Open access

C-reactive protein and other biomarkers—the sense and non-sense of using inflammation biomarkers for the diagnosis of severe bacterial infection

Publication: LymphoSign Journal
9 April 2018

Abstract

Severe bacterial infection (SBI) poses a significant clinical problem as its mortality and morbidity is still unacceptably high. A systematic literature analysis was performed with an emphasis on recent meta analyses examining the specificity and sensitivity of conventional inflammation biomarkers (C-reactive protein, procalcitonin, interleukin-6, interleukin-8) for diagnosing SBI. Most inflammation biomarkers do not show high sensitivity and are of limited value regarding SBI detection. To the practicing clinician, the sole use of inflammation markers is not useful for differentiating between viral or bacterial origin of infection in an individual patient. Thus, only in combination with clinical biometric markers, taken from patient history and physical examination, is the analysis of inflammation biomarkers to some degree helpful in clinical practice. To date, their sensitivity and specificity have been best captured in the field of neonatology, where levels of interleukin-6 have been measured in combination with relevant perinatal factors. The indiscriminate use of inflammation biomarkers for the diagnosis of SBI may lead to over diagnosis. Novel technologies for pathogen detection and more precise measurement of the host-response using microarrays, allowing for simultaneous detection of multiple genes or proteins, promise to improve the value of laboratory biomarkers for the diagnosis of SBI.
Statement of novelty: Presented here is an up-to-date systematic analysis of C-reactive protein and inflammation biomarkers with regard to their use in the diagnosis of SBI. I question whether a broad use of C-reactive protein is useful in patients presenting with infection. The results of the systematic analysis are put into context with recent concerns about over-diagnosing in medicine. This paper is adapted from a publication in the German journal Monatsschrift Kinderheilkunde.

Formats available

You can view the full content in the following formats:

