Association of peripheral inflammatory markers with chronic fatigue in a population-based sample☆
Introduction
Chronic fatigue syndrome (CFS) frequently devastates the lives of its sufferers (Buchwald et al., 1996, Komaroff et al., 1996, Solomon et al., 2003, Wessely et al., 1997). Yet despite almost two decades of intensive study the condition remains without diagnostic laboratory findings or an established pathophysiology (Cho et al., 2006, Henningsen et al., 2007). This lack of etiologic clarity contributes to the stigmatization of patients and represents a primary impediment toward progress in understanding and treating the condition.
Early conceptualizations of CFS focused on the role of viral infection and subsequent abnormal immune responses (DeFreitas et al., 1991, Jones et al., 1985, Landay et al., 1991, Straus et al., 1985). Although confidence in the link between infection and CFS pathogenesis has waned over subsequent years (Wessely et al., 1998), the immune system and interrelated central nervous system stress outflow pathways such as the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis have remained active areas of investigation (Aslakson et al., 2006, Cho et al., 2006, Demitrack et al., 1991, Glaser and Kiecolt-Glaser, 1998, Lyall et al., 2003). While initial studies generally suggested immunosuppression (Lyall et al., 2003), recent years have seen increased interest in the possibility that activation of the innate immune response might contribute to symptom development in patients with CFS (Cho et al., 2006, Kerr et al., 2008, Klimas and Koneru, 2007, Lyall et al., 2003).
Several lines of evidence suggest a role for activation of innate immune pathways in the pathogenesis of CFS. Studies have reported increased plasma concentrations and in vitro stimulated production of pro-inflammatory cytokines (Gupta et al., 1999) (for a review see (Lyall et al., 2003) and increased plasma concentrations of the acute phase reactant c-reactive protein (CRP) in patients with CFS (Buchwald et al., 1997, Spence et al., 2007). More recently, increased production of the pro-inflammatory transcription molecule nuclear factor kappa beta (Maes et al., 2007), increased gene expression in pathways linked to cytokines and their receptors (Fang et al., 2006, Kerr et al., 2008) and increased prevalence of an allele in the tumor necrosis factor (TNF)-α gene associated with enhanced inflammatory activity (Carlo-Stella et al., 2006) have been reported to be associated with CFS. Moreover, chronic cytokine exposure, such as occurs during treatment with interferon-alpha, frequently leads to severe fatigue and other symptoms common in CFS (Capuron et al., 2002, Maddock et al., 2005), demonstrating that innate immune cytokines are capable of producing a CFS-like clinical picture. Consistent with these findings, a recent study indicates that a polymorphism in the promoter region of the TNF-α gene that increases inflammatory activity is associated with severity of fatigue in distressed, but medically healthy subjects (Jeanmonod et al., 2004). Conversely, the use of medications that block pro-inflammatory cytokines has been repeatedly shown to reduce fatigue and other symptoms common in CFS such as pain, in patients with autoimmune conditions (Strand and Singh, 2007, Tyring et al., 2006).
However, despite these positive findings the literature relating innate immune inflammatory processes to CFS remains mixed. A meta-analysis of studies published through 2003 found no convincing evidence for increased inflammation in the disorder, and several recent studies have also reported negative findings (Amel Kashipaz et al., 2003, Gaab et al., 2005, Lyall et al., 2003, Natelson et al., 2005, ter Wolbeek et al., 2007, Vollmer-Conna et al., 2007, Winkler et al., 2004). Consistent with this, in a previous population-based study by our group, no differences were observed in white blood cell count (WBC) or other immune measures between patients with CFS and well controls. (Mawle et al., 1997) A variety of factors may contribute to these discrepancies.
CFS is likely a heterogenous condition composed of more etiologically consistent subtypes (Aslakson et al., 2006, Janal et al., 2006, King and Jason, 2005, Nisenbaum et al., 2004, Wilson et al., 2001), only some of which may be associated with innate immune pathway activation, and clinical studies likely suffer from recruitment bias with respect to the subtypes. This is particularly likely because published studies of immune system function have evaluated patients identified through tertiary referral centers rather than through a population-based approach, so it is also possible that conflicting results reflect differences in systematic biases in the types of patients referred to each center (Wessely et al., 1997). Finally, although diagnostic criteria for CFS have been elaborated, published studies do not typically assess symptom domains with standardized measures that can be replicated across study sites, limiting the generalizability of immune findings between studies (Reeves et al., 2003).
