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Acute phase reactants

Irving Kushner, MD
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD


Increase in concentration of acute phase reactants (APR) comprises a major pathophysiologic phenomenon that accompanies inflammation and tissue injury [1,2]. With the acute phase response, normal homeostatic mechanisms are replaced by new set points that presumably contribute to defensive or adaptive capabilities.

Focus on the acute phase phenomenon first occurred with the discovery of C-reactive protein (CRP) in the serum of patients during the acute phase of pneumococcal pneumonia [3,4]. CRP consists of five identical, non-covalently associated subunits, each with a molecular weight of approximately 23 kD, which are arranged symmetrically around a central pore [5]. CRP and related proteins with this structure are termed pentraxins; others include serum amyloid P and a number of pattern recognition molecules referred to as long pentraxins [6]. (See "An overview of the innate immune system", section on 'Pentraxins'.)

Despite its name, APR accompany both acute and chronic inflammatory states. They can occur in association with a wide variety of disorders, including infection, trauma, infarction, inflammatory arthritides, and various neoplasms.

Acute phase proteins are defined as those proteins whose serum concentrations increase or decrease by at least 25 percent during inflammatory states [1]. Such proteins are termed either positive or negative APR, respectively. Changes in the levels of APR largely reflect altered production by hepatocytes.

Increases in APR can vary from approximately 50 percent for ceruloplasmin and several components of the complement cascade to 1000-fold or more for CRP and serum amyloid A. Other positive APR include fibrinogen, alpha-1 antitrypsin, haptoglobin, interleukin (IL)-1 receptor antagonist, hepcidin, ferritin, procalcitonin, and others [7-9]. Procalcitonin is of particular interest; while it behaves as a rapidly responding acute phase protein, it has relatively high specificity for infection [10-12]. In contrast to other recognized APR, which are synthesized by hepatocytes, its site of origin is uncertain. (See 'Infection' below.)


