This is the first study to examine CFS/ME patients that fulfil the ICC definition in an Australian sample. As all ICC defined patients complied with 1994 CDC definition, this study supports findings that ICC defined patients may be classified as a subgroup found within the broader category of CFS/ME . Though broad criteria may be particularly useful for the identification of potential cases among small samples, it could inadvertently select those that do not have the illness . The symptoms of chronic fatigue, post-exertional malaise, short-term memory and concentration problems reported in 1994 CDC defined CFS/ME cases are found to overlap with cases of depression . The Canadian definition however, has been shown to effectively differentiate between those with CFS/ME and depression . In another study, 96% of self-reporting cases of CFS/ME were found to comply with the 1994 CDC, compared to 77% of that complied with the Canadian definition . These findings are consistent with the findings of this study, which is based on a similar method of recruitment and case ascertainment as, 91% of self-reporting cases fulfilled the 1994 CDC definition, 60% also fulfilled the Canadian definition, and 49% fulfilled the 1994 CDC, Canadian and ICC definitions.
An important consideration is a consistent method of applying criteria . Reliance on self-reporting versus evaluation of cases by a physician can be a particular source of variability in reported cases of CFS/ME . The symptom checklist used to verify the study criteria is limited to self-reporting of symptoms present during the past 30 days, and reporting of existing physical and psychiatric diagnoses. Self-reporting however, can be a useful tool for the initial evaluation of cases of research. Like the Canadian definition, the ICC definition was devised for clinical applications. Accordingly, the International Primer was published in 2012 , to aid clinicians in their evaluation of symptoms according to the ICC definition. The availability of this tool could contribute to the selection of homogenous patient sets in research settings and help exclude other causes of illness. The current primer however, does lack specifications on how to apply the definition in a research setting. This includes quantifiable measures on the severity and frequency of symptoms, in order to be considered significant in CFS/ME and its operationalization is discussed further by Johnston et al. .
As part of recruitment however, this study screened patients for reported medical history of chronic conditions such as heart disease, diabetes, and primary psychiatric disorder, as well as conducted standard blood tests as part of routine screening of disease. While all CFS/ME patients were found to have different results from controls in some parameters, no difference was found between the 1994 CDC and ICC patient groups. If the ICC definition identifies a subgroup with a less heterogeneous clinical presentation, important differences may be found in more specific biological markers than the ones examined in this study. While basic haematological abnormalities have not been previously reported in CFS/ME in relation to FBC, ESR, CRP and electrolytes, immunological abnormalities have been increasingly documented in cases of CFS/ME. Subsequently, salient differences have been detected in immunological parameters between 1994 CDC and ICC patient subgroups. In particular, significant differences in human neutraphil antigen .
The SF-36 survey that was used to evaluate the study groups is widely recognised as a valid and reliable tool for assessment of physical and social functioning in chronic illnesses , and has previously demonstrated impairment in 1994 CDC cases of CFS/ME [35, 44, 45]. It has also been used to contrast between patients fulfilling the 1994 CDC and Canadian definitions . The comparison between 1994 CDC and ICC defined patients has been made in a US sample . ICC defined patients reported significantly greater impairment in their physical functioning, bodily pain, physical role, as well as social functioning, which is consistent with the results from the Australian sample of this study. The WHO DAS 2.0 was further found to support the findings from the SF-36. Hence, there is evidence to suggest that inclusion of more symptoms in the ICC definition may select a significantly more impaired group.
The 1994 CDC definition for CFS/ME can represent an illness that ranges from mild impairment in daily activities, to severe cases where patients are bedridden and unable to care for themselves. For many chronic illnesses, the most severe cases often present themselves to primary or secondary care and mild cases often go unreported. The characteristics of CFS/ME can be quite the opposite, as the most debilitating cases can leave patients housebound or bedridden, and often overlooked by clinicians and researchers alike. The use of broad criteria with symptoms that overlap with other conditions can also make cardinal features of CFS/ME difficult to identify.
The current study suggests that the ICC definition may identify a more severe subgroup found within traditional CFS/ME and this may be consistent across samples in different geographic locations. The I994 CDC definition is limited to a nominal list of symptoms that may only capture the basic characteristics of the illness. As the ICC definition introduces a spectrum of symptoms affecting the neurological, immune and metabolic systems, it is expected that patients experiencing these further manifestations be more debilitated.
Limitations in this study include the application of the ICC definition as further research and consistency is required on the operationalization of the criteria that is not currently found in the primer. This study relied on whether patients had experienced any of the symptoms within the past 30 days. This time period is consistent with the time period measured in the SF-36 and WHO DAS 2.0. However, introducing thresholds for severity and frequency may provide further insight on the impact of this illness. It was also found that the majority of those that also fulfilled the ICC definition were female. To investigate whether females tended to report greater symptom severity than males in this subgroup, further comparison needs to be made in a larger sample size. A larger sample would also allow for further analysis of critical symptoms. This could contribute to more accurate and homogenous patient sets for further research on the aetiology and underlying pathomechanism of the illness.
The ICC definition has suggested that this subgroup should be referred to exclusively as Myalgic Encephalomyelitis (ME) patients. This proposal however, remains controversial as the term implies inflammation of the central nervous system that is not necessarily exhibited in all cases that fulfil the criteria. The term ME alone, may be viewed as pathogen-related initiation associated with onset as seen in bacterial, viral or parasitic infection and resultant inflammation of the nervous system. However use of the term in this context may result in misleading assignation of the syndrome directly and solely to an infectious agent. This has been seen previously during the XMRV expedition [46–51]. Alternatively the identification of this illness as due to immune dysfunction following infection or other initiating event represents a paradigm in closer fit with observable clinical signs and laboratory findings. Ongoing discoveries in immune dysfunction are likely to harmonise with more accurate case definitions over time.