Statement of principal findings

Our study has revealed three main features of long-term patterns in health care resource use before and after a diagnosis of CFS/ME: 1) adults and children diagnosed with CFS/ME have greater health care needs than the rest of the population for at least ten years before the diagnosis; 2) from this higher baseline, there were steep increases in use of health care resources 2–4 years before diagnosis in adults and 1–2 years before diagnosis in children; and 3) a steep drop in resource use immediately after diagnosis was followed by sustained higher levels of health care resource use for at least ten years after diagnosis. These patterns were broadly similar in women and men, and in social strata defined by IMD quintiles, and were also seen in rates of symptoms generally and fatigue symptoms specifically.

The second of these three features was not unexpected. We had hypothesised that health care resource use would increase from around the time of patient-reported onset of illness, and the dramatic peaks in health care resource use and symptoms are consistent with CFS/ME being defined clinically as a disease of new or distinct onset. However, the higher levels of health needs and symptoms predating diagnosis by up to 15 years is a somewhat unexpected finding. It conflicts with patients reporting that they were fit and well prior to the onset of their illness [11, 12] (albeit in small qualitative studies), and it raises interesting questions about the natural history of CFS/ME.

Our study in relation to other studies

In relation to onset of illness, seven case definitions for CFS/ME have been used in clinical practice and research since the first was published in 1988, and these definitions have differed mainly in the minimum duration of fatigue and the type and number of additional symptoms [13]. That the fatigue must be of new or distinct onset was a feature of the original CDC case definition [14], and was also part of the Fukuda [15], Oxford [16], and the (original) Canadian [17] case definition. The Canadian criteria and its subsequent revision allowed for a gradual onset, but recognised that onset was typically distinct [18]. The recently-introduced US Institute of Medicine criteria for Systemic Exercise Intolerance Disease (SEID) require that the fatigue be “of new or definite onset (not lifelong)” [19], as do current UK National Institute of Health and Care Excellence (NICE) clinical guidelines [20].

The distinct peak in health care resource use that we observed matches the duration of illness reported to clinicians by patients when first assessed by specialist CFS/ME services in England. For patients assessed during the period 2004–2014, the median (IQR) duration of illness for adult patients was 3 (1–8) years, and for adolescent patients (who comprise the majority of child patients) it was 1.5 (1 to 2) years [1]. The upper and lower bounds of these IQR encompass the steep upward slope in health care resource use in each patient group, i.e. the rapid increase in health care needs is consistent with patients’ (or parents’) self-report of the time since onset.

However, the sustained higher use of health care resources and numbers of symptoms predating this onset is inconsistent with patients’ (or parents’) recollections that they (or their child) had been healthy prior to the onset of CFS/ME [11, 12], and conflicts somewhat with case definitions worded to exclude fatigue that is lifelong or not of new onset. There are several possible explanations for this discrepancy.

Firstly, people may simply have had CFS/ME for a very long time. The previously quoted durations of illness (3 years for adults, 18 months for children) were self-reported, and people with CFS/ME may be under-estimating the length of time for which they have been ill. Also, these are patients who access specialist services, who will not include all patients with CFS/ME. CFS/ME may begin as a mild form which develops quite suddenly into more severe CFS/ME, thereby setting the patient on a pathway to diagnosis. Patients’ (and parents’) recall of their health status prior to the onset of more severe symptoms could be distorted by the debilitating nature of moderate to severe CFS/ME, leading them to report having been healthy. This is particularly plausible if the milder form of CFS/ME had not prevented them from being in full-time employment or had not led to notable absences from school or college. We know that adults often persevere in employment whilst coping with the symptoms of CFS/ME for years before obtaining a diagnosis [2], and an active case finding study in three secondary schools in England led to 5% (23/461) of children whose attendance was below 80% being diagnosed with CFS/ME, giving a CFS/ME prevalence of 1% (28/2855) in the three schools in the study [21]. Also, CFS/ME is accompanied by comorbidities including depression, anxiety, chronic pain, migraine and irritable bowel disease [1], which can mask CFS/ME as the primary disorder.

Secondly, it is possible that people who develop CFS/ME have pre-existing risk factors which lead to higher rates of health care resource use. Presentation for other illnesses would be consistent with a subsequent diagnosis of CFS/ME if patients were generally more susceptible to illness, e.g. immunologically or if patients with CFS/ME have different health care seeking behaviour. A small case–control study in England reported higher GP consultation rates over three 5-year periods before a diagnosis of CFS/ME, as we observed in our study [22]. The consultations were for a wide range of symptoms, and the authors concluded that behaviour traits such as disease conviction and somatic concern could not be discounted as aetiological factors. Finally, it is possible that patients who present repeatedly and regularly to primary care are more likely to be given a diagnosis of CFS/ME by their GP.

