Based on the observed changes in the NOI (Normoxia Oscillatory Index) and RHR (Reactive Hyperemia Response) parameters measured with the FMSF technique, it was found that chronic fatigue associated with post-COVID syndrome is comparable with transient fatigue caused by high-intensity exercise in terms of vascular effects, which are associated with vascular stress in the macrocirculation and microcirculation. Acute and chronic fatigue symptomatology shared similarly altered changes in the NOI and RHR parameters and both can be linked to calcium homeostasis modification.

Conclusion: The NOI and RHR parameters measured with the FMSF technique can be used for non-invasive clinical assessment of post-COVID syndrome as well as for monitoring the rehabilitation process.

Source: Chudzik M, Cender A, Mordaka R, Zielinski J, Katarzynska J, Marcinek A, Gebicki J. Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects? Vasc Health Risk Manag. 2022 Sep 6;18:711-719. doi: 10.2147/VHRM.S371468. PMID: 36097586; PMCID: PMC9464031.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9464031/ (Full text)

Repeated maximal exercise tests of peak oxygen consumption in people with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis

Abstract:

Background: Repeated maximal exercise separated by 24 hours may be useful in identifying possible objective markers in people with ME/CFS that are not present in healthy controls.

Aim: We aimed to synthesise studies in which the test-to-retest (24 hours) changes in VO2 and work rate have been compared between people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and controls.

Methods: Seven databases (CINAHL, PubMed, PsycINFO, Web of Knowledge, Embase, Scopus and MEDLINE) were searched. Included studies were observational studies that assessed adults over the age of 18 years with a clinical diagnosis of ME/CFS compared to healthy controls. The methodological quality of included studies was assessed using the Systematic Appraisal of Quality for Observational Research critical appraisal framework. Data from included studies were synthesised using a random effects meta-analysis.

Results: The pooled mean decrease in peak work rate (five studies), measured at retest, was greater in ME/CFS by −8.55 (95% CI −15.38 to –1.72) W. The pooled mean decrease in work rate at anaerobic threshold (four studies) measured at retest was greater in ME/CFS by −21 (95%CI −38 to −4, tau = 9.8) W. The likelihood that a future study in a similar setting would report a difference in work rate at anaerobic threshold which would exceed a minimal clinically important difference (10 W) is 78% (95% CI 40%–91%).

Conclusion: Synthesised data indicate that people with ME/CFS demonstrate a clinically significant test–retest reduction in work rate at the anaerobic threshold when compared to apparently healthy controls.

Source: John Derek Franklin & Michael Graham (2022) Repeated maximal exercise tests of peak oxygen consumption in people with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2022.2108628  https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2108628 (Full text)

Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes?

Abstract:

A variety of rehabilitation programmes can be offered to Long COVID patients, specifically physical training. Indeed 90% of these patients reports impairments of verticalization, stability and spatial orientation, making difficult exercise in the gym. The aim of our study was to assess the effectiveness and safety of aquatic exercise techniques as part of a comprehensive rehabilitation program for patients with Long COVID.

The first of a two-stage program involved development of aquatic exercises technique, which was evaluated in 12 patients with impaired upright posture control before and after exercising by “Habilect” video gait analysis system. During the second phase, effectiveness and safety of aqua exercises were tested in water pool as part of a comprehensive rehabilitation programme conducted in 23 patients with Long COVID outcomes. Physical examination, 6-minute step test, Euro-QL-5D questionnaire, Borg scale, laser Doppler flowmetry, cardiointervalography, and spirometry were performed before and after the aquatic exercises program.

After the training with aquatic exercises, indices of deviations of the main body axes of the head and the body mass centre ameliorated, as well as direction of body movement vector decreased (p<0.05). This study demonstrated a statistically significant improvement in exercise tolerance in both groups, as measured by the 6-minute step test after rehabilitation. The comparison group averaged 236.7 metres [126; 380] (T=8, p=0.047) after the rehabilitation course and the intervention group averaged 233.71 metres [150; 320] (T=8.0, p=0.047). When tested with the Euro-QL-5D questionnaire, a post-treatment improvement was noted in the comparison group on the anxiety/depression subscale (3 [3;3] (T=0, p=0.043)).

In the intervention group, laser Doppler flowmetry revealed a statistically significant increase in microcirculation (6.36 standard units after rehabilitation) [5.54; 8.17] (T=7.0, p=0.004), and a decrease of oxidative metabolism index of 6.89 standard units. [4.76; 6.96] (T=4.0, p=0.03). No serious adverse events were reported. In conclusion, the developed aquatic exercises technique seems to contribute to recovery of impaired upright posture and motor function, normalizing the walking pattern.