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Literature review current through: Jan 2015. | This topic last updated: Jul 15, 2014.
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  1. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982; 389:39.
  2. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340:448.
  4. Kushner I, Samols D. Oswald Avery and the pneumococcus. Pharos Alpha Omega Alpha Honor Med Soc 2011; 74:14.
  5. Osmand AP, Friedenson B, Gewurz H, et al. Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins). Proc Natl Acad Sci U S A 1977; 74:739.
  6. Inforzato A, Bottazzi B, Garlanda C, et al. Pentraxins in humoral innate immunity. Adv Exp Med Biol 2012; 946:1.
  7. Gabay C, Smith MF, Eidlen D, Arend WP. Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. J Clin Invest 1997; 99:2930.
  8. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101:2461.
  9. Nijsten MW, Olinga P, The TH, et al. Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. Crit Care Med 2000; 28:458.
  10. Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med 2011; 9:107.
  11. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13:426.
  12. Riedel S. Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis. Diagn Microbiol Infect Dis 2012; 73:221.
  13. Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med 1985; 78:1001.
  14. Gauldie J, Richards C, Harnish D, et al. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A 1987; 84:7251.
  15. Moshage HJ, Janssen JA, Franssen JH, et al. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation. J Clin Invest 1987; 79:1635.
  16. Bode JG, Albrecht U, Häussinger D, et al. Hepatic acute phase proteins--regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling. Eur J Cell Biol 2012; 91:496.
  17. Loyer P, Ilyin G, Abdel Razzak Z, et al. Interleukin 4 inhibits the production of some acute-phase proteins by human hepatocytes in primary culture. FEBS Lett 1993; 336:215.
  18. Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S. Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol 1992; 149:2021.
  19. Dinarello C. Cytokines as endogenous pyrogens. In: Fever: Basic mechanisms and management, Mackowiak P (Ed), Lippincott-Raven, Philadelphia 1997. p.87.
  20. Goldbach JM, Roth J, Zeisberger E. Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration. Am J Physiol 1997; 272:R675.
  21. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332:1351.
  22. Sarraf P, Frederich RC, Turner EM, et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 1997; 185:171.
  23. Krueger JM. Cytokine involvement in sleep responses to infection and physiological sleep. In: Cytokines in the Nervous System, Rothwell NJ (Ed), Landes Publishing, Austin 1996. p.41.
  24. Moldawer LL, Copeland EM 3rd. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer 1997; 79:1828.
  25. Wolf M, Böhm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 1996; 135:729.
  26. Li YP, Schwartz RJ, Waddell ID, et al. Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J 1998; 12:871.
  27. Means RT. Hepcidin and cytokines in anaemia. Hematology 2004; 9:357.
  28. Kushner I. Semantics, inflammation, cytokines and common sense. Cytokine Growth Factor Rev 1998; 9:191.
  29. Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem 2004; 279:48487.
  30. Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117:104.
  31. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001; 38:189.
  32. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002; 20:197.
  33. Rhodes B, Fürnrohr BG, Vyse TJ. C-reactive protein in rheumatology: biology and genetics. Nat Rev Rheumatol 2011; 7:282.
  34. Ballou SP, Lozanski G. Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein. Cytokine 1992; 4:361.
  35. Cermak J, Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82:513.
  36. Jones SA, Novick D, Horiuchi S, et al. C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J Exp Med 1999; 189:599.
  37. Griselli M, Herbert J, Hutchinson WL, et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 1999; 190:1733.
  38. Ahmed N, Thorley R, Xia D, et al. Transgenic mice expressing rabbit C-reactive protein exhibit diminished chemotactic factor-induced alveolitis. Am J Respir Crit Care Med 1996; 153:1141.
  39. Xia D, Samols D. Transgenic mice expressing rabbit C-reactive protein are resistant to endotoxemia. Proc Natl Acad Sci U S A 1997; 94:2575.
  40. Jiang S, Xia D, Samols D. Expression of rabbit C-reactive protein in transgenic mice inhibits development of antigen-induced arthritis. Scand J Rheumatol 2006; 35:351.
  41. Zouki C, Beauchamp M, Baron C, Filep JG. Prevention of In vitro neutrophil adhesion to endothelial cells through shedding of L-selectin by C-reactive protein and peptides derived from C-reactive protein. J Clin Invest 1997; 100:522.
  42. Gershov D, Kim S, Brot N, Elkon KB. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med 2000; 192:1353.
  43. Tam SP, Flexman A, Hulme J, Kisilevsky R. Promoting export of macrophage cholesterol: the physiological role of a major acute-phase protein, serum amyloid A 2.1. J Lipid Res 2002; 43:1410.
  44. Kisilevsky R, Manley PN. Acute-phase serum amyloid A: perspectives on its physiological and pathological roles. Amyloid 2012; 19:5.
  45. Su SB, Gong W, Gao JL, et al. A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells. J Exp Med 1999; 189:395.
