Unsupervised cluster analysis reveals distinct subtypes of ME/CFS patients based on peak oxygen consumption and SF-36 scores

Abstract:

Purpose: Myalgic encephalomyelitis, commonly referred to as chronic fatigue syndrome (ME/CFS), is a severe, disabling chronic disease and an objective assessment of prognosis is crucial to evaluate the efficacy of future drugs. Attempts are ongoing to find a biomarker to objectively assess the health status of (ME/CFS), patients. This study therefore aims to demonstrate that oxygen consumption is a biomarker of ME/CFS provides a method to classify patients diagnosed with ME/CFS based on their responses to the Short Form-36 (SF-36) questionnaire, which can predict oxygen consumption using cardiopulmonary exercise testing (CPET).

Methods: Two datasets were used in the study. The first contained SF-36 responses from 2,347 validated records of ME/CFS diagnosed participants, and an unsupervised machine learning model was developed to cluster the data. The second dataset was used as a validation set and included the cardiopulmonary exercise test (CPET) results of 239 participants diagnosed with ME/CFS. Participants from this dataset were grouped by peak oxygen consumption according to Weber’s classification. The SF-36 questionnaire was correctly completed by only 92 patients, who were clustered using the machine learning model. Two categorical variables were then entered into a contingency table: the cluster with values {0,1} and Weber classification {A, B, C, D} were assigned. Finally, the Chi-square test of independence was used to assess the statistical significance of the relationship between the two parameters.

Findings: The results indicate that the Weber classification is directly linked to the score on the SF-36 questionnaire. Furthermore, the 36-response matrix in the machine learning model was shown to give more reliable results than the subscale matrix (p – value < 0.05) for classifying patients with ME/CFS.

Implications: Low oxygen consumption on CPET can be considered a biomarker in patients with ME/CFS. Our analysis showed a close relationship between the cluster based on their SF-36 questionnaire score and the Weber classification, which was based on peak oxygen consumption during CPET. The dataset for the training model comprised raw responses from the SF-36 questionnaire, which is proven to better preserve the original information, thus improving the quality of the model.

Source: Lacasa M, Launois P, Prados F, Alegre J, Casas-Roma J. Unsupervised cluster analysis reveals distinct subtypes of ME/CFS patients based on peak oxygen consumption and SF-36 scores. Clin Ther. 2023 Oct 4:S0149-2918(23)00352-1. doi: 10.1016/j.clinthera.2023.09.007. Epub ahead of print. PMID: 37802746. https://www.clinicaltherapeutics.com/article/S0149-2918(23)00352-1/fulltext (Full text)

HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia (FM) are chronic diseases with poorly understood pathophysiology and diagnosis based on clinical assessment of unspecific symptoms. The recent post-COVID-19 condition, which shares similarities with ME/CFS and FM, has raised concerns about viral-induced transcriptome changes in post-viral syndromes. Viral infections, and other types of stress, are known to unleash human endogenous retroviruses (HERV) repression that if maintained could lead to symptom chronicity. This study evaluated this possibility for ME/CFS and FM on a selected cohort of female patients complying with diagnosis criteria for ME/CFS, FM, or both, and matched healthy controls (n=43).

The results show specific HERV fingerprints for each disease, confirming biological differences between ME/CFS and FM. Unexpectedly, HERV profiles segregated patients that met both ME/CFS and FM clinical criteria from patients complying only with ME or FM criteria, while clearly differentiating patients from healthy subjects, supporting that the highly prevalent comorbidity condition must constitute a different nosological entity.

Moreover, HERV profiles exposed significant quantitative differences within the ME/CFS group that correlated with differences in immune gene expression and patient symptomatology, supporting ME/CFS patient subtyping and confirming immunological disturbances in this disease. Pending issues include validation of HERV profiles as disease biomarkers of post-viral syndromes and understanding the role of HERV during infection and beyond.

Source: Karen Gimenez-Orenga, Eva Martin-Martinez, Lubov Nathanson, Elisa Oltra. HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria. bioRxiv 2023.10.05.561025; doi: https://doi.org/10.1101/2023.10.05.561025 https://www.biorxiv.org/content/10.1101/2023.10.05.561025v1 (Full text available as PDF file)

 

Identifying, synthesising and appraising existing evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome and pregnancy: a mixed-methods systematic review

Abstract

Objectives: To identify, synthesise and appraise evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and pregnancy.

