Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study

Abstract:

Background: In the Netherlands, the prevalence of post COVID-19 condition is estimated at 12.7% at 90-150 days after SARS-CoV-2 infection. This study aimed to determine the occurrence of fatigue and other symptoms, to assess how many patients meet the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) criteria, to identify symptom-based clusters within the P4O2 COVID-19 cohort and to compare these clusters with clusters in a ME/CFS cohort.

Methods: In this multicentre, prospective, observational cohort in the Netherlands, 95 post COVID-19 patients aged 40-65 years were included. Data collection at 3-6 months after infection included demographics, medical history, questionnaires, and a medical examination. Follow-up assessments occurred 9-12 months later, where the same data were collected. Fatigue was determined with the Fatigue Severity Scale (FSS), a score of ≥ 4 means moderate to high fatigue. The frequency and severity of other symptoms and the percentage of patients that meet the ME/CFS criteria were assessed using the DePaul Symptom Questionnaire-2 (DSQ-2). A self-organizing map was used to visualize the clustering of patients based on severity and frequency of 79 symptoms. In a previous study, 337 Dutch ME/CFS patients were clustered based on their symptom scores. The symptom scores of post COVID-19 patients were applied to these clusters to examine whether the same or different clusters were found.

Results: According to the FSS, fatigue was reported by 75.9% of the patients at 3-6 months after infection and by 57.1% of the patients 9-12 months later. Post-exertional malaise, sleep disturbances, pain, and neurocognitive symptoms were also frequently reported, according to the DSQ-2. Over half of the patients (52.7%) met the Fukuda criteria for ME/CFS, while fewer patients met other ME/CFS definitions. Clustering revealed specific symptom patterns and showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort, where 2 clusters had > 10 patients.

Conclusions: This study shows persistent fatigue and diverse symptomatology in post COVID-19 patients, up to 12-18 months after SARS-CoV-2 infection. Clustering showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort.

Source: Cornelissen MEB, Bloemsma LD, Vaes AW, Baalbaki N, Deng Q, Beijers RJHCG, Noij LCE, Houweling L, Bazdar S, Spruit MA, Maitland-van der Zee AH; on behalf of the P4O2 Consortium. Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study. J Transl Med. 2024 Feb 21;22(1):191. doi: 10.1186/s12967-024-04979-1. PMID: 38383493. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-04979-1 (Full text)

The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE)

Abstract:

We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment.

However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries.

We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.

Source: Pheby DFH, Araja D, Berkis U, Brenna E, Cullinan J, de Korwin JD, Gitto L, Hughes DA, Hunter RM, Trepel D, Wang-Steverding X. The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE). Healthcare (Basel). 2020 Apr 7;8(2). pii: E88. doi: 10.3390/healthcare8020088. https://www.ncbi.nlm.nih.gov/pubmed/32272608

Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been emerging as a significant health issue worldwide. This study aimed to systemically assess the prevalence of CFS/ME in various aspects of analyses for precise assessment.

METHODS: We systematically searched prevalence of CFS/ME from public databases from 1980 to December 2018. Data were extracted according to 7 categories for analysis: study participants, gender and age of the participants, case definition, diagnostic method, publication year, and country of the study conducted. Prevalence data were collected and counted individually for studies adopted various case definitions. We analyzed and estimated prevalence rates in various angles: average prevalence, pooled prevalence and meta-analysis of all studies.

RESULTS: A total of 1291 articles were initially identified, and 45 articles (46 studies, 56 prevalence data) were selected for this study. Total 1085,976 participants were enrolled from community-based survey (540,901) and primary care sites (545,075). The total average prevalence was 1.40 ± 1.57%, pooled prevalence 0.39%, and meta-analysis 0.68% [95% CI 0.48-0.97]. The prevalence rates were varied by enrolled participants (gender, study participants, and population group), case definitions and diagnostic methods. For example, in the meta-analysis; women (1.36% [95% CI 0.48-0.97]) vs. men (0.86% [95% CI 0.48-0.97]), community-based samples (0.76% [95% CI 0.53-1.10]) vs. primary care sites (0.63% [95% CI 0.37-1.10]), adults ≥ 18 years (0.65% [95% CI 0.43-0.99]) vs. children and adolescents < 18 years (0.55% [95% CI 0.22-1.35]), CDC-1994 (0.89% [95% CI 0.60-1.33]) vs. Holmes (0.17% [95% CI 0.06-0.49]), and interviews (1.14% [95% CI 0.76-1.72]) vs. physician diagnosis (0.09% [95% CI 0.05-0.13]), respectively.