  46. Mullan RH, Bresnihan B, Golden-Mason L, et al. Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway. Arthritis Rheum 2006; 54:105.
  47. Boretti FS, Buehler PW, D'Agnillo F, et al. Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs. J Clin Invest 2009; 119:2271.
  48. Schaer DJ, Buehler PW, Alayash AI, et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013; 121:1276.
  49. Kilpatrick L, McCawley L, Nachiappan V, et al. Alpha-1-antichymotrypsin inhibits the NADPH oxidase-enzyme complex in phorbol ester-stimulated neutrophil membranes. J Immunol 1992; 149:3059.
  50. Cid MC, Grant DS, Hoffman GS, et al. Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest 1993; 91:977.
  51. Bone RC. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med 1996; 24:163.
  52. Malle E, De Beer FC. Human serum amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. Eur J Clin Invest 1996; 26:427.
  53. Ham TC, Curtis FC. Sedimentation rate of erythrocytes. Medicine (Baltimore) 1938; 17:447.
  54. Hayes GS, Stinson IN. Erythrocyte sedimentation rate and age. Arch Ophthalmol 1976; 94:939.
  55. Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983; 286:266.
  56. Leff RD, Akre SP. Obesity and the erythrocyte sedimentation rate. Ann Intern Med 1986; 105:143.
  57. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19:972.
  58. Fincher RM, Page MI. Clinical significance of extreme elevation of the erythrocyte sedimentation rate. Arch Intern Med 1986; 146:1581.
  59. Bathon J, Graves J, Jens P, et al. The erythrocyte sedimentation rate in end-stage renal failure. Am J Kidney Dis 1987; 10:34.
  60. Shusterman N, Kimmel PL, Kiechle FL, et al. Factors influencing erythrocyte sedimentation in patients with chronic renal failure. Arch Intern Med 1985; 145:1796.
  61. Arik N, Bedir A, Günaydin M, et al. Do erythrocyte sedimentation rate and C-reactive protein levels have diagnostic usefulness in patients with renal failure? Nephron 2000; 86:224.
  62. Liverman PC, Tucker FL, Bolton WK. Erythrocyte sedimentation rate in glomerular disease: association with urinary protein. Am J Nephrol 1988; 8:363.
  63. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Engl J Med 2005; 352:1611.
  64. Vanderschueren S, Deeren D, Knockaert DC, et al. Extremely elevated C-reactive protein. Eur J Intern Med 2006; 17:430.
  65. Le Gall C, Désidéri-Vaillant C, Nicolas X. [Significations of extremely elevated C-reactive protein: about 91 cases in a French hospital center]. Pathol Biol (Paris) 2011; 59:319.
  66. Krüger S, Ewig S, Papassotiriou J, et al. Inflammatory parameters predict etiologic patterns but do not allow for individual prediction of etiology in patients with CAP: results from the German competence network CAPNETZ. Respir Res 2009; 10:65.
  67. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39:206.
  68. Wener MH, Daum PR, McQuillan GM. The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration. J Rheumatol 2000; 27:2351.
  69. Ranganath VK, Elashoff DA, Khanna D, et al. Age adjustment corrects for apparent differences in erythrocyte sedimentation rate and C-reactive protein values at the onset of seropositive rheumatoid arthritis in younger and older patients. J Rheumatol 2005; 32:1040.
  70. Slade GD, Ghezzi EM, Heiss G, et al. Relationship between periodontal disease and C-reactive protein among adults in the Atherosclerosis Risk in Communities study. Arch Intern Med 2003; 163:1172.
  71. Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify? Am J Med 2006; 119:166.e17.
  72. Giles JT, Bartlett SJ, Andersen R, et al. Association of body fat with C-reactive protein in rheumatoid arthritis. Arthritis Rheum 2008; 58:2632.
  73. Vuong J, Qiu Y, La M, et al. Reference intervals of complete blood count constituents are highly correlated to waist circumference: should obese patients have their own "normal values?". Am J Hematol 2014; 89:671.
  74. van Leeuwen MA, van der Heijde DM, van Rijswijk MH, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis. A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants. J Rheumatol 1994; 21:425.
  75. Kushner I, Samols D, Magrey M. A unifying biologic explanation for "high-sensitivity" C-reactive protein and "low-grade" inflammation. Arthritis Care Res (Hoboken) 2010; 62:442.
  76. Casas JP, Shah T, Hingorani AD, et al. C-reactive protein and coronary heart disease: a critical review. J Intern Med 2008; 264:295.
  77. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454:428.
  78. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81:1.
  79. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444:860.
  80. Gaitonde S, Samols D, Kushner I. C-reactive protein and systemic lupus erythematosus. Arthritis Rheum 2008; 59:1814.
  81. Kay J, Morgacheva O, Messing SP, et al. Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Res Ther 2014; 16:R40.
  82. Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum 1994; 24:91.
  83. Donald F, Ward MM. Evaluative laboratory testing practices of United States rheumatologists. Arthritis Rheum 1998; 41:725.
  84. Larsen A. The relation of radiographic changes to serum acute-phase proteins and rheumatoid factor in 200 patients with rheumatoid arthritis. Scand J Rheumatol 1988; 17:123.
  85. Cohick CB, Furst DE, Quagliata S, et al. Analysis of elevated serum interleukin-6 levels in rheumatoid arthritis: correlation with erythrocyte sedimentation rate or C-reactive protein. J Lab Clin Med 1994; 123:721.
