Tag: PEM

Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.

Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.

Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.

Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Source: Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, Bateman L. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work. 2023 Mar 7. doi: 10.3233/WOR-220581. Epub ahead of print. PMID: 36911963. https://content.iospress.com/articles/work/wor220581 (Full text)

A case of post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome characterized by post-exertional malaise and low serum acylcarnitine level

Abstract:

COVID-19 afflicts patients with acute symptoms and longer term sequelae. One of the sequelae is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often difficult to diagnose, having no established tests. In this article, we synthesize information from literature reviews on patients with ME/CSF that developed after recovery from COVID-19.

Source: Jinushi R, Nishiguchi S, Masuda S, Sasaki A, Koizumi K, Ryozawa S. A case of post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome characterized by post-exertional malaise and low serum acylcarnitine level. Clin Case Rep. 2023 Feb 10;11(2):e6930. doi: 10.1002/ccr3.6930. PMID: 36789311; PMCID: PMC9913186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913186/ (Full text)

Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM.
The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds.
Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline).
Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.
Source: Glass KA, Germain A, Huang YV, Hanson MR. Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients. International Journal of Molecular Sciences. 2023; 24(4):3685. https://doi.org/10.3390/ijms24043685 https://www.mdpi.com/1422-0067/24/4/3685 (Full text available as PDF file)

Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort

Abstract:

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a complex, heterogenous disease. It has been suggested that subgroups of people with ME/CFS exist, displaying a specific cluster of symptoms. Investigating symptom-based clusters may provide a better understanding of ME/CFS. Therefore, this study aimed to identify clusters in people with ME/CFS based on the frequency and severity of symptoms.

Methods: Members of the Dutch ME/CFS Foundation completed an online version of the DePaul Symptom Questionnaire version 2. Self-organizing maps (SOM) were used to generate symptom-based clusters using severity and frequency scores of the 79 measured symptoms. An extra dataset (n = 252) was used to assess the reproducibility of the symptom-based clusters.

Results: Data of 337 participants were analyzed (82% female; median (IQR) age: 55 (44–63) years). 45 clusters were identified, of which 13 clusters included ≥ 10 patients. Fatigue and PEM were reported across all of the symptom-based clusters, but the clusters were defined by a distinct pattern of symptom severity and frequency, as well as differences in clinical characteristics. 11% of the patients could not be classified into one of the 13 largest clusters. Applying the trained SOM to validation sample, resulted in a similar symptom pattern compared the Dutch dataset.

Conclusion: This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options.

Source: Vaes, A.W., Van Herck, M., Deng, Q. et al. Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort. J Transl Med 21, 112 (2023). https://doi.org/10.1186/s12967-023-03946-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03946-6 (Full text)

Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM.
Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells.
During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
Source: Van Booven DJ, Gamer J, Joseph A, Perez M, Zarnowski O, Pandya M, Collado F, Klimas N, Oltra E, Nathanson L. Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures. International Journal of Molecular Sciences. 2023; 24(3):2698. https://doi.org/10.3390/ijms24032698 https://www.mdpi.com/1422-0067/24/3/2698 (Full text)

ME/CFS and Post-Exertional Malaise among Patients with Long COVID

Abstract:

This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID. The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise.
The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks. Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 70.57% met criteria for ME/CFS and of those who did not report they had ME/CFS, 29.43% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report. This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms.
Source: Jason LA, Dorri JA. ME/CFS and Post-Exertional Malaise among Patients with Long COVID. Neurology International. 2023; 15(1):1-11. https://doi.org/10.3390/neurolint15010001 https://www.mdpi.com/2035-8377/15/1/1 (Full text)

The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome

Background: Fatigue is common after viral infections, including SARS-CoV-2.1 Our purpose was to report the prevalence and impact of persistent fatigue 6 months after SARS-CoV-2 infection, considering post-exertional malaise2 and criteria for chronic fatigue syndrome.3

Methods: Since March 2020, individuals tested for SARS-CoV-2 at the Geneva University Hospitals outpatient testing center benefit from remote ambulatory follow-up (COVICARE). This study included all individuals tested between March 2020 and December 2020 and whose follow-up was at 6 months or more after their test date.

