Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-27T22:18:28.843Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  14 November 2012

H. J. Cho ,
M. Kivimäki ,
J. E. Bower  and
M. R. Irwin
H. J. Cho*
Affiliation:
Cousins Center for Psychoneuroimmmunology, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
M. Kivimäki
Affiliation:
Department of Epidemiology and Public Health, University College London, UK
J. E. Bower
Affiliation:
Cousins Center for Psychoneuroimmmunology, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
M. R. Irwin
Affiliation:
Cousins Center for Psychoneuroimmmunology, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA
*
*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: hjcho@mednet.ucla.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

C-reactive proteinfatigueinflammationinterleukin-6prospective cohort study
Type
Original Articles
Information
Psychological Medicine , Volume 43 , Issue 8 , August 2013 , pp. 1773 - 1783
Copyright
Copyright © Cambridge University Press 2012 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 340–344.CrossRefGoogle ScholarPubMed
Anderson, JS, Ferrans, CE (1997). The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease 185, 359–367.CrossRefGoogle ScholarPubMed
Andrykowski, MA, Curran, SL, Lightner, R (1998). Off-treatment fatigue in breast cancer survivors: a controlled comparison. Journal of Behavioral Medicine 21, 1–18.CrossRefGoogle ScholarPubMed
Black, PH (2002). Stress and the inflammatory response: a review of neurogenic inflammation. Brain, Behavior, and Immunity 16, 622–653.CrossRefGoogle ScholarPubMed
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, 372–376.Google Scholar
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, 253–261.CrossRefGoogle Scholar
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, 414–421.CrossRefGoogle ScholarPubMed
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, 643–652.CrossRefGoogle ScholarPubMed
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, 190–196.CrossRefGoogle ScholarPubMed
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, 2384–2392.CrossRefGoogle ScholarPubMed
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, 292–298.CrossRefGoogle ScholarPubMed
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, 117–122.CrossRefGoogle ScholarPubMed
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, 871–878.CrossRefGoogle ScholarPubMed
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, 1173–1180.CrossRefGoogle Scholar
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, 2759–2766.CrossRefGoogle ScholarPubMed
Compston, A, Coles, A (2002). Multiple sclerosis. Lancet 359, 1221–1231.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Curt, G (2000). Impact of fatigue on quality of life in oncology patients. Seminars in Hematology 37, 14–17.CrossRefGoogle ScholarPubMed
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, 5–11.CrossRefGoogle ScholarPubMed
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, 199–204.CrossRefGoogle ScholarPubMed
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, 46–56.CrossRefGoogle ScholarPubMed
Dimsdale, JE, Dantzer, R (2007). A biological substrate for somatoform disorders: importance of pathophysiology. Psychosomatic Medicine 69, 850–854.CrossRefGoogle ScholarPubMed
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, 558–563.CrossRefGoogle ScholarPubMed
Fava, M (2006). Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology 20, 29–34.CrossRefGoogle Scholar
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, 165–169.CrossRefGoogle ScholarPubMed
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, 135–144.CrossRefGoogle Scholar
Giovannoni, G, Thompson, AJ, Miller, DH, Thompson, EJ (2001). Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 57, 676–681.CrossRefGoogle Scholar
Goldberg, DP (1972). The Detection of Psychiatric Illness by Questionnaire. Oxford University Press: London.Google Scholar
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, 149–156.CrossRefGoogle ScholarPubMed
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, 34–39.CrossRefGoogle ScholarPubMed
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, 360–365.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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, 1873–1880.CrossRefGoogle ScholarPubMed
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, 135–142.CrossRefGoogle ScholarPubMed
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, 825–830.CrossRefGoogle ScholarPubMed
Marmot, M, Brunner, E (2005). Cohort profile: the Whitehall II study. International Journal of Epidemiology 34, 251–256.CrossRefGoogle ScholarPubMed
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, 971–982.CrossRefGoogle ScholarPubMed
Moss, RB, Mercandetti, A, Vojdani, A (1999). TNF-α and chronic fatigue syndrome. Journal of Clinical Immunology 19, 314–316.CrossRefGoogle ScholarPubMed
O'Connor, PJ (2004). Evaluation of four highly cited energy and fatigue mood measures. Journal of Psychosomatic Research 57, 435–441.CrossRefGoogle ScholarPubMed
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, 763–766.CrossRefGoogle ScholarPubMed
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, 499–511.CrossRefGoogle Scholar
Pepys, MB, Hirschfield, GM (2003). C-reactive protein: a critical update. Journal of Clinical Investigation 111, 1805–1812.CrossRefGoogle ScholarPubMed
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, 1–10.CrossRefGoogle ScholarPubMed
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, 31–38.CrossRefGoogle ScholarPubMed
Saligan, LN, Kim, HS (2012). A systematic review of the association between immunogenomic markers and cancer-related fatigue. Brain, Behavior, and Immunity 26, 830–848.CrossRefGoogle ScholarPubMed
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, 413–427.CrossRefGoogle ScholarPubMed
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, 1573–1579.Google ScholarPubMed
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, 739–749.CrossRefGoogle ScholarPubMed
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, 3135–3144.CrossRefGoogle ScholarPubMed
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, 2443–2454.CrossRefGoogle ScholarPubMed
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, 1059–1079.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
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, 1063–1074.CrossRefGoogle ScholarPubMed
Valdini, AF (1985). Fatigue of unknown aetiology – a review. Family Practice 2, 48–53.CrossRefGoogle ScholarPubMed
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, 732–735.Google Scholar
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, 220–233.CrossRefGoogle ScholarPubMed
Ware, JE (1993). SF-36 Health Survey: Manual and Interpretation Guide. The Health Institute, New England Medical Center: Boston.Google Scholar
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, 2351–2359.Google ScholarPubMed
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, 823–836.CrossRefGoogle Scholar
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, 1896–1902.Google ScholarPubMed
Zajecka, JM (2000). Clinical issues in long-term treatment with antidepressants. Journal of Clinical Psychiatry 61, 20–25.Google ScholarPubMed
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, 6–13.CrossRefGoogle Scholar
Supplementary material: File

Cho Supplementary Material

Appendix

Download Cho Supplementary Material(File)
File 127 KB