A systematic review and critical evaluation of the immunology of chronic fatigue syndrome

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Abstract

Objective: Immune dysfunction in patients with chronic fatigue syndrome (CFS) has been widely but inconsistently reported. Traditional reviews of the literature have produced a variety of conclusions. We present the results of the first systematic review of the subject. Methods: EMBASE, MEDLINE and PSYCHINFO databases were searched, and leading researchers in the field were contacted. Inclusion criteria were applied, and studies were then divided into groups based on the quality of their methodology. Study results were collated and described. Results: Studies ranged widely in quality. There was an inverse association between study quality and finding low levels of natural killer cells, suggesting that the association may be related to study methodology. On the other hand, reports of abnormalities in T cells and cytokine levels were not related to study quality. Conclusions: The conclusions of this systematic review differ from a recent traditional narrative review of the immunology of CFS. No consistent pattern of immunological abnormalities is identified.

Introduction

Chronic fatigue syndrome (CFS) is characterized by disabling physical and mental fatigue, lasting at least 6 months, without an apparent physical cause [1]. The aetiology of CFS is unclear, but many have suggested a role for infection, and for changes in the immune system. Papers reporting immunological changes in CFS are numerous. However, taken as a whole, the body of literature is inconsistent and, in places, contradictory. Few firm conclusions have been drawn.

What are the reasons for this? Strober has suggested several: using groups of patients with differing primary symptoms and differing duration of illness, failing to control for potential confounding factors and using different laboratory procedures when analysing samples [2].

Several reviews of the immunology of CFS have been published. Buchwald and Komaroff [3] found “evidence of diffuse immunological dysfunction… it has not been shown that immunologic findings explain… the symptomatology of CFS.” Similarly, Wessely et al. [4] concludes that “there is evidence of some abnormality of immune function, but such changes are inconsistent, nonspecific and rarely correlate with the clinical condition” and Lloyd and Klimas [5] that “no clear conclusions can be drawn from the data.” Most recently, Patarca-Montero et al. [6] have written that “CFS is associated with immune abnormalities that can potentially account for physio- and psychopathological symptomatology” and also that “assessment of immune status reveals a heterogeneity among CFS patients.”

No systematic review has been completed. The importance of systematic reviews—which can be loosely defined as reviews in which there is a methods section—is established beyond doubt if unbiased conclusions are to be reached [7], [8]. Our group has already shown that nonsystematic general reviews in the field of CFS are associated with bias, influenced by professional affiliations and country of origin of the authors [9]. The aim of this paper is a systematic review of the immunology of CFS.

Section snippets

Method

EMBASE, MEDLINE and PSYCHINFO databases were searched from 1966 to 2000 using the strategy presented in Fig. 1. Additional checks were made with key investigators and using a personal database of 3000 CFS references maintained by one of the authors in which immunological measures are coded after visual inspection (in contrast to MESH terms). Contact was made with leading researchers in the field to check for missing/unpublished studies.

Certain a priori criteria were set for inclusion in the

Results

Over 390 studies were located in the original broad literature search. However, when located many of these were only peripherally concerned with CFS, and many others had a sample size of less than 10. Fifty-eight articles met the inclusion criteria. Although one study was principally concerned with Gulf War veterans, subjects were also stated to meet criteria for CFS and hence this was included [22].

Before rating the studies, it was decided to analyse the results in three groups: those studies

Discussion

By using a variety of sources, this literature review has sought to be comprehensive. The inclusion criteria served to limit the review to papers considering subjects with CFS conforming to standard operational definitions. Analysing studies in four groups had certain disadvantages notably that papers using different methodological approaches, and with different strengths and weaknesses, were considered as having a similar importance. However, the sheer number of papers limited the ability to

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