In a community sample, higher plasma CRP concentration predicted higher fatigue level five years later independently of a series of risk factors such as BMI, depressive symptoms, sleep quality, pain, and physical activity. To our knowledge, this is the first study to demonstrate a prospective association between a marker of systemic inflammation and fatigue in a general population. In addition, among participants without comorbid medical disorders, the association between CRP and fatigue was significant, demonstrating that the prospective influence of CRP on fatigue cannot be explained simply by the presence or development of comorbid medical disorders. Moreover, fatigue was predicted by a persistent, as opposed to a transient, elevation of CRP. Lastly, the nature of the association between CRP and fatigue seems bidirectional as higher fatigue level at baseline also independently predicted higher CRP concentration at follow-up five years later. Interestingly, the latter relationship was partly mediated by physical activity level, whereas the prospective effect of CRP on fatigue was neither mediated by physical activity nor any of the following variables including BMI, depressive symptoms, sleep quality, and pain.
Although an association between systemic inflammation and fatigue has been reported in cancer survivors (42
), the implications of these data for non-medical community sample is unknown (see Miller et al (44
) and Schubert et al (45
) for a review) due to the confounding influence of cancer diagnosis and related treatments. Among persons with chronic fatigue syndrome as compared to controls, overproduction (15
), reduced production (25
), and no difference (21
) of proinflammatory cytokines have been reported, with similar conflicting results in patients with multiple sclerosis (26
). In a correlational study of 40 healthy young adults, no association of fatigue with TNF-α or CRP was found although this could have been due to limited statistical power (46
Derived from a community-based prospective study, the current data overcome the limitations of prior studies in humans and translate evidence generated in animals that systemic inflammation induces fatigue-like behaviors. The following features further strengthen the current findings. First, the possibility of selection bias or information bias was less likely than in previous studies, given that the study sample was randomly chosen from the community and the exposure variable was an objective biological measure. Second, as noted above, the association between CRP and fatigue was independent of a series of confounding variables such as obesity, depression, sleep quality, pain, and physical activity. Third, given that the findings were generated in community-dwelling adults including those without medical comorbidity, it does not appear fatigue is simply a byproduct of medical disorders and related inflammation. Fourth, there was two-fold evidence of a dose-response relationship between CRP and fatigue: higher CRP levels were linearly associated with higher fatigue levels; and persistently elevated, but not transiently elevated, CRP concentration predicted fatigue.
The mechanisms that drive increases of inflammation and symptoms of fatigue in a healthy community dwelling sample are unknown. Experimental studies suggest that physical and psychological stressors activate the peripheral immune system, mounting an inflammatory response with the release of proinflammatory cytokines and acute phase proteins (`signal generated') (47
). These peripheral inflammatory signals are then transduced to the brain through specific pathways across the blood-brain barrier such as vagal nerve afference and IL-1 receptors located on endothelial cells of brain venules (`signal received'), and the brain finally may produce sickness behaviors including fatigue (`response to signal') (48
). While extensive research efforts have accumulated mechanistic evidence on the `generation' and `reception' of inflammatory signals (47
), the specific mechanisms of how the brain `responds' to these signals producing the symptom of fatigue are still to be elucidated. To date, basal ganglia hypermetabolism - hence altered dopaminergic activities - has been related to physical fatigue and anterior cingulate activation to mental fatigue during interferon-α therapy of patients with malignant melanoma (13
). Interestingly, although systemic inflammation has been also linked to depressed mood, the nature and mechanism of this link seem to be distinct from the association between inflammation and fatigue. Among interferon-α treated patients, while fatigue has been related to alterations in dopamine neurotransmission in the basal ganglia, depressed mood has been linked to alterations in corticotropin-releasing hormone pathways and serotonin metabolism (50
). Furthermore, fatigue occurs earlier in interferon-α therapy and responds less to antidepressant treatment (12
), supporting distinct mechanisms for depression and fatigue.
Persistent inflammation may be a particularly important factor involved with fatigue. Interestingly, data from the CARDIA study reported elsewhere suggest that this persistent inflammation may be driven by genetic predisposition (CRP promoter gene polymorphisms) (52
) and early life stress (low childhood socioeconomic status and harsh early family environment) (53
). Furthermore, we have previously demonstrated that cytokine gene polymorphisms, which are thought to be associated with persistent elevations of inflammatory markers, correlate with fatigue in breast cancer survivors (54
As to the association in which higher fatigue level leads to higher CRP concentration, physical activity level was shown to partly mediate it. Fatigued individuals may be less physically active, and low physical activity may lead to increased CRP level. Clinical trials have indeed shown physical exercise decreases CRP level (55
The following limitations should be considered. First, the assessment of fatigue relied on a single item rather than a composite measure that evaluates the multidimensional nature of this construct. Thus, the current findings should be interpreted taking this limitation into account and future research should employ a more nuanced measure of fatigue such as the Multidimensional Fatigue Symptom Inventory. However, as previously discussed, SF-12 Vitality Subscale is a valid and reliable measure of energy-fatigue. Additionally, supporting the usefulness of this measure, which enquires about energy level, is a previous report that the energy subscale of a composite fatigue measure was the best correlate of the biological substrate for cytokine-induced fatigue (13
). Second, CRP was the only marker of systemic inflammation measured in the current study although it is the most extensively researched and the most clinically useful inflammatory marker (57
). Third, the magnitude of the association between CRP and fatigue was small, albeit statistically significant. Nevertheless, it was greater than the magnitude of the association between CRP and depressive symptoms in the current sample. The association between CRP and depression, examined by numerous previous studies, is currently considered an established research finding despite its small effect size. A recent meta-analysis has reported Cohen's d
of 0.15 overall and 0.11 in community studies (58
), both values considered small (59
These findings suggest that plasma CRP, especially its persistent elevation, is an independent risk factor for fatigue. Despite the study limitations, these prospective observations provide novel information on the role of systemic inflammation on fatigue within the context of a large sample of non-medical, community-dwelling persons. These data should also motivate further investigations to define the effects of proximal factors for persistent inflammation (e.g. CRP gene polymorphism, childhood stress) on fatigue risk. Testing of interventions that target inflammation might identify new strategies to constrain fatigue onset.