Follow-up included questions about the prevalence of symptoms (yes/no) and their severity using a Likert scale (mild, moderate, or severe). Fatigue was assessed using the Eastern Cooperative Oncology Group (ECOG) scale and the Chalder fatigue scale. The Chalder fatigue scale was scored using the 4-item Likert and the bimodal scoring schemes. A score of ≥ 4 on bimodal scoring indicated severe fatigue.

The DePaul brief questionnaire was used to identify post-exertional malaise and criteria for chronic fatigue syndrome.

The Sheehan Disability Scale was used to assess functional impairment. Reduced work capacity was defined as missing days off work or having a reduced productivity on the Sheehan disability scale.

Comorbidities were considered present if pre-existing prior to SARS-CoV-2 infection. Statistical analysis included descriptive comparisons of percentages using chi-square tests and Student’s t test.

Results: Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207–398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2-negative individuals. Characteristics are presented in Table 1.

Out of SARS-CoV-2-positive participants with fatigue (n = 258), 35.3% had moderate to severe limitations on the ECOG scale, and 83.0% had a score ≥ 4 on the Chalder fatigue scale. The Chalder fatigue scale revealed a mean score of 19 out of 33, SD 5.4, and a mean score of 6.7 out of 11, SD 3.3 using bimodal scoring. After adjusting for age and sex, 47.7% of SARS-CoV-2-positive individuals with fatigue at 6 months or more had the frequency and severity criteria for post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome.

Individuals had a higher prevalence of insomnia, cognitive impairment, headaches, generalized pain, functional impairment, reduced work capacity, and decreased physical activity, after SARS-CoV-2 infection. The prevalence of these sequelae was adjusted for age and sex and was increasingly higher with severe fatigue, with post-exertional malaise, or when criteria for chronic fatigue syndrome were present (Fig. 1).

Discussion: Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity.

Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise.

Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated.

Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome. Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.

Limitations include the self-reported nature of this follow-up with individuals infected in 2020 and follow-up in 2021, lacking comparisons to individuals infected with other variants. Additionally, this study considered having received at least 2 doses as full vaccination, a concept that continues to evolve with time.

Physicians, employers, and insurance companies should address fatigue on a spectrum, accounting for the correlated functional impairment, decreased activity levels, and potentially poorer quality of life.

Source: Nehme M, Chappuis F, Kaiser L, Assal F, Guessous I. The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome. J Gen Intern Med. 2022 Nov 10:1–5. doi: 10.1007/s11606-022-07882-x. Epub ahead of print. PMID: 36357723; PMCID: PMC9648889. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648889/ (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

Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

in English, German

Background: A sizable part of post-COVID syndrome meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A doubling of cases of ME/CFS within the next years is therefore projected.

Objectives: Presentation of the current state of knowledge on ME/CFS.

Materials and methods: Unsystematic review of the literature and of own contributions in research and patient care.

Results and conclusions: ME/CFS is a neuroimmunological disease, mostly infection-induced, usually persisting throughout life. Clinically it is characterized by fatigue lasting at least 6 months and the defining core feature of exercise intolerance (post-exertional malaise, PEM). Exercise intolerance is defined as a worsening of symptoms after (even mild) everyday exertion, which usually begins after several hours or on the following day, is still noticeable at least 14 h after exertion, and often lasts for several days (up to weeks or longer). Furthermore, ME/CFS is characterized by pain, disturbances of sleep, thinking and memory, and dysregulation of the circulatory, endocrine, and immune systems.

As a separate clinical entity, ME/CFS should be distinguished from chronic fatigue, which occurs as a symptom of a range of very different diseases. The diagnosis of ME/CFS is made clinically using established international diagnostic criteria and requires careful stepwise diagnosis to exclude other diagnoses. A causal therapy for ME/CFS has not been established; the focus is on symptoms relief, treatment of the often accompanying orthostatic intolerance, and assistance with anticipatory energy management (pacing).

Source: Renz-Polster H, Scheibenbogen C. Post-COVID-Syndrom mit Fatigue und Belastungsintoleranz: Myalgische Enzephalomyelitis bzw. Chronisches Fatigue-Syndrom [Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome]. Inn Med (Heidelb). 2022 Aug;63(8):830-839. German. doi: 10.1007/s00108-022-01369-x. Epub 2022 Jul 13. PMID: 35925074. https://pubmed.ncbi.nlm.nih.gov/35925074/  https://link.springer.com/article/10.1007/s00108-022-01369-x (Full text in German)