Evidence for the Presence of Immune Dysfunction in Chronic Fatigue Syndrome

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Abstract
Chronic fatigue syndrome is a medically unexplained ail- ment characterized by new onset of fatigue accompanied by rheumatological, infectious, and neuropsychiatric symptoms. Because the ailment often begins suddenly with a flu-like pre- sentation, early pathophysiological ideas as to cause included viral infection and immune activation. When early reports identified putative immunological abnormalities in this illness, it was given the name of chronic fatigue and immune dysfunc- tion syndrome, or CFIDS. The purpose of this review is to evaluate the immunological literature to determine if strong evidence to support this no- tion exists. We collected and reviewed 239 published papers, of which only 72 fulfilled a set of criteria for use in this review. For this review, we developed the following criteria: papers had to be published in the peer review literature; patients had to be from a group with substantial fatigue lasting at least 6 months (the vast majority fulfilled either the 1988 (21) or the 1994 (13) case definition of chronic fatigue syndrome (CFS)); papers had to compare CFS patients to healthy controls; and actual data had to be shown with evidence of testing for sta- tistical significance. So, for example, when a paper reported no difference between patients and controls for some immunolog- ical variables but actual data were not included, we did not include it. Also, if a report compared patient data to normative values rather than to the study's own control group, we did not include it. The numbers of immunologically active cells and immuno- logically active substances such as cytokines reported in the literature have mushroomed in the past decade. To keep this review manageable, we are reporting scientific papers only on those variables for which either consistent or inconsistent ab- normalities were reported by more than one group. We did not review papers reporting immunological variables to be within normal limits but have listed those studies in which more than one group found such results in a table. We have chosen not to list those variables reported abnormal in only one study be- cause those results have not yet been replicated. When incon- sistent results among laboratories were found for any immu- nological variable, we reviewed the methods described in those papers in an effort to identify reasons for such discrepancies. Note: when a group published more than one paper and it was apparent that the two studies used many if not all of the patients whose data are in the second paper, we chose to include only the more recent paper or the one with the largest number of subjects. To provide several examples, Tirelli pub- lished two papers, the first with 205 subjects and the second with 265 patients (66, 67). When data from one variable ap- peared in both papers, we included data from only the latter. Our own group has published three papers using different statistical methods and making different comparisons when reviewing lymphocyte populations. Thus, we used the one pa- per that controlled for multiple comparisons (74), except in those situations where variables not included in that paper were published elsewhere. Table 1 lists those immune variables that were found to be normal in at least two studies.