Source: Lobanov AA, Irina A Grishechkina, Andronov SV, Gleb N Barashkov, Andrey I Popov, Anatoliy D Fesyun, Elena P Ivanova, Maccarone MC, Stefano Masiero. Can aquatic exercises contribute to the improvement of the gait stereotype function in patients with Long COVID outcomes? Eur J Transl Myol. 2022 Jul 14. doi: 10.4081/ejtm.2022.10698. Epub ahead of print. PMID: 35833897.  https://pubmed.ncbi.nlm.nih.gov/35833897/ (Full text: Follow link on page)

The Qigong of Prolong Life With Nine Turn Method Relieve Fatigue, Sleep, Anxiety and Depression in Patients With Chronic Fatigue Syndrome: A Randomized Controlled Clinical Study

Abstract

Background: Chronic fatigue syndrome (CFS) is a complex disease of unknown etiology and mechanism. The purpose of this study was to investigate the effect of Prolong Life with Nine Turn Method (PLWNT) Qigong exercise on CFS focusing on fatigue, sleep quality, depression, and anxiety.

Methods: A total of 90 participants diagnosed with CFS were randomly assigned into two parallel groups: PLWNT and cognitive behavioral therapy (CBT). The participants in the PLWNT or CBT group participated in qigong exercise or cognitive behavior education program, respectively, once a week in-person and were supervised online during the remaining 6 days at home, over 12 consecutive weeks. The primary outcome was fatigue (Multi-dimensional Fatigue Inventory 20 [MFI-20]), and secondary outcomes were sleep quality (Pittsburgh Sleep Quality Index [PSQI]), anxiety, depression (Hospital Anxiety and Depression Scale [HADS]), and changes in the Neuropeptide Y (NPY) of peripheral blood.

Results: The within-group comparisons of the PLWNT and CBT groups revealed significant improvement in both groups in MFI-20, PSQI, and HADS scores (P < 0.05). No significant difference were found between the PLWNT and CBT groups, even though the effective rate of the PLWNT group was 62.22%, which is slightly than 50.00% of the CBT group. The fatigue scores in the PLWNT group were positively correlated with sleep degree (r = 0.315) and anxiety degree (r = 0.333), only anxiety degree (r = 0.332) was found to be positively correlated with fatigue in the CBT group. The analysis of peripheral blood showed that NPY decreased after PLWNT intervention but increased significantly in the CBT.

Conclusion: The PLWNT qigong exercise has potential to be an effective rehabilitation method for CFS symptoms including fatigue, sleep disturbance, anxiety, and depression. Future studies should expand study sample size for in-depth investigation to determine the optimal frequency and intensity of PLWNT qigong intervention in CFS patients. The study was registered in the ClinicalTrials.gov database on April 12, 2018, with registration number NCT03496961.

Source: Xie F, You Y, Guan C, Xu J, Yao F. The Qigong of Prolong Life With Nine Turn Method Relieve Fatigue, Sleep, Anxiety and Depression in Patients With Chronic Fatigue Syndrome: A Randomized Controlled Clinical Study. Front Med (Lausanne). 2022 Jun 30;9:828414. doi: 10.3389/fmed.2022.828414. PMID: 35847786; PMCID: PMC9280429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280429/ (Full text)

Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness

Abstract:

Background/objective: Evidence has suggested abnormal cardiac autonomic responses to exercise in patients with fibromyalgia (FM). However, it is not clear whether the dysautonomia represents a reduced physical fitness rather directly related to FM pathogenesis. Thus, we aimed to verify the cardiac autonomic responses before, during, and after a maximal incremental exercise in women with FM and whether these hypothesized alterations would be dependent with their physical fitness.

Methods: This is a cross-sectional study with 23 FM women and 17 healthy women. The participants performed a maximal incremental cycling test to determine their maximal workload (Wmax) and were further matched by their Wmax (14 FM patients, Wmax: 128.6 ± 16.2 W; and 14 healthy women, Wmax: 131.9 ± 15.9 W). Beat-to-beat heart rate (HR) was continuously monitored to calculate HR variability indexes at rest, chronotropic reserve during exercise, and HR recovery.

Results: Heart rate variability indexes related to vagal modulation were significantly lower in FM patients than in healthy women (p < 0.05). The chronotropic reserve and the HR recovery at 30, 120, 180, 300, and 600 seconds after exercise were all lower in FM patients compared with those of healthy women (p < 0.05). Similar findings were found when analysis was performed using the matched physical fitness subgroup.

Conclusions: The documented cardiac autonomic abnormalities at rest, during, and after exercise in FM patients persist even when physical fitness status is taken in account. Thus, strategies to attenuate the dysautonomia in FM patients must be considered.

Source: Schamne JC, Ressetti JC, Lima-Silva AE, Okuno NM. Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness. J Clin Rheumatol. 2021 Sep 1;27(6S):S278-S283. doi: 10.1097/RHU.0000000000001518. PMID: 32826659. https://pubmed.ncbi.nlm.nih.gov/32826659/

Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.

