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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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MP Amato , G Ponziani , F Rossi , CL Liedl , C Stefanile , L Rossi (2001). Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Multiple Sclerosis 7, 340344.

JS Anderson , CE Ferrans (1997). The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease 185, 359367.

MA Andrykowski , SL Curran , R Lightner (1998). Off-treatment fatigue in breast cancer survivors: a controlled comparison. Journal of Behavioral Medicine 21, 118.

PH Black (2002). Stress and the inflammatory response: a review of neurogenic inflammation. Brain, Behavior, and Immunity 16, 622653.

JG Cannon , JB Angel , LW Abad , E Vannier , MD Mileno , L Fagioli , SM Wolff , AL Komaroff (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.

JG Cannon , JB Angel , RW Ball , LW Abad , L Fagioli , AL Komaroff (1999). Acute phase responses and cytokine secretion in chronic fatigue syndrome. Journal of Clinical Immunology 19, 414421.

L Capuron , JF Gumnick , DL Musselman , DH Lawson , A Reemsnyder , CB Nemeroff , AH Miller (2002). Neurobehavioral effects of interferon-α in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26, 643652.

L Capuron , G Pagnoni , M Demetrashvili , BJ Woolwine , CB Nemeroff , GS Berns , AH Miller (2005). Anterior cingulate activation and error processing during interferon-alpha treatment. Biological Psychiatry 58, 190196.

L Capuron , G Pagnoni , MF Demetrashvili , DH Lawson , FB Fornwalt , B Woolwine , GS Berns , CB Nemeroff , AH Miller (2007). Basal ganglia hypermetabolism and symptoms of fatigue during interferon-α therapy. Neuropsychopharmacology 32, 23842392.

CC Chao , EN Janoff , SX Hu , K Thomas , M Gallagher , M Tsang , PK Peterson (1991). Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine 3, 292298.

HJ Cho , PR Menezes , M Hotopf , D Bhugra , S Wessely (2009 a). Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition. British Journal of Psychiatry 194, 117122.

HJ Cho , TE Seeman , JE Bower , CI Kiefe , MR Irwin (2009 b). Prospective association between C-reactive protein and fatigue in the Coronary Artery Risk Development in Young Adults study. Biological Psychiatry 66, 871878.

SW Cole , JM Arevalo , K Manu , EH Telzer , L Kiang , JE Bower , MR Irwin , AJ Fuligni (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.

A Collado-Hidalgo , JE Bower , PA Ganz , SW Cole , MR Irwin (2006). Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clinical Cancer Research 12, 27592766.

A Compston , A Coles (2002). Multiple sclerosis. Lancet 359, 12211231.

EJ Corwin , LC Klein , K Rickelman (2002). Predictors of fatigue in healthy young adults: moderating effects of cigarette smoking and gender. Biological Research for Nursing 3, 223.

G Curt (2000). Impact of fatigue on quality of life in oncology patients. Seminars in Hematology 37, 1417.

H Dagfinrud , NK Vollestad , JH Loge , TK Kvien , AM Mengshoel (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.

J Danesh , P Whincup , M Walker , L Lennon , A Thomson , P Appleby , JR Gallimore , MB Pepys (2000). Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. British Medical Journal 321, 199204.

R Dantzer , JC O'Connor , GG Freund , RW Johnson , KW Kelley (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 4656.

JE Dimsdale , R Dantzer (2007). A biological substrate for somatoform disorders: importance of pathophysiology. Psychosomatic Medicine 69, 850854.

NI Eisenberger , TK Inagaki , NM Mashal , MR Irwin (2010). Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain, Behavior, and Immunity 24, 558563.

M Fava (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology 20, 2934.

P Flachenecker , I Bihler , F Weber , M Gottschalk , KV Toyka , P Rieckmann (2004). Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Multiple Sclerosis 10, 165169.

D Gimeno , GL Delclos , JE Ferrie , R De Vogli , M Elovainio , MG Marmot , M Kivimäki (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.

G Giovannoni , AJ Thompson , DH Miller , EJ Thompson (2001). Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 57, 676681.

S Gupta , S Aggarwal , D See , A Starr (1997). Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. Journal of Psychiatric Research 31, 149156.

C Heesen , L Nawrath , C Reich , N Bauer , KH Schulz , SM Gold (2006). Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? Journal of Neurology, Neurosurgery and Psychiatry 77, 3439.

