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Prospective Association Between C-Reactive Protein and Fatigue in the Coronary Artery Risk Development in Young Adults Study

  • Hyong Jin Cho
    Correspondence
    Address correspondence to Hyong Jin Cho, M.D., Ph.D., UCLA Semel Institute for Neuroscience and Human Behavior, Cousins Center for Psychoneuroimmunology, 300 Medical Plaza, Suite 3156, Los Angeles, CA 90095
    Affiliations
    Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, California
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  • Teresa E. Seeman
    Affiliations
    Division of Geriatrics, Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California
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  • Julienne E. Bower
    Affiliations
    Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, California

    Department of Psychology, University of California, Los Angeles (UCLA), Los Angeles, California
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  • Catarina I. Kiefe
    Affiliations
    Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Michael R. Irwin
    Affiliations
    Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, California
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      Background

      Fatigue is highly prevalent and causes serious disruption in quality of life. Although the underlying biological mechanism is unknown, increases in inflammation have been implicated. This prospective study examined the association between C-reactive protein (CRP), a biomarker of systemic inflammation, and fatigue 5 years later.

      Methods

      The Coronary Artery Risk Development in Young Adults (CARDIA) study is a population-based longitudinal study conducted in four U.S. cities. Highly sensitive CRP concentration and fatigue were measured in 2983 African American and white adults at both year 15 (2000–2001, ages 33–45 years) and year 20 (2005–2006) examinations. Fatigue was assessed using the vitality subscale of the 12-item Short Form Health Survey.

      Results

      Plasma CRP concentration at baseline (i.e., CARDIA year 15) was a significant predictor of fatigue level 5 years later (unadjusted β = .126, p < .001). After adjustment for potential confounders, this association remained significant (adjusted β = .044, p = .033). Additionally, baseline CRP independently predicted fatigue in the subgroup of participants without medical comorbidity (adjusted β = .051, p = .039). Fatigue was associated with a persistent elevation of CRP at both examinations but not with a transient elevation of CRP at only one of the examinations.

      Conclusions

      This is the first study to demonstrate a prospective association between an inflammatory marker and fatigue in a general population. Furthermore, the association between low-grade systemic inflammation and fatigue seems primarily driven by persistent immune activation and not explained by the presence or development of medical comorbidity.