REFERENCES

Appenzeller C., Ammann R.A., Duppenthaler A., Gorgievski-Hrisoho M., and Aebi C. 2002. Serum C-reactive protein in children with adenovirus infection. Swiss Med. Wkly. 132:345–350.
Bauchner H. 2016. Genetics and the evaluation of the febrile child. JAMA. 316:824–825.
Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69:89–95.
Bomela H.N., Ballot D.E., Cory B.J., and Cooper P.A. 2000. Use of C-reactive protein to guide duration of empiric antibiotic therapy in suspected early neonatal sepsis. Pediatr. Infect. Dis. J. 19:531–535.
Bradley J.S.Byington C.L.Shah S.S.Alverson B.Carter E.R.Harrison C.Kaplan S.L.Mace S.E.Mccracken G.H. Jr.Moore M.R.St Peter S.D.Stockwell J.A.Swanson J.T., and Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. 2011. The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin. Infect. Dis. 53:e25–e76.
Chiesa C., Osborn J.F., Pacifico L., Natale F., and de Curtis M. 2011. Gestational- and age-specific CRP reference intervals in the newborn. Clin. Chim. Acta. 412:1889–1890.
Dagan R., Powell K.R., Hall C.B., and Menegus M.A. 1985. Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. J. Pediatr. 107:855–860.
du Clos T.W. 2013. Pentraxins: Structure, function, and role in inflammation. ISRN Inflamm. 2013:379040.
Dupuy A.M.Philippart F.Pean Y.Lasocki S.Charles P.E.Chalumeau M.Claessens Y.E.Quenot J.P.Guen C.G.Ruiz S.Luyt C.E.Roche N.Stahl J.P.Bedos J.P.Pugin J.Gauzit R.Misset B.Brun-Buisson C., and Maurice Rapin Institute Biomarkers Group. 2013. Role of biomarkers in the management of antibiotic therapy: an expert panel review: I—currently available biomarkers for clinical use in acute infections. Ann. Intensive Care. 3:22.
Ehl S., Gering B., Bartmann P., Hogel J., and Pohlandt F. 1997. C-reactive protein is a useful marker for guiding duration of antibiotic therapy in suspected neonatal bacterial infection. Pediatrics, 99:216–221.
Friedman J.N.Rieder M.J.Walton J.M., and Canadian Paediatric Society, Acute Care Committee, Drug Therapy and Hazardous Substances Committee. 2014. Bronchiolitis: Recommendations for diagnosis, monitoring and management of children one to 24 months of age. Paediatr. Child Health. 19:485–491.
Haeusler G.M., Mechinaud F., Daley A.J., Starr M., Shann F., Connell T.G., Bryant P.A., Donath S., and Curtis N. 2013. Antibiotic-resistant Gram-negative bacteremia in pediatric oncology patients—risk factors and outcomes. Pediatr. Infect. Dis. J. 32:723–726.
Hedegaard S.S., Wisborg K., and Hvas A.M. 2015. Diagnostic utility of biomarkers for neonatal sepsis—a systematic review. Infect. Dis. (Lond). 47:117–124.
Herberg J.A., Kaforou M., Wright V.J., Shailes H., Eleftherohorinou H., Hoggart C.J., Cebey-Lopez M., Carter M.J., Janes V.A., Gormley S., Shimizu C., Tremoulet A.H., Barendregt A.M., Salas A., Kanegaye J., Pollard A.J., Faust S.N., Patel S., Kuijpers T., Martinon-Torres F., Burns J.C., Coin L.J., Levin M., and Consortium I. 2016. Diagnostic test accuracy of a 2-transcript Host RNA signature for discriminating bacterial vs viral infection in febrile children. JAMA. 316:835–845.
Hornik C.P., Benjamin D.K., Becker K.C., Benjamin D.K. Jr., Li J., Clark R.H., Cohen-Wolkowiez M., and Smith P.B. 2012. Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr. Infect. Dis. J. 31:803–807.
Jaskiewicz J.A., Mccarthy C.A., Richardson A.C., White K.C., Fisher D.J., Dagan R., and Powell K.R. 1994. Febrile infants at low risk for serious bacterial infection—an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. Pediatrics. 94:390–396.
Jin M. and Khan A.I. 2010. Procalcitonin: Uses in the clinical laboratory for the diagnosis of sepsis. Labmedicine. 41:173–177.
Kapasi A.J., Dittrich S., Gonzalez I.J., and Rodwell T.C. 2016. Host biomarkers for distinguishing bacterial from non-bacterial causes of acute febrile illness: A comprehensive review. PLoS ONE, 11:e0160278.