CONCLUSIONS: This study comprehensively estimated the prevalence of CFS/ME; 0.89% according to the most commonly used case definition CDC-1994, with women approximately 1.5 to 2 folds higher than men in all categories. However, we observed the prevalence rates are widely varied particularly by case definitions and diagnostic methods. An objective diagnostic tool is urgently required for rigorous assessment of the prevalence of CFS/ME.

Source: Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020 Feb 24;18(1):100. doi: 10.1186/s12967-020-02269-0. https://www.ncbi.nlm.nih.gov/pubmed/32093722

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union

Abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches.

For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

Source: Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, Krumina A, Alegre-Martin J, Efrim-Budisteanu M, Sekulic S, Pheby D, Sakkas GK, Sirbu CA, Authier FJ; European Network on ME/CFS (EUROMENE). Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLoS One. 2019 Dec 5;14(12):e0225995. doi: 10.1371/journal.pone.0225995. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225995 (Full article)

Chronic Fatigue Syndrome prevalence is grossly overestimated using Oxford criteria compared to Centers for Disease Control (Fukuda) criteria in a U.S. population study

Abstract:

BACKGROUND: Results from treatment studies using the low threshold Oxford criteria for recruitment may have been overgeneralized to patients diagnosed by more stringent CFS criteria.

PURPOSE: To compare the selectivity of Oxford and Fukuda criteria in a U.S. population.

METHODS: Fukuda (Center for Disease Control (CDC)) criteria, as operationalized with the CFS Severity Questionnaire (CFSQ), were included in the nationwide rc2004 HealthStyles survey mailed to 6,175 participants who were representative of the US 2003 Census population. The 9 questionnaire items (CFS symptoms) were crafted into proxies for Oxford criteria (mild fatigue, minimal exclusions) and Fukuda criteria (fatigue plus ≥4 of 8 ancillary criteria at moderate or severe levels with exclusions). The comparative prevalence estimates of CFS were then determined. Severity scores for fatigue were plotted against the sum of severities for the 8 ancillary criteria. The 4 quadrants of scatter diagrams assessed putative healthy controls, CFS, chronic idiopathic fatigue, and CFS-like with insufficient fatigue subjects.

RESULTS: The Oxford criteria designated CFS in 25.5% of 2,004 males and 19.9% of 1,954 females. Based on quadrant analysis, 85% of Oxford-defined cases were inappropriately classified as CFS. Fukuda criteria identified CFS in 2.3% of males and 1.8% of females.

DISCUSSION: CFS prevalence using Fukuda criteria and quadrant analysis were near the upper limits of previous epidemiology studies. The CFSQ may have utility for on-line and outpatient screening. The Oxford criteria were untenable because they inappropriately selected healthy subjects with mild fatigue and chronic idiopathic fatigue and mislabeled them as CFS.

Source: Baraniuk JN. Chronic Fatigue Syndrome prevalence is grossly overestimated using Oxford criteria compared to Centers for Disease Control (Fukuda) criteria in a U.S. population study. Fatigue. 2017;5(4):215-230. doi: 10.1080/21641846.2017.1353578. Epub 2017 Jul 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407870/ (Full article)

Can a Chronic BPPV With a History of Trauma be the Trigger of Symptoms in Vestibular Migraine, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Whiplash Associated Disorders (WAD)? A Retrospective Cohort Study

Abstract:

BACKGROUND: In patients with chronic benign paroxysmal positional vertigo (BPPV), i.e., chronic vestibular multicanalicular canalithiasis (CVMCC), abnormal signals are transmitted from diseased labyrinths via the healthy vestibular nuclei complex to their end organs. The vestibulo-thalamo-cortical reflex as proposed in vestibular migraine is just one of these reflexes. In a group of patients diagnosed with CVMCC otolith repositioning maneuvers specific for each semicircular canal (SCC) ameliorated pain and other symptoms in 90%. Increased awareness of CVMCC may reduce suffering and continuous medication.

OBJECTIVE: To evaluate if CVMCC can be the trigger of symptoms in vestibular migraine, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and whiplash associated disorders (WAD).

STUDY DESIGN: Retrospective consecutive observational cohort study.

SETTING: Ambulatory at a private Otoneurology Centre.

PATIENTS: One hundred sixty-three patients with CVMCC and a history of trauma.