Design: Mixed-methods systematic review, using convergent segregated design.

Data sources: MEDLINE, EMBASE, Scopus, PsycINFO, CINAHL, MedRxiv, PROSPERO and grey literature sources through 6 August 2023.

Eligibility criteria: We included original research studies, expert opinion and grey literature reporting on ME/CFS and pregnancy/post partum (up to 2 years), risk of pregnancy outcomes with ME/CFS or experiences during pregnancy for mother, partner or health and social care professionals following ME/CFS during pregnancy, all where the evidence was relevant to a confirmed ME/CFS diagnosis prior to pregnancy.

Data extraction and synthesis: Three independent reviewers completed all screening, data extraction and quality assessment. Risk of bias was assessed using the mixed-methods appraisal tool V.2018. Qualitative and quantitative literature was analysed separately using thematic and descriptive syntheses. Findings were integrated through configuration.

Results: Searches identified 3675 articles, 16 met the inclusion criteria: 4 quantitative (1 grey), 11 qualitative (9 grey) and 1 grey mixed-methods study. Of the four quantitative studies that reported on ME/CFS severity during pregnancy, two suggested pregnancy negatively impacted on ME/CFS, one found most women had no change in ME/CFS symptoms and one found ME/CFS improved; this difference in symptom severity across studies was supported by the qualitative evidence. The qualitative literature also highlighted the importance of individualised care throughout pregnancy and birth, and the need for additional support during family planning, pregnancy and with childcare. Only one quantitative study reported on pregnancy outcomes, finding decreased vaginal births and higher rates of spontaneous abortions and developmental and learning delays associated with pregnancies in those with ME/CFS.

Conclusions: Current evidence on ME/CFS in pregnancy is limited and findings inconclusive. More high-quality research is urgently needed to support the development of evidence-based guidelines on ME/CFS and pregnancy.

Source: Slack E, Pears KA, Rankin J, Newton JL, Pearce M. Identifying, synthesising and appraising existing evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome and pregnancy: a mixed-methods systematic review. BMJ Open. 2023 Oct 5;13(10):e070366. doi: 10.1136/bmjopen-2022-070366. PMID: 37798026. https://bmjopen.bmj.com/content/13/10/e070366 (Full text)

Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic neurologic disease often preceded by infection. There has been increased interest in ME/CFS recently because of its significant overlap with the post-COVID syndrome (long COVID or post-acute sequelae of COVID), with several studies estimating that half of patients with post-COVID syndrome fulfill ME/CFS criteria. Our concise review describes a generalist approach to ME/CFS, including diagnosis, evaluation, and management strategies.

Source: Grach SL, Seltzer J, Chon TY, Ganesh R. Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mayo Clin Proc. 2023 Oct;98(10):1544-1551. doi: 10.1016/j.mayocp.2023.07.032. PMID: 37793728. https://www.mayoclinicproceedings.org/article/S0025-6196(23)00402-0/fulltext (Full text)

Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19

Abstract:

Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC.

In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells.

IFN-g emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-g post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.

Source: Jie Sun, Chaofan Li, Wei Qian, Xiaoqin Wei. Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19. bioRxiv 2023.10.03.560739; doi: https://doi.org/10.1101/2023.10.03.560739 https://www.biorxiv.org/content/10.1101/2023.10.03.560739v1

What Role Does Microthrombosis Play in Long COVID?

Abstract:

Soon after the outbreak of coronavirus disease 2019 (COVID-19), unexplained sustained fatigue, cognitive disturbance, and muscle ache/weakness were reported in patients who had recovered from acute COVID-19 infection. This abnormal condition has been recognized as “long COVID (postacute sequelae of COVID-19 [PASC])” with a prevalence estimated to be from 10 to 20% of convalescent patients. Although the pathophysiology of PASC has been studied, the exact mechanism remains obscure.

Microclots in circulation can represent one of the possible causes of PASC. Although hypercoagulability and thrombosis are critical mechanisms of acute COVID-19, recent studies have reported that thromboinflammation continues in some patients, even after the virus has cleared. Viral spike proteins and RNA can be detected months after patients have recovered, findings that may be responsible for persistent thromboinflammation and the development of microclots. Despite this theory, long-term results of anticoagulation, antiplatelet therapy, and vascular endothelial protection are inconsistent, and could not always show beneficial treatment effects.

In summary, PASC reflects a heterogeneous condition, and microclots cannot explain all the presenting symptoms. After clarification of the pathomechanisms of each symptom, a symptom- or biomarker-based stratified approach should be considered for future studies.