  86. Nielen MM, van Schaardenburg D, Reesink HW, et al. Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum 2004; 50:2423.
  87. Cush JJ, Lipsky PE, Postlethwaite AE, et al. Correlation of serologic indicators of inflammation with effectiveness of nonsteroidal antiinflammatory drug therapy in rheumatoid arthritis. Arthritis Rheum 1990; 33:19.
  88. Amos RS, Crockson RA, Crockson AP, et al. Rheumatoid arthritis: C-reactive protein and erythrocyte sedimentation rate during initial treatment. Br Med J 1978; 1:1396.
  89. Coste J, Spira A, Clerc D, Paolaggi JB. Prediction of articular destruction in rheumatoid arthritis: disease activity markers revisited. J Rheumatol 1997; 24:28.
  90. Matsuda Y, Yamanaka H, Higami K, Kashiwazaki S. Time lag between active joint inflammation and radiological progression in patients with early rheumatoid arthritis. J Rheumatol 1998; 25:427.
  91. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis Rheum 1998; 41:1571.
  92. Plant MJ, Jones PW, Saklatvala J, et al. Patterns of radiological progression in early rheumatoid arthritis: results of an 8 year prospective study. J Rheumatol 1998; 25:417.
  93. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998; 57:350.
  94. Fujinami M, Sato K, Kashiwazaki S, Aotsuka S. Comparable histological appearance of synovitis in seropositive and seronegative rheumatoid arthritis. Clin Exp Rheumatol 1997; 15:11.
  95. Gough A, Sambrook P, Devlin J, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 1998; 25:1282.
  96. Wolfe F, Hawley DJ. The longterm outcomes of rheumatoid arthritis: Work disability: a prospective 18 year study of 823 patients. J Rheumatol 1998; 25:2108.
  97. Proven A, Gabriel SE, O'Fallon WM, Hunder GG. Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 1999; 26:1333.
  98. González-Gay MA, Rodríguez-Valverde V, Blanco R, et al. Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. A more benign syndrome. Arch Intern Med 1997; 157:317.
  99. Helfgott SM, Kieval RI. Polymyalgia rheumatica in patients with a normal erythrocyte sedimentation rate. Arthritis Rheum 1996; 39:304.
  100. Weyand CM, Fulbright JW, Evans JM, et al. Corticosteroid requirements in polymyalgia rheumatica. Arch Intern Med 1999; 159:577.
  101. Salvarani C, Hunder GG. Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurence in a population-based study. Arthritis Rheum 2001; 45:140.
  102. Cantini F, Salvarani C, Olivieri I. Erythrocyte sedimentation rate and C-reactive protein in the diagnosis of polymyalgia rheumatica. Ann Intern Med 1998; 128:873.
  103. Vilá LM, Alarcón GS, McGwin G Jr, et al. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXIX. Elevation of erythrocyte sedimentation rate is associated with disease activity and damage accrual. J Rheumatol 2005; 32:2150.
  104. Enocsson H, Sjöwall C, Skogh T, et al. Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares? Arthritis Rheum 2009; 60:3755.
  105. Pepys MB, Lanham JG, De Beer FC. C-reactive protein in SLE. Clin Rheum Dis 1982; 8:91.
  106. ter Borg EJ, Horst G, Limburg PC, et al. C-reactive protein levels during disease exacerbations and infections in systemic lupus erythematosus: a prospective longitudinal study. J Rheumatol 1990; 17:1642.
  107. Moutsopoulos HM, Mavridis AK, Acritidis NC, Avgerinos PC. High C-reactive protein response in lupus polyarthritis. Clin Exp Rheumatol 1983; 1:53.
  108. De Beer FC, Mallya RK, Fagan EA, et al. Serum amyloid-A protein concentration in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982; 2:231.
  109. Liu X, Mayes MD, Pedroza C, et al. Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis? Arthritis Care Res (Hoboken) 2013; 65:1375.
  110. Legouffe E, Rodriguez C, Picot MC, et al. C-reactive protein serum level is a valuable and simple prognostic marker in non Hodgkin's lymphoma. Leuk Lymphoma 1998; 31:351.
  111. Tefferi A, Ho TC, Ahmann GJ, et al. Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis. Am J Med 1994; 97:374.
  112. Nozoe T, Matsumata T, Kitamura M, Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer. Am J Surg 1998; 176:335.
  113. Alexandrakis MG, Passam FH, Ganotakis ES, et al. The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma. Clin Lab Haematol 2003; 25:41.
  114. Tamaki K, Kogata Y, Sugiyama D, et al. Diagnostic accuracy of serum procalcitonin concentrations for detecting systemic bacterial infection in patients with systemic autoimmune diseases. J Rheumatol 2008; 35:114.
  115. Eberhard OK, Haubitz M, Brunkhorst FM, et al. Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody-associated vasculitis) and invasive bacterial infection. Arthritis Rheum 1997; 40:1250.
  116. Brunkhorst R, Eberhardt OK, Haubitz M, Brunkhorst FM. Procalcitonin for discrimination between activity of systemic autoimmune disease and systemic bacterial infection. Intensive Care Med 2000; 26 Suppl 2:S199.
  117. Wu JY, Lee SH, Shen CJ, et al. Use of serum procalcitonin to detect bacterial infection in patients with autoimmune diseases: a systematic review and meta-analysis. Arthritis Rheum 2012; 64:3034.
  118. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999; 106:506.
  119. Kushner I. C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biologic aging. Cleve Clin J Med 2001; 68:535.