Immunological aspects of chronic fatigue syndrome

Abstract

Chronic fatigue syndrome (CFS) is a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months, in the absence of a medical diagnosis that would otherwise explain the clinical presentation. Other common symptoms include headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years. The estimated worldwide prevalence of CFS is 0.4–1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK. No physical examination signs are specific to CFS and no diagnostic tests identify this syndrome. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people. The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed. This review discusses the immunological aspects of CFS and offers an immunological hypothesis for the disease processes.

Introduction

The term “chronic fatigue syndrome” was proposed in 1988 by the United States Centres for Disease Control to describe a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms [1]. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis [2], [3]. Chronic fatigue syndrome is a diagnosis of exclusion. CFS can be diagnosed after ruling out other medical or psychiatric causes of chronic fatigue [4], [5], [6]. No clinical examination signs, no diagnostic tests are specific, no definitive treatments exist for CFS. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years [7], [8], [9].

The estimated worldwide prevalence of CFS is 0.4–1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK [4], [10]. However, a recent report pointed to the variability of CFS prevalence based on differing studies [4], [9]. Another important question is whether CFS is a homogeneous or heterogeneous disorder: various researchers have called for investigation of subgroups by features such as chronicity, immunological activity and neurobiology [9], [10], [11], [12]. This disorder does not seem to prevail in definite geographic areas and ethnic groups [8], [9], [11], but predominantly affects young adults, with a peak age of onset of between 20 and 40 years, and women, with a female to male ratio of 6:1. Mean illness duration ranges from 3 to 9 years [4], [11], [12]. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people [13], [14], [15], [16], [17], [18], [19], [20]. Heterogeneity within patient groups diagnosed as having CFS suggests multiple contributing factors to the disorder Fig. 1) [4], [6], [9], [11], [18], [20], [21], [22], [23], [24], [25]. Further epidemiological studies and differing research approaches will contribute to evaluating the real incidence of the pathology. The results of an Australian study, for example, showed that people affected by bacterial and viral infections have a relatively uniform post infective syndrome that persists over six months in a minority of patients (12%) with CFS features [3], [16], [19], [26]. Evidence of enteroviruses infection persistence was founded in CFS patients [13], [14], [15], [19], [27]. These findings are in agreement with a genetic basis of the response by subjects with CFS syndrome to an infectious agent [5], [13], [14], [16], [17], [18], [25].