      Key Words

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      References

        • Valdini A.F.
        Fatigue of unknown aetiology—A review.
        Fam Pract. 1985; 2: 48-53
        • Pawlikowska T.
        • Chalder T.
        • Hirsch S.R.
        • Wallace P.
        • Wright D.J.
        • Wessely S.C.
        Population based study of fatigue and psychological distress.
        BMJ. 1994; 308: 763-766
        • Curt G.
        Impact of fatigue on quality of life in oncology patients.
        Semin Hematol. 2000; 37: 14-17
        • Amato M.P.
        • Ponziani G.
        • Rossi F.
        • Liedl C.L.
        • Stefanile C.
        • Rossi L.
        Quality of life in multiple sclerosis: The impact of depression, fatigue and disability.
        Mult Scler. 2001; 7: 340-344
        • Anderson J.S.
        • Ferrans C.E.
        The quality of life of persons with chronic fatigue syndrome.
        J Nerv Ment Dis. 1997; 185: 359-367
        • Ricci J.A.
        • Chee E.
        • Lorandeau A.L.
        • Berger J.
        Fatigue in the US workforce: Prevalence and implications for lost productive work time.
        J Occup Environ Med. 2007; 49: 1-10
        • Stewart W.F.
        • Ricci J.A.
        • Chee E.
        • Morganstein D.
        • Lipton R.
        Lost productive time and cost due to common pain conditions in the US workforce.
        JAMA. 2003; 290: 2443-2454
        • Stewart W.F.
        • Ricci J.A.
        • Chee E.
        • Hahn S.R.
        • Morganstein D.
        Cost of lost productive work time among US workers with depression.
        JAMA. 2003; 289: 3135-3144
        • Netea M.G.
        • Kullberg B.J.
        • Vonk A.G.
        • Verschueren I.
        • Joosten L.A.
        • van der Meer J.W.
        Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.
        Eur J Clin Invest. 2007; 37: 737-741
        • Krzyszton C.P.
        • Sparkman N.L.
        • Grant R.W.
        • Buchanan J.B.
        • Broussard S.R.
        • Woods J.
        • et al.
        Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation.
        Am J Physiol Regul Integr Comp Physiol. 2008; 295: R1109-R1114
        • Spath-Schwalbe E.
        • Hansen K.
        • Schmidt F.
        • Schrezenmeier H.
        • Marshall L.
        • Burger K.
        • et al.
        Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men.
        J Clin Endocrinol Metab. 1998; 83: 1573-1579
        • Capuron L.
        • Gumnick J.F.
        • Musselman D.L.
        • Lawson D.H.
        • Reemsnyder A.
        • Nemeroff C.B.
        • et al.
        Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions.
        Neuropsychopharmacology. 2002; 26: 643-652
        • Capuron L.
        • Pagnoni G.
        • Demetrashvili M.F.
        • Lawson D.H.
        • Fornwalt F.B.
        • Woolwine B.
        • et al.
        Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy.
        Neuropsychopharmacology. 2007; 32: 2384-2392
        • Danesh J.
        • Whincup P.
        • Walker M.
        • Lennon L.
        • Thomson A.
        • Appleby P.
        • et al.
        Low grade inflammation and coronary heart disease: Prospective study and updated meta-analyses.
        BMJ. 2000; 321: 199-204
        • Chao C.C.
        • Janoff E.N.
        • Hu S.X.
        • Thomas K.
        • Gallagher M.
        • Tsang M.
        • et al.
        Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome.
        Cytokines. 1991; 3: 292-298
        • Buchwald D.
        • Wener M.H.
        • Pearlman T.
        • Kith P.
        Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome.
        J Rheumatol. 1997; 24: 372-376
        • Cannon J.G.
        • Angel J.B.
        • Abad L.W.
        • Vannier E.
        • Mileno M.D.
        • Fagioli L.
        • et al.
        Interleukin-1β, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome.
        J Clin Immunol. 1997; 17: 253-261
        • Gupta S.
        • Aggarwal S.
        • See D.
        • Starr A.
        Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome.
        J Psychiatr Res. 1997; 31: 149-156
        • Cannon J.G.
        • Angel J.B.
        • Ball R.W.
        • Abad L.W.
        • Fagioli L.
        • Komaroff A.L.
        Acute phase responses and cytokine secretion in chronic fatigue syndrome.
        J Clin Immunol. 1999; 19: 414-421
        • Moss R.B.
        • Mercandetti A.
        • Vojdani A.
        TNF-a and chronic fatigue syndrome.
        J Clin Immunol. 1999; 19: 314-316
        • LaManca J.J.
        • Sisto S.A.
        • Zhou X.
