Elsevier

Journal of Psychosomatic Research

Volume 81, February 2016, Pages 14-23
Journal of Psychosomatic Research

Chronic fatigue syndrome (CFS) symptom-based phenotypes in two clinical cohorts of adult patients in the UK and The Netherlands

https://doi.org/10.1016/j.jpsychores.2015.12.006Get rights and content

Highlights

  • We explore chronic fatigue syndrome (CFS) phenotypes in two large clinical cohorts.

  • Adults with CFS may have one of 6 symptom-based phenotypes.

  • Phenotypes were associated with sex, duration of illness, and comorbidity.

  • Polysymptomatic patients had more severe illness and more comorbidities.

  • Phenotypes in UK patients were replicated in Dutch patients.

Abstract

Objective

Studies have provided evidence of heterogeneity within chronic fatigue syndrome (CFS), but few have used data from large cohorts of CFS patients or replication samples.

Methods

29 UK secondary-care CFS services recorded the presence/absence of 12 CFS-related symptoms; 8 of these symptoms were recorded by a Dutch tertiary service. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Regression models were fitted with phenotype as outcome (in relation to age, sex, BMI, duration of illness) and exposure (in relation to comorbidities and patient-reported measures).

Results

Data were available for 7041 UK and 1392 Dutch patients. Almost all patients in both cohorts presented with post-exertional malaise, cognitive dysfunction and disturbed/unrefreshing sleep, and these 3 symptoms were excluded from LCA. In UK patients, six phenotypes emerged: ‘full’ polysymptomatic (median 8, IQR 7-9 symptoms) 32.8%; ‘pain-only’ (muscle/joint) 20.3%; ‘sore throat/painful lymph node’ 4.5%; and ‘oligosymptomatic’ (median 1, IQR 0-2 symptoms) 4.7%. Two ‘partial’ polysymptomatic phenotypes were similar to the ‘full’ phenotype, bar absence of dizziness/nausea/palpitations (21.4%) or sore throat/painful lymph nodes (16.3%). Women and patients with longer duration of illness were more likely to be polysymptomatic. Polysymptomatic patients had more severe illness and more comorbidities. LCA restricted to 5 symptoms recorded in both cohorts indicated 3 classes (polysymptomatic, oligosymptomatic, pain-only), which were replicated in Dutch data.

Conclusions

Adults with CFS may have one of 6 symptom-based phenotypes associated with sex, duration and severity of illness, and comorbidity. Future research needs to determine whether phenotypes predict treatment outcomes, and require different treatments.

Introduction

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) or, more recently, systemic exertion intolerance disease (SEID) [24], is defined as persistent or recurrent debilitating fatigue that is not lifelong, or the result of ongoing exertion, or alleviated by rest, or explained by other conditions, and which results in a substantial reduction in activity [36]. CFS imposes a huge burden on patients, carers and families [23], [34], [46]. In the UK, adults who attend NHS specialist CFS services have been ill for a median duration of 3°years, and half of those who were employed at the onset of their illness have ceased working [12]. A meta-analysis of prevalence studies based on clinically-confirmed cases in several countries indicates a prevalence of 0.76% (95% CI 0.23% to 1.29%) [28].

CFS is an illness of unknown aetiology and pathogenesis, and of varied symptomatology [43]. Heterogeneity in the symptom profile of CFS can be confusing for clinicians, fuelling debate over diagnostic criteria, and posing an obstacle to biomedical research that aims to find biomarkers of CFS [26]. Several studies have investigated heterogeneity (phenotypes) in adult [21], [22], [25], [48], [49], [55], [57] and paediatric [33] CFS patients. Despite between-study variation in the factors analysed and the methods used, these studies have demonstrated some consistency in classifying CFS phenotypes, including: a ‘polysymptomatic’ phenotype; a ‘sore throat/painful lymph node’ phenotype; phenotypes classified according to the presence/absence of musculoskeletal pain; and a dose-response effect in the number of symptoms and the overall severity of CFS. However, only one of the above studies conducted a replication analysis [2].

The relationship between CFS phenotypes and treatment outcomes remains relatively unexplored. Three studies have shown that CFS patients who present with pain symptoms have less favourable outcomes [10], [14], [30]. If symptom-based CFS phenotypes predict treatment outcomes, then simple decision-making algorithms based on symptom profiles could be used by clinicians and therapists to deliver individualised treatments.

In our study, we aimed to delineate symptom-based CFS phenotypes using data from a large clinical cohort of CFS patients from the UK, and to replicate our results in a clinical cohort of Dutch CFS patients. We aimed to investigate how these phenotypes were related to age, sex, and duration of illness, common CFS comorbidities (migraine, irritable bowel syndrome, anxiety and depression), and patient-reported measures of illness severity and quality-of-life.

Section snippets

Study population

Patient data were extracted from the CFS National Outcomes Database (NOD). The NOD is a centralized repository of pseudonymised clinical assessment and patient-reported outcome data which are routinely collected by NHS specialist CFS services across England. The NOD has been hosted by the University of Bristol since 2006, primarily for the purpose of evaluating NHS adult and paediatric CFS services. For this study, we used data from patients assessed and treated by 29 NHS services during the

UK and Dutch patient characteristics

Data were available for 7041 UK and 1392 Dutch patients. Demographic characteristics of the UK and Dutch patients were broadly similar (Table S1), although the Dutch cohort was slightly younger (mean age 37.2 (95% CI 36.6 to 37.9) years, compared to 40.5 (40.2 to 40.7) years, P < 0.001) and had a slightly higher proportion of men (25.6% compared to 22.1%, P = 0.004). Dutch patients had lower Chalder fatigue (median 25 compared to 28) and higher SF36 physical function (median 55 compared to 40,

Discussion

In the largest study of CFS patients to date, we found 6 phenotypes based on 9 common symptoms in CFS patients attending UK specialist services, and we replicated 3 phenotypes (based on 5 of these symptoms) in CFS patients attending a Dutch specialist service. It is clear from both patient cohorts that post-exertional malaise, cognitive dysfunction and disturbed/unrefreshing sleep were near universal symptoms, although this may reflect the diagnostic processes in each country. We found that

Conclusion

We have identified CFS phenotypes that are consistent with earlier studies, are replicated in two large patient cohorts, and have potential diagnostic and prognostic utility because they are based on routinely-recorded CFS-related symptoms. We have shown that, among the 8–12 symptoms listed in the diagnostic criteria for patients in our two study cohorts, post-exertional malaise, cognitive dysfunction and disturbed/unrefreshing sleep could be regarded as cardinal symptoms. We further

Competing interests

All authors have completed the Unified Competing Interest form at www.icmje.org and have no competing interests to report.

Acknowledgements

We thank the clinical leads and team members of all services participating in the UK CFS National Outcomes Database, Jan Wiborg and Lianne Vermeeren for their assistance in forming the Dutch database. This paper presents independent research funded by the NIHR (PDF-2013-06-011). The views expressed are those of the authors, and not necessarily those of the NHS, the NIHR or the Department of Health. EC is funded by an NIHR Senior Research Fellowship (SRF-2013-06-013). SN, HK and PDW did not

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