Relative rates of health care resource use and symptoms 6–10 years after diagnosis were not substantially different from rate ratios 6–10 years before diagnosis, except perhaps for lower relative rates of diagnostic tests and (in child patients) fatigue symptoms, and higher relative rates of prescriptions and referrals post-diagnosis. The overall patterns in our study were similar to those observed in a study of fibromyalgia using data from the General Practice Research Database (GPRD, the precursor to CPRD) [23]. We are unable to determine from our data whether the type of health care resource use by patients changes following diagnosis, and we do not know how many patients in our study received specialist treatment. Receiving a diagnosis may change health care resource use, because patients have an identifiable illness which explains the fatigue and symptoms that they have been experiencing and GPs may be able to provide specific advice. Adult patients in England have access to approximately 50 NHS specialist services, many of which were established under the CFS/ME Service Investment Programme (2004–2006) [24]. These services follow NICE guidance, including specific guidelines for diagnosis, specialist care, and ongoing management, with an overall patient-centred approach to treatment [20]. Although outcomes up to 20 months after treatment are favourable for some patients [25], long-term treatment outcomes for these services have not been reported. Children have better prognosis than adults [26], but specialist service provision for is much less comprehensive, with one large paediatric service in the south west of England, and patchy or non-existent provision elsewhere in the UK.

Strengths and limitations

The main strength of our study is that it is based on a large sample from a cohort of approximately four million patients registered with a GP, representing approximately 7% of the population in the UK [5]. Patients have a median of 9.4 years (IQR 3.4-13.9) of data [5], which gives us some (but not absolute) confidence in classifying diagnoses as ‘new’ if the patient’s medical record has no previously recorded diagnoses. Two limitations of our study are that we do not know how many cases of CFS/ME in the population are undiagnosed or misdiagnosed, or what proportion of CFS/ME cases in our study were correctly diagnosed. Although knowledge and awareness of CFS/ME in primary care has improved over the past decade [27], some GPs still lack confidence in diagnosing CFS/ME [28]. This is consistent with a relatively high rate of misdiagnosis by GPs when referring to specialist services [29, 30]. The estimated incidence of adult CFS/ME diagnoses in CPRD data in the period 2008–2010 was broadly consistent with incidence estimated from data obtained directly from NHS specialist CFS/ME services in 2009, which gives some reassurance that CFS/ME diagnoses recorded by GPs towards the end of the period covered by our study were made or confirmed by a specialist CFS/ME service [7]. However, CFS/ME diagnoses in CPRD data have yet to be validated through linkage or other means.

Two other potential limitations of our study were that people who contributed the longest durations of pre- and post-diagnosis data may not have been representative of CFS/ME patients and healthy controls, and that biases in rate ratios could be introduced at the extremes of follow-up if there were differential losses between the case–control pairs. However, there were no differential losses by age, sex and IMD quintile, and sensitivity analyses restricted to patients who had either 10 years of pre-diagnosis or 10 years of post-diagnosis data yielded rate ratios which were similar to those in our main analysis.

Unanswered questions and future research

The extent to which the elevated health care needs of adults and children who were subsequently diagnosed with CFS/ME reflect long-term undiagnosed illness requires further investigation. Ideally this would be accomplished by means of a large long-term prospective cohort study with deep phenotyping of participants, including repeated measurements of symptoms, biological markers, psychological states, and objective measures of health and function. The sample size for such studies could be reduced by following patients who have an acute infectious illness, given that CFS/ME will be triggered in a fairly constant proportion of patients [31]. However, these patients will not represent all patients who develop CFS/ME if the illness is triggered by other events. Electronic primary care records can be used to investigate whether specific illnesses occur more frequently in patients who are subsequently diagnosed with CFS/ME [32], and to investigate what the overall higher rates of health care resource use actually represent, in terms of specific tests, prescriptions, and referrals. With regard to post-diagnosis health care resource use, cohort studies are needed to quantify long-term treatment outcomes among patients who are treated by specialist CFS/ME services after diagnosis. Qualitative methods could be used to investigate how health care needs before and after diagnosis relate to patients’ health status and quality of life.