This study investigated the epidemiology of ME/CFS in primary care in parts of East Anglia, London and East Yorkshire in England, using three case definitions. Primary care services in the UK can be used as an adequate setting for population based studies, due to their virtually universal population coverage [26–28]. While we do not claim to have systematically sampled communities to ensure UK representativeness, these three regions between them manifest most of the community types found in England [22, 23, 25].
The overall prevalence rate, for all case definitions combined, was 0.2%. Nevertheless, the population prevalence rate may be higher than that, as some people may not consult their GPs, or do not receive a diagnosis. Most cases conformed to the CDC-1994 definition, for which the prevalence was 0.19%, while about half (prevalence 0.11%) conformed to the Canadian definition. All but one of the cases who met the Canadian definition also met the CDC-1994 criteria, which suggests that the former may represent a particular subgroup of the latter. Rates according to the ECD were much lower, suggesting this case definition does not have sufficient diagnostic sensitivity to be useful on its own and we were therefore unable to validate it. Symptom prevalence and severity of cases, as indicated by the pain and fatigue scales were greater among those conforming to the Canadian definition than among those who did not, further enhancing the proposition that these patients may represent a distinct sub-group among those conforming to the CDC-1994 criteria. We have also compared quality of life of those meeting each of these case definitions, showing those meeting the Canadian criteria presented in general poorer results .
The overall prevalence rate of 0.2% in this study, or of 0.19% when only CDC-1994 criteria was used, is in the lower range of the commonly assumed population prevalence for the UK . In general, these prevalence rates are also lower than those previously reported in primary care settings, such as 2.6% (or 0.5% when psychological morbidity was excluded) from a study carried out in the UK ; and 0.3% to 1.6% shown in studies from other countries [31–34], where the CDC-1994 was used. However, the rate we found is higher than in other studies based on case reports in the UK , Netherlands  and the US , which may have been subject to considerable under-reporting. This prevalence is similar to that of a seminal community based study carried out in the US of 0.24% , which also used a robust methodology for case detection. It is slightly lower than the prevalence found in other community based studies carried out in the US - 0.42%  and in Nigeria - 0.68% , which used similar methodologies. Studies using more inclusive diagnostic criteria have yielded prevalence rates up to ten times higher, for example 2.5% , and 1% , although potential for misclassification was higher, with some people with other fatiguing conditions perhaps being wrongly included. Bierl et al  studied CFS-like syndromes, and did not include clinical evaluation of patients.
Annual incident risks also varied among and within the three regions, with an overall risk of 0.15‰. Other estimates of incidence risk in the UK range from 0.05‰  to 0.37‰ , and in the US, 0.18‰ . Although we studied a large population, our findings, particularly for incidence estimates, should be interpreted with caution, due to the small number of cases and wide confidence intervals. It should also be noted that these are cases presenting for the first time with fatigue lasting for at least six months, but possibly following longer preceding periods of illness, due to possible delays in diagnosis; so, strictly speaking, they are not incident cases but rather new diagnoses of prevalent cases.
Possible reasons for the variation in results between studies include methodological differences, the exclusion, in our study, of potential cases which did not meet strict case definitions, under-diagnosis of cases, due to either lack of disease recognition or misconceptions about it by health professionals who may not accurately distinguish ME/CFS from other conditions presenting with chronic fatigue, or limited access to services.
Initial GP diagnoses may not always be accurate, and in our study 11% of those who had been labelled with one of the primary diagnoses were, on review, found by their GPs not to be cases, while 24% of GP-diagnosed cases did not fulfil the study case definitions. GP diagnoses alone would have generated a prevalence rate of 0.33%, reduced to 0.29% following GP case review. Reasons why GPs might not diagnose ME/CFS cases may include limited knowledge, or inability or unwillingness to recognise ME/CFS as a genuine disorder; lack of access of patients with ME/CFS to their GPs, due to symptom severity, disillusionment with health services and low expectations of finding help , or cultural reasons.
