Aussie Immune Study Raises Questions About Chronic Fatigue Syndrome Research Definition

The more specific requirements of the ICC however, may select patients that are less clinically diverse. This could improve detection of immunological findings in CFS/ME.       Study authors.

How much of a difference the International Consensus Criteria (or any definition) makes is a major question in chronic fatigue syndrome.Dr. Sonya Marshall-Gradisnik's team in Australia, who just celebrated the grand opening of the National Centre for Neuroimmune and Emerging Diseases at Griffith Univeristy, examines this question in a recent study. Dr. Marshall is a leading ME/CFS researcher, as well as a member of Simmaron's Scientific Advisory Board.Proponents of using a more restrictive definition such as the CCC/ICC believe that winnowing out a homogeneous group in research studies  could be the key to figuring out ME/CFS.  Once 'non-ME/CFS patients are eliminated, core factor will pop out and be quickly replicated.  It's an enticing vision.Others worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The 'wider net' approach, may have been embodied in the 'empirical definition', which grabbed a large set of 'CFS' patients, from which subsets could conceivably have been winnowed.This strategy would have the benefit of applying to a larger population (up to 4 million in the US), and might work well if the funds and will had been available. Without that commitment that  strategy runs the risk of producing almost meaningless results.A recent publication by Dr. Sonya Marshall-Gradisnik's team compares the immune functioning of ME/CFS patients meeting the International Consensus Criteria vs. those meeting the Fukuda/1994 CDC definition, giving us a start on determining the pros and cons of a more narrow vs. a broader approach to ME/CFS research.

Fukuda/1994 CDC Definition

The fact that few research papers in the last twenty years used something other than the 1994 Fukuda definition to define their participants means that virtually all the findings in ME/CFS from the natural killer cell dysfunctions to low blood volume to exercise intolerance, etc., have all been found using the Fukuda definition. By putting all researchers on the same playing field, the Fukuda definition has played an important place in the history of ME/CFS research, but its vagueness and its inability to highlight what many believe to be the key symptom in ME/CFS means it almost certainly allows several questionable subsets into research studies.

The Study

Sixty-three participants including 41 people with ME/CFS and 22 controls answered questionnaires and gave blood samples. The blood samples were assessed for immune functioning. All patients had been previously diagnosed with chronic fatigue syndrome at the National Centre for Neuroimmunology and Emerging Diseases, a top ME/CFS research lab (and soon to be clinic) led by Dr. Sonya Marshall-Gradisnik in Australia. (Dr. Marshall-Gradisnik serves on the Simmaron Research Foundation's Board).

Results

The breakdown was fascinating. Seventeen people met the Fukuda criteria but not the ICC, and 18 people met both the ICC and the Fukuda criteria. Five people -- over 10 percent -- of the ME/CFS patients met neither criteria. This was one small study, but it did suggest that a large percentage of people that doctors identify with 'chronic fatigue syndrome' may not meet the ICC, and another substantial subset may not meet either criteria. It does not bode well for a more restrictive approach to ME/CFS.

Natural Killer Cells

It was no surprise to see reduced NK cell functioning show up in both the ICC and Fukuda groups. This reduced natural killer cell functioning is believed to inhibit the ME/CFS patient’s ability to clear new infections and/or stop recurring infections. (Interestingly, reduced NK cell function was not associated with alterations in the cytotoxic factors - granzymes and perforin - that NK cells use to kill cells, as has been seen in the past. The authors suggested, however, that this might have been due to the small sample size.)

Immune Suppression Enhanced in the ICC Group

Both groups demonstrated immune suppression, but the immune suppression was significantly increased in the ICC patients. The increased prevalence of two inhibitory or suppressive immune factors in the ICC group suggested a) they were a distinct group, (b) the promise of more abnormalities showing up when a more restrictive definition was used was fulfilled and c) that their immune system was having more trouble than the Fukuda group's in becoming properly activated. Treg or T regulatory cells or 'suppressor' T-cells are rather new to the scene in ME/CFS, but this is the third study showing significant increases in these cells. That suggests they may play an important role in chronic fatigue syndrome. High levels of Treg cells could be suppressing natural killer cell functioning in ME/CFS.KIR Receptors - High levels of 'KIR' receptors on the NK cells of the ICC group (but not the CDC group) could further suppress NK cell function. The presence of two 'profoundly' inhibiting factors suggested the ICC group's immune systems were getting particularly hammered. (Increased levels of an 'activating' NK cell receptor were also found. The authors felt this resulted from an attempt to balance the 'overwhelming' inhibitory signals from the two inhibitory receptors.) (Receptors on the surface of a cell greatly influence what the cell does. NK cells that are dotted with inhibitory receptors, for instance, can be easily turned off. Conversely, NK cells with few inhibitory receptors will be difficult to turn off.) The authors suggested, but could not prove, that the ICC group carried genes that promoted a tendency towards NK inhibition.

Hitting Home - Physical Functioning Affected

One of the vital questions regarding the abnormalities in ME/CFS is how much they matter. Ironically, THE immune finding in ME/CFS, poor NK cell functioning, didn't pan out in this regard. While low NK cell functioning was associated with poorer health in the healthy controls, it didn't appear, at least in this small study, to be correlated with poorer health in the ME/CFS groups. Decreased CD39+ and altered KIR receptors were, however, 'strongly' associated with poorer health in the ICC (but not the Fukuda delineated patients). This  suggested that immune suppression was having an impact in the ICC delineated patients.

Touchy Situation Ahead

The increased  amount of immune suppression in the ICC group suggested that the ICC criteria did select a more immune-challenged set of patients and that group should be set apart for separate study. The immune findings in the Fukuda group (low NK cell functioning/increased Tregs) were nothing to sneeze at, however. Plus, the high percentage (almost 50%) of patients meeting the Fukuda criteria, but not the ICC criteria indicated that group cannot be ignored. The ten percent of people with ME/CFS that met neither criteria suggested an important subset of people who are sick, but don't meet either criteria, may be present. The fact that all the study participants were identified by ME/CFS researchers/doctors working at an ME/CFS lab suggested they were indeed ME/CFS patients. These researchers proposed that both groups should be included in studies. Since all the people that met the ICC also met the Fukuda/1994 CDC criteria, starting off with the Fukuda criteria and then examining the ICC criteria patients could achieve this.

Conclusion

"These findings are highly suggestive of a need to incorporate both the 1994 CDC and the ICC in future clinical research"Study authors

With a new research definition coming up on the docket, it was good a see a study examining a prominent candidate -- the International Consensus Criteria.The IOM contract for a clinical definition was really just a prelude to the big problem looming ahead, which is creating an appropriate research definition.Since the research definition defines what types of patients participate in a study, its use can fundamentally alter how a disorder is viewed or researched.The suppressive nature of the immune dysfunctions found in the ICC group suggested, to my mind, that they might be 'Fukuda plus' patients dogged by increased levels of immune suppression.This study gave no clear answers. It suggested that patients that meet the Fukuda criteria but not the ICC criteria are an important subset of ME/CFS, but it also suggested that segregating patients meeting the ICC criteria could help uncover more immune abnormalities.