Original articleImpaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup?☆
Introduction
Chronic fatigue syndrome (CFS) has been labeled a “controversial illness,” with no known diagnostic markers or pathophysiology [1]. However, CFS afflicts approximately 800,000 people in the United States, approximately 80% of whom are women [2]. It is characterized by great variability in clinical presentation, including flu-like symptoms, cognitive impairment, neurological symptoms, and pain [3], [4]. CFS is frequently associated with comorbidities, ranging from other chronic illnesses with heterogeneous sets of symptoms (such as fibromyalgia and multiple chemical sensitivities) to atopic disease and psychiatric illness (e.g., depression) [1]. CFS patients experience substantial reductions in occupational, educational, and social functioning, which collectively contribute to decrements in quality of life [1]. CFS may also represent an economic burden for society (e.g., high rates of unemployment due to disability) and health care institutions [5], [6]. Several etiologies have been proposed—immunological, neuroendocrine, and autonomic—and yet no physiological mechanism has been consistently and uniquely related to CFS [7], [8], [9], [10], [11], [12], [13]. As a result, current CFS treatments are symptom-focused and relatively ineffective [14]. Improved treatment options for CFS will likely only come with a better understanding of the syndrome's underlying pathophysiology.
The present study sought to improve the understanding of CFS pathophysiology by investigating the existence of patient subgroups. It has been proposed [3], [15], [16] that CFS may have multiple causes, with a different underlying pathophysiology for each subgroup of patients. Evidence in support of this subgroup hypothesis begins with CFS diagnostic criteria [3], which are thought to define a heterogeneous population composed of several relatively homogenous subgroups. First, CFS diagnostic criteria are polythetic, allowing for patients with wide-ranging clinical presentations to receive the same diagnosis. Second, the diagnostic criteria were not derived empirically, but were developed by consensus among a panel of investigators based on anecdotal evidence. Third, CFS has no diagnostic laboratory test, but is rather a diagnosis of exclusion. Calls have been made to identify CFS subgroup markers, including recommendations from the authors of the diagnostic criteria [3].
Past attempts to identify patient subgroups have typically focused on clinical presentation without considering underlying physiology. For example, one study found that CFS patients who described a gradual onset of physical symptoms had higher rates of psychiatric illness relative to patients who reported an acute onset [15], but this finding has been difficult to replicate (e.g., Buchwald et al. [17]). Other investigations have relied on factor analysis to identify symptom clusters such as flu-like, cognitive, and neurologic symptoms [18]. In contrast to these symptom-focused approaches, Buchwald et al. [17] investigated several markers of inflammation (e.g., C-reactive protein) in attempting to describe an immune activation subgroup of CFS patients. However, because the magnitude of the associations among the inflammatory markers was small, and because absolute blood levels of inflammatory markers were of questionable clinical significance, Buchwald et al. recommended against the use of these criteria for differentiating CFS subgroups.
The present study specifically investigated the existence of an immunological subgroup of CFS patients. It has been suggested that CFS clinical presentation may implicate an immunological pathophysiology [19], [20], [21]. However, reviews of research on potential immunological abnormalities (e.g., lymphocyte count and proliferation, cytokine production, and neopterin) in CFS patients have shown the literature to be inconsistent and often contradictory [22], [23]. In the present investigation, natural killer cell activity (NKCA) was chosen as the criterion by which CFS patients were categorized into “immunological” and “nonimmunological” subgroups. NKCA is an in vitro measure of NK effector functions and is presumed to correspond to NK cells' ability, in vivo, to eliminate virally infected and cancerous somatic cells. Unlike other immunological variables, research has reliably shown NKCA to be reduced in CFS patients compared to healthy controls [22], [24], [25]. Furthermore, although CFS samples as a whole have been characterized by reduced NKCA, closer examination has demonstrated that only subgroups of CFS patients manifest with reduced NKCA (e.g., Whiteside and Friberg [26] and Levine et al. [27]).