Source: Iba T, Connors JM, Levy JH. What Role Does Microthrombosis Play in Long COVID? Semin Thromb Hemost. 2023 Sep 25. doi: 10.1055/s-0043-1774795. Epub ahead of print. PMID: 37748518. https://pubmed.ncbi.nlm.nih.gov/37748518/

How methodological pitfalls have created widespread misunderstanding about long COVID

Key messages:

  • The existing epidemiological research on long COVID has suffered from overly broad case definitions and a striking absence of control groups, which have led to distortion of risk.

  • The unintended consequences of this may include, but are not limited to, increased societal anxiety and healthcare spending, a failure to diagnose other treatable conditions misdiagnosed as long COVID and diversion of funds and attention from those who truly suffer from chronic conditions secondary to COVID-19.

  • Future research should include properly matched control groups, sufficient follow-up time after infection and internationally-established diagnostic or inclusion and exclusion criteria.

Source: Høeg TB, Ladhani S, Prasad V. How methodological pitfalls have created widespread misunderstanding about long COVID. BMJ Evid Based Med. 2023 Sep 25:bmjebm-2023-112338. doi: 10.1136/bmjebm-2023-112338. Epub ahead of print. PMID: 37748921. https://ebm.bmj.com/content/early/2023/08/10/bmjebm-2023-112338 (Full text)

Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review

Abstract:

Introduction: SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has brought a conglomerate of novel chronic disabling conditions described as ‘Long COVID/Post-COVID-19 Syndrome’. Recent evidence suggests that the multifaceted nature of this syndrome results in both pulmonary and extrapulmonary sequelae, chronic dyspnoea, persistent fatigue, and cognitive dysfunction being the most common, debilitating symptoms. Several mechanisms engender or exacerbate cognitive impairment, including central nervous system (CNS) and extra-CNS causes, although the exact mechanism remains unclear. Both hospitalized and non-hospitalized patients may suffer varying degrees of cognitive impairment, ranging from fatigue and brain fog to prolonged deficits in memory and attention, detrimental to the quality-of-life years post-recovery. The aim of this review is to understand the underlying mechanisms, associations, and attempts for prevention with early intervention of long-term cognitive impairment post-COVID-19.

Methodology: A systematic search was conducted through multiple databases such as Medline, National Library of Medicine, Ovid, Scopus database to retrieve all the articles on the long term sequalae of cognitive dysfunction after Sars-Cov2 infection. The inclusion criteria included all articles pertinent to this specific topic and exclusion criteria subtracted studies pertaining to other aetiologies of cognitive dysfunction. This search was carefully screened for duplicates and the relevant information was extracted and analysed.

Results/discussion: To date, the exact pathogenesis, and underlying mechanisms behind cognitive dysfunction in COVID-19, remain unclear, hindering the development of adequate management strategies. However, the proposed mechanisms suggested by various studies include direct damage to the blood-brain barrier, systemic inflammation, prolonged hypoxia, and extended intensive care admissions. However, no clear-cut guidelines for management are apparent.

Conclusion: This review of the COVID-19 pandemic has elucidated a new global challenge which is affecting individuals’ quality of life by inducing long-term impaired cognitive function. We have found that comprehensive evaluations and interventions are crucial to address the cognitive sequelae in all COVID-19 patients, especially in patients with pre-existing cognitive impairment. Nevertheless, the authors recommend further research for the development of relevant, timely neurocognitive assessments and treatment plans.

Source: Shariff, Sanobar; Uwishema, Olivier; Mizero, Jocelyn; Devi Thambi, Vimala; Nazir, Abubakar; Mahmoud, Ashraf; Kaushik, Ikshwaki; Khayat, Saadeddine; Yusif Maigoro, Abdulkadir; Awde, Sara; Al Maaz, Zeina; Alwan, Iktimal; Hijazi, Mahdi; Wellington, Jack MSc (LSHTM) FGMS; Soojin, Lee. Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review. Annals of Medicine & Surgery ():10.1097/MS9.0000000000001265, September 8, 2023. | DOI: 10.1097/MS9.0000000000001265 https://journals.lww.com/annals-of-medicine-and-surgery/abstract/9900/long_term_cognitive_dysfunction_after_the_covid_19.1011.aspx

Prevalence of musculoskeletal pain as a long-covid symptom after hospitalisation in covid-19 survivors