        • Ottenweller J.E.
        • Cook S.
        • Peckerman A.
        • et al.
        Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion.
        J Clin Immunol. 1999; 19: 135-142
        • Zhang Q.
        • Zhou X.D.
        • Denny T.
        • Ottenweller J.E.
        • Lange G.
        • LaManca J.J.
        • et al.
        Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome.
        Clin Diagn Lab Immunol. 1999; 6: 6-13
        • Kashipaz M.R.A.
        • Swinden D.
        • Todd I.
        • Powell R.J.
        Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells.
        Clin Exp Immunol. 2003; 132: 360-365
        • Vollmer-Conna U.
        • Cameron B.
        • Hadzi-Pavlovic D.
        • Singletary K.
        • Davenport T.
        • Vernon S.
        • et al.
        Postinfective fatigue syndrome is not associated with altered cytokine production.
        Clin Infect Dis. 2007; 45: 732-735
        • ter Wolbeek M.
        • van Doornen L.J.P.
        • Kavelaars A.
        • van de Putte E.M.
        • Schedlowski M.
        • Heijnen C.J.
        Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents.
        Brain Behav Immun. 2007; 21: 1063-1074
        • Giovannoni G.
        • Thompson A.J.
        • Miller D.H.
        • Thompson E.J.
        Fatigue is not associated with raised inflammatory markers in multiple sclerosis.
        Neurology. 2001; 57: 676-681
        • Flachenecker P.
        • Bihler I.
        • Weber F.
        • Gottschalk M.
        • Toyka K.V.
        • Rieckmann P.
        Cytokine mRNA expression in patients with multiple sclerosis and fatigue.
        Mult Scler. 2004; 10: 165-169
        • Heesen C.
        • Nawrath L.
        • Reich C.
        • Bauer N.
        • Schulz K.H.
        • Gold S.M.
        Fatigue in multiple sclerosis: An example of cytokine mediated sickness behaviour?.
        J Neurol Neurosurg Psychiatry. 2006; 77: 34-39
        • Friedman G.D.
        • Cutter G.R.
        • Donahue R.P.
        • Hughes G.H.
        • Hulley S.B.
        • Jacobs Jr, D.R.
        • et al.
        CARDIA: Study design, recruitment, and some characteristics of the examined subjects.
        J Clin Epidemiol. 1988; 41: 1105-1116
        • Ware Jr, J.
        • Kosinski M.
        • Keller S.D.
        A 12-Item Short-Form Health Survey: Construction of scales and preliminary tests of reliability and validity.
        Med Care. 1996; 34: 220-233
        • Jenkinson C.
        • Layte R.
        • Jenkinson D.
        • Lawrence K.
        • Petersen S.
        • Paice C.
        • et al.
        A shorter form health survey: Can the SF-12 replicate results from the SF-36 in longitudinal studies?.
        J Pub Health. 1997; 19: 179-186
        • Hurst N.P.
        • Ruta D.A.
        • Kind P.
        Comparison of the MOS short form-12 (SF12) health status questionnaire with the SF36 in patients with rheumatoid arthritis.
        Rheumatology. 1998; 37: 862-869
        • Han C.
        • Pulling C.C.
        • Telke S.E.
        • Hullsiek K.H.
        Assessing the utility of five domains in SF-12 health status questionnaire in an AIDS clinical trial.
        AIDS. 2002; 16: 431
        • Powers D.A.
        • Xie Y.
        Statistical Methods for Categorical Data Analysis.
        Academic Press, San Diego2000
        • Marmot M.
        • Brunner E.
        Cohort Profile: The Whitehall II study.
        Int J Epidemiol. 2005; 34: 251-256
        • Ganz P.A.
        • Kwan L.
        • Stanton A.L.
        • Krupnick J.L.
        • Rowland J.H.
        • Meyerowitz B.E.
        • et al.
        Quality of life at the end of primary treatment of breast cancer: First results from the moving beyond cancer randomized trial.
        J Natl Cancer Inst. 2004; 96: 376-387
        • Hann D.M.
        • Jacobsen P.B.
        • Azzarello L.M.
        • Martin S.C.
        • Curran S.L.
        • Fields K.K.
        • et al.
        Measurement of fatigue in cancer patients: Development and validation of the Fatigue Symptom Inventory.
        Qual Life Res. 1998; 7: 301-310
        • Pearson T.A.
        • Mensah G.A.
        • Alexander R.W.
        • Anderson J.L.
        • Cannon R.O.
        • Criqui M.
        • et al.
        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. 2003; 107: 499-511
        • Parker E.D.
        • Schmitz K.H.
        • Jacobs Jr, D.R.
        • Dengel D.R.
        • Schreiner P.J.
        Physical activity in young adults and incident hypertension over 15 years of follow-up: The CARDIA Study.
        Am J Pub Health. 2007; 97: 703-709