Research Question: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?

Methods: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.

Results: Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.

Interpretation: Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

Abbreviations List: Ca-vO2 (arterial-venous oxygen content difference), iCPET (Invasive cardiopulmonary exercise test), MAP (Mean arterial pressure), mPAP (Mean pulmonary artery pressure), ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome), PASC (Post-acute sequelae of SARS-CoV-2 infection), PAWP (Pulmonary arterial wedge pressure), POTS (Postural orthostatic tachycardia syndrome), Qc (Cardiac output), RAP (Right atrial pressure), SE (Standard error), SFN (Small fiber neuropathy), VE/VCO2 (Ventilatory efficiency), VO2 (Oxygen uptake)

Source: Phillip Joseph, MD, Rosa Pari, MD, Sarah Miller, BS, Arabella Warren, BS, Mary Catherine Stovall, BS, Johanna Squires, MSc, Chia-Jung Chang, PhD, Wenzhong Xiao, PhD, Aaron B. Waxman, MD, PhD, David M. Systrom, MD. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest, Published: May 05, 2022. DOI: https://doi.org/10.1016/j.chest.2022.04.146

The Relationship between Physical Activity and Long COVID: A Cross-Sectional Study

The relationship between Long Covid (LC) symptoms and physical activity (PA) levels are unclear. In this cross-sectional study, we examined this association, and the advice that individuals with LC received on PA. Adults with LC were recruited via social media. The New Zealand physical activity questionnaire short form (NZPAQ-SF) was adapted to capture current and pre-COVID-19 PA levels and activities of daily living (ADLs).
Participants reported how PA affected their symptoms, and what PA recommendations they had received from healthcare professionals and other resources; 477 participants completed the survey. Mean age (SD) was 45.69 (10.02) years, 89.1% female, 92.7% white, and median LC duration was 383.5 days (IQR: 168.25,427). Participants were less active than pre-COVID-19 (26.88 ± 74.85 vs. 361.68 ± 396.29 min per week, p < 0.001) and required more assistance with ADLs in a 7-day period compared to pre-COVID-19 (2.23 ± 2.83 vs. 0.11 ± 0.74 days requiring assistance, p < 0.001). No differences were found between the number of days of assistance required with ADLs, or the amount of PA, and the different durations of LC illness (p > 0.05).
Participants reported the effect of PA on LC symptoms as: worsened (74.84%), improved (0.84%), mixed effect (20.96%), or no effect (28.72%). Participants received contradictory advice on whether to be physically active in LC. LC is associated with a reduction in PA and a loss of independence, with most participants reporting PA worsened LC symptoms. PA level reduction is independent of duration of LC. Research is needed to understand how to safely return to PA without worsening LC symptoms.
Source: Wright J, Astill SL, Sivan M. The Relationship between Physical Activity and Long COVID: A Cross-Sectional Study. International Journal of Environmental Research and Public Health. 2022; 19(9):5093. https://doi.org/10.3390/ijerph19095093  https://www.mdpi.com/1660-4601/19/9/5093/htm (Full text)

Risk factors and multidimensional assessment of long COVID fatigue: a nested case-control study

Abstract:

Background: Fatigue is the most prevalent and debilitating long COVID symptom, however risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long COVID fatigue and explored its possible pathophysiology.

Methods: Nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long COVID fatigue.

Results: Total of 141 individuals were included. Mean age was 47 (SD 13) years; 115 (82%) were recovering from mild COVID-19. Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long COVID fatigue. They had significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness and long COVID symptoms, and of physical limitation in daily activities. Individuals with fatigue had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53), p=0.038] and oxygen consumption per Kg [27.69 (7.52) vs 30.71 (7.52), p=0.036] at peak exercise. The two independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (odds ratio [OR] 0.79 per 10 beats/minute, 95% confidence interval [CI] 0.65-0.96, p=0.019); and long COVID memory impairment (OR 3.76, 95% CI 1.57-9.01, p=0.003).

Conclusions: Long COVID fatigue may be related to autonomic dysfunction, impaired cognition and decreased mood. This may suggest a limbic-vagal pathophysiology. Clinical Trial registration: NCT04851561.

Source: Margalit I, Yelin D, Sagi M, Rahat MM, Sheena L, Mizrahi N, Gordin Y, Agmon H, Epstein NK, Atamna A, Tishler O, Daitch V, Babich T, Abecasis D, Yarom Y, Kazum S, Shitenberg D, Baltaxe E, Elkana O, Shapira-Lichter I, Leibovici L, Yahav D. Risk factors and multidimensional assessment of long COVID fatigue: a nested case-control study. Clin Infect Dis. 2022 Apr 11:ciac283. doi: 10.1093/cid/ciac283. Epub ahead of print. PMID: 35403679.  https://pubmed.ncbi.nlm.nih.gov/35403679/