Abstract:

Background and aims: Up to 60% of COVID-19 survivors develop long-COVID symptomatology with 90 different manifestations. The aim of this large cohort study was to study the prevalence of persistent musculoskeletal pain as a long-COVID symptom in COVID-19 survivors.
Methods: This cross-sectional exploratory study was based on responses to pain-related questionnaires from a national survey including data from 1) 4.833 previously hospitalised patients with a confirmed SARS-CoV-2 infection and from 2) a population of 132.427 non-hospitalised SARS-CoV-2 infected persons. Time from confirmed infection to response was 8-30 months. The questionnaire was designed to focus specifically on the type of post-COVID persistent pain, pain intensities, and quality of life.
Results: Data from 1.000 randomly selected previously hospitalised (51.2% males; 60.4±15.2 years; 85.6±18.5 kg) and 1.000 randomly selected non-hospitalised COVID-19 survivors (43.5% males; 50.4±15.9 years; 79.2±16.6 kg) were included. Long-COVID pain symptoms were more prevalent within the hospital group (38.8% vs. 12.7%, p<0.001). When analysing specifically for de novo musculoskeletal pain, the prevalence was likewise highest in the hospital group (20% vs. 4.2%, p<0.001). A higher proportion (p<0.001) of previously hospitalised survivors (20%) reported presence of widespread pain when compared with non-hospitalised patients (4.2%). Long-COVID pain intensities were not different between groups (p<0.329).
Conclusions: This study showed that long-COVID musculoskeletal pain was more prevalent in the hospital group compared to a non-hospitalised group. The high prevalence of long-COVID musculoskeletal and widespread pain symptoms following SARS-CoV-2 infection highlights the need of attention to this new group of pain patients.
Source: Ebbesen, B. D., Giordano, R., Varol, U., Fernández-de-Las-Peñas, C., Rasmussen, B. S., Nielsen, H., Schiøttz-Christensen, B., Lykke Petersen, P., Castaldo, M., & Arendt-Nielsen, L. (2023). Prevalence of musculoskeletal pain as a long-covid symptom after hospitalisation in covid-19 survivors. Abstract from 13th Congress of the European Pain Federation EFIC, Budapest, Hungary. https://vbn.aau.dk/en/publications/prevalence-of-musculoskeletal-pain-as-a-long-covid-symptom-after-

Autonomic dysregulation in long-term patients suffering from Post-COVID-19 Syndrome assessed by heart rate variability

Abstract:

Post-COVID-19 Syndrome (PCS) is a condition with multiple symptoms partly related to dysregulation of the autonomic nerve system. Assessment of heart rate variability (HRV) using 24 h Holter-ECG may serve as a surrogate to characterize cardiac autonomic activity. A prospective study including 103 PCS patients (time after infection = 252 days, age = 49.0 ± 11.3 years, 45.7% women) was performed and patients underwent detailed clinical screening, cardiopulmonary exercise testing, and 24 h Holter monitoring.

Data of PCS patients was compared to 103 CAD patients and a healthy control group (n = 90). After correction for age and sex, frequency-related variables differed in PCS patients compared to controls including LF/HFpower, LF/HFnu, and LF/HF ratio (24 h; p ≤ 0.001). By contrast, these variables were largely comparable between PCS and CAD patients, while sympathetic activation was highest in PCS patients during the 24 h period.

Overall, PCS patients showed disturbed diurnal adjustment of HRV, with impaired parasympathetic activity at night. Patients hospitalized during acute infection showed an even more pronounced overactivation of sympathetic activity compared to patients who underwent ambulant care.

Our data demonstrate persistent HRV alterations in PCS patients with long-term symptom duration, suggesting a sustained impairment of sympathovagal balance. Moreover, sympathetic overstimulation and diminished parasympathetic response in long-term PCS patients are comparable to findings in CAD patients. Whether HRV variables have a prognostic value in PCS and/or might serve as biomarkers indicating a successful interventional approach warrants further longitudinal studies.

Source: Mooren FC, Böckelmann I, Waranski M, Kotewitsch M, Teschler M, Schäfer H, Schmitz B. Autonomic dysregulation in long-term patients suffering from Post-COVID-19 Syndrome assessed by heart rate variability. Sci Rep. 2023 Sep 22;13(1):15814. doi: 10.1038/s41598-023-42615-y. PMID: 37739977; PMCID: PMC10516975. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516975/ (Full text)