Evidence has shown that immune dysregulation is associated with fatigue and cognitive impairment in both CFS [20], [28] and non-CFS populations [29], [30], [31] (for reviews, see Dantzer [32] and Larson and Dunn [33]). For example, an increased production of proinflammatory cytokines has been associated with a constellation of symptoms known as sickness behavior, including fatigue, cognitive impairment, and reduced activity. Reduced NKCA may contribute to enhanced cytokine production. In addition to its role in antiviral immunity, NK cells down-regulate immunological activity following microbial clearance of pathogens by eliminating antigen-presenting cells [34]. For example, animal research has shown that mice deficient in perforin (a mediator of NK effector functions) exhibit prolonged and enhanced production of the cytokine interferon-γ. Based on these reported findings, we hypothesized in this study that patients in the immunological group, characterized by reduced NKCA, would demonstrate greater fatigue, cognitive impairment, and disability than patients in the nonimmunological group.
Section snippets
Participants
CFS participants were recruited from a tertiary care clinic at the Veterans Affairs Medical Center, University of Miami (Miami, FL) and through distribution of recruitment brochures, local newspaper advertising, and internet advertising. Because of the poor recruitment of male participants, which is attributable to the low prevalence of diagnosed CFS among men relative to women and/or known gender differences in health-care-seeking behaviors, we included only female participants in this study.
Discussion
The clinical presentation associated with CFS—fatigue, flu-like symptoms, and cognitive impairment—implicates an immunological-based pathophysiology. Indeed, there are empirical findings to support this hypothesis, but, taken as a whole, the literature is both inconsistent and contradictory [22]. Therefore, the main focus of this investigation was to test the hypothesis that CFS patients can be categorized into subgroups that differ with respect to the underlying physiology and clinical
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2012, Brain, Behavior, and ImmunityCitation Excerpt :As this syndrome is a public health concern, research has attempted to better understand the physiological mechanisms by which it operates. Much of the ongoing work focuses on putative latent viral infections (Glaser and Kiecolt-Glaser, 1998; Lombardi et al., 2009) and neuroimmune mechanisms (Klimas and Koneru, 2007; Siegel et al., 2006; Tomoda et al., 2005; Torres-Harding et al., 2008; Fletcher et al., 2010) that may underlie the symptom expression and chronicity of this condition. Neuroimmune research has repeatedly implicated dysregulation in the hypothalamic pituitary adrenal (HPA) axis and “overactivation” of some aspects of the immune system as indicated by increased circulating pro-inflammatory cytokines in subgroups of patients diagnosed with CFS (Broderick et al., 2010; Brenu et al., 2011; Heim et al., 2009; Lorusso et al., 2009; Nater et al., 2008; Roberts et al., 2004).
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2011, Brain, Behavior, and ImmunityCitation Excerpt :CD25+/CD56+ and CD2−/CD56+ fractions also appeared higher in CFS but not with statistical significance. While NK cells may be greater in number we have found they display an impaired cytotoxicity (Fletcher et al., 2002; Siegel et al., 2006), a result confirmed by other groups (Vojdani and Thrasher, 2004). Indeed significantly reduced levels of intracellular perforin have been observed in CD3−/CD56+ NK and CD3+/CD8+ cytotoxic T cells in these veterans (Whistler et al., 2009).
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2010, Brain, Behavior, and ImmunityCitation Excerpt :Therefore this illness has far-reaching consequences and constitutes a significant public health concern. Evidence of chronic immune dysfunction in CFS has been reported by several groups (Klimas et al., 1990; Straus et al., 1993; Hilgers and Frank, 1994; Keller et al., 1994; Tirelli et al., 1996; Gupta et al., 1997; Patarca et al., 1997; Patarca-Montero et al., 2001; Siegel et al., 2006) though the exact nature of this dysfunction remains unclear (Maher et al., 2003). A principal avenue of investigation has been the measurement in blood of immune signals conducted by cytokines.
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This work was supported by research grant 1U01AI45940.