INTERVENTION: Based on the symptoms (structured symptom questionnaire), the patients are post hoc sub grouped according to the criteria of the different diagnoses.

MAIN OUTCOME MEASURE: Frequency of patients with CVMCC who fulfill the criteria of the different diagnoses.

RESULTS: 98% of all patients with CVMCC fulfill the Barany Society criteria of a probable vestibular migraine; 17% fulfill the International Classification of Headache Disorders defined vestibular migraine criteria; 63% fulfill the Fukuda criteria of ME/CFS; 100% of the patients with WAD suffer from CVMCC.

CONCLUSION: This survey supports the hypothesis that CVMCC can be the trigger of symptoms in vestibular migraine, ME/CFS, and WAD. The actual diagnosis the patient receives is often in accordance with the patient’s dominant symptom.

Source: Tjell C, Iglebekk W, Borenstein P. Can a Chronic BPPV With a History of Trauma be the Trigger of Symptoms in Vestibular Migraine, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Whiplash Associated Disorders (WAD)? A Retrospective Cohort Study. Otol Neurotol. 2018 Oct 9. doi: 10.1097/MAO.0000000000002020. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30303941

Contrasting Chronic Fatigue Syndrome versus Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Much debate is transpiring regarding whether chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) are different illnesses. Several prior studies that compared the Fukuda et al. CFS criteria to the Canadian ME/CFS criteria found that the Canadian criteria identified patients with more functional impairments and greater physical, mental, and cognitive problems than those who met Fukuda et al. criteria.[3,4] These samples were located in the Chicago metropolitan area, so the results could not be generalized to other locations. In addition, past studies used a symptom questionnaire that was not specifically developed to tap the Canadian criteria.

PURPOSE: The present comparative study of CFS and ME/CFS criteria was intended to correct the methodological problems of prior studies.

METHODS: This article used data from three distinct samples to compare patients who met criteria for the ME/CFS Canadian clinical case definition [1] to those who met the Fukuda et al. CFS case definition.[2].

RESULTS: Findings indicated that fewer individuals met the Canadian criteria than the Fukuda et al. criteria. Those who met the Canadian criteria evidenced more severe symptoms and physical functioning impairment.

CONCLUSIONS: Future research should continue to compare existing case definitions and determine which criteria best select for this illness.

 

Source: Jason LA, Brown A, Evans M, Sunnquist M, Newton JL. Contrasting Chronic Fatigue Syndrome versus Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fatigue. 2013 Jun 1;1(3):168-183. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728084/ (Full article)

 

A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: The Holmes and Fukuda criteria are widely used criteria all over the world, yet a specific European study regarding chronic fatigue syndrome (CFS) patient symptomatology has not been conducted so far. This study was performed to answer the need to assess the homogeneity of a large CFS population in relationship to the Fukuda or Holmes definitions and to assess the importance of a symptom severity scale.

DESIGN: Multivariate analyses were performed to assess the symptom presentation within a fatigued population and the differences between the Fukuda and Holmes definitions compared with an excluded chronic fatigued group in a large cohort of fatigued patients.

SETTING: An outpatient tertiary care setting fatigue clinic in Brussels.

MAIN OUTCOME MEASURES: Prevalence and severity of symptoms and signs in a CFS population and in a chronic fatigued population.

SUBJECTS AND METHODS: A total of 2073 consecutive patients with major complaints of prolonged fatigue participated in this study. Multivariate analyses were performed to assess the symptom presentation and severity and the differences between the Fukuda and Holmes definitions.

RESULTS: Of the 2073 patients complaining of chronic fatigue (CF), 1578 CFS patients fulfilled the Fukuda criteria (100% of CFS group) and 951 (60.3% of the CFS group) fulfilled the Holmes criteria. Discriminant function analysis revealed that the Fukuda and Holmes definitions can be differentiated by symptom severity and prevalence. The Holmes definition was more strongly associated than the Fukuda definition with the symptoms that differentiated the CFS patients from the patients that did not comply with the CFS definitions. The inclusion of 10 additional symptoms was found to improve the sensitivity/specificity and accuracy for selection of CFS patients.

CONCLUSIONS: The CFS patients fulfilling the Holmes criteria have an increased symptom prevalence and severity of many symptoms. Patients fulfilling the Fukuda criteria were less severely affected patients which leads to an increase in clinical heterogeneity. Addition of certain symptoms and removal of others would strengthen the ability to select CFS patients.

 

Source: De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med. 2001 Sep;250(3):234-40. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2001.00890.x/full (Full article)