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Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II prospective cohort study

  • H. J. Cho (a1), M. Kivimäki (a2), J. E. Bower (a1) and M. R. Irwin (a1)

Although basic research on neuroimmune interactions suggests that inflammatory processes may play a role in the development of fatigue, population-based evidence on this association is limited. This study examined whether plasma C-reactive protein (CRP) and interleukin-6 (IL-6), biomarkers of systemic inflammation, predict fatigue onset.


The Whitehall II study is a large-scale cohort study conducted in 20 civil service departments in London. Plasma CRP and IL-6 were measured in 4847 non-fatigued participants at phase 3 (1991–1993, aged 39–63 years). Fatigue was assessed using the Vitality subscale of the 36-item Short Form Health Survey (SF-36) at phase 3 and phase 4 (1995–1996).


During a mean follow-up of 3.1 years, 957 new fatigue cases (19.7%) were identified using the pre-established cut-off score of ⩽50 on the Vitality subscale. CRP values were dichotomized as low (<1.0 mg/l ) or high (⩾1.0 mg/l) using the Centers for Disease Control/American Heart Association recommendations. Similarly, IL-6 values were also dichotomized as low (<1.5 pg/ml) or high (⩾1.5 pg/ml). After full adjustment for sociodemographic and biobehavioral covariates, the odds ratios for new-onset fatigue were 1.28 [95% confidence interval (CI) 1.09–1.49, p = 0.003] for high CRP and 1.24 (95% CI 1.06–1.45, p = 0.008) for high IL-6. Similar results were found when CRP and IL-6 were treated as continuous variables.


Plasma CRP and IL-6 were prospectively associated with new-onset fatigue, supporting the hypothesis that low-grade inflammation has a role in the development of fatigue.

Corresponding author
*Address for correspondence: H. J. Cho, M.D., Ph.D., Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for Neuroscience and Human Behavior, 300 Medical Plaza, Suite 3156, Los Angeles, CA 90095, USA. (Email:
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