Karakurt D.G., Demirsoy U., Corapcioglu F., Oncel S., Karadogan M., and Arisoy E.S. 2014. Do proinflammatory cytokine levels predict serious complication risk of infection in pediatric cancer patients? Pediatr. Hematol. Oncol. 31:415–424.
Kruger S., Ewig S., Papassotiriou J., Kunde J., Marre R., von Baum H., Suttor N., Welte T., and Group C.S. 2009. 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. 10:65.
Kushner, I. 2015. Acute phase reactants. UpToDate. Wolters Kluwer.
Lehmann C., Berner R., Bogner J.R., Cornely O.A., de With K., Herold S., Kern W.V., Lemmen S., Pletz M.W., Ruf B., Salzberger B., Stellbrink H.J., Suttorp N., Ullmann A.J., Fatkenheuer G., and Jung N. 2017. The “Choosing Wisely” initiative in infectious diseases. Infection. 45:263–268.
Lin S.G., Hou T.Y., Huang D.H., He S.Y., Lin Y.D., Zhang L.Y., and Hsieh P.S. 2012. Role of procalcitonin in the diagnosis of severe infection in pediatric patients with fever and Neutropenia—a systemic review and meta-analysis. Pediatr. Infect. Dis. J. 31:e182–e188.
Linscheid P., Seboek D., Nylen E.S., Langer I., Schlatter M., Becker K.L., Keller U., and Muller B. 2003. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology. 144:5578–5584.
Liu R.S., Aiello A.E., Mensah F.K., Gasser C.E., Rueb K., Cordell B., Juonala M., Wake M., and Burgner D.P. 2017. Socioeconomic status in childhood and C reactive protein in adulthood: A systematic review and meta-analysis. J. Epidemiol. Community Health. 71:817–826.
Machado J.R., Soave D.F., da Silva M.V., de Menezes L.B., Etchebehere R.M., Monteiro M.L., Dos Reis M.A., Correa R.R., and Celes M.R. 2014. Neonatal sepsis and inflammatory mediators. Mediators Inflamm. 2014:269681.
Mahajan P.Kuppermann N.Mejias A.Suarez N.Chaussabel D.Casper T.C.Smith B.Alpern E.R.Anders J.Atabaki S.M.Bennett J.E.Blumberg S.Bonsu B.Borgialli D.Brayer A.Browne L.Cohen D.M.Crain E.F.Cruz A.T.Dayan P.S.Gattu R.Greenberg R.Hoyle J.D. Jr.Jaffe D.M.Levine D.A.Lillis K.Linakis J.G.Muenzer J.Nigrovic L.E.Powell E.C.Rogers A.J.Roosevelt G.Ruddy R.M.Saunders M.Tunik M.G.Tzimenatos L.Vitale M.Dean J.M.Ramilo O., and for the Pediatric Emergency Care Applied Research Network (PECARN). 2016. Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. JAMA, 316:846–857.
Milcent K., Faesch S., Gras-le Guen C., Dubos F., Poulalhon C., Badier I., Marc E., Laguille C., de Pontual L., Mosca A., Nissack G., Biscardi S., le Hors H., Louillet F., Dumitrescu A.M., Babe P., Vauloup-Fellous C., Bouyer J., and Gajdos V. 2016. Use of procalcitonin assays to predict serious bacterial infection in young febrile infants. JAMA Pediatr, 170:62–69.
Niehues T. 2013. The febrile child: diagnosis and treatment. Dtsch. Arztebl. Int. 110, 764–773; quiz 774.
Niehues T. 2017. C-reaktives Protein und andere immunologische Biomarker. Monatsschrift Kinderheilkunde, 165:560–571.
Nuriel-Ohayon M., Neuman H., and Koren O. 2016. Microbial changes during pregnancy, birth, and infancy. Front Microbiol. 7:1031.
Oved K., Cohen A., Boico O., Navon R., Friedman T., Etshtein L., Kriger O., Bamberger E., Fonar Y., Yacobov R., Wolchinsky R., Denkberg G., Dotan Y., Hochberg A., Reiter Y., Grupper M., Srugo I., Feigin P., Gorfine M., Chistyakov I., Dagan R., Klein A., Potasman I., and Eden E. 2015. A novel host-proteome signature for distinguishing between acute bacterial and viral infections. PLoS ONE, 10:e0120012.
Phillips R.S., Wade R., Lehrnbecher T., Stewart L.A., and Sutton A.J. 2012. Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer. BMC Med. 10:6.
Simons J.P., Loeffler J.M., Al-Shawi R., Ellmerich S., Hutchinson W.L., Tennent G.A., Petrie A., Raynes J.G., de Souza J.B., Lawrence R.A., Read K.D., and Pepys M.B. 2014. C-reactive protein is essential for innate resistance to pneumococcal infection. Immunology. 142:414–420.
Slaats J., Ten Oever J., van de Veerdonk F.L., and Netea M.G. 2016. IL-1beta/IL-6/CRP and IL-18/ferritin: Distinct inflammatory programs in infections. PLoS Pathog. 12:e1005973.
Strimbu K. and Tavel J.A. 2010. What are biomarkers? Curr. Opin. HIV AIDS. 5:463–466.
Toikka P., Irjala K., Juven T., Virkki R., Mertsola J., Leinonen M., and Ruuskanen O. 2000. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr. Infect. Dis. J. 19:598–602.
Thompson M., van den Bruel A., Verbakel J., Lakhanpaul M., Haj-Hassan T., Stevens R., Moll H., Buntinx F., Berger M., Aertgeerts B., Oostenbinrk R., and Mant D. 2012. Systematic review and validation of prediction rules for identifying children with serious infections in emergency departments and urgent-access primary care. Health Technol Assess, 16, 1–100.
van den Bruel A. 2015. The triumph of medicine: How overdiagnosis is turning healthy people into patients. Fam. Pract. 32:127–128.
van den Bruel A.Haj-Hassan T.Thompson M.Buntinx F.Mant D., and European Research Network on Recognising Serious Infection Investigators. 2010. Diagnostic value of clinical features at presentation to identify serious infection in children in developed countries: A systematic review. Lancet. 375:834–845.
van den Bruel, A., Thompson, M. J., Haj-Hassan, T., Stevens, R., Moll, H., Lakhanpaul, M., and Mant, D. 2011. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ, 342, d3082.
van den Bruel A., Thompson M., Buntinx F., and Mant D. 2012. Clinicians’ gut feeling about serious infections in children: Observational study. BMJ. 345:e6144.
van den Bruel A., Jones C., Thompson M., and Mant D. 2016. C-reactive protein point-of-care testing in acutely ill children: A mixed methods study in primary care. Arch. Dis. Child. 101:382–386.
van Houten C.B., de Groot J.A.H., Klein A., Srugo I., Chistyakov I., de Waal W., Meijssen C. B., Avis W., Wolfs T.F.W., Shachor-Meyouhas Y., Stein M., Sanders E.A.M., and Bont L.J. 2017. A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): A double-blind, multicentre, validation study. Lancet Infect. Dis. 17:431–440.
Verbakel J.Y., Lemiengre M.B., de Burghgraeve T., de Sutter A., Aertgeerts B., Shinkins B., Perera R., Mant D., van den Bruel A., and Buntinx F. 2016. Should all acutely ill children in primary care be tested with point-of-care CRP: A cluster randomised trial. BMC Med. 14:131.
Waage A., Brandtzaeg P., Halstensen A., Kierulf P., and Espevik T. 1989. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J. Exp. Med. 169:333–338.
Yo C.H., Hsieh P.S., Lee S.H., Wu J.Y., Chang S.S., Tasi K.C., and Lee C.C. 2012. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: A systematic review and meta-analysis. Ann. Emerg. Med. 60:591–600.
Zhang H., Morrison S., and Tang Y. 2015. Multiplex PCR tests for detection of pathogens associated with gastroenteritis. Clin. Lab. Med. 35:461–486.
Ziegler I., Fagerstrom A., Stralin K., and Molling P. 2016. Evaluation of a commercial multiplex PCR assay for detection of pathogen DNA in blood from patients with suspected sepsis. PLoS ONE. 11:e0167883.

Information & Authors

Information

Published In

cover image LymphoSign Journal
LymphoSign Journal
Volume 5Number 2June 2018
Pages: 35 - 47

History

Received: 19 January 2018
Accepted: 19 March 2018
Accepted manuscript online: 9 April 2018

Authors

Affiliations

Tim Niehues [email protected]
Centre for Child Health and Adolescence, Helios Klinikum Krefeld, Krefeld, Germany

Competing Interests

Tim Niehues receives honoraria as an author/reviewer from up2date.com

Metrics & Citations

Metrics

Other Metrics

Citations

Cite As

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

There are no citations for this item

View Options

View options

PDF

View PDF

Full Text

View Full Text

Get Access

Login options

Check if you access through your login credentials or your institution to get full access on this article.

Subscribe

Click on the button below to subscribe to LymphoSign Journal

Purchase options

Purchase this article to get full access to it.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Media

Media

Other

Tables

Share Options

Share

Share the article link

Share on social media