        • Steyerberg E.W.
        • Eijkemans M.J.
        • Harrell Jr, F.E.
        • Habbema J.D.
        Prognostic modelling with logistic regression analysis: A comparison of selection and estimation methods in small data sets.
        Stat Med. 2000; 19: 1059-1079
        • MacKinnon D.P.
        • Lockwood C.M.
        • Hoffman J.M.
        • West S.G.
        • Sheets V.
        A comparison of methods to test mediation and other intervening variable effects.
        Psychol Methods. 2002; 7: 83-104
        • Bower J.E.
        • Ganz P.A.
        • Aziz N.
        • Fahey J.L.
        Fatigue and proinflammatory cytokine activity in breast cancer survivors.
        Psychosom Med. 2002; 64: 604-611
        • Collado-Hidalgo A.
        • Bower J.E.
        • Ganz P.A.
        • Cole S.W.
        • Irwin M.R.
        Inflammatory biomarkers for persistent fatigue in breast cancer survivors.
        Clin Cancer Res. 2006; 12: 2759-2766
        • Miller A.H.
        • Ancoli-Israel S.
        • Bower J.E.
        • Capuron L.
        • Irwin M.R.
        Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer.
        J Clin Oncol. 2008; 26: 971-982
        • Schubert C.
        • Hong S.
        • Natarajan L.
        • Mills P.J.
        • Dimsdale J.E.
        The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review.
        Brain Behav Immun. 2007; 21: 413-427
        • Corwin E.J.
        • Klein L.C.
        • Rickelman K.
        Predictors of fatigue in healthy young adults: Moderating effects of cigarette smoking and gender.
        Biol Res Nurs. 2002; 3: 222-233
        • Black P.H.
        Stress and the inflammatory response: A review of neurogenic inflammation.
        Brain Behav Immun. 2002; 16: 622-653
        • Dantzer R.
        • O'Connor J.C.
        • Freund G.G.
        • Johnson R.W.
        • Kelley K.W.
        From inflammation to sickness and depression: When the immune system subjugates the brain.
        Nat Rev Neurosci. 2008; 9: 46-56
        • Capuron L.
        • Pagnoni G.
        • Demetrashvili M.
        • Woolwine B.J.
        • Nemeroff C.B.
        • Berns G.S.
        • et al.
        Anterior cingulate activation and error processing during interferon-alpha treatment.
        Biol Psychiatry. 2005; 58: 190-196
        • Capuron L.
        • Raison C.L.
        • Musselman D.L.
        • Lawson D.H.
        • Nemeroff C.B.
        • Miller A.H.
        Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.
        Am J Psychiatry. 2003; 160: 1342-1345
        • Bull S.J.
        • Huezo-Diaz P.
        • Binder E.B.
        • Cubells J.F.
        • Ranjith G.
        • Maddock C.
        • et al.
        Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
        Mol Psychiatry. 2008; ([published online ahead of print May 6])
        • Carlson C.S.
        • Aldred S.F.
        • Lee P.K.
        • Tracy R.P.
        • Schwartz S.M.
        • Rieder M.
        • et al.
        Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels.
        Am J Hum Genet. 2005; 77: 64-77
        • Taylor S.E.
        • Lehman B.J.
        • Kiefe C.I.
        • Seeman T.E.
        Relationship of early life stress and psychological functioning to adult C-reactive protein in the Coronary Artery Risk Development in Young Adults Study.
        Biol Psychiatry. 2006; 60: 819-824
        • Collado-Hidalgo A.
        • Bower J.E.
        • Ganz P.A.
        • Irwin M.R.
        • Cole S.W.
        Cytokine gene polymorphisms and fatigue in breast cancer survivors: Early findings.
        Brain Behav Immun. 2008; ([published online ahead of print July 8])
        • Kohut M.L.
        • McCann D.A.
        • Russell D.W.
        • Konopka D.N.
        • Cunnick J.E.
        • Franke W.D.
        • et al.
        Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults.
        Brain Behav Immun. 2006; 20: 201-209
        • You T.
        • Berman D.M.
        • Ryan A.S.
        • Nicklas B.J.
        Effects of hypocaloric diet and exercise training on inflammation and adipocyte lipolysis in obese postmenopausal women.
        J Clin Endocrinol Metab. 2004; 89: 1739-1746
        • Pepys M.B.
        • Hirschfield G.M.
        C-reactive protein: A critical update.
        J Clin Invest. 2003; 111: 1805-1812
        • Howren M.B.
        • Lamkin D.M.
        • Suls J.
        Associations of depression with C-reactive protein, IL-1, and IL-6: A Meta-analysis.
        Psychosom Med. 2009; 71: 171-186
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences.
        2nd ed. Lawrence Erlbaum Associates, Hillsdale, NJ1988