We used a robust methodology that involved the employment of specific diagnostic criteria and rigorously sequenced filter procedures before confirming cases. To maximize the identification of cases by GPs, in contrast to previous studies with primary care patients, we assessed recruited patients with unexplained chronic fatigue as well as those who had been labelled with a range of diagnoses that indicated they might be cases of ME/CFS. Failure to recognize cases was therefore much less likely in this study, except perhaps for individuals from ethnic minorities (see later), particularly as we worked with selected practices where the GPs were experienced in diagnosing and less likely to be unsympathetic to ME/CFS. While this may have compromised the representativeness of the study, we believe that working with non-engaged health professionals unwilling or unable to diagnose ME/CFS would have been more disadvantageous.
Despite the lower disease frequency we found compared to some other studies [30–34, 39–41], the consequences for health and social care are still considerable, given the disabling nature of ME/CFS and the high economic impact for patients, families and the wider society [15, 44, 45]. Moreover the use of a large study population with a relatively wide geographical distribution enhanced the study validity.
Our findings of a higher risk of ME/CFS in women in all regions confirm previous findings [14, 39, 41, 46]. The majority of our cases were reportedly white British, which contradicts previous studies that found similar or even higher prevalence rates in primary care among non-white groups [32–34, 39–41]. It may be that ME/CFS is less commonly diagnosed among ethnic minority patients in UK primary care, and this under-diagnosis may well have contributed to the relatively low prevalence rate. A corollary of this may be the report by Haines et al of a higher prevalence of severe fatigue in adolescent girls from practices in less deprived areas, and their suggestion that this could reflect consulting behaviours . Ethnicity would not, however, explain the higher rates in London, which are more likely due to consulting behaviours or disease recognition in densely populated urban areas. In addition, it is worth noting the relatively small number of cases used for inferences, particularly in London.
The cases recruited for this study had been ill for varying periods of time, but their fatigue and pain scores were still moderate to severe in most cases. Pain and fatigue scores were significantly lower in those chronically fatigued patients assessed as non-cases than in those who conformed to CDC-1994 or Canadian criteria, while the highest scores were found among those meeting this latter case definition. While symptom reporting is necessarily subjective, there was nevertheless a consistent and significant variation in the proportions of symptoms reported in these three groups. This suggests not only a distinction between ME/CFS and other chronically fatigued cases, but also that there is a distinction between ME/CFS patients who conform to the CDC-1994 alone, and those who conform also to the Canadian criteria. This is in line with the findings of Jason et al  and also reflect the stringency of the Canadian definition, in for instance requiring post-exertional fatigue. However, we have not found a higher frequency of GP diagnosis of fibromyalgia in Canadian positive cases (data not shown, P = 0.9), compared to CDC 1994. It is unclear whether cases conforming to the Canadian criteria represent the severe end of a disease spectrum, or if they represent a distinct clinical entity with distinct aetiology.
There is some evidence which indicates differences between ME/CFS and other chronically fatigued cases in relation to the type and severity of fatigue, somatic symptoms and biological abnormalities . In the absence, at present, of reliable biomarkers, the choice of the most stringent available diagnostic criteria for ME/CFS for clinical and epidemiological studies is justified for its ability to distinguish true cases from non-cases, so as to enable reliable epidemiological inferences and to ensure study validity . However, the ideal would be to sub-group research cases according to clinical and laboratory features [5, 47, 49–51] that may reflect different aetiologies and pathophysiologies. Use of the CDC-1994 definition in research is desirable as it has been widely used and has shown in our study to capture effectively nearly all cases studied. The improvement in criteria to incorporate more objective measures of severity and functional status, as suggested by Reeves , is desirable, and should reflect the true levels of limitation experienced by those with ME/CFS, to avoid any artificial inflation of prevalence statistics  and so encourage trivialization of the impact of such a severe disease on those who live with it.