Because immune markers in patients with CFS do not typically meet or surpass cut-offs for established disease processes, claims of immune abnormalities in CFS are always relative to a comparison group, with the result that study findings are as dependent upon the composition of these comparator groups as they are upon the identified patient population. In this regard, it is of concern that most studies include controls of convenience that are not identified through the same assessment or recruitment processes as the CFS patients, which greatly increases the risk that controls will not be epidemiologically comparable to cases. This is of direct relevance, given increasing evidence that demographic and lifestyle factors can themselves be associated with inflammatory biomarkers (Alley et al., 2006, Banks et al., 2006, McDade et al., 2006). Furthermore, much evidence suggests that fatigue and other CFS-defining symptoms (e.g., pain, sleep difficulties) are normally distributed in the population (Sha et al., 2005, Wessely, 2001). Thus, it is possible that differences in immune biomarkers that would be apparent between patients with CFS and completely healthy controls are diluted in studies in which some proportion of comparison subjects have even subsyndromal levels of fatigue or other symptoms. In support of this, Buchwald et al. found that patients with CFS had higher plasma concentrations of CRP than healthy controls, but did not differ from subjects with subsyndromal fatigue states (Buchwald et al., 1997).
Another potential confound is the unrecognized or unaccounted presence of other conditions associated with increased inflammation in either CFS patients or control subjects. For example, depression is highly comorbid with CFS (Deale and Wessely, 2000, ter Wolbeek et al., 2007, Wessely et al., 1996) and has been repeatedly reported to be associated with increases in inflammatory markers in both clinical (Cizza et al., 2008, Kling et al., 2007, Miller et al., 2005) and population-based samples (Elovainio et al., 2006, Ford and Erlinger, 2004). Similarly, undiagnosed medical conditions or the use of medications that affect immune functioning may confound findings. Finally, it is unknown whether particular CFS symptoms are more likely than others to be associated with activation of inflammatory pathways (Dantzer et al., 2008).
Using a population-based approach, the current study attempted to address these issues by examining whether CFS is associated with increased high-sensitivity CRP (hs-CRP) and white blood cell count (WBC)—as well as an inflammatory factor composed of these two peripheral immune markers—when compared to both well controls and individuals with subsyndromic levels of fatigue or other CFS-defining symptoms. We identified persons suffering with CFS, those with subsyndromic levels of fatigue and other CFS symptoms, and well controls from defined metropolitan, urban, and rural populations to enhance the generalizability of findings to the general United States population. As recommended by the International CFS Study Group (Reeves et al., 2003), we used internationally validated standardized questionnaires to diagnose CFS (Reeves et al., 2005). All participants underwent rigorous medical and psychiatric evaluations and complete review of all current medications/supplements to identify exclusionary and comorbid conditions. To evaluate whether innate immune activity was more closely associated with physical or emotional functional impairment in the entire study population, we utilized the physical component summary (PCS) and mental component summary (MCS) scores from the Medical Outcomes Short Form (SF)-36 (Ware, 2000). We utilized hs-CRP as a primary marker of innate immune activation because it reflects summed activity of important inflammatory pathways and because of its health relevance, given that even mildly elevated values of hs-CRP have been consistently associated with increased risk for many medical conditions (e.g., vascular disease, diabetes, and dementia) (Hage and Szalai, 2007, Kuo et al., 2005, Pearson et al., 2003, Pradhan et al., 2001). We also examined white blood cell count and an inflammatory index that combined hs-CRP and WBC into a single measure (Danese et al., 2008).
Section snippets
Methods
This study adhered to human experimentation guidelines of the US Department of Health and Human Services and the Helsinki Declaration. The CDC Institutional Review Board approved the study protocol. All participants were volunteers who gave informed consent.
Results
Table 1 presents demographic characteristics of the study population. We classified 96 subjects as CFS, 226 as ISF and 111 were classified as well. These groups did not differ in terms of sex, age, race or place of residence. CFS and ISF subjects were more likely than well subjects to have a BMI in the overweight or obese range, but did not differ from each other. As would be expected, CFS and ISF subjects had significantly higher scores on each of the five MFI fatigue subscales, but lower
Discussion
Results from this population-based study indicate that persons with CFS had increased markers of peripheral inflammation when compared to well controls, but had a similar inflammatory profile when compared to unwell subjects who did not meet criteria for CFS (i.e., those considered ISF). However, despite observing no differences in inflammatory markers between subjects with CFS and ISF, multivariate modeling indicated that ISF, but not CFS, remained independently associated with increases in
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.
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Please see Brief Commentary by Carmine M. Pariante in this issue.