Aim: High-frequency longitudinal tracking of inflammation using dried blood microsamples provides a new window for personalized monitoring of infections, chronic inflammatory disease and clinical trials of anti-inflammatory drugs. Results/methodology: Using 1662 dried blood spot samples collected by 16 subjects over periods of weeks to years, we studied the behavior of 12 acute phase response and related proteins in inflammation events correlated with infection, vaccination, surgery, intense exercise and Crohn's disease. Proteins were measured using SISCAPA mass spectrometry and normalized to constant plasma volume using low-variance proteins, generating high precision within-person biomarker trajectories with well-characterized personal baselines. Discussion/conclusion: The results shed new light on the dynamic regulation of APR responses, offering a new approach to visualization of multidimensional inflammation trajectories.

Keywords:

References

1. Bassini A, Cameron LC. Sportomics: building a new concept in metabolic studies and exercise science. Biochem. Biophys. Res. Commun. 445(4), 708–716 (2014).
Medline CASGoogle Scholar
2. Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front. Immunol. 9, 754 (2018).
MedlineGoogle Scholar
3. Ridker PM. C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin. Chem. 55(2), 209–215 (2008).
MedlineGoogle Scholar
4. Thompson D, Milford-Ward A, Whicher JT. The value of acute phase protein measurements in clinical practice. Ann. Clin. Biochem. 29, (Pt 2), 123–131 (1992).
MedlineGoogle Scholar
5. Kawamura M, Nishida H. The usefulness of serial C-reactive protein measurement in managing neonatal infection. Acta Paediatr. 84(1), 10–13 (1995).
Medline CASGoogle Scholar
6. Dixon JS, Bird HA, Sitton NG, Pickup ME, Wright V. C-reactive protein in the serial assessment of disease activity in rheumatoid arthritis. Scand. J. Rheumatol. 13(1), 39–44 (2009).
Google Scholar
7. Chen X-X, Wang T, Li J, Kang H. Relationship between inflammatory response and estimated complication rate after total hip arthroplasty. Chin. Med. J. 129(21), 2546–2551 (2016).
Medline CASGoogle Scholar
8. Bessa A, Nissenbaum M, Monteiro A et al. High-intensity ultraendurance promotes early release of muscle injury markers. Br. J. Sports Med. 42(11), 589–593 (2008).
Google Scholar
9. Bouloukaki I, Mermigkis C, Tzanakis N et al. Evaluation of inflammatory markers in a large sample of obstructive sleep apnea patients without comorbidities. Mediators Inflamm. 2017(1), 4573756 (2017).
MedlineGoogle Scholar
10. Maes M, Delange J, Ranjan R et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res. 66(1), 1–11 (1997).
Medline CASGoogle Scholar
11. Li H, Zhou L, Wang C et al. Associations between air quality changes and biomarkers of systemic inflammation during the 2014 Nanjing Youth Olympics: a quasi-experimental study. Am. J. Epidemiol. 185(12), 1290–1296 (2017).
MedlineGoogle Scholar
12. Markert A, Baumann R, Gerhards B et al. Single and combined exposure to zinc- and copper-containing welding fumes lead to asymptomatic systemic inflammation. J. Occup. Environ. Med. 58(2), 127–132 (2016).
Medline CASGoogle Scholar
13. Song IU, Cho HJ, Kim JS, Park IS, Lee KS. Serum hs-CRP levels are increased in de Novo Parkinson's disease independently from age of onset. Eur. Neurol. 72(5–6), 285–289 (2014).
Medline CASGoogle Scholar
14. de Oliveira LC, Franco-Sena AB, Rebelo F et al. Factors associated with maternal serum C-reactive protein throughout pregnancy: a longitudinal study in women of Rio de Janeiro, Brazil. Nutrition 31(9), 1103–1108 (2015).
MedlineGoogle Scholar
15. Franks I. IBD: CRP is a good long-term biomarker. Nat. Rev. Gastroenterol. Hepatol. 8(7), 359–359 (2011).
Google Scholar
16. 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. 176(4), 335–338 (1998).
Medline CASGoogle Scholar
17. Jürgens M, Mahachie John JM, Cleynen I et al. Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease. Clin. Gastroenterol. Hepatol. 9(5), 421.e1–427.e1 (2011).
Google Scholar
18. Kiss LS, Szamosi T, Molnar T et al. Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease. Aliment. Pharmacol. Ther. 34(8), 911–922 (2011).
Medline CASGoogle Scholar
19. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. The Lancet 356(9227), 385–390 (2000).
Medline CASGoogle Scholar
