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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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Amato, MP, Ponziani, G, Rossi, F, Liedl, CL, Stefanile, C, Rossi, L (2001). Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Multiple Sclerosis 7, 340344.
Anderson, JS, Ferrans, CE (1997). The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease 185, 359367.
Andrykowski, MA, Curran, SL, Lightner, R (1998). Off-treatment fatigue in breast cancer survivors: a controlled comparison. Journal of Behavioral Medicine 21, 118.
Black, PH (2002). Stress and the inflammatory response: a review of neurogenic inflammation. Brain, Behavior, and Immunity 16, 622653.
Buchwald, D, Wener, MH, Pearlman, T, Kith, P (1997). Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. Journal of Rheumatology 24, 372376.
Cannon, JG, Angel, JB, Abad, LW, Vannier, E, Mileno, MD, Fagioli, L, Wolff, SM, Komaroff, AL (1997). Interleukin-1β, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. Journal of Clinical Immunology 17, 253261.
Cannon, JG, Angel, JB, Ball, RW, Abad, LW, Fagioli, L, Komaroff, AL (1999). Acute phase responses and cytokine secretion in chronic fatigue syndrome. Journal of Clinical Immunology 19, 414421.
Capuron, L, Gumnick, JF, Musselman, DL, Lawson, DH, Reemsnyder, A, Nemeroff, CB, Miller, AH (2002). Neurobehavioral effects of interferon-α in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26, 643652.
Capuron, L, Pagnoni, G, Demetrashvili, M, Woolwine, BJ, Nemeroff, CB, Berns, GS, Miller, AH (2005). Anterior cingulate activation and error processing during interferon-alpha treatment. Biological Psychiatry 58, 190196.
Capuron, L, Pagnoni, G, Demetrashvili, MF, Lawson, DH, Fornwalt, FB, Woolwine, B, Berns, GS, Nemeroff, CB, Miller, AH (2007). Basal ganglia hypermetabolism and symptoms of fatigue during interferon-α therapy. Neuropsychopharmacology 32, 23842392.
Chao, CC, Janoff, EN, Hu, SX, Thomas, K, Gallagher, M, Tsang, M, Peterson, PK (1991). Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine 3, 292298.
Cho, HJ, Menezes, PR, Hotopf, M, Bhugra, D, Wessely, S (2009 a). Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition. British Journal of Psychiatry 194, 117122.
Cho, HJ, Seeman, TE, Bower, JE, Kiefe, CI, Irwin, MR (2009 b). Prospective association between C-reactive protein and fatigue in the Coronary Artery Risk Development in Young Adults study. Biological Psychiatry 66, 871878.
Cole, SW, Arevalo, JM, Manu, K, Telzer, EH, Kiang, L, Bower, JE, Irwin, MR, Fuligni, AJ (2011). Antagonistic pleiotropy at the human IL6 promoter confers genetic resilience to the pro-inflammatory effects of adverse social conditions in adolescence. Developmental Psychology 47, 11731180.
Collado-Hidalgo, A, Bower, JE, Ganz, PA, Cole, SW, Irwin, MR (2006). Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clinical Cancer Research 12, 27592766.
Compston, A, Coles, A (2002). Multiple sclerosis. Lancet 359, 12211231.
Corwin, EJ, Klein, LC, Rickelman, K (2002). Predictors of fatigue in healthy young adults: moderating effects of cigarette smoking and gender. Biological Research for Nursing 3, 223.
Curt, G (2000). Impact of fatigue on quality of life in oncology patients. Seminars in Hematology 37, 1417.
Dagfinrud, H, Vollestad, NK, Loge, JH, Kvien, TK, Mengshoel, AM (2005). Fatigue in patients with ankylosing spondylitis: a comparison with the general population and associations with clinical and self-reported measures. Arthritis Care and Research 53, 511.
Danesh, J, Whincup, P, Walker, M, Lennon, L, Thomson, A, Appleby, P, Gallimore, JR, Pepys, MB (2000). Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. British Medical Journal 321, 199204.
Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 4656.
Dimsdale, JE, Dantzer, R (2007). A biological substrate for somatoform disorders: importance of pathophysiology. Psychosomatic Medicine 69, 850854.
Eisenberger, NI, Inagaki, TK, Mashal, NM, Irwin, MR (2010). Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain, Behavior, and Immunity 24, 558563.
Fava, M (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology 20, 2934.
Flachenecker, P, Bihler, I, Weber, F, Gottschalk, M, Toyka, KV, Rieckmann, P (2004). Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Multiple Sclerosis 10, 165169.
Gimeno, D, Delclos, GL, Ferrie, JE, De Vogli, R, Elovainio, M, Marmot, MG, Kivimäki, M (2011). Association of CRP and IL-6 with lung function in a middle-aged population initially free from self-reported respiratory problems: the Whitehall II study. European Journal of Epidemiology 26, 135144.
Giovannoni, G, Thompson, AJ, Miller, DH, Thompson, EJ (2001). Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 57, 676681.
Goldberg, DP (1972). The Detection of Psychiatric Illness by Questionnaire. Oxford University Press: London.
Gupta, S, Aggarwal, S, See, D, Starr, A (1997). Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. Journal of Psychiatric Research 31, 149156.
Heesen, C, Nawrath, L, Reich, C, Bauer, N, Schulz, KH, Gold, SM (2006). Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? Journal of Neurology, Neurosurgery and Psychiatry 77, 3439.
Kashipaz, MRA, Swinden, D, Todd, I, Powell, RJ (2003). Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells. Clinical and Experimental Immunology 132, 360365.
Klimas, NG, Broderick, G, Fletcher, MA (2012). Biomarkers for chronic fatigue. Brain, Behavior, and Immunity. Published online 23 06 2012. doi:10.1016/j.bbi.2012.06.006.
Kumari, M, Head, J, Marmot, M (2004). Prospective study of social and other risk factors for incidence of type 2 diabetes in the Whitehall II study. Archives of Internal Medicine 164, 18731880.
LaManca, JJ, Sisto, SA, Zhou, X, Ottenweller, JE, Cook, S, Peckerman, A, Zhang, Q, Denny, TN, Gause, WC, Natelson, BH (1999). Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion. Journal of Clinical Immunology 19, 135142.
Liukkonen, T, Silvennoinen-Kassinen, S, Jokelainen, J, Rasanen, P, Leinonen, M, Meyer-Rochow, VB, Timonen, M (2006). The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biological Psychiatry 60, 825830.
Marmot, M, Brunner, E (2005). Cohort profile: the Whitehall II study. International Journal of Epidemiology 34, 251256.
Miller, AH, Ancoli-Israel, S, Bower, JE, Capuron, L, Irwin, MR (2008). Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. Journal of Clinical Oncology 26, 971982.
Moss, RB, Mercandetti, A, Vojdani, A (1999). TNF-α and chronic fatigue syndrome. Journal of Clinical Immunology 19, 314316.
O'Connor, PJ (2004). Evaluation of four highly cited energy and fatigue mood measures. Journal of Psychosomatic Research 57, 435441.
Pawlikowska, T, Chalder, T, Hirsch, SR, Wallace, P, Wright, DJ, Wessely, SC (1994). Population based study of fatigue and psychological distress. British Medical Journal 308, 763766.
Pearson, TA, Mensah, GA, Alexander, RW, Anderson, JL, Cannon, RO, Criqui, M, Fadl, YY, Fortmann, SP, Hong, Y, Myers, GL, Rifai, N, Smith, SC Jr., Taubert, K, Tracy, RP, Vinicor, F; Centers for Disease Control and Prevention; American Heart Association (2003). Markers of inflammation and cardiovascular disease application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107, 499511.
Pepys, MB, Hirschfield, GM (2003). C-reactive protein: a critical update. Journal of Clinical Investigation 111, 18051812.
Ricci, JA, Chee, E, Lorandeau, AL, Berger, J (2007). Fatigue in the U.S. workforce: prevalence and implications for lost productive work time. Journal of Occupational and Environmental Medicine 49, 110.
Ritsner, M, Ponizovsky, A, Endicott, J, Nechamkin, Y, Rauchverger, B, Silver, H, Modai, I (2002). The impact of side-effects of antipsychotic agents on life satisfaction of schizophrenia patients: a naturalistic study. European Neuropsychopharmacology 12, 3138.
Saligan, LN, Kim, HS (2012). A systematic review of the association between immunogenomic markers and cancer-related fatigue. Brain, Behavior, and Immunity 26, 830848.
Schubert, C, Hong, S, Natarajan, L, Mills, PJ, Dimsdale, JE (2007). The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain, Behavior, and Immunity 21, 413427.
Spath-Schwalbe, E, Hansen, K, Schmidt, F, Schrezenmeier, H, Marshall, L, Burger, K, Fehm, HL, Born, J (1998). Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. Journal of Clinical Endocrinology and Metabolism 83, 15731579.
Stansfeld, S, Marmot, M (1992). Social class and minor psychiatric disorder in British civil servants: a validated screening survey using the General Health Questionnaire. Psychological Medicine 22, 739749.
Stewart, WF, Ricci, JA, Chee, E, Hahn, SR, Morganstein, D (2003 a). Cost of lost productive work time among US workers with depression. Journal of the American Medical Association 289, 31353144.
Stewart, WF, Ricci, JA, Chee, E, Morganstein, D, Lipton, R (2003 b). Lost productive time and cost due to common pain conditions in the US workforce. Journal of the American Medical Association 290, 24432454.
Steyerberg, EW, Eijkemans, MJ, Harrell, FE Jr., Habbema, JD (2000). Prognostic modelling with logistic regression analysis: a comparison of selection and estimation methods in small data sets. Statistics in Medicine 19, 10591079.
ter Wolbeek, M, van Doornen, LJP, Kavelaars, A, van de Putte, EM, Schedlowski, M, Heijnen, CJ (2007). Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain, Behavior, and Immunity 21, 10631074.
Valdini, AF (1985). Fatigue of unknown aetiology – a review. Family Practice 2, 4853.
Vollmer-Conna, U, Cameron, B, Hadzi-Pavlovic, D, Singletary, K, Davenport, T, Vernon, S, Reeves, W, Hickie, I, Wakefield, D, Lloyd, A (2007). Postinfective fatigue syndrome is not associated with altered cytokine production. Clinical Infectious Diseases 45, 732735.
Ware, J Jr., Kosinski, M, Keller, SD (1996). A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical Care 34, 220233.
Ware, JE (1993). SF-36 Health Survey: Manual and Interpretation Guide. The Health Institute, New England Medical Center: Boston.
Wener, MH, Daum, PR, McQuillan, GM (2000). The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration. Journal of Rheumatology 27, 23512359.
White, PD, Goldsmith, KA, Johnson, AL, Potts, L, Walwyn, R, DeCesare, JC, Baber, HL, Burgess, M, Clark, LV, Cox, DL, Bavinton, J, Angus, BJ, Murphy, G, Murphy, M, O'Dowd, H, Wilks, D, McCrone, P, Chalder, T, Sharpe, M (2011). Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 377, 823836.
Wolfe, F (2004). Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. Journal of Rheumatology 31, 18961902.
Zajecka, JM (2000). Clinical issues in long-term treatment with antidepressants. Journal of Clinical Psychiatry 61, 2025.
Zhang, Q, Zhou, XD, Denny, T, Ottenweller, JE, Lange, G, LaManca, JJ, Lavietes, MH, Pollet, C, Gause, WC, Natelson, BH (1999). Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology 6, 613.
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