MRA Kashipaz , D Swinden , I Todd , RJ Powell (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.

NG Klimas , G Broderick , MA Fletcher (2012). Biomarkers for chronic fatigue. Brain, Behavior, and Immunity. Published online 23062012. doi:10.1016/j.bbi.2012.06.006.

M Kumari , J Head , M Marmot (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.

JJ LaManca , SA Sisto , X Zhou , JE Ottenweller , S Cook , A Peckerman , Q Zhang , TN Denny , WC Gause , BH Natelson (1999). Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion. Journal of Clinical Immunology 19, 135142.

T Liukkonen , S Silvennoinen-Kassinen , J Jokelainen , P Rasanen , M Leinonen , VB Meyer-Rochow , M Timonen (2006). The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biological Psychiatry 60, 825830.

M Marmot , E Brunner (2005). Cohort profile: the Whitehall II study. International Journal of Epidemiology 34, 251256.

AH Miller , S Ancoli-Israel , JE Bower , L Capuron , MR Irwin (2008). Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. Journal of Clinical Oncology 26, 971982.

RB Moss , A Mercandetti , A Vojdani (1999). TNF-α and chronic fatigue syndrome. Journal of Clinical Immunology 19, 314316.

PJ O'Connor (2004). Evaluation of four highly cited energy and fatigue mood measures. Journal of Psychosomatic Research 57, 435441.

T Pawlikowska , T Chalder , SR Hirsch , P Wallace , DJ Wright , SC Wessely (1994). Population based study of fatigue and psychological distress. British Medical Journal 308, 763766.

TA Pearson , GA Mensah , RW Alexander , JL Anderson , RO Cannon , M Criqui , YY Fadl , SP Fortmann , Y Hong , GL Myers , N Rifai , SC Smith Jr., K Taubert , RP Tracy , F Vinicor ; 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.

MB Pepys , GM Hirschfield (2003). C-reactive protein: a critical update. Journal of Clinical Investigation 111, 18051812.

JA Ricci , E Chee , AL Lorandeau , J Berger (2007). Fatigue in the U.S. workforce: prevalence and implications for lost productive work time. Journal of Occupational and Environmental Medicine 49, 110.

M Ritsner , A Ponizovsky , J Endicott , Y Nechamkin , B Rauchverger , H Silver , I Modai (2002). The impact of side-effects of antipsychotic agents on life satisfaction of schizophrenia patients: a naturalistic study. European Neuropsychopharmacology 12, 3138.

LN Saligan , HS Kim (2012). A systematic review of the association between immunogenomic markers and cancer-related fatigue. Brain, Behavior, and Immunity 26, 830848.

C Schubert , S Hong , L Natarajan , PJ Mills , JE Dimsdale (2007). The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain, Behavior, and Immunity 21, 413427.

E Spath-Schwalbe , K Hansen , F Schmidt , H Schrezenmeier , L Marshall , K Burger , HL Fehm , J Born (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.

WF Stewart , JA Ricci , E Chee , SR Hahn , D Morganstein (2003 a). Cost of lost productive work time among US workers with depression. Journal of the American Medical Association 289, 31353144.

WF Stewart , JA Ricci , E Chee , D Morganstein , R Lipton (2003 b). Lost productive time and cost due to common pain conditions in the US workforce. Journal of the American Medical Association 290, 24432454.

EW Steyerberg , MJ Eijkemans , FE Harrell Jr., JD Habbema (2000). Prognostic modelling with logistic regression analysis: a comparison of selection and estimation methods in small data sets. Statistics in Medicine 19, 10591079.

M ter Wolbeek , LJP van Doornen , A Kavelaars , EM van de Putte , M Schedlowski , CJ Heijnen (2007). Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain, Behavior, and Immunity 21, 10631074.

AF Valdini (1985). Fatigue of unknown aetiology – a review. Family Practice 2, 4853.

J Ware Jr., M Kosinski , SD Keller (1996). A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical Care 34, 220233.

PD White , KA Goldsmith , AL Johnson , L Potts , R Walwyn , JC DeCesare , HL Baber , M Burgess , LV Clark , DL Cox , J Bavinton , BJ Angus , G Murphy , M Murphy , H O'Dowd , D Wilks , P McCrone , T Chalder , M Sharpe (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.

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