20. Puchalski T, Prabhakar U, Jiao Q, Berns B, Davis HM. Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 16(5), 1652–1661 (2010).
Medline CASGoogle Scholar
21. Kretsos K, Golor G, Jullion A et al. Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: a randomized phase I study: Clinical Pharmacology in Drug Development. Clin. Pharmacol. Drug Dev. 3(5), 388–395 (2014).
Medline CASGoogle Scholar
22. Isaacs JD, Harari O, Kobold U, Lee JS, Bernasconi C. Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis. Arthritis Res. Ther. 15(6), R204 (2013).
MedlineGoogle Scholar
23. Noe A, Howard C, Thuren T, Taylor A, Skerjanec A. Pharmacokinetic and pharmacodynamic characteristics of single-dose canakinumab in patients with Type 2 diabetes mellitus. Clin. Ther. 36(11), 1625–1637 (2014).
Medline CASGoogle Scholar
24. Urien S, Bardin C, Bader-Meunier B et al. Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacol. Toxicol. 14(1), 40 (2013).
Medline CASGoogle Scholar
25. Warren MS, Hughes SG, Singleton W, Yamashita M, Genovese MC. Results of a proof of concept, double-blind, randomized trial of a second generation antisense oligonucleotide targeting high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis. Arthritis Res. Ther. 17(1), 80 (2015).
MedlineGoogle Scholar
26. Ogami C, Tsuji Y, Muraki Y, Mizoguchi A, Okuda M, To H. Population pharmacokinetics and pharmacodynamics of teicoplanin and C-reactive protein in hospitalized patients with gram-positive infections. Clin. Pharmacol. Drug Dev. (2019). https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.684
MedlineGoogle Scholar
27. Rawson TM, Charani E, Moore LSP et al. Exploring the use of C-reactive protein to estimate the pharmacodynamics of vancomycin. Ther. Drug Monit. 40(3), 315–321 (2018).
Medline CASGoogle Scholar
28. Jansson M. Using pharmacokinetic and pharmacodynamic principles to evaluate individualisation of antibiotic dosing – emphasis on Cefuroxime. Acta Universitatis Upsaliensis ISBN 91Y554Y6499Y8 1–58 (2006).
Google Scholar
29. Ridker PM, Rifai N, Pfeffer MA. C-reactive protein levels and outcomes after statin therapy. N. Engl. J. Med. 352, 20–28 (2005).
Medline CASGoogle Scholar
30. Doherty N, Littman B, Reilly K, Swindell A, Buss J, Anderson NL. Analysis of changes in acute-phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis 19(2), 355–363 (1998).
Medline CASGoogle Scholar
31. Seideman P. Methotrexate – the relationship between dose and clinical effect. Rheumatology 32(8), 751–753 (1993).
CASGoogle Scholar
32. Held C, White HD, Stewart RAH et al. Inflammatory biomarkers interleukin-6 and c-reactive protein and outcomes in stable coronary heart disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial. J. Am. Heart Assoc. 6(10), (2017). www.ahajournals.org/doi/10.1161/JAHA.116.005077
Google Scholar
33. Yang S, Dumitrescu TP. Population pharmacokinetics and pharmacodynamics modelling of dilmapimod in severe trauma subjects at risk for acute respiratory distress syndrome. Drugs RD. 17(1), 145–158 (2017).
Medline CASGoogle Scholar
34. Moshage H. Cytokines and the hepatic acute phase response. J. Pathol. 181(3), 257–266 (1997).
Medline CASGoogle Scholar
35. Nishimoto N, Yoshizaki K, Tagoh H et al. Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation. Clin. Immunol. Immunopathol. 50(3), 399–401 (1989).
Medline CASGoogle Scholar
36. Epstein FH, Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med. 340(6), 448–454 (1999).
Medline CASGoogle Scholar
37. Razavi M, Leigh Anderson N, Pope ME, Yip R, Pearson TW. High precision quantification of human plasma proteins using the automated SISCAPA Immuno-MS workflow. New Biotechnol. 33(5 Pt A), 494–502 (2016).
Medline CASGoogle Scholar
38. Anderson NL, Anderson NG, Haines LR, Hardie DB, Pearson TW. Mass spectrometric quantitation of peptides and proteins using Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA). J. Proteome Res. 3(2), 235–244 (2004).
Medline CASGoogle Scholar
39. Razavi M, Anderson NL, Yip R, Pope ME, Pearson TW. Multiplexed longitudinal measurement of protein biomarkers in DBS using an automated SISCAPA workflow. Bioanalysis 8(15), 1597–1609 (2016).
CASGoogle Scholar
40. Thavendiranathan P, Bagai A, Ebidia A, Detsky AS, Choudhry NK. Do blood tests cause anemia in hospitalized patients? J. Gen. Intern. Med. 20(6), 520–524 (2005).
MedlineGoogle Scholar
41. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32(3), 338–343 (1963).
Medline CASGoogle Scholar
42. Fraser CG. Biological Variation: From Principles to Practice. American Association for Clinical Chemistry, DC, USA (2001)
Google Scholar
43. Shih AWY, McFarlane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am. J. Hematol. 89(4), 443–447 (2014).
Medline CASGoogle Scholar
44. Ascensão A, Rebelo A, Oliveira E, Marques F, Pereira L, Magalhães J. Biochemical impact of a soccer match – analysis of oxidative stress and muscle damage markers throughout recovery. Clin. Biochem. 41(10–11), 841–851 (2008).
Medline CASGoogle Scholar
45. Schneider DS. Tracing personalized health curves during Infections. PLoS Biol. 9(9), e1001158(2011).
Medline CASGoogle Scholar
46. Razavi M, Farrokhi V, Yip R, Anderson NL, Pearson TW, Neubert H. Measuring the turnover rate of clinically important plasma proteins using an automated SISCAPA workflow. Clin. Chem. 65(3), 492–494 (2019).
Medline CASGoogle Scholar
47. Huttunen T, Teppo A, Lupisan S, Ruutu P, Nohynek H. Correlation between the severity of infectious diseases in children and the ratio of serum amyloid a protein and C-reactive protein. Scand. J. Infect. Dis. 35(8), 488–490 (2003).
Medline CASGoogle Scholar
48. Louizos C, Yáñez JA, Forrest ML, Davies NM. Understanding the hysteresis loop conundrum in pharmacokinetic/pharmacodynamic relationships. J. Pharm. Pharm. Sci. 17(1), 34 (2014).
MedlineGoogle Scholar
49. Gliddon T, Salman S, Robinson JO, Manning L. Modeling C-reactive protein kinetic profiles for use as a clinical prediction tool in patients with Staphylococcus aureus bacteremia. Biomark. Med. 9(10), 947–955 (2015).
Medline CASGoogle Scholar
50. Bailey DN, Briggs JR. The binding of selected therapeutic drugs to human serum alpha-1 acid glycoprotein and to human serum albumin in vitro. Ther. Drug Monit. 26(1), 40–43 (2004).
Medline CASGoogle Scholar
51. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).
MedlineGoogle Scholar
52. Landewé R, Nurminen T, Davies O, Baeten D. A single determination of C-reactive protein does not suffice to declare a patient with a diagnosis of axial spondyloarthritis ‘CRP-negative’. Arthritis Res. Ther. 20(1), 209 (2018).
MedlineGoogle Scholar
53. Santonocito C, De Loecker I, Donadello K et al. C-reactive protein kinetics after major surgery. Anesth. Analg. 119(3), 624–629 (2014).
Medline CASGoogle Scholar
54. Neumaier M, Metak G, Scherer MA. C-reactive protein as a parameter of surgical trauma: CRP response after different types of surgery in 349 hip fractures. Acta Orthop. 77(5), 788–790 (2009).
Google Scholar
55. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER. Neutrophil kinetics in health and disease. Trends Immunol. 31(8), 318–324 (2010).
Medline CASGoogle Scholar
56. Bouguen G, Levesque BG, Feagan BG et al. Treat to target: a proposed new paradigm for the management of Crohn's disease. Clin. Gastroenterol. Hepatol. 13(6), 1042–1050.e2 (2015).
MedlineGoogle Scholar
57. Lippi G, Sanchis-Gomar F. Epidemiological, biological and clinical update on exercise-induced hemolysis. Ann. Transl. Med. 7(12), 270–270 (2019).
Medline CASGoogle Scholar

Vol. 12, No. 13

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Received 18 November 2019

Accepted 18 March 2020

Published online 7 April 2020

Published in print July 2020

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Keywords

Acknowledgments

The authors thank all sample donors for their participation, and J Kallman and S Skates for helpful, insightful discussions.

Financial & competing interests disclosure

This study was funded by SISCAPA Assay Technologies, Inc. NL Anderson, M Razavi, ME Pope, R Yip, TW Pearson are affiliated with SISCAPA Assay Technologies, Inc., which provides services, reagents and licenses for the SISCAPA sample preparation workflow. LC Cameron and A Bassini-Cameron acknowledge support from the Brazilian Olimpic Comitte (BOC), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Financiadora de Estudos e Projetos (FINEP), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Merck-Sigma-Aldrich; Universidade Federal do Estado do Rio de Janeiro (UNIRIO) and Waters Corporation. No writing assistance was utilized in the production of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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