Psychological Medicine

Original Articles

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

H. J. Choa1 c1, M. Kivimäkia2, J. E. Bowera1 and M. R. Irwina1

a1 Cousins Center for Psychoneuroimmmunology, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA

a2 Department of Epidemiology and Public Health, University College London, UK


Background 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.

Method 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).

Results 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.

Conclusions 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.

(Received February 22 2012)

(Revised September 27 2012)

(Accepted September 28 2012)

(Online publication November 14 2012)

Key words

  • C-reactive protein;
  • fatigue;
  • inflammation;
  • interleukin-6;
  • prospective cohort study


c1 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: