How to use: C-reactive protein

S McWilliam; A Riordan

doi:10.1136/adc.2009.174367

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How to use: C-reactive protein

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Non infectious CRP elevation and correlation with gestational age
Nora Hofer
Published on: 23 March 2016
How to use CRP - authors reply
Andrew Riordan
Published on: 23 March 2016
CRP is a useful marker in preterm infants
David Burgner
Published on: 23 March 2016
CRP - a marker of systemic inflammation
Jonathan L Marks
Published on: 23 March 2016
CRP and the Newborn Infant
Anthony J Emmerson
Published on: 23 March 2016

Published on: 23 March 2016
Non infectious CRP elevation and correlation with gestational age
- Nora Hofer, Division of Neonatology
- Other Contributors:
  Bernhard Resch
Non infectious CRP elevation and correlation with gestational age
Dear editor, We read with interest the discussion on the reliability of CRP as a sepsis marker in the newborn in the context of non infectious conditions following the interesting article on the use of CRP by McWilliam and Riordan (1). We have recently conducted an analysis on this topic including 690 newborns having CRP values done within the firs...
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Non infectious CRP elevation and correlation with gestational age
Dear editor, We read with interest the discussion on the reliability of CRP as a sepsis marker in the newborn in the context of non infectious conditions following the interesting article on the use of CRP by McWilliam and Riordan (1). We have recently conducted an analysis on this topic including 690 newborns having CRP values done within the first three days of life. (2) Meconium aspiration syndrome was significantly associated with elevated CRP values up to 86 mg/L in term newborns (p=.009) and application of (in our case naturally porcine) surfactant with elevated CRP values up to 32 mg/L in term and preterm newborns (p<.001). A CRP response to surfactant was already reported in previous studies (3-4) but the mechanisms of pathophysiology are not clear. Concerning the correlation of CRP response to infection with gestational age, we provide further evidence for a more marked CRP response in term compared to preterm newborns with mean values of 23 mg/L vs. 10 mg/L (95th percentile 99 mg/L vs. 40 mg/L). Similarly, Turner et al. described higher CRP values in term compared to preterm newborns after any proinflammatory stimulus. (5) Interestingly, the literature provides little information on this correlation with gestational age even though CRP is surely one of the best studied infection markers for neonatal sepsis.
Yours sincerely, Nora Hofer
References
1. McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pract Ed. 2010;95(2):55-8. 2. Hofer N, Mueller W, Resch B. Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin Chem Lab Med. 2011;49(2):297-302. 3. Walti H, Eahat M, Desfreres L, Relier J. Natural Exogenous Surfactant Therapy Stimulates the Acute Phase Reaction in Premature Neonates. Pediatr Research. 1996;39(4):355 4. Kukkonen AK, Virtanen M, Jaervenpaeae AL, Pokela ML, Ikonen S, Fellman V. Randomized trial comparing natural and synthetic surfactant: increased infection rate after natural surfactant? Acta Paediatr 2000;89(5):556-61. 5. Turner MA, Power S, Emmerson AJB. Gestational age and the C reactive protein response. Arch Dis Child Fetal Neonatal Ed 2004;89(3):F272-3.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 23 March 2016
How to use CRP - authors reply
- Andrew Riordan, Consultant in Paediatric Infectious Diseases and Immunology
- Other Contributors:
  Stephen McWilliam
We were grateful to a number of people who contacted us about our article on How to use C - reactive protein [1].
Dr Abelian of Wrexham Maelor Hospital drew out attention to data on plasma half-life suggesting this was 19 hours in an adult [2] rather than the previously quoted 4-7 hours [3,4].
Dr Emmerson asked if there was robust data in support of the range of non infectious conditions quoted to cause...
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We were grateful to a number of people who contacted us about our article on How to use C - reactive protein [1].
Dr Abelian of Wrexham Maelor Hospital drew out attention to data on plasma half-life suggesting this was 19 hours in an adult [2] rather than the previously quoted 4-7 hours [3,4].
Dr Emmerson asked if there was robust data in support of the range of non infectious conditions quoted to cause a rise in CRP in the newborn period. Our article had quoted a review by Hengst [5]. We therefore reviewed the papers referenced in this review. Chiesa et al [6] showed that mean CRP concentration at birth was increased by a factor of 1.50 (95% CI, 1.32 to 2.03) if the 5-min Apgar score was <8 and by a factor of 1.32 (95% CI, 1.07 to 1.61) if the time from rupture of membranes was >18 hours. This effect on CRP was no longer present by 48 hours of life. Other studies quoted were observational studies which describe findings in neonates with raised serum CRP who did not have evidence of bacterial infection on blood culture [7-9]. Meconium aspiration syndrome, pneumothorax, intraventricular haemorrhage and severe asphyxia were reported in these studies but they were unable to rule out co-existing infection as a cause for the rise in CRP. A literature search provided some further information. Wasunna et al found no evidence that intraventricular haemorrhage was associated with elevation of CRP in neonates with no evidence of infection [10]. Schouten- Van Meeteren et al demonstrated no significant difference between the CRP levels of neonates with perinatal asphyxia, prolonged rupture of membranes, hyperbilirubinaemia or respiratory distress syndrome, and those of a control group [11]. Xanthou et al also found no difference between the CRP levels in neonates with asphyxia compared to controls [12].
There is thus some evidence that low Apgar scores and rupture of membranes can increase CRP at birth [6], but this rise is small and the effect is not present by 48 hours of age. We agree with Dr Emmerson that there is a lack of robust evidence to support a claim that CRP can be raised in neonates as a result of non-infectious causes, and would certainly not advocate withholding antibiotics in neonates with a raised CRP. We disagree, however, with the statement that reference to old papers is of "suspect value". In assessing evidence we must look at its quality, not at its age.
Howman et al question if preterm infants mount a lower CRP response compared to term infants and older children. There is good evidence to show that neonates with infection have lower CRP responses than older children (median CRP in preterm neonates with sepsis 40mg/l vs median in children 1-36 months old with bacterial infection 97 mg/l [13; 14]). 75% of preterm infants with sepsis have maximum CRP levels below 80mg/l [13], it is thus not true that preterm infants with proven infection often have CRP values of >100mg/L.
Dr Marks commented that CRP is a non-specific indicator of systemic inflammation, as stated in our article. We did not elaborate on this as the scenarios we chose all featured bacterial infection as the diagnosis to be confirmed or excluded. Dr Marks referenced a textbook for his assertions, so we reviewed the literature to confirm his statements. Juvenile idiopathic arthritis is associated with a raised CRP early in the course of the disease, especially in those with systemic or polyarticular onset [15]. However in children presenting with arthritis an elevated CRP is an independent predictor of septic arthritis in patients with acute monoarthritis, whereas a low CRP value is an independent predictor for the diagnosis of Juvenile idiopathic arthritis in patients whose disease duration exceeds two weeks [16].
The correct use of CRP requires careful review of the literature. We are grateful to those who have highlighted areas in our article which required better evidence and hope this response will improve our review.
References
1. McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pract Ed, 2010. 95(2):55-8
2. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest. 1993 Apr;91(4):1351-7.
3. Young B, Gleeson M, Cripps AW. C-reactive protein: a critical review. Pathology 1991;23:118-24.
4. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentraxins) and serum amyloid A protein. Adv Immunol 1983;34:141-211
5. Hengst, J.M., The role of C-reactive protein in the evaluation and management of infants with suspected sepsis. Adv Neonatal Care, 2003. 3(1):3-13
6. Chiesa C, Fabrizio S, Assumma M, Buffone E, Tramontozzi P, et al. Serial measurements of C-reactive protein and interleukin-6 in the immediate postnatal period: reference intervals and analysis of maternal and perinatal confounders. Clin Chem 2001;47:1016-1022.
7. Berger, C., et al., Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia. Eur J Pediatr, 1995. 154(2): p. 138-44. 8. Ainbender, E., et al., Serum C-reactive protein and problems of newborn infants. J Pediatr, 1982. 101(3):438-40.
9. Pourcyrous, M., et al., Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics, 1993. 92(3):431-5
10. Wasunna, A., et al., C-reactive protein and bacterial infection in preterm infants. Eur J Pediatr, 1990. 149(6):424-7
11. Schouten-Van Meeteren, N.Y., et al., Influence of perinatal conditions on C-reactive protein production. J Pediatr, 1992. 120(4 Pt 1):621-4.
12. Xanthou, M., et al., Inflammatory mediators in perinatal asphyxia and infection. Acta Paediatr Suppl, 2002. 91(438):92-7.
13. Ng PC, Cheng SH, Chui KM, Fok TF, Wong MY, Wong W, Wong RP, Cheung KL. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1997 Nov;77(3):F221-7.
14. Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics. 2001;108(6):1275-9.
15. Gwyther M, Schwarz H, Howard A, Ansell BM. C-reactive protein in juvenile chronic arthritis: an indicator of disease activity and possibly amyloidosis. Ann Rheum Dis. 1982 Jun;41(3):259-6
16. Kunnamo I, Kallio P, Pelkonen P, Hovi T. Clinical signs and laboratory tests in the differential diagnosis of arthritis in children. Am J Dis Child. 1987 Jan;141(1):34-40.
Conflict of Interest:
None declared
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Published on: 23 March 2016
CRP is a useful marker in preterm infants
- David Burgner, Principal Research Fellow, Infection, Immunity & Environment
- Other Contributors:
  Rebecca Howman, Tobias Strunk, Karen Simmer
Dear Editors
Re: How to use: C-reactive protein. McWilliam, et al. 95:55-58
McWilliam and Riordan recently reviewed the use and limitations of C- reactive protein (CRP) in clinical practice, particularly in the diagnosis of infection.(1) The authors imply the authors suggest preterm infants cannot mount a CRP response (CRP levels remain low) when compared to term infants and older children. In the cont...
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Dear Editors
Re: How to use: C-reactive protein. McWilliam, et al. 95:55-58
McWilliam and Riordan recently reviewed the use and limitations of C- reactive protein (CRP) in clinical practice, particularly in the diagnosis of infection.(1) The authors imply the authors suggest preterm infants cannot mount a CRP response (CRP levels remain low) when compared to term infants and older children. In the context of neonatal infection this is clearly an important issue, as the burden of morbidity and mortality related to infection falls largely on the preterm population. However we can find no evidence to support this assertion; indeed the reference quoted (2) actually states that CRP concentrations are not affected by gestational age (GA). Data from preterm neonates (> 28 weeks GA) with infection show that CRP concentrations of >40mg/L are common (3, 4) and clinical experience would support this, with preterm infants with proven infection often having CRP values of >100mg/L. Although, as discussed, CRP is a far from perfect investigation, it is widely used used to assist in the diagnosis of infection, or more appropriately, serial measures are used to exclude infection and allow antibiotics to be stopped.(5)
The authors also highlight the potential confounding effects of perinatal events, such as prolonged rupture of membranes and fetal distress, on immediate post-natal CRP levels. Chorioamnionitis, which complicates up 25% of deliveries <36 weeks GA and is often subclinical, may cause a marked rise in CRP that can persist for a number of days post -delivery (6)(Howman et al, unpublished observations). This may compromise the specificity of CRP in the diagnosis of early onset sepsis in preterm infants born following clinically unapparent - but immunologically significant - chorioamnionitis.
Yours sincerely
Rebecca Howman, Tobias Strunk, Karen Simmer and David Burgner
Schools of Paediatrics and Child Health and Women and Infants' Health, University of Western Australia
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia
References
1. McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pract Ed. Apr;95(2):55-8.
2. Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J. 1997 Aug;16(8):735-46; quiz 46-7.
3. Ainbender E, Cabatu EE, Guzman DM, Sweet AY. Serum C-reactive protein and problems of newborn infants. J Pediatr. 1982 Sep;101(3):438- 40.
4. Cetinkaya M, Ozkan H, Koksal N, Celebi S, Hacimustafaoglu M. Comparison of serum amyloid A concentrations with those of C-reactive protein and procalcitonin in diagnosis and follow-up of neonatal sepsis in premature infants. J Perinatol. 2009 Mar;29(3):225-31.
5. Pourcyrous M, Bada HS, Korones SB, Baselski V, Wong SP. Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics. 1993;92(3):431-5.
6. Wu HC, Shen CM, Wu YY, Yuh YS, Kua KE. Subclinical histologic chorioamnionitis and related clinical and laboratory parameters in preterm deliveries. Pediatr Neonatol. 2009 Oct;50(5):217-21.
Conflict of Interest:
None declared
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None declared.
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Published on: 23 March 2016
CRP - a marker of systemic inflammation
- Jonathan L Marks, Specialty Registrar, Rheumatology
- Other Contributors:
  Dr Richard G Hull
Dear Editor we read with interest the recent article regarding how to use C- reactive protein (CRP). While the authors discuss the role of CRP as a non-specific indicator of serious bacterial infection (SBI) they do not acknowledge that CRP is a non-specific indicator of systemic inflammation, the causes of which are many and varied with acute infective processes being only one.
It is important to consider alter...
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Dear Editor we read with interest the recent article regarding how to use C- reactive protein (CRP). While the authors discuss the role of CRP as a non-specific indicator of serious bacterial infection (SBI) they do not acknowledge that CRP is a non-specific indicator of systemic inflammation, the causes of which are many and varied with acute infective processes being only one.
It is important to consider alternative conditions that may cause a rise in CRP levels, especially when these diseases can mimic systemic infection. Juvenile idiopathic arthritis (JIA) and vasculitis are very commonly associated with significant rises in CRP, often in association with other systemic features such as fever, rash and constitutional upset. Children presenting with this constellation of clinical features may be misdiagnosed as suffering from SBI. In these conditions, CRP is often used as a marker of ongoing disease activity and may be persistently and markedly elevated in uncontrolled disease. Acute reactive arthritis is also associated with a significantly raised CRP level reflecting the degree of ongoing synovitis.
A normal CRP can also be falsely reassuring even in the presence of acute inflammation. This is especially true in patients with acute flares of systemic lupus erythematosus (SLE) where typically CRP levels may remain normal in the presence of marked inflammation despite significant changes in other markers of inflammation such as ESR and compliment levels [1].
Reference: Szer I S; Kimura Y; Malleson P N; Southwood TR. Arthritis in children and adolescents. Chapter 1.6. Oxford University Press, 2006.
Conflict of Interest:
None declared
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Published on: 23 March 2016
CRP and the Newborn Infant
- Anthony J Emmerson, Neonatologist
I was interested in the excellent article on How to use C-Reactive Protein in Education and Practice by McWilliam and Riordan. I was particularly interested in your comments in the article on Ruling in Sepsis and the comment that CRP is not diagnostic for sepsis in the neonate because it may be raised for other reasons. The article quotes - prolonged rupture of membranes - (most frequently caused by local sepsis and is...
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I was interested in the excellent article on How to use C-Reactive Protein in Education and Practice by McWilliam and Riordan. I was particularly interested in your comments in the article on Ruling in Sepsis and the comment that CRP is not diagnostic for sepsis in the neonate because it may be raised for other reasons. The article quotes - prolonged rupture of membranes - (most frequently caused by local sepsis and is a common reason for early delivery and may lead to infection in the neonate); maternal fever - whilst this does not mean that the baby is necessarily infected, infection in the newborn infant with an elevated CRP could not be excluded and is corroborated with positive cultures in some cases. Listed also is fetal distress, perinatal asphyxia, shock and periventricular or intraventricular haemorrhages. Fetal distress, perinatal asphyxia and shock can all be aggravated by infection, but when this is not the case such as acute cord prolapse leading to fetal distress / perinatal asphyxia - there is no evidence for a rise in CRP. In addition I am unaware of evidence for a rise in CRP in periventricular and intraventricular haemorrhages. Listed also was pneumothorax and meconium aspiration again there is little evidence that these result in a rise in CRP without added infection.
I noted the reference quoted in support was a review by Joan Hengst in a journal from 2003. She herself quotes other papers from 1982 and 1985 as her evidence for CRP being elevated in non infectious situations such as maternal fever during labour and prolonged rupture of membranes. Clearly reference to papers from so long ago as the source of this information is of suspect value. I am unaware of any robust data in support of this very wide range of neonatal conditions as the cause of a non infectious rise in CRP in the newborn period. The evidence for rises in CRP not linked to infection in neonates is very limited and relates to immunisation where the CRP rises just above 10 for less than 24 hours only and other non infectious inflammatory processes such as laser therapy to the retinae do not cause a rise in CRP. I support the view that antibiotics should not be withheld in the case of a low CRP (especially as there is the lag phase) but am concerned that an elevated CRP could be discounted on the basis of it being the result of perinatal asphyxia or an IVH for example. Caution is required in interpretation of uncorroborated data from so long ago especially where there is not clear evidence that infection